Hyperglycemic Crises: Diabetic Ketoacidosis (DKA), And

Hyperglycemic Hyperosmolar State (HHS)

Adair R Gosmanov, M.D., Ph.D., F.A.C.E., Elvira O Gosmanova, M.D., F.A.S.N., and Abbas E Kitabchi, M.D., Ph.D., M.A.C.E.

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Last Update: May 19, 2015.

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ABSTRACT
Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute metabolic complications of diabetes mellitus
that can occur in patients with both type 1 and 2 diabetes mellitus. Timely diagnosis, comprehensive clinical and biochemical
evaluation, and effective management is key to the successful resolution of DKA and HHS. Critical components of the hyperglycemic
crises management include coordinating fluid resuscitation, insulin therapy, and electrolyte replacement along with the continuous
patient monitoring using available laboratory tools to predict the resolution of the hyperglycemic crisis. Understanding and prompt
awareness of potential of special situations such as DKA or HHS presentation in comatose state, possibility of mixed acid-base
disorders obscuring the diagnosis of DKA, and risk of brain edema during the therapy are important to reduce the risks of
complications without affecting recovery from hyperglycemic crisis. Identification of factors that precipitated DKA or HHS during the
index hospitalization should help prevent subsequent episode of hyperglycemic crisis. For extensive review of all related areas of
Endocrinology, visit WWW.ENDOTEXT.ORG.

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INTRODUCTION
Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) represent two extremes in the spectrum of decompensated
diabetes. DKA and HHS remain important causes of morbidity and mortality among diabetic patients despite well developed
diagnostic criteria and treatment protocols (1). The annual incidence of DKA from population-based studies is estimated to range from
4 to 8 episodes per 1,000 patient admissions with diabetes (2). The incidence of DKA continues to increase and it accounts for about
140,000 hospitalizations in the US in 2009 (Figure 1 a) (3). The rate of hospital admissions for HHS is lower than of DKA and is less
than 1% of all diabetic-related admissions (4,5). Decompensated diabetes imposes a heavy burden in terms of economics and patient
outcomes. DKA is responsible for more than 500,000 hospital days per year at an estimated annual direct medical expense and indirect
cost of 2.4 billion USD in 1997 (CDC) (6). The mortality rate for DKA and hyperglycemic crises has been falling over the years
(Figure 1b) (3). The mortality rate of HHS is higher compared with DKA (7,8). Severe dehydration, older age, and the presence of
comorbid conditions in patients with HHS account for the higher mortality in these patients (8).

Figure 1aIncidence of DKA 1980-2009

Figure 1bCrude and Age-Adjusted Death Rates for Hyperglycemic Crises as Underlying Cause per 100,000
Diabetic Population, United States, 1980–2009

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DEFINITIONS
DKA consists of the biochemical triad of hyperglycemia, ketonemia and high anion gap metabolic acidosis (9) (Figure 2). The terms
“hyperglycemic hyperosmolar nonketotic state” and “hyperglycemic hyperosmolar nonketotic coma” have been replaced with the
term “hyperglycemic hyperosmolar state” (HHS) to highlight that 1) the hyperglycemic hyperosmolar state may consist of moderate to
variable degrees of clinical ketosis detected by nitroprusside method, and 2) alterations in consciousness may often be present without
coma.
Figure 2

The triad of DKA (hyperglycemia, acidemia, and ketonemia) and other conditions with which the individual components are
associated. From Kitabchi and Wall (9).
Both DKA and HHS are characterized by absolute or relative insulinopenia. Clinically, they differ only by the severity of dehydration,
ketosis and metabolic acidosis (8).

DKA most often occurs in patients with type 1 diabetes mellitus (T1DM). It also occurs in type 2 diabetes under conditions of extreme
stress such as serious infection, trauma, cardiovascular or other emergencies, and, less often, as a presenting manifestation of type 2
diabetes, a disorder called ketosis-prone type 2 diabetes (7). Similarly, whereas HHS occurs most commonly in T2DM, it can be seen
in T1DM in conjunction with DKA.

PATHOGENESIS

The underlying defects in DKA and HHS are 1) reduced net effective action of circulating insulin as a result of decreased insulin
secretion (DKA) or ineffective action of insulin in HHS (10-12), 2) elevated levels of counter regulatory hormones: glucagon (13,14),
catecholamines (13,15), cortisol (13), and growth hormone (16,17), resulting in increased hepatic glucose production and impaired
glucose utilization in peripheral tissues, and 3) dehydration and electrolyte abnormalities, mainly due to osmotic diuresis caused by
glycosuria (18) (Figure 3). Diabetic ketoacidosis is also characterized by increased gluconeogenesis, lipolysis, ketogenesis, and
decreased glycolysis (7).

Diabetic Ketoacidosis

In DKA, there is severe alteration of carbohydrate, protein, and lipid metabolism (4). In general, the body is shifted into a major
catabolic state with breakdown of glycogen stores, hydrolysis of triglycerides from adipose tissues, and mobilization of aminoacids
from muscle (7). The released triglycerides and amino acids from the peripheral tissues will become substrates for the production of
glucose and ketone bodies by the liver (19). Hyperglycemia and ketone bodies production play central roles in developing this
metabolic decompensation (20).

Hyperglycemia

The hyperglycemia in DKA is the result of three events: (a) increased gluconeogenesis; (b) increased glycogenolysis, and (c)
decreased glucose utilization by liver, muscle and fat. Insulinopenia and elevated cortisol levels also lead to a shift from protein
synthesis to proteolysis with resultant increase in production of amino acids (alanine and glutamine), which further serve as substrates
for gluconeogenesis (4,21). Furthermore, muscle glycogen is catabolized to lactic acid via glycogenolysis. The lactic acid is
transported to the liver in the Cori cycle where it serves as a carbon skeleton for gluconeogenesis (22). Increased levels of glucagon,
cathecholamines and cortisol with concurrent insulinopenia stimulate gluconeogenic enzymes, especially phosphoenol pyruvate
carboxykinase (PEPCK) (16,23). Decreased glucose utilization is further exaggerated by increased levels of circulating
catecholamines and FFA (24).

Ketogenesis

Excess catecholamines coupled with insulinopenia promote triglyceride breakdown (lipolysis) to free fatty acids (FFA) and glycerol.
The latter provides a carbon skeleton for gluconeogenesis, while the former serves as a substrate for the formation of ketone bodies
(25,26). The key regulatory site for fatty acid oxidation is known to be carnitine palmitoyltransferase 1(CPT1) which is inhibited by
malonyl CoA in the normal non-fasted state but the increased ratio of glucagon and other counter regulatory hormones to insulin
disinhibit fatty acid oxidation and incoming fatty acids from fat tissue can be converted to ketone bodies (27,28). Increased production
of ketone bodies (acetoacetate, and ß- hydroxybutyrate) leads to ketonemia (29). Ketonemia is further is maintained by the reduced
liver clearance of ketone bodies in DKA. Extracellular and intracellular buffers neutralize hydrogen ions produced during hydrolysis
of ketoacids. When overwhelming ketoacid production exceeds buffering capacity, a high anion gap metabolic acidosis develops.
Studies in diabetic and pancreatectomized patients have demonstrated the cardinal role of hyperglucagonemia and insulinopenia in the
genesis of DKA (30) . In the absence of stressful situations such as dehydration, vomiting or intercurrent illness, ketosis is usually
mild (7,31).
Figure 3

Pathogenesis of DKA and HHS: stress, infection, or insufficient insulin. FFA, free fatty acid. Adapted from Kitabchi et al. (1).

Elevated levels of pro-inflammatory cytokines and lipid peroxidation markers, as well as procoagulant factors such as plasminogen
activator inhibitor-1 (PAI-1) and C-reactive protein (CRP) have been demonstrated in DKA. The levels of these factors return to
normal with insulin therapy and correction of hyperglycemia (32). This inflammatory and procoagulant state may explain the well-
known association between hyperglycemic crisis and thrombotic state.

Hyperglycemic Hyperosmolar State

While DKA is a state of near absolute insulinopenia, there is sufficient amount of insulin present in HHS to prevent lipolysis and
ketogenesis but not adequate to cause glucose utilization (as it takes 1/10 as much insulin to suppress lipolysis as it does to stimulate
glucose utilization) (23,24). In addition, in HHS there is a smaller increase in counter regulatory hormones (10,33).

Precipitating factors

The two most common precipitating factors in the development of DKA or HHS are inadequate insulin therapy (whether omitted or
inadequate insulin regimen) or the presence of infection (34,35). Other provoking factors include myocardial infarction,
cerebrovascular accidents, pulmonary embolism, pancreatitis, alcohol abuse and drugs (Table 1). In addition, numerous underlying
medical illness and medications that cause the release of counter regulatory hormones and/or compromise the access to water can
result in severe dehydration and HHS (34). Drugs such as corticosteroids, thiazide diuretics, sympathomimetic agents
(e.g.,dobutamine and terbutaline), and second generation antipsychotic agents may precipitate DKA or HHS (8). In young patients
with type 1 diabetes, insulin omission due to fear of hypoglycaemia or weight gain, the stress of chronic disease, and eating disorders,
may contribute in 20 % of recurrent DKA (36). Cocaine use also is associated with recurrent DKA (37,38). Mechanical problems with
continuous subcutaneous insulin infusion (CSII) devices can precipitate DKA (39); however, with an improvement in technology and
better education of patients, the incidence of DKA have been declining in insulin pump users (40). There are also case reports of
patients with DKA as the primary manifestation of acromegaly (41-43).

Increasing numbers of DKA cases have been reported in patients with Type 2 DM. Available evidence shows that almost 50 % of
newly diagnosed adult African American and Hispanic patients with DKA have type 2 diabetes (44). These ketosis– prone type 2
diabetic patients develop sudden-onset impairment in insulin secretion and action, resulting in profound insulinopenia (45). Clinical
and metabolic features of these patients include high rates of obesity, a strong family history of diabetes, a measurable pancreatic
insulin reserve, and a low prevalence of autoimmune markers of ß-cell destruction (46-48). Aggressive management with insulin
improves ß cell function, leading to discontinuance of insulin therapy within a few months of follow-up and 40 % of these patients
remain non insulin dependent for 10 years after the initial episode of DKA (47). The etiology of acute transient failure of ß-cells
leading to DKA in these patients is not known, however, the suggested mechanisms include glucotoxicity, lipotoxicity, and genetic
predisposition (49,50). A genetic disease, glucose-6-phosphate dehydrogenase deficiency, has been also linked with ketosis-prone
diabetes (51).

Table 1 summarizes the common precipitating factors in DKA.

CLINICAL FEATURES

Symptoms and signs

DKA usually evolves rapidly within a few hours of the precipitating event(s). On the other hand, development of HHS is insidious and
may occur over days or weeks (7). The common clinical presentation of DKA and HHS is due to hyperglycemia and include polyuria,
polyphagia, polydipsia, weight loss, weakness, and physical signs of dehydration such as dry buccal mucosa, sunken eye balls, poor
skin turgor, tachycardia, hypotension and shock in severe cases. Kussmaul respiration, acetone breath, nausea, vomiting and
abdominal pain may also occur primarily in DKA. Abdominal pain, which correlates with the severity of acidosis (52), may be severe
enough to be confused with acute abdomen in 50-75% of cases (53). Therefore, in the presence of acidosis, DKA as an etiology of
abdominal pain should be considered. Patients usually have normal body temperature or mild hypothermia regardless of presence of
infection (54). Therefore, a careful search for a source of infection should be performed even in the absence of fever. Neurological
status in patients with DKA may vary from full alertness to a profound lethargy and coma, However, mental status changes in DKA
are less frequent than HHS. The relationship of depressed consciousness and severity of hyperosmolality or DKA causes has been
controversial (55,56). Some studies suggested that pH is the cause of mental status changes (57); while, others concluded that
osmolality (58) is responsible for the comatose state. More recently, it has been proposed that consciousness level in adolescents with
DKA was related to the severity of acidosis (pH) and not to a blood glucose levels (59). In our earlier studies of patients with DKA
using low dose versus high dose insulin therapy, we evaluated the initial biochemical values of 48 patients with stupor/coma versus
non comatose patients (60). Our study showed that glucose, bicarbonate, BUN and osmolality, and not pH were significantly different
between non-comatose and comatose patients. Furthermore, in 3 separate studies in which 123 cases of DKA were evaluated, serum
osmolality was also the most important determinant of mental status changes (9). However, in our recent retrospective study, it was
shown that acidosis was independently associated with altered sensorium, but hyperosmolarity and serum “ketone” levels were not
(61). In that study, a combination of acidosis and hyperosmolarity at presentation may identify a subset of patients with severe DKA
(7% in this study) who may benefit from more aggressive treatment and monitoring. Identifying this class of patients, who are at a
higher risk for poorer prognosis, may be helpful in triaging them, thus further improving the outcome (61). Furthermore, according to
one study, ICU-admitted patients with DKA are less ill, and have lower disease severity scores, mortality, and shorter length of ICU
and hospital stay, than non-DKA patients. Disease severity scores are not, but precipitating cause is, predictive of prolonged hospital
stays in patients with DKA (62).

Table 2. Admission clinical and biochemical profile in comatose versus non-comatose patients with DKA (61).
In patients with HHS, neurological symptoms include clouding of sensorium which can progress to mental obtundation and coma (63).
Occasionally, patients with HHS may present with focal neurological deficit and seizures (64,65). Most of the patients with HHS and
an effective osmolality of >320 mOsm/kg are obtunded or comatose; on the other hand, the altered mental status rarely exists in
patients with osmolality of <320 mOsm/kg (4). Therefore, severe alteration in the level of consciousness in patients with osmolality of
<320 mOsm/kg requires evaluation for other causes including CVA and other catastrophic events like myocardial and bowel
infarctions.

LABORATORY ABNORMALITIES AND DIAGNOSIS OF HYPERGLYCEMIC CRISES

The initial laboratory evaluation of patients with suspected DKA or HHS should include determination of plasma glucose, blood urea
nitrogen, serum creatinine, serum ketones, electrolytes (with calculated anion gap), osmolality, urinalysis, urine ketones by dipstick,
arterial blood gases, and complete blood count with differential. An electrocardiogram, blood, urine or sputum cultures and chest X-
ray should also be performed, if indicated. HbA1c may be useful in differentiating chronic hyperglycemia of uncontrolled diabetes
from acute metabolic decompensation in a previously well-controlled diabetic patient (8). Table 3 summarizes the biochemical criteria
for DKA and HHS and electrolyte deficits in these two conditions. It also provides a simple method for calculating anion gap and
serum osmolality.

Table 3. Diagnostic Criteria and Typical Total Body Deficits of Water and Electrolytes in Diabetic Ketoacidosis (DKA) and
Hyperglycemic Hyperosmolar Syndrome (HHS)
DKA can be classified as mild, moderate, or severe based on the severity of metabolic acidosis and the presence of altered mental
status (8). Over 30% of patients have features of both DKA and HHS (7). Patients with HHS typically have pH >7.30, bicarbonate
level >20 mEq/L, and negative ketone bodies in plasma and urine. However, some of them may have ketonemia. Several studies on
serum osmolarity and mental alteration have established a positive linear relationship between osmolarity, pH and mental obtundation
(60). Therefore, the occurrence of coma in the absence of definitive elevation of serum osmolality requires immediate consideration of
other causes of mental status change. The levels of β-OHB of ≥3.8mmol/L measured by a specific assay were shown to be highly
sensitive and specific for DKA diagnosis (66). In patients with chronic kidney disease stage 4-5, the diagnosis of DKA could be
challenging due to the presence of concomitant underlying chronic metabolic acidosis or mixed acid-base disorders. An anion gap of
>20 usually supports the diagnosis of DKA in these patients (67).

The major cause of water deficit in DKA and HHS is glucose-mediated osmotic diuresis, which leads to loss of water in excess of
electrolytes (68). Despite the excessive water loss, the admission serum sodium tends to be low because serum glucose in the presence
of insulinopenia of DKA and HHS cannot penetrate to cells. In hyperglycemic crises, glucose becomes osmotically effective and
causes water shifts from intracellular space to the extra cellular space resulting in dilution of sodium concentration – dilutional or
hyperosmolar hyponatremia. Initially it has been thought that true sodium concentration (millimolar) can be obtained by multiplying
excess glucose above 100 mg/dl by 1.6 /100 (69). It is however accepted now that true or corrected serum sodium concentration in
patients experiencing hyperglycemic crisis should be calculated by adding 2.4 mmol/L to the measured serum sodium concentration
for every 100 mg/dl incremental rise in serum glucose concentration above serum glucose concentration of 100 mg/dl (70). If the
corrected sodium level is extremely low, hypertriglyceridemia (secondary to uncontrolled diabetes) should be also suspected. In this
condition the plasma becomes milky and lipemia retinalis may be visible in physical examination (71). Serum potassium may be
elevated on arrival due to insulin deficiency, dehydration and a shift of potassium from intracellular to extra cellular compartments in
response to acidosis (72). However, total body potassium deficit is usually present from urinary potassium losses due to osmotic
diuresis and during ketone excretion. More frequently, the initial serum potassium level is normal or low which is a danger sign.
Initiation of insulin therapy, which leads to the transfer of potassium into cells, may cause fatal hypokalemia if potassium is not added
early. Phosphate depletion in DKA is universal but on admission, like the potassium, it may be low, normal or high (73).

Leukocytosis is a common finding in patients with DKA or HHS, but leukocytosis greater than 25,000 /μL suggests ongoing infection
requiring further work up (74). The exact etiology of this non-specific leukocytosis is not known. A recent study also showed
nonspecific leukocytosis in subjects with hyoglycaemia induced by insulin injection and suggested that this phenomenon may be due
to the increased levels of cathecholamine, cortisol, and proinflammatory cytokines such as TNF-α during acute stress (75).
Hypertriglyceridemia may be present in HHS (76) and is almost always seen in DKA (52). Hyperamylasemia, which correlates with
pH and serum osmolality and elevated level of lipase, may occur in 16 - 25% of patients with DKA (77). The origin of amylase in
DKA is usually non-pancreatic tissue such as the parotid gland (78).
The differences and similarities in the admission biochemical data in patients with DKA or HHS are shown in Table 4.

Table 4. Biochemical data in patients with HHS and DKA (1).

Pitfalls of laboratory tests and diagnostic considerations for interpreting acid based status in DKA
False positive values for lipase may also be seen if plasma glycerol levels are very high due to rapid breakdown of adipose tissue
triglycerides (glycerol is the product measured in most assays for plasma lipase). Therefore, elevated pancreatic enzymes may not be
reliable for the diagnosis of pancreatitis in the DKA setting. Other pitfalls include artificial elevation of serum creatinine, either as a
result of dehydration or interference from ketone bodies when a colorimetric method is used (79). Most of the laboratory tests for
ketone bodies use the nitroprusside method, which detects acetoacetate, but not β-hydroxybutyrate (β-OHB). Since β-OHB is
converted to acetoacetate during treatment (80), the ketone test may show high values suggesting erroneously that ketonemia is
deteriorating; therefore the follow up measurement of ketones during the treatment by nitroprusside method is not recommended (7).
Newer glucose meters have the capability to measure β-OHB, which overcomes this problem (81,82). Furthermore drugs that have
sulfhydryl groups can interact with the reagent in the nitroprusside reaction, giving a false positive result (83). Particularly important
in this regard is captopril, an angiotensin converting enzyme inhibitor prescribed for the treatment of hypertension and diabetic
nephropathy. Therefore for the diagnosis of DKA, clinical judgment and consideration of other biochemical data are required to
interpret the value of positive nitroprusside reactions in patients on captopril.

The classical presentation of acid-base disorders in DKA consists of increased anion gap metabolic acidosis where the relation of
plasma anion gap change and bicarbonate change (Δ- Δ, ratio of AG change over change in bicarbonate) equals to 1 due to parallel
reduction in plasma bicarbonate with the addition of ketoacids into the extravascular fluid space. With frequent additional bicarbonate
losses in urine in the form of ketoanions during DKA, the initiation of intravenous volume resuscitation with chloride-containing
solutions can further lower plasma bicarbonate and unmask non-anion gap metabolic acidosis when Δ- Δ becomes less than 1 due to
changes in plasma bicarbonate that exceed the expected changes in AG. Respiratory compensation will accompany metabolic acidosis
with reduction in PCO2 in arterial blood gas. The expected changes in PCO2 can be calculated using Winter’s formula: PCO2 (mmHg)
= 1.5 (Bicarbonate) + 8 + 2 (84). Therefore, inappropriately high or low levels of PCO2, determined by ABG will suggest the presence
of a mixed acid-based disorder. For example, DKA patients with concomitant fever or sepsis may have additional respiratory alkalosis
manifesting by lower than expected PCO2. In contrast, a higher than calculated PCO2 level signifies additional respiratory acidosis and
can be seen in patients with underlying chronic lung disease. Vomiting is a common clinical manifestation in DKA and leads to a loss
of hydrogen ions in gastric content and the development of metabolic alkalosis. Patients with DKA and vomiting may have relatively
normal plasma bicarbonate levels and close to normal pH. However, AG will remain elevated and be an important clue for DKA. In
addition, Δ-Δ ratio will be over 2 suggesting that there is less than expected reduction in bicarbonate as compared with increase in AG
and confirm the presence of a mixed acid-base disorder (combination of metabolic acidosis and metabolic alkalosis). We recommend
measurement of β-OHB in instances when a mixed acid-base disorder is present in patients with hyperglycemic crisis and DKA is
suspected.

DIFFERENTIAL DIAGNOSIS
Patients may present with metabolic conditions resembling DKA or HHS. For example, in alcoholic ketoacidosis (AKA), total ketone
bodies are much greater than in DKA with a higher β-OHB to acetoacetate ratio of 7:1 versus a ratio of 3:1 in DKA (4). The AKA
patients seldom present with hyperglycemia (85). It is also possible that patients with a low food intake may present with mild
ketoacidosis (starvation ketosis); however serum bicarbonate concentration of less than 18 or hyperglycemia will be rarely present.
Additionally, DKA has to be distinguished from other causes of high anion gap metabolic acidosis including lactic acidosis, advanced
chronic renal failure, as well as ingestion of drugs such as salicylate, methanol and ethylene glycol. Isopropyl alcohol, which is
commonly available as rubbing alcohol, can cause considerable ketosis and high serum osmolar gap without metabolic acidosis.
Moreover, there is a tendency to hypoglycemia rather than hyperglycemia with isopropyl alcohol injection (86,87). Finally, patients
with diabetes insipidus presenting with severe polyuria and dehydration, who are subsequently treated with free water in a form of
intravenous dextrose water, can have hyperglycemia- a clinical picture that can be confused with HHS (88) (Table 5).

Table 5. Laboratory evaluation of metabolic causes of acidosis and coma (7).

TREATMENT OF DKA

The goals of therapy in patients with hyperglycemic crises include: 1) improvement of circulatory volume and tissue perfusion, 2)
gradual reduction of serum glucose and plasma osmolarity, 3) correction of electrolyte imbalance, and 4) identification and prompt
treatment of co-morbid precipitating causes (4). It must be emphasized that successful treatment of DKA and HHS requires frequent
monitoring of patients regarding the above goals by clinical and laboratory parameters. Suggested approaches for the management of
patients with DKA and HHS are illustrated in Figures 4 and 5.

Fluid Therapy

DKA and HHS are volume-depleted states with total body water deficit of approximately 6 L in DKA and 9 L in HHS (7,89).
Therefore, the initial fluid therapy is directed toward expansion of intravascular volume and securing adequate urine flow. The initial
fluid of choice is isotonic saline at the rate of 15–20 ml /kg body weight per hour or 1–1.5 L during the first hour. The choice of fluid
for further repletion depends on the hydration status, serum electrolyte levels, and urinary output. In patients who are hypernatremic or
eunatremic, 0.45% NaCl infused at 4–14 ml/kg/hour is appropriate, and 0.9% NaCl at a similar rate is preferred in patients with
hyponatremia. The goal is to replace half of the estimated water deficit over a period of 12- 24 hours [161]. In patients with
hypotension, aggressive fluid therapy with isotonic saline should continue until blood pressure is stabilized. The administration of
insulin without fluid replacement in such patients may further aggravate hypotension (7). Furthermore, the use of hydrating fluid in
the first hour of therapy before insulin administration provides time to obtain serum potassium value before insulin administration,
prevents possible deterioration of hypotensive patients with the use of insulin without adequate hydration, and decreases serum
osmolality (8). Hydration alone may also reduce the level of counterregulatory hormones and hyperglycemia (18). Hydration reduces
serum blood glucose, BUN, and potassium levels without significant changes in pH or HCO3.The mechanism for lowering glucose is
believed to be due to osmotic diuresis and modulation of conterregulatory hormone release (13,90). We recommend avoiding too rapid
correction of hyperglycemia (which may be associated with cerebral edema especially in children) and also inhibiting hypoglycemia
(13,90). In HHS, the reduction in insulin infusion rate and/or use of D5 ½ NS should be started when blood glucose reaches 300
mg/dL, because overzealous use of hypotonic fluids has been associated with the development of cerebral edema (91). It should be
emphasized that urinary losses of water and electrolytes are also need to be considered.

Insulin Therapy

The cornerstone of DKA and HHS therapy is insulin in physiologic doses. Insulin should only be started after serum potassium value
is > 3.3 mEq/l (4). We recommend using IV bolus of regular insulin (0.1 u/kg body weight) followed by a continuous infusion of
regular insulin at the dose of 0.1u/kg/hr. The optimal rate of glucose reduction is between 50- 70 mg/hr. If desirable glucose reduction
is not achieved in the first hour, an additional insulin bolus at 0.1 u/kg can be given. As mentioned earlier, when plasma glucose
reaches 200 mg/dl in DKA or 300 in HHS, insulin rate should be decreased to 0.05 U/kg/hr, followed, as indicated, by the change in
hydration fluid to D5 ½ NS. The rate of insulin infusion should be adjusted to maintain blood glucose between 150-200 mg/dl in DKA
until it is resolved, and 250-300 mg/dl in HHS until mental obtundation and hyperosmolar state are corrected.
A study that investigated the optimum route of insulin therapy in DKA demonstrated that the time for resolution of DKA was identical
in patients who received regular insulin via intravenous, intramuscular, or subcutaneous routes (92). However, patients who received
intravenous insulin showed a more rapid decline in blood glucose and ketone bodies in the first 2 hours of treatment. Patients who
received intravenous insulin attained an immediate pharmacologic level of insulin concentration. Thus, it was established that an
intravenous loading dose of insulin would be beneficial regardless of the subsequent route of insulin administration during treatment.
A follow up study demonstrated that a priming or loading dose given as one half by IV route and another half by intramuscular route
was as effective as one dose given intravenously in lowering the level of ketone bodies in the first hour (93). A bolus or priming dose
of insulin has been used in a number of studies. The need of such a method, when using intravenous infusion of insulin, is not clear, as
there is no prospective randomized study to establish efficacy of bolus or priming dose before infusion of insulin. However, our study
in children demonstrated the effectiveness of intravenous injection of insulin without a bolus dose (94). Therefore, it would appear
that if intravenous insulin is used, priming or bolus dose insulin might not be necessary.

Recent clinical studies have shown the potency and cost effectiveness of subcutaneous rapid-acting insulin analogs (lispro or aspart) in
the management of patients with uncomplicated mild to moderate DKA (95,96). The patients received subcutaneous rapid-acting
insulin doses of 0.2 U/kg initially, followed by 0.1 U/kg every 1 hour or an initial dose of 0.3 U/kg followed by 0.2 U/kg every 2
hours until blood glucose was < 250 mg/dl. Then the insulin dose was decreased by half to 0.05, or 0.1 U/kg respectively, and
administered every 1 or 2 hours until resolution of DKA. There were no differences in length of hospital stay, total amount of insulin
needed for resolution of hyperglycemia or ketoacidosis, or in the incidence of hypoglycemia among treatment groups. The use of
insulin analogs allowed treatment of DKA in general wards or the emergency department and so reduced cost of hospitalization by
30% without any significant changes in hypoglycaemic events (95). Similar results have been reported recently in pediatric patients
with DKA (97). The administration of continuous intravenous infusion of regular insulin is the preferred route because of its short
half-life and easy titration and the delayed onset of action and prolonged half-life of subcutaneous regular insulin. It is important to
point out that the use of fast-acting insulin analogs is not recommended for patients with severe DKA or HHS, as there are no studies
to support their use. Again these agents may not be effective in patients with severe fluid depletion since they are given
subcutaneously.

Potassium Therapy

Although total-body potassium is depleted (98,99), mild to moderate hyperkalemia is frequently seen in patients with DKA, due to
acidosis, proteolysis and insulinopenia. Insulin therapy, correction of acidosis, and volume expansion decrease serum potassium
concentrations. To prevent hypokalemia, potassium replacement is initiated after serum levels fall below 5.3 mEq/l, in patients with
adequate urine output (50 ml/h). Adding 20–30 mEq potassium to each liter of infused fluid is sufficient to maintain a serum
potassium concentration within the normal range of 4–5 mEq/L (4). Patients with DKA who had severe vomiting or had been on
diuretics may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy, and insulin
treatment should be postponed until potassium concentration becomes > 3.3 mEq/L; in order to prevent arrhythmias and respiratory
muscle weakness (100).

Figure 4

Protocol for the management of adult patients with DKA. Adapted from (67).
Bicarbonate Therapy

The use of bicarbonate in treatment of DKA remains controversial. In patients with pH >7.0, insulin therapy inhibits lipolysis and also
corrects ketoacidosis without use of bicarbonate. Bicarbonate therapy has been associated with some adverse effects, such as
hypokalemia (101), decreased tissue oxygen uptake and cerebral edema (102,103) and delay in the resolution of ketosis (104).
However, patients with severe DKA (low bicarbonate <10, or Pco2 < 12) may experience deterioration of pH if not treated with
bicarbonate. A prospective randomized study in patients with pH between 6.9 and 7.1 showed that bicarbonate therapy had no risk or
benefit in DKA (105). Therefore, in patients with pH between 6.9 and 7.0, it may be beneficial to give 50 mmol of bicarbonate in 200
ml of sterile water with 10 mEq KCL over two hours to maintain the pH at > 7.0 (4,106,107). Considering the adverse effects of
severe acidosis such as impaired myocardial contractility, adult patients with pH < 6.9 should be given 100 mmol sodium bicarbonate
in 400 ml sterile water (an isotonic solution) with 20 mEq KCl administered at a rate of 200 ml/h for two hours until the venous pH
becomes greater than 7.0. Venous pH should be assessed every 2 hours until the pH rises to 7.0; treatment can be repeated every 2
hours if necessary.

Phosphate Therapy

There is no evidence that phosphate therapy is necessary in treatment for better outcome of DKA (108-111). However, in patients with
potential complications of hypophosphatemia, including cardiac and skeletal muscle weakness, the use of phosphate may be
considered (112). Phosphate administration may result in hypocalcemia when used in high dose (108,111).

TREATMENT OF HHS

A similar therapeutic approach can be also recommended for treatment of HHS, but no bicarbonate therapy is needed for HHS, and
changing to glucose-containing fluid is done when blood glucose reaches 300 mg/dl.
Figure 5Protocol for the management of adult patients with HHS.

Severe hyperosmolarity and dehydration associated with insulin resistance and presence of detectable plasma insulin level are the
hallmarks of HHS pathophysiology. The main emphasis in the management of HHS is effective volume repletion and normalization of
osmolarity. There are no randomized controlled studies that evaluated safe and effective strategies in the treatment of HHS (91). It is
important to start HHS therapy with the infusion of normal saline and monitor corrected serum sodium in order to determine
appropriate timing of the change to hypotonic fluids. Insulin substitution approach should be very conservative as it is expected that
insulin resistance will improve with rehydration. We recommend against rapid decreases in serum glucose and correction of serum
sodium in order to avoid untoward effects of shifts in osmolarity on brain volume. This notion should particularly apply in the
management of HHS in elderly and patients with multiple medical problems in whom it may not be clear how long these subjects
experienced severe hyperglycemia prior to the admission to the hospital.

RESOLUTION OF DKA AND HHS

During follow up, blood should be drawn every 2–4 h for determination of serum electrolytes, glucose, blood urea nitrogen, creatinine,
osmolality, and venous pH. After the initial arterial pH is drawn, venous pH can be used to assess the acid/base status. An equivalent
arterial pH value is calculated by adding 0.03 to the venous pH value (113). The resolution of DKA is reached when the blood glucose
is < 200 mg/dl, serum bicarbonate is ³15, pH is > 7.30 and anion gap is < 12 (8). HHS is resolved when osmolarity is < 320 mOsm/kg
with a gradual recovery to mental alertness. The latter may take twice as long as to achieve blood glucose control. Ketonemia typically
takes longer to clear than hyperglycemia.

The proposed ADA criteria for DKA resolution include serum glucose level <200 mg/dL and two of the following: serum bicarbonate
level ³15 mEq/L, pH >7.3, and anion gap <12 mEq/L (1). Therefore, the treatment goal of DKA is to improve hyperglycemia and to
stop ketosis with subsequent resolution of acidosis. In this regard, it is important to distinguish ketosis and acidosis, as the two terms
are not always synonymous in DKA. Ketoacid production in DKA results in reduction in plasma bicarbonate (HCO3-) levels due to
neutralization of hydrogen ion produced during dissociation of ketoacids in the extravascular fluid space. Concomitantly, ketoacid
anion is added into extravascular space resulting in anion gap (AG) increase. The change in HCO3- concentration (Δ HCO3-: normal
serum HCO3- minus observed serum HCO3-) usually corresponds to equal changes in serum anion gap (Δ AG: observed AG minus
normal AG, both corrected for decreases and increases in plasma albumin concentration). Therefore, the ratio of AG excess to HCO3-
deficit (delta-delta, or Δ- Δ) is close to 1.(112,114,115) In most patients with DKA bicarbonate deficit exceeds the addition of
ketoanions, even though Δ- Δ ratio remains close to 1(116). This is observed due to several reasons. First, hyperglycemia-induced
osmotic diuresis leads to excretion of large amounts of sodium and potassium ions that is accompanied by the excretion of ketoanions.
Ultimately, the amount of excreted ketoanions depends on degree of kidney function preservation with the largest amount of
ketoanion loss in patients with relatively preserved glomerular filtration rate.(114) Each ketoanion can be converted back to HCO3-
during resolution of DKA and, therefore, ketoanion loss results in the loss of HCO3-. Additionally, extravascular fluid space
contraction during DKA, leads to elevation of plasma HCO3-. Therefore, intravenous administration of sodium and chloride-containing
fluids leads to further HCO3- reduction and hyperchloremic metabolic acidosis.(112,114) This is an important point as persistent
decrease in plasma HCO3-concentration should not be interpreted as a sign of continuous DKA if ketosis and hyperglycemia are
resolving. Although not evaluated in prospective studies, measurement of serial levels of blood beta-hydroxybutirate (β-OHB) can be
useful adjunct to monitor the resolution of DKA(117). The expected fall in β-OHB with the adequate insulin dosing is 1mmol/L/hr; a
lower decrease in blood β-OHB may suggest inadequate insulin provision.

Once DKA has resolved, patients who are able to eat can be started on a multiple dose insulin regimen with long acting insulin and
short/rapid acting insulin given before meals as needed to control plasma glucose. Intravenous insulin infusion should be continued for
2 hours after giving the subcutaneous insulin to maintain adequate plasma insulin levels. Immediate discontinuation of intravenous
insulin may lead to hyperglycemia or recurrence of ketoacidosis. If the patient is unable to eat, it is preferable to continue the
intravenous insulin infusion and fluid replacement. Patients with known diabetes may be given insulin at the dose they were receiving
before the onset of hyperglycaemic crises. In patients with new onset diabetes, a multi-dose insulin regimen should be started at a dose
of 0.5-0.8 U/kg per day, including regular or rapid-acting and basal insulin until an optimal dose is established (8).

COMPLICATIONS

The most common complications of DKA and HHS include hypoglycemia and hypokalemia due to overzealous treatment with insulin
and bicarbonate (hypokalemia), but these complications occur infrequently with current low dose insulin regimens. During the
recovery phase of DKA, patients commonly develop a short-lived hyperchloremic non-anion gap acidosis, which usually has few
clinical consequences (118). Hyperchloremic acidosis is caused by the loss of large amounts of ketoanions, which are usually
metabolized to bicarbonate during the evolution of DKA, and excess infusion of chloride containing fluids during treatment (119).

Cerebral edema, a frequently fatal complication of DKA, occurs in 0.7–1.0% of children, particularly those with newly diagnosed
diabetes (90). It may also occur in patients with known diabetes and in very young adults usually under 20 years of age (120,121).
Cerebral edema has also been reported in patients with HHS, with some cases of mortality (63). Clinically, cerebral edema is
characterized by deterioration in the level of consciousness, lethargy, decreased arousal, and headache. Headache is the earliest
clinical manifestation of cerebral edema. This is followed by altered level of consciousness and lethargy. Neurological deterioration
may lead to seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest. It may be so rapid in onset due to brain stem
herniation that no papilledema is found. If deteriorating clinical symptoms occur, the mortality rate may become higher than 70%,
with only 7–14% of patients recovering without permanent neurological deficit. Manitol infusion and mechanical ventilation are used
to combat cerebral edema. The cause of cerebral edema is not known with certainty. It may result from osmotically driven movement
of water into the central nervous system when plasma osmolality declines too rapidly during treatment of DKA or HHS. As glucose
concentration improves following insulin infusion and administration of the intravenous fluids, serum osmotic gradient previously
contributed by hyperglycemia reduces which limits water shifts from the intracellular compartment. However, hyperglycemia
treatment is associated with “recovery” in serum sodium that restores water transfer between extracellular and intracellular
compartments and prevents water accumulation in cells (70). In cases when the serum glucose concentration improves to a greater
extent than the serum sodium concentration rises, serum effective osmolality will decrease and may precipitate brain edema (122,123).
Although the osmotically mediated mechanism seems most plausible, one study using magnetic resonance imaging (MRI) showed that
cerebral edema was due to increased cerebral perfusion (104). Another postulated mechanism for cerebral edema in patients with
DKA involves the cell membrane Na+/H+ exchangers, which are activated in DKA. The high H+ level allows more influx of Na+
thus increasing more influx of water to the cell with consequent edema (124). ß-hydoxybutyrate and acetoacetate may also play a role
in the pathogenesis of cerebral edema. These ketone bodies have been shown to affect vascular integrity and permeability, leading to
edema formation (125). In summary, reasonable precautionary measures to decrease the risk of cerebral edema in high-risk patients
include 1) avoidance of overenthusiastic hydration and rapid reduction of plasma osmolality and 2) closed hemodynamic monitoring
(126).

Hypoxemia and rarely non-cardiogenic pulmonary edema may complicate the treatment of DKA [242]. Hypoxemia may be related to
the reduction in colloid osmotic pressure that leads to accumulation of water in lungs and decreased lung compliance. The
pathogenesis of pulmonary edema may be similar to that of cerebral edema suggesting that the sequestration of fluid in the tissues may
be more widespread than is thought. Thrombotic conditions and disseminated intravascular coagulation may contribute to the
morbidity and mortality of hyperglycemic emergencies (127-129). Prophylactic use of heparin, if there is no gastrointestinal
hemorrhage, should be considered.

PREVENTION

Several studies suggested that the omission of insulin is one of the most common precipitating factors of DKA, sometimes because
patients are socio-economically underprivileged, and may not have access to or afford medical care (130-132). In addition, they may
have a propensity to use illicit drugs such as cocaine, which has been associated with recurrent DKA (37). Therefore, it is important
that medical care be provided for these patients. Education of the patient about sick day management is very vital to prevent DKA, and
should include information on when to contact the health care provider, blood glucose goals, use of insulin and initiation of
appropriate nutrition during illness and should be reviewed with patients periodically. Patients must be advised to continue insulin and
to seek professional advice early in the course of the illness. Close follow up is very important, as it has been shown that three-
monthly visits to the endocrine clinic will reduce the number of ER admission for DKA (133). Close observation, early detection of
symptoms and appropriate medical care would be helpful in preventing HHS in the elderly.

A study in adolescents with type 1 diabetes suggests that some of the risk factors for DKA include higher HbA1c, uninsured children
and psychological problems (134). In other studies, education of primary care providers and school personnel in identifying the signs
and symptoms of DKA has been shown to be effective in decreasing the incidence of DKA at the onset of diabetes (135). In another
study outcome data of 556 patients with diabetes under continuing care over a 7-year period were examined. The hospitalization rates
for DKA and amputation were decreased by 69 % due to continuing care and education (136). Considering DKA and HHS as
potentially fatal and economically burdensome complications of diabetes, every effort for diminishing the possible risk factors is
worthwhile.

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hypomagnesemia by phosphate therapy. The American journal of medicine 1979; 67:897-900
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Cholesterol Lowering Drugs
Kenneth R Feingold, MD and Carl Grunfeld, MD, PhD.

Author Information

Last Update: August 10, 2016.

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ABSTRACT
There are currently six different classes of drugs available for lowering cholesterol levels. There are currently seven HMG-CoA
reductase inhibitors (statins) approved for lowering cholesterol levels and they are the first line drugs for treating lipid disorders and
can lower LDL cholesterol levels by as much as 60%. Statins also are effective in reducing triglyceride levels in patients with
hypertriglyceridemia. Statins lower LDL levels by inhibiting HMG-CoA reductase activity leading to decreases in hepatic cholesterol
content resulting in an up-regulation of hepatic LDL receptors, which increases the clearance of LDL. The major side effects are
muscle complications and an increased risk of diabetes. The different statins have varying drug interactions. Ezetimibe lowers LDL
cholesterol levels by approximately 20% by inhibiting cholesterol absorption by the intestines leading to the decreased delivery of
cholesterol to the liver, a decrease in hepatic cholesterol content, and an up-regulation of hepatic LDL receptors. Ezetimibe is very
useful as add on therapy when statin therapy is not sufficient or in statin intolerant patients. Ezetimibe has few side effects. Bile acid
sequestrants lower LDL cholesterol by10-30% by decreasing the absorption of bile acids in the intestine which decreases the bile acid
pool consequently stimulating the synthesis of bile acids from cholesterol leading to a decrease in hepatic cholesterol content and an
up-regulation of hepatic LDL receptors. Bile acid sequestrants can be difficult to use as they decrease the absorption of multiple drugs,
increase triglyceride levels, and cause constipation and other GI side effects. They do improve glycemic control in patients with
diabetes which is an additional benefit. PCSK9 monoclonal antibodies lower LDL cholesterol by 50-60% by binding PCSK9, which
decreases the degradation of LDL receptors. PCSK9 inhibitors also decrease Lp(a) levels. PCSK9 inhibitors are very useful when
maximally tolerated statin therapy does not reduce LDL sufficiently and in statin intolerant patients. PCSK9 inhibitors have very few
side effects. Mipomersen and lomitapide are approved for lowering LDL levels in patients with Homozygous Familiar
Hypercholesterolemia. Mipomersen is a second generation apolipoprotein anti-sense oligonucleotide that decreases apolipoprotein B
synthesis resulting in a reduction in the formation and synthesis of VLDL. Lomitapide inhibits microsomal triglyceride transfer
protein decreasing the formation of chylomicrons in the intestine and VLDL in the liver. Both mipomersen and lomitapide have the
potential to cause liver toxicity and therefore they were approved with a risk evaluation and mitigation strategy (REMS) to reduce
risk. For complete coverage of all related aeas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

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INTRODUCTION
This chapter will discuss the currently available drugs for lowering cholesterol levels, especially LDL cholesterol: statins, ezetimibe,
bile acid sequestrants, PCSK9 inhibitors, lomitapide, and mipomersen. We will not discuss the effect of lifestyle changes on LDL
cholesterol as this is addressed in detail in chapter 23 [1]. Additionally, we will not discuss the effect of food additives, such as
phytosterols, on LDL cholesterol as these are also discussed in chapter 23 [1]. Finally, we will not discuss guidelines for determining
who to treat, how aggressively to treat, or targets of treatment as these issues are discussed in detail in chapter 4 [2].

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STATINS
Introduction

In the 1970s Dr. Akira Endo, working at Sankyo, discovered that compounds isolated from fungi inhibited the activity of HMG-CoA
reductase, a key enzyme in the synthesis of cholesterol [3]. Further studies at Merck led to the development of the first HMG-CoA
reductase inhibitor, lovastatin, approved in 1987 for the treatment of hypercholesterolemia [4]. There are currently seven HMG-CoA
reductase inhibitors (statins) approved in the United States for lowering cholesterol levels. Three statins are derived from fungi
(lovastatin, simvastatin, and pravastatin) and four statins are synthesized (atorvastatin, rosuvastatin, fluvastatin, and pitavastatin). Most
of these statins are now generic drugs and therefore they are relatively inexpensive. Which particular statin one elects to use may
depend on the degree of cholesterol lowering needed and the potential of drug-drug interactions. Statins are the first line drugs for
treating lipid disorders and therefore one of the most widely utilized class of drugs. Statins have revolutionized the field of preventive
cardiology and making an important contribution to the reduction in atherosclerotic cardiovascular events.

Effect on Statins on Lipid and Lipoprotein Levels

The major effect of statins is lowering LDL cholesterol levels. The effect of the various statins at different doses on LDL cholesterol
levels is shown in Table 1. As can be seen in Table 1 different statins have varying abilities to lower LDL with maximal reductions of
approximately 60% seen with rosuvastatin 40mg. Doubling the dose of a statin results in an approximate 6% further decrease in LDL
levels. The percent reduction in LDL cholesterol levels is similar in patients with high and low starting LDL levels but the absolute
decrease is greater if the starting LDL is high. Because of this profound ability of statins to lower LDL cholesterol levels, treatment
with these drugs as monotherapy is often sufficient to lower LDL cholesterol below target levels.

Table 1Approximate effect of different doses of statins on LDL cholesterol levels

% LDL Reduction Simvastatin Atorvastatin Lovastatin Pravastatin Fluvastatin Rosuvastatin Pitavastatin

(Pravachol)
(Zocor) (Lipitor) (Mevacor) (Lescol) (Crestor) (Livalo)
27 10mg - 20mg 20mg 40mg - -
34 20mg 10mg 40mg 40mg 80mg - 1mg
41 40mg 20mg 80mg 80mg - - 2mg
48 80mg 40mg - - - 10mg 4mg
54 - 80mg - - - 20mg -
60 - - - - - 40mg -

Data modified from package inserts

As would be predicted from the effect of statins on LDL cholesterol levels, statins are also very effective in lowering non-HDL
cholesterol levels (LDL cholesterol is the major contributor to non-HDL cholesterol levels) [5, 6]. In addition statins also lower
plasma triglyceride levels [7, 8]. The ability of statins to lower triglyceride levels correlates with the reduction in LDL cholesterol [8].
Statins that are most efficacious in lowering LDL cholesterol are also most efficacious in lowering plasma triglyceride and VLDL
cholesterol levels. Notably the percent reduction in plasma triglyceride levels is dependent on the baseline triglyceride levels [8]. For
example in patients with normal triglyceride levels (<150mg/dl), simvastatin 80mg per day lowered plasma triglyceride levels by
11%. In contrast, if plasma triglyceride levels were elevated (> 250mg/dl), simvastatin 80mg per day lowered triglyceride levels by
40% [8]. In patients with both elevated LDL cholesterol and triglyceride levels statin therapy can be very effective in improving the
lipid profile and are therefore the first line class of drugs to treat patients with mixed hyperlipidemia unless the triglyceride levels are
markedly elevated (>500-1000mg/dl). As expected, given the ability of statins to lower LDL cholesterol and triglyceride/VLDL
levels, statin therapy is very effective in lowering apolipoprotein B levels [5, 6].
Of note despite the ability of statins to lower LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels, statins do not lower
Lp(a) levels [9]. Finally statins modestly increase HDL cholesterol levels [7, 10, 11]. In most studies HDL cholesterol levels increase
between 5-10% with statin therapy. Interestingly, while low dose atorvastatin increases HDL levels similar to other statins at high
doses the effect of atorvastatin is blunted with either very modest increases or no change observed [10].

Non-Lipid Effects of Statins

In addition to effects on lipid metabolism statins also have pleiotropic effects that may not be directly related to alterations in lipid
metabolism [12]. For example, statins are anti-inflammatory and consistently decrease CRP levels [13]. Other pleiotropic effects of
statins include anti-proliferative effects, antioxidant properties, anti-thrombosis, improving endothelial dysfunction, and attenuating
vascular remodeling [12]. Whether these pleiotropic effects contribute to the beneficial effects of statins in preventing cardiovascular
disease is uncertain and much of the beneficial effect of statins on cardiovascular disease can be attributed to reductions in lipid levels.

Mechanism Accounting for the Statin Induced Lipid Effects

Statins are competitive inhibitors of HMG-CoA reductase, which leads to a decrease in cholesterol synthesis in the liver. This
inhibition of hepatic cholesterol synthesis results in a decrease in cholesterol in the endoplasmic reticulum resulting in the movement
of sterol regulatory element binding proteins (SREBPs) from the endoplasmic reticulum to the golgi where they are cleaved by
proteases into active transcription factors [14]. The SREBPs then translocate to the nucleus where they increase the expression of a
number of genes including HMG-CoA reductase and, most importantly, the LDL receptor [14]. The increased expression of HMG-
CoA reductase restores hepatic cholesterol synthesis towards normal while the increased expression of the LDL receptor results in an
increase in the number of LDL receptors on the plasma membrane of hepatocytes leading to the accelerated clearance of
apolipoprotein B and E containing lipoproteins (LDL and VLDL) (Figure 1) [14]. The increased clearance of LDL and VLDL
accounts for the reduction in plasma LDL and triglyceride levels. In patients with a total absence of LDL receptors (Homozygous
Familiar Hypercholesterolemia) statin therapy is not very effective in lowering LDL cholesterol levels.

Figure 1: Mechanism for the Decrease in LDL Levels

In addition to lowering LDL and VLDL levels by accelerating the clearance of lipoproteins some studies have also shown that statins
reduce the production and secretion of VLDL particles by the liver [15]. This could contribute to the decrease in triglyceride levels.
The mechanism by which statins increase HDL cholesterol levels is not clear.

Pharmacokinetics and Drug Interactions

Statins have different pharmacokinetic properties which can explain clinically important differences in safety and drug interactions
[16-18]. Most statins are lipophilic except for pravastatin and rosuvastatin, which are hydrophilic. Lipophilic statins can enter cells
more easily but the clinical significance of this difference is not clear. Most of the clearance of statins is via the liver and GI tract [16-
18]. Renal clearance of statins in general is low with atorvastatin having a very low renal clearance making this particular drug the
statin of choice in patients with significant renal disease. The half-life of statins varies greatly with lovastatin, pravastatin, simvastatin,
and fluvastatin having a short half-life (1-3 hours) while atorvastatin, rosuvastatin, and pitavastatin having a long half-life [16-18]. In
patients intolerant of statins the use of a long acting statin every other day or 2 times per week has been employed. Additionally, while
all statins are most effective when administered in the evening when HMG-CoA reductase activity is maximal the long acting statins
are preferred in patients that desire to take their statin in the morning.

A key difference between statins is their pathway of metabolism. Simvastatin, lovastatin, and atorvastatin are metabolized by the
CYP3A4 enzymes and drugs that affect the CYP3A4 pathway can alter the metabolism of these statins [16-19]. Fluvastatin is
metabolized mainly by CYP2C9 with a small contribution by CYP2C8 [16-19]. Pitavastatin and rosuvastatin are minimally
metabolized by the CYP2C9 pathway [16-19]. Pravastatin is not metabolized at all via the CYP enzyme system [16-18].

Drugs that inhibit CYP3A4 can impede the metabolism of simvastatin, lovastatin, and to a smaller extent atorvastatin resulting in high
serum levels of these drugs [16-19]. These higher levels are associated with adverse effects particularly muscle toxicity. Drugs that
inhibit CYP3A4 include intraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors (amprenavir, darunavir,
fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), amiodarone, diltiazem, verapamil, and cyclosporine [16-19]. It should
be noted that grapefruit juice contains compounds that inhibit CYP3A4 and the consumption of grapefruit juice can significantly
increase statin blood levels [20]. The inhibition of CYP3A4 by grapefruit juice is dose dependent and increases with the concentration
and volume of grapefruit juice ingested. One glass of grapefruit juice everyday can influence the metabolism of statins that are
metabolized by the CYP3A4 pathway [20]. If a patient requires treatment with a drug that inhibits CYP3A4 the clinician has a number
of options to avoid potential drug interactions. One could use a statin that is not metabolized via the CYP3A4 system such as
pravastatin or rousuvastatin, one could use an alternative drug to the CYP3A4 inhibitor (for example instead of using erythromycin
use azithromycin), or one could temporary suspend for a short period of time the use of the statin that is metabolized by the CYP3A4
pathway (this is particularly useful when a short course of treatment with an antifungal or antibiotic is required). Drugs that inhibit
CYP2C9 do not seem to increase the toxicity of fluvastatin, pitavastatin, or rosuvastatin probably because metabolism via the
CYP2C9 pathway is not a dominant pathway.

Most statins are transported into the liver and other tissues by organic anion transporting polypeptides, particularly OATP1B1 [16-19].
Drugs, such as clarithromycin, ritonavir, indinavir, saquinavir, and cyclosporine that inhibit OATP1B1 can increase serum statin
levels thereby increasing the risk of statin muscle toxicity [16-19]. Fluvastatin is the statin that is least affected by OATP1B1
inhibitors. In fact fluvastatin 40mg per day has been studied in patients receiving renal transplants concomitantly treated with
cyclosporine and over a five year study period the risk of myopathy or rhabdomyolysis was not increased in the fluvastatin treated
patients compared to those treated with placebo [21].

Gemfibrozil inhibits the glucuronidation of statins, which accounts for a significant portion of the metabolism of most statins [19].
This can lead to the reduced clearance of statins and elevated blood levels increasing the risk of muscle toxicity [19]. The only statin
whose metabolism is not altered by gemfibrozil is fluvastatin [19]. Notably, fenofibrate, another fibrate that has very similar effects on
lipid and lipoprotein levels as gemfibrozil, does not inhibit statin glucuronidation [19]. Therefore in patients on statin therapy who also
need treatment with a fibrate one should use fenofibrate and not gemfibrozil in combination with statin therapy. Studies have shown
that fenofibrate combined with statins does not increase toxicity [22].

There are other drug interactions with statins whose mechanisms are unknown. For example, the lopinavir/ritonavir combination used
to treat HIV increases rosuvastatin levels by 2-5 fold and atazanavir/ritonavir increases rosuvastatin levels by 2-6 fold [23-27].
Similarly, the tipranavir/ritonavir combination increases rosuvastatin levels 2 fold and atorvastatin levels 8 fold [26]. When HIV
patients are on these drugs other statins should be used to lower LDL cholesterol levels.

Thus despite the excellent safety record of statins, careful attention must be paid to the potential drug-drug interactions.

Effect of Statin Therapy on Clinical Outcomes

A large number of studies using a variety of statins in diverse patient populations have shown that statin therapy reduces
atherosclerotic cardiovascular disease. The Cholesterol Treatment Trialists have published meta-analyses derived from individual
subject data. Their first publication included data from 14 trials with over 90,000 subjects [28]. There was a 12% reduction in all-
cause mortality in the statin treated subjects, which was mainly due to a 19% reduction in coronary heart disease deaths. Non-vascular
causes of death were similar in the statin and placebo groups indicating that statin therapy and lowering LDL did not increase the risk
of death from other causes such as cancer, respiratory disease, etc. Of particular note there was a 23% decrease in major coronary
events per 1 mmol/L (39mg/dl) reduction in LDL cholesterol. Decreases in other vascular outcomes including non-fatal MI, coronary
heart disease death, vascular surgery and stroke were also reduced by 20-25% per 1 mmol/L (39mg/dl) reduction in LDL cholesterol.
Additionally, analysis of these studies demonstrated that the greater the reduction in absolute LDL cholesterol levels the greater the
decrease in cardiovascular events. For example, while a 40mg/dl decrease in LDL cholesterol will reduce coronary events by
approximately 20%, an 80mg/dl decrease in LDL cholesterol will reduce events by approximately 40%. These results support
aggressive lipid lowering with statin therapy.

Of note the decrease in the number of events begins to be seen in the first year of therapy indicating that the ability of statins to reduce
events occurs quickly and increases over time. The ability of statins to reduce cardiovascular events was seen in a wide diversity of
patients including those with and without a history of prior cardiovascular disease, patients over age 65 and younger than age 65,
males and females, and patients with and without a history of diabetes or hypertension. Additionally, the beneficial effects of statins
were seen regardless of the baseline lipid levels. Subjects with elevated or low LDL, HDL, or triglyceride levels all had similar
decreases in the relative risk of cardiovascular events.

A subsequent publication by the Cholesterol Treatment Trialists has focused on five studies with over 39,000 subjects that have
compared usual vs. intensive statin therapy [29]. It was noted that there was a 0.51mmol/L (20mg/dl) further reduction in LDL
cholesterol in the intensively treated subjects. This further decrease in LDL resulted in a15% reduction in cardiovascular events. The
strong numerical relationship between decreases in LDL cholesterol levels and the reduction in cardiovascular events provides
evidence indicating that much of the beneficial effect of statins is accounted for by lipid lowering.

In addition, the authors added 7 additional trials to their original comparison of statin treatment vs. placebo for a total of 21 trials with
over 129,000 subjects. In this larger cohort a 1mmol/L (39mg/dl) decrease in LDL was associated with a 21% reduction in major
cardiovascular events. As seen previously the benefits of statin therapy were seen in a wide variety of subjects including patients older
than age 75, obese patients, cigarette smokers, patients with decreased renal function, and patients with low and high HDL levels.
Additionally, a reduction of cardiovascular events with statin therapy was seen regardless of baseline LDL levels.

A more recent meta-analysis by the Cholesterol Treatment Trialists examined the effect of statins in 27 trials that included 46,675
women and 127,474 men [30]. They found that statin therapy was similarly effective in reducing cardiovascular events in both men
and women. Thus there is an overwhelming database of randomized clinical outcome trials showing the benefits of statin therapy in
reducing cardiovascular disease, which, coupled with their excellent safety profile, has resulted in statins becoming a very widely used
class of drugs and first line therapy for the prevention of cardiovascular disease.

Effect of Statins Therapy on Clinical Outcomes in Specific Patient Groups

Primary Prevention:

While there is no doubt that individuals with pre-existing cardiovascular disease require statin therapy, the use of statins for primary
prevention was initially debated. There are now a large number of statin primary prevention studies. The Cholesterol Treatment
Trialists reported that statin therapy was very effective in reducing cardiovascular events in subjects without a history of vascular
disease and the magnitude of risk reduction was similar to subjects with a history of cardiovascular events [29]. Additionally, vascular
deaths were reduced by statin treatment even in subjects without a history of vascular disease. As expected, non-vascular deaths were
not altered in these subjects without a history of pre-existing vascular disease. Additionally, the Cholesterol Treatment Trialists
compared the benefits of statin therapy based on baseline risk of developing cardiovascular disease (<5%, ≥5% to <10%, ≥10% to
<20%, ≥20% to <30%, ≥30%) [31]. The proportional reduction in major vascular events was at least as big in the two lowest risk
categories as in the higher risk categories indicating that subjects at low risk benefit from statin therapy. Similar to the Cholesterol
Treatment Trialists analysis, a Cochrane review published in 2013 on the effect of statins in primary prevention patients reached the
following conclusion: “Reductions in all-cause mortality, major vascular events, and revascularisations were found with no excess
adverse events among people without evidence of CVD treated with statins” [32]. Recently, an additional study has been completed
that focused on intermediate risk patients without cardiovascular disease. In this trial 12,705 men and women who had at least one risk
factor for cardiovascular disease were randomized to 10mg rosuvastatin vs. placebo [33]. Rosuvastatin treatment resulted in a 27%
reduction in LDL cholesterol levels and a 24% decrease in cardiovascular events providing additional evidence that statin treatment
can reduce events in primary prevention patients. It is therefore clear that statins are effective in safely reducing events in primary
prevention patients.

The key issue is “which primary prevention patients should be treated” and this is still controversial. It should be noted that the higher
the baseline risk the greater the absolute reduction in events with statin therapy. For example, in a high risk patient with a 20% risk of
developing a vascular event, a 25% risk reduction will result in a 15% risk of an event (absolute decrease of 5%). In contrast in a low
risk patient with a 4% risk of developing a vascular event, a 25% risk reduction will result in a 3% risk (absolute decrease of only
1%). Thus, the absolute benefit of statin therapy over the short term will depend on the risk of developing cardiovascular disease.

Additionally, based on the Cholesterol Treatment Trialists results the reduction in cardiovascular events is dependent on the absolute
decrease in LDL cholesterol levels. Thus the effect of statin treatment will be influenced by baseline LDL levels. For example a 50%
decrease in LDL is 80mg/dl if the starting LDL is 160mg/dl and only 40mg/dl if the starting LDL is 80mg/dl. Based on studies
showing that a decrease in LDL of 1 mmol/L (40mg/dl) reduces cardiovascular events by ~20% the relative benefit of statin therapy
will be greater in the patient with the starting LDL of 160mg/dl (40% decrease in events) than in the patient with the starting LDL of
80mg/dl (20% decrease in events). Thus, decisions on treatment need to factor in both relative risk and baseline LDL levels.
Elderly:

The Cholesterol Treatment Trialists reported that cardiovascular events were reduced by 22% in subjects age 65 years or younger,
22% in subjects 66 to 75 years old, and 16% for those older than 76 years for every 1mmol/L (39mg/dl) decrease in LDL cholesterol
[29]. The Prosper Study was specifically designed to determine the effect of pravastatin 40mg per day in patients 70-82 years of age
with either evidence of vascular disease or risk factors for vascular disease [34]. Pravastatin therapy reduced LDL cholesterol levels
by 27% and after 3.2 years decreased the risk of coronary heart disease events by 19%. Thus, the data clearly indicate that statin
induced reductions in LDL cholesterol will decrease cardiovascular events in the elderly. Unfortunately studies on the very old (>85
year) are not available.

Women:

As noted above a recent meta-analysis by the Cholesterol Treatment Trialists examined the effect of statins in 27 trials that included
46,675 women and 127,474 men [30]. They found that statin therapy was similarly effective in reducing cardiovascular events in both
men and women.

Asians:

Pharmacokinetic data have shown that the serum levels of statins are higher in Asians than in Caucasians [35]. Moreover, Asians
achieve similar LDL lowering at lower statin doses than Caucasians [35]. Therefore the statin dose used should be lower in Asians.
For example the starting dose of rosuvastatin is 5mg in Asians as compared to 10mg in Caucasians. Additionally, the maximum
recommended dose of statin is lower in Japan vs. the United States (Table 2).

Table 2Maximum Statin Dose in Japan and United States

Statin Japan United States

Atorvastatin 40 80
Fluvastatin 60 80
Pravastatin 20 80
Rosuvastatin 20 40
Simvastatin 20 40

Diabetes:
Statin trials, including both primary and secondary prevention trials, have consistently shown the beneficial effect of statins on
cardiovascular disease in patients with diabetes [36]. The Cholesterol Treatment Trialists analyzed data from 18,686 subjects with
diabetes (mostly type 2 diabetes) from 14 randomized trials [37]. In the statin treated group there was a 9% decrease in all-cause
mortality, a 13% decrease in vascular mortality, and a 21% decrease in major vascular events per 1mmol/L (39mg/dl) reduction in
LDL cholesterol. The beneficial effect of statin therapy was seen in both primary and secondary prevention patients. The effect of
statin treatment on cardiovascular events in patients with diabetes was similar to that seen in non-diabetic subjects. It should be noted
that while the data for patients with type 2 diabetes is robust, the number of patients with type 1 diabetes in these trials is relatively
small and the results less definitive. Also of note is that information on young patients with diabetes (< age 40) is very limited. Thus,
these studies indicate that statins are beneficial in reducing cardiovascular disease in patients with diabetes.

Renal Disease:

The Cholesterol Treatment Trialists examined the effect of renal function on statin effectiveness. They reported that the relative risk
reduction for cardiovascular events was similar if the eGFR was < 60ml/min as compared to > 90 or 60-90 [29]. Similarly, a recent
meta-analysis of 57 studies with >143,000 participants with renal disease not on dialysis reported a 31 % reduction in major
cardiovascular events in statin treated subjects compared to placebo groups [38]. Thus, in patients with renal disease not on dialysis,
treatment with statins is beneficial and should be utilized in this population at high risk for vascular disease.

In contrast to the above results, studies examining the role of statins in dialysis patients have not found a benefit from statin therapy.
The Deutsche Diabetes Dialyse Studie (4D) randomized 1255 type 2 diabetic subjects on hemodialysis to either 20 mg atorvastatin or
placebo [39]. The LDL-cholesterol reduction was similar to that seen in non-dialysis patients but there was no significant reduction in
cardiovascular death, nonfatal myocardial infarction, or stroke in the atorvastatin treated compared to the placebo group. Similarly, A
Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA) randomized 2776 subjects on
hemodialysis to rosuvastatin 10 mg or placebo [40]. Again, the LDL-cholesterol lowering in dialysis patients was similar to that seen
in other studies but there was no significant effect on the primary endpoint of cardiovascular death, nonfatal myocardial infarction, or
stroke. A meta-analysis of 25 studies involving 8289 dialysis patients found no benefit of statin therapy on major cardiovascular
events, cardiovascular mortality, all-cause mortality or myocardial infarction, despite efficacious lipid lowering. The reason for the
failure of statins in patients on maintenance dialysis is unclear but could be due to a number of factors including the possibility that the
marked severity of atherosclerosis in end stage renal disease may limit reversal, that different mechanisms of atherosclerosis
progression occurs in dialysis patients (for example an increased role for inflammation, oxidation, or thrombosis), or that
cardiovascular events in this patient population may not be due to atherosclerosis. We would recommend continuing statin therapy in
patients on dialysis who have been previously treated with statins but not initiating therapy in the rare statin naïve patient beginning
dialysis.
Statins are primarily metabolized in the liver and therefore the need to adjust the statin dose is not usually needed in patients with
renal disease until the eGFR is < 30ml/min. The effect of renal dysfunction on statin clearance varies from statin to statin [41]. For
some statins such as atorvastatin, there is no need to adjust the dose in renal disease because there is limited renal clearance [41].
However, for other statins it is recommended to adjust the dose in patients when the eGFR is < 30ml/min. In patients with an eGFR <
30ml/min the maximum dose of rosuvastatin is 10mg, simvastatin 40mg, pitavastatin 2mg, pravastatin 20mg, lovastatin 20mg, and
fluvastatin 40mg per day [41].

Congestive Heart Failure:

In the Corona study 5011 patients with systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per
day [42]. While rosuvastatin treatment reduced LDL cholesterol levels by 45% compared to placebo, rosuvastatin did not decrease
death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Why statin treatment was not beneficial in this
patient population with congestive heart failure is unknown.

Liver Disease:

Many patients with liver disease, particularly those with nonalcoholic fatty liver disease (NAFLD), are at high risk for cardiovascular
disease and therefore require statin therapy [43]. There have been concerns that these patients would not tolerate statin therapy and
that statin therapy would worsen their underlying liver disease. Fortunately, there are now studies of statin therapy in patients with
abnormal liver function tests and underlying liver disease at baseline [43-45]. With a variety of statins studies have demonstrated no
significant worsening of liver disease and in fact several studies have suggested improvement in liver function tests with statin therapy
[45]. This is true for patients with hepatitis C, NAFLD/NASH, and primary biliary cirrhosis. Additionally, in the GREACE trial, statin
treatment reduced cardiovascular events in patients with moderately abnormal liver function tests (transaminases < 3x the upper limit
of normal) [46]. Thus, in patients with mild liver disease without elevations in bilirubin or abnormalities in synthetic function, statins
are safe and reduce the risk of cardiovascular disease.

Statin Side Effects

Diabetes:

After many years of statin use it was recognized that statins increase the risk of developing diabetes. In a meta-analysis of 13 trials
with over 90,000 subjects, there was a 9% increase in the incidence of diabetes during follow-up among subjects receiving statin
therapy [47]. All statins appear to increase the risk of developing diabetes. In comparisons of intensive vs. moderate statin therapy,
Preiss et al observed that patients treated with intensive statin therapy had a 12% greater risk of developing diabetes compared to
subjects treated with moderate dose statin therapy [48]. Older subjects, obese subjects, and subjects with high glucose levels were at a
higher risk of developing diabetes while on statin therapy [36]. Thus, statins may be unmasking and accelerating the development of
diabetes that would have occurred naturally in these subjects at some point in time. In patients without risk factors for developing
diabetes, treatment with statins does not appear to increase the risk of developing diabetes. In patients with diabetes, an analysis of 9
studies with over 9,000 patients with diabetes reported that the patients randomized to statin therapy had a 0.12% higher A1c than the
placebo group indicating that statin therapy is associated with only a very small increase in A1c levels in patients with diabetes that is
unlikely to be clinically significant [49]. Individual studies, such as CARDS and the Heart Protection Study, have also shown only a
very modest effect of statins on A1c levels in patients with diabetes [50, 51].

The mechanism by which statins increase the risk of developing diabetes is unknown. A recent study has demonstrated that a
polymorphism in the gene for HMG-CoA reductase that results in a decrease in HMG-CoA reductase activity and a small decrease in
LDL levels is also associated with an increase in body weight and plasma glucose and insulin levels [52]. This observation suggests
that the inhibition of HMG-CoA reductase per se may be leading to the statin induced increased risk of diabetes. In balancing the
benefits and risks of statin therapy it is important to recognize that an increase in plasma glucose levels is a surrogate marker for an
increased risk of developing micro and macrovascular disease (i.e. an increase in plasma glucose per se is not an event but rather
increases the risk of future events). In contrast, statin therapy is preventing actual clinical events that cause morbidity and mortality.
Furthermore, it may take many years for an elevated blood glucose to induce diabetic complications while the reduction in
cardiovascular events with statin therapy occurs relatively quickly. Patients on statin therapy should be periodically screened for the
development of diabetes with measurement of fasting glucose levels or A1c levels.

Cancer:

Analysis of 14 trials with over 90,000 subjects by the Cholesterol Clinical Trialists did not demonstrate an increased risk of cancer or
any specific cancer with statin therapy [28]. An update with an analysis of 27 trials with over 174,000 participants also did not observe
an increase in cancer incidence or death [30]. Additionally, no differences in cancer rates were observed with any particular statin.

Cognitive Dysfunction:

Several randomized clinical trials have examined the effect of statin therapy on cognitive function and have not indicated any
increased risk [53-55]. The Prosper Trial was designed to determine whether statin therapy will reduce cardiovascular disease in older
subjects (age 70-82) [34]. In this trial cognitive function was assessed repeatedly and no difference in cognitive decline was found in
subjects treated with pravastatin compared to placebo [34, 56]. In the Heart Protection Study over 20,000 patients were randomized to
simvastatin 40mg or placebo and again no significant differences in cognitive function was observed between the statin vs. placebo
group [57]. Additionally, a Cochrane review examined the effect of statin therapy in patients with established dementia and identified
4 studies with 1154 participants [58]. In this analysis no benefit or harm of statin therapy on cognitive function could be demonstrated
in this high risk group of patients. Thus, while the FDA has mandated warnings regarding statin induced cognitive dysfunction
randomized clinical trials do not indicate a significant association.

Liver Disease:

It was in initially thought that statins induced liver dysfunction and it was recommended that liver function tests be routinely obtained
while patients were taking statins. However, studies have now shown that the risk of liver function test abnormalities in patients taking
statins is very small [44]. For example, in a survey of 35 randomized studies involving > 74,000 subjects, elevations in transaminases
were seen in 1.4% of statin treated subjects and 1.1% of controls [59]. Similarly, in a meta-analysis of > 49,000 patients from 13
placebo controlled studies, the incidence of transaminase elevations greater than three times the upper limit of normal was 1.14% in
the statin group and 1.05% in the placebo group [60]. Moreover, even when the transaminase levels are elevated, repeat testing often
demonstrates a return towards normal levels [61]. The increases in transaminase levels with statin therapy are dose related with high
doses of statins leading to more frequent elevations [62]. At this time, routine monitoring of liver function tests in patients taking
statins is no longer recommended. However, obtaining baseline liver function tests prior to starting statin therapy is indicated [44]. If
liver function tests are obtained during statin treatment, one should not be overly concerned with modestly elevated transaminase
levels (less than 3x the upper limit of normal) [44]. If the transaminase is greater than 3x the upper limit of normal the test should be
repeated and if it remains > 3x the upper limit of normal, statin therapy should be stopped and the patient evaluated [44].

A more clinically important issue is whether statins lead to an increased risk of liver failure. Studies have suggested that the incidence
of liver failure in patients taking statins is very similar to the rate observed in the general population (approx. 1 case per 1 million
patient years) [63, 64]. Thus statin therapy causing serious liver injury is a very rare event.

Muscle:

The most common side effect of statin therapy is muscle symptoms. These can range from life threatening rhabdomyolysis to
myalgias (Table 3) [65].

Table 3

Spectrum of Statin Induced Muscle Disorders (Adapted from J. Clinical Lipidology 8:S58-71, 2014)
Myalgia- aches, soreness, stiffness, tenderness, cramps with normal CK levels
Myopathy- muscle weakness with or without increased CK
Myositis- muscle inflammation
Myonecrosis- mild (CK >3x ULN); moderate (CK> 10x ULN); severe (CK> 50x ULN)
Rhabdomyolysis- myonecrosis with myoglobinuria or acute renal failure

Many patients will discontinue the use of statins due to muscle symptoms. Risk factors associated with an increased incidence of statin
associated muscle symptoms are listed in Table 4 [66, 67].

Table 4Risk factors for Statin Myopathy

Medications that alter statin metabolism

Older age
Female
Hypothyroidism
Excess alcohol
Vitamin D deficiency
History of muscle disorders
Renal disease
Liver disease
Personal or family history of statin intolerance
Low BMI
Polymorphism in SLCO1B1 gene
High dose statin
Drug-drug interactions

In most randomized clinical trials, the incidence of myalgia was similar in the statin and placebo groups (see table 5) [68]. For
example, in the AFCAPS/TexCAPS trial in the 3,301 subjects treated with 20-40mg lovastatin, 2,053 reported musculoskeletal
symptoms [69]. However, in the 3,301 subjects in the placebo group 1,971 also reported musculoskeletal symptoms. Similarly, in the
Jupiter trial, where 18,902 subjects were randomized to rosuvastatin 20mg per day or placebo 16% of the subjects treated with
rosuvastatin had muscle symptoms [70]. However, in the placebo group muscle symptoms occurred in 15.4% of subjects.
Table 5: Muscle Disorders in Randomized Controlled Statin Trials

Myalgia % Myopathyb % Rhabdomyolysisc %

Trial Drug Dose Sa Pa S P S P

4S Simva 20-40 3.7 3.2 0.05 0 0 0
WOSCOPS Prava 40 3.5 3.7 0 0 0 0
HPS Simva 40 NR NR 0.07 0.02 0.04 0.01
PROSPER Prava 40 1.2 1.1 0 0 0 0
CARDS Atorva 10 4.0 4.8 0 0 0 0
ASPEN Atorva 10 3.0 1.6 0 0 0.08 0.08
SPARCL Atorva 80 5.5 6.0 0.3 0.3 0.1 0.1
JUPITER Rosuva 20 7.9 6.9 0.1 0.1 0.01 0

a- S= statin, P= placebo; b- muscle pain of weakness with CK > 10x ULN; c- myopathy with CK > 40x ULN and/or renal impairment;
d- HPS asked about muscle symptoms at each visit

While the results of the randomized trials suggest that muscle symptoms are not induced by statin therapy, in typical clinical settings a
significant percentage of patients are unable to tolerate statins due to muscle symptoms (in many studies as high as 5-25% of patients)
[71-73]. Recently there was a randomized trial that explored the issue of myopathy with statin therapy in great detail [74]. In this trial
the effect of atorvastatin 80mg a day vs. placebo for 6 months on creatine kinase (CK), exercise capacity, and muscle strength was
studied in 420 healthy, statin-naive subjects. Atorvastatin treatment led to a modest increase in CK levels (20.8U/L) with no change
observed in the placebo group. None of the subjects had an elevation of CK > 10x the upper limits of normal. There were no changes
in muscle strength or exercise capacity with atorvastatin treatment. However, myalgia was reported in 19 subjects (9.4%) in the
atorvastatin group compared to 10 subjects (4.6%) in the placebo group (p=0.05). In this study “myalgia” was considered to be present
if all of the following occurred: (1) subjects reported new or increased muscle pain, cramps, or aching not associated with exercise; (2)
symptoms persisted for at least 2 weeks; (3) symptoms resolved within 2 weeks of stopping the study drug; and (4) symptoms
reoccurred within 4 weeks of restarting the study medication. Notably these myalgias were not associated with elevated CK levels. In
the atorvastatin group the myalgias tended to occur soon after therapy (average 35 days) whereas in the placebo group myalgias occur
later (average 61 days). In the atorvastatin group the symptoms were predominantly localized to the legs and included aches, cramps,
and fatigue, whereas in the placebo group they were more diverse including whole body fatigue, foot cramps, worsening of pain in
previous injuries, and groin pain. A number of conclusions can be reached from this study. First, statin treatment does in fact increase
the incidence of myalgias. Second, a substantial number of patients treated with placebo will also develop myalgias. Third, clinically
differentiating statin induced myalgias from placebo induced myalgias is difficult, as there are no specific symptoms, signs, or
biomarkers that clearly distinguish between the two. It should be recognized that the patient population typically treated with statins
(patients 50-80 years of age) often have muscle symptoms in the absence of statin therapy and it is therefore difficult to be certain that
the muscle symptoms described by the patient are actually due to statin therapy.

In a very small study in the Annals of Internal Medicine eight patients with “statin related myalgia” were re-challenged with statin or
placebo and there were no statistically significant differences in the recurrence of myalgias on the statin or placebo [75]. This
approach has been expanded upon in two larger studies. In 120 patients with “statin induced myalgia” patients were randomized in a
double blinded crossover trial to either simvastatin 20mg per day or placebo and the occurrence of muscle symptoms was determined
[76]. Only 36% of these patients were confirmed to actually have statin induced myalgia (presence of symptoms on simvastatin
without symptoms on placebo). In a similar study, Nissen and colleagues studied 491 patients with “statin induced myalgia” treating
with either atorvastatin 20mg per day or placebo in a double-blind crossover trial [77]. In this trial 42.6% of patients were confirmed
to have statin induced muscle symptoms. Thus while statin induced myalgias are a real entity, in the clinic it is difficult to be certain
whether the muscle symptoms are actually due to true statin intolerance or to other factors. The approach to treating these patients will
be discussed later in this chapter (Treatment of Stain Intolerant Patients). While some patients will not tolerate statin therapy due to
myalgias, this side effect does not appear to result in serious morbidity or long term consequences.

Fortunately the more serious muscle related side effects of statin therapy are rare (table 5). In a meta-analysis of 21 statin vs. placebo
trials there was an excess risk of rhabdomyolysis of 1.6 patients per 100,000 patient years or a standardized rate of 0.016/patient years
[61]. Other studies report a rate of rhabdomyolysis between 0.03- 0.16 per 1,000 patient years [78]. Similarly, the risk of statin
induced myositis (muscle symptoms with an increase in CK 10 times the upper limits of normal) is also very low (table 5). In an
analysis of 21 randomized trials myositis occurred in only 5 patients per 100,000 person years or 0.05/1000 patient years [61]. The
higher the dose of statin used the greater the risk of myositis and rhabdomyolysis. In a comparison of five trials that compared high
dose statin vs. low dose statin there was an excess risk of rhabdomyolysis of 4 per 10,000 people treated [29]. The likely basis for an
increased risk of myositis or rhabdomyolysis is elevated statin blood levels, which are more likely to occur with high doses of statins.
In the development of statins, manufacturers have studied higher doses that are not approved for clinical use. For example, simvastatin
and pravastatin at 160mg per day were studied but discontinued due to an increased incidence of muscle side effects [79, 80]. Recently
the use of simvastatin 80mg per day, a previously approved dose, was restricted due to an increased risk of muscle side effects.
Similarly, pitavastatin at doses greater than 4mg per day was investigated, but development was abandoned when an increased risk of
rhabdomyolysis was observed. Along similar lines, in many of the patients that develop rhabdomyolysis, the etiology can be linked to
the use of other drugs that alter statin metabolism thereby increasing statin blood levels [67]. For example, prior to drug interactions
being recognized the use of cyclosporine, gemfibrozil, HIV protease inhibitors, and erythromycin in conjunction with certain statins
was linked with the development of rhabdomyolysis [67]. Finally, common variants in SLCO1B1, which encodes the organic anion-
transporting polypeptide OATP1B1, are strongly associated with an increased risk of statin-induced myopathy [81]. OATP1B1
facilitates the transport of statins into the liver and certain polymorphisms are associated with an increased risk of developing statin
induced muscle disorders, due to a the decreased transport of statins into the liver resulting in increased blood levels [82]. The exact
mechanism by which elevated blood levels induce muscle toxicity remains to be elucidated.

Recently it has been recognized that a very small number of patients taking statins develop a progressive autoimmune necrotizing
myopathy, which is characterized by progressive symmetric proximal muscle weakness, elevated CK levels (typically >10x the ULN),
and antibodies against HMG-CoA reductase [83]. It is estimated that this occurs in 2 or 3 per 100,000 patients treated with a statin
[83]. This myopathy may begin soon after initiating statin therapy or develop after a patient has been on statins for many years [83].
Muscle biopsy reveals necrotizing myopathy without severe inflammation [83]. In contrast to the typical muscle disorders induced by
statin therapy, the autoimmune myopathy progresses despite discontinuing therapy. Spontaneous improvement is not typical and most
patients will need to be treated with immunosuppressive therapy (glucocorticoids plus methotrexate, azathioprine, or mycophenolate
mofetil) [83].

From the above certain conclusions can be reached. First, the risk of serious muscle disorders due to statin therapy is very small,
particularly if one is aware of the potential drug interactions that increase the risk. Second, the muscle toxicity is usually linked to
elevated statin blood levels and the higher the dose of the statin the more likely the chance of developing toxicity. Third, myalgias in
patients taking statins are very common and can be due to statin treatment. However, in the individual patient, it is very difficult to
know if the myalgia is actually secondary to statin therapy and in many patients the myalgias are not due to the statin therapy. Fourth,
the muscle symptoms that occur in association with statin treatment are a major reason why patients discontinue statin use and
therefore better diagnostic algorithms and treatments are required to allow patients to better comply with these highly effective
treatments to reduce cardiovascular disease.

Contraindications

Statins are contraindicated in pregnant women or lactating women. In women of child bearing age birth control should be discussed
and statins should be discontinued prior to conception. In addition, liver function tests should be obtained prior to initiating statin
treatment and moderate to severe liver disease is a contraindication to statin therapy [44].

Summary
An enormous data base has been accumulated which demonstrates that statins are very effective at reducing the risk of cardiovascular
disease and that statins have an excellent safety profile. The risk benefit ratio of treating patients with statins is very favorable and has
resulted in this class of drugs being widely utilized to lower serum lipid levels and to reduce the risk of cardiovascular disease and
death.

Go to:

EZETIMBE
Introduction

Ezetimibe (Zetia) inhibits the absorption of cholesterol by the intestine thereby resulting in modest decreases in LDL cholesterol levels
[84]. Ezetimibe is primarily used in combination with statin therapy when statin treatment alone does not lower LDL levels
sufficiently. It may also be used as monotherapy to lower LDL cholesterol levels in patients with statin intolerance. Finally, it is the
drug of choice in patients with the rare genetic disorder sitosterolemia (discussed in detail in chapter 9) [85].

Effect of Ezetimibe on Lipid and Lipoprotein Levels

Pandor and colleagues have published a meta-analysis of ezetimibe monotherapy that included 8 studies with 2,722 patients [86].
They reported that ezetimibe decreased LDL cholesterol levels by 18.6%, decreased triglyceride levels by 8.1%, and increased HDL
cholesterol levels by 3% compared to placebo. In a pooled analysis by Morrone and colleagues of 27 studies with 11, 714 subjects
treated with ezetimibe in combination with statin therapy similar results were observed [87]. Specifically, LDL cholesterol levels were
decreased by 15.1%, non-HDL cholesterol levels by 13.5%, triglycerides by 4.7%, apolipoprotein B levels by 10.8%, and HDL
cholesterol levels were increased by 1.6%. The combination of a high dose potent statin plus ezetimibe can lower LDL cholesterol
levels by 70% [88]. The effect of ezetimibe on lipid parameters occurs quickly and can be seen after 2 weeks of treatment. In patients
with Heterozygous Familial Hypercholesterolemia who have marked elevations in LDL cholesterol levels, the addition of ezetimibe to
statin therapy resulted in similar changes with a further 16.5% decrease in LDL cholesterol levels [89]. Thus in comparison with
statins, ezetimibe treatment produces modest decreases in LDL cholesterol levels (15-20%). In addition to these changes in lipid
parameters, ezetimibe in combination with a statin decreased hs-CRP by 10-19% compared to statin monotherapy [90, 91]. However,
ezetimibe alone does not decrease hs-CRP levels [91].

Mechanisms Accounting for the Ezetimibe Induced Lipid Effects

NPC1L1 (Niemann-Pick C1-like 1 protein) is highly expressed in the intestine with the greatest expression in the proximal jejunum,
which is the major site of intestinal cholesterol absorption [92, 93]. Knock out animals deficient in NPC1L1 have been shown to have
a decrease in intestinal cholesterol absorption [92]. Ezetimibe binds to NPC1L1 and inhibits cholesterol absorption [84, 92, 93]. In
animals lacking NPC1L1, ezetimibe has no effect on intestinal cholesterol absorption, demonstrating that ezetimibe’s effect on
cholesterol absorption is mediated via NPC1L1 [84, 93]. Thus, a major site of action of ezetimibe is to block the absorption of
cholesterol by the intestine [84, 93]. Cholesterol in the intestinal lumen is derived from both dietary cholesterol (approximately 25%)
and biliary cholesterol (approximately 75%); thus the majority is derived from the bile [93]. As a consequence, even in patients that
have very little cholesterol in their diet ezetimibe will decrease cholesterol absorption. While ezetimibe is very effective in blocking
intestinal cholesterol absorption it does not interfere with the absorption of triglycerides, fatty acids, bile acids, or fat soluble vitamins
including vitamin D and K.

When intestinal cholesterol absorption is decreased the chylomicrons formed by the intestine contain less cholesterol and thus the
delivery of cholesterol from the intestine to the liver is diminished [94]. This results in a decrease in the cholesterol content of the
liver, leading to the activation of SREBPs, which enhance the expression of LDL receptors resulting in an increase in LDL receptors
on the plasma membrane of hepatocytes (Figure 1) [94]. Thus, similar to statins the major mechanism of action of ezetimibe is to
decrease the levels of cholesterol in the liver resulting in an increase in the number of LDL receptors leading to the increased
clearance of circulating LDL [94]. In addition, the decreased cholesterol delivery to the liver may also decrease the formation and
secretion of VLDL [94].

In addition to NPC1L1 expression in the intestine this protein is also expressed in the liver where it mediates the transport of
cholesterol from the bile back into the liver [95]. The inhibition of NPC1L1 in the liver will result in the increased secretion of
cholesterol in bile and thereby could also contribute to a decrease in the cholesterol content of the liver and an increase in LDL
receptor expression and a decrease in VLDL production.

Pharmacokinetics and Drug Interactions

Following absorption by intestinal cells ezetimibe is rapidly glucuronidated. The glucuronidated ezetimibe is then secreted into the
portal circulation and rapidly taken up by the liver where it is secreted into the bile and transported back to the intestine [84]. This
enterohepatic circulation repeatedly returns the ezetimibe to its site of action (note glucuronidated ezetimibe is a very effective
inhibitor of NPC1L1) [84]. Additionally, this enterohepatic circulation accounts for the long duration of action of ezetimibe and limits
peripheral tissue exposure [84]. Ezetimibe is not significantly excreted by the kidneys and thus the dose does not need to be adjusted
in patients with renal disease.
Ezetimibe is not metabolized by the P450 system and does not have many drug interactions [84]. It should be noted that cyclosporine
does increase ezetimibe levels.

Effect of Ezetimibe Therapy on Clinical Outcomes

There have been a limited number of ezetimibe clinical outcome trials. Two have studied the effect of ezetimibe in combination with a
statin vs. placebo making it virtually impossible to determine if ezetimibe per se has beneficial effects. However, one study has
compared ezetimibe plus a statin vs. a statin alone.

The SEAS Trial was a randomized trial of 1873 patients with mild-to-moderate, asymptomatic aortic stenosis [96]. The patients
received either simvastatin 40mg per day in combination with ezetimibe 10mg per day vs. placebo daily. The primary outcome was a
composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, non-fatal myocardial
infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary
intervention, and non-hemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic
cardiovascular events. Simvastatin plus ezetimibe lowered LDL cholesterol levels by 61% compared to placebo. There were no
significant differences in the primary outcome between the treated vs. placebo groups. Similarly, the need for aortic valve replacement
was also not different between the treated and placebo groups. However, fewer patients had ischemic cardiovascular events in the
simvastatin plus ezetimibe treated group than in the placebo group (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), which was
primarily accounted for by a decrease in the number of patients who underwent coronary-artery bypass grafting. The design of this
study does not allow for one to determine if the beneficial effect on ischemic cardiovascular events typically produced by statin
therapy was enhanced by the addition of ezetimibe.

The SHARP Trial was a randomized trial of 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not on dialysis)
with no known history of myocardial infarction or coronary revascularization [97]. Patients were randomly assigned to simvastatin 20
mg plus ezetimibe 10 mg daily vs. placebo. The primary outcome was first major atherosclerotic event (non-fatal myocardial
infarction or coronary death, non-hemorrhagic stroke, or any arterial revascularization procedure). Treatment with simvastatin plus
ezetimibe resulted in a decrease in LDL cholesterol of 0·85 mmol/L (~34mg/dl). This decrease in LDL cholesterol was associated
with a 17% reduction in major atherosclerotic events. In patients on hemodialysis there was a 5% decrease in cardiovascular events
that was not statistically significant. Unfortunately similar to the SEAS Trial, it is impossible to tell whether the addition of ezetimibe
improved outcomes above and beyond what would occur with statin treatment alone.

The IMPROVE-IT Trial tested whether the addition of ezetimibe to statin therapy will provide an additional beneficial effect in
patients with the acute coronary syndrome [98]. The IMPROVE-IT Trial was a large trial with over 18,000 patients randomized to
simvastatin 40mg per day vs. simvastatin 40mg per day + ezetimibe 10mg per day. On treatment LDL cholesterol levels were 70mg/dl
in the statin alone group vs. 54mg/dl in the statin + ezetimibe group. There was a small but significant 6.4% decrease in major
cardiovascular events (Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization,
or stroke) in the statin + ezetimibe group (HR 0.936 CI (0.887, 0.988) p=0.016). Cardiovascular death, non-fatal MI, or non-fatal
stroke were reduced by 10% (HR 0.90 CI (0.84, 0.97) p=0.003). The results of this study have a number of important implications.
First, it demonstrates that combination therapy may have benefits above and beyond statin therapy alone. Second, it provides further
support for the hypothesis that lowering LDL per se will reduce cardiovascular events. Third, it suggests that lowering LDL levels into
the 50s will have benefits above and beyond lowering LDL levels to the 70mg/dl range. These results have implications for
determining goals of therapy and provide support for combination therapy.

Side Effects

Ezetimibe has not demonstrated significant side effects. In monotherapy trials, the effect on liver function tests was similar to placebo.
In a meta-analysis by Toth et al. of 27 randomized trials in > 20,000 participants evaluating statin plus ezetimibe vs. statin alone the
incidence of liver function test abnormalities was slightly greater in the combination therapy group (statin alone- 0.35% vs. statin plus
ezetimibe 0.56%) [99]. In contrast, Luo and colleagues in a meta-analysis of 20 randomized with > 14,000 subjects did not observe a
difference in liver function tests in the ezetimibe plus statin vs. statin alone group [100]. With regards to muscle side effects, a meta-
analysis of seven randomized trials by Kashani and colleagues found that monotherapy with ezetimibe or ezetimibe in combination
with a statin did not increase the risk of myositis compared to placebo or monotherapy with a statin [101]. Similarly, Luo et al also did
not observe that combination therapy with ezetimibe and a statin increased the risk of myositis [100]. In a meta-analysis by Savarese
et al. of 7 randomized long term studies including SEAS, SHARP, and IMPROVE-IT, the incidence of cancer was similar in patients
treated with ezetimibe vs. patients not treated with ezetimibe [102]. This confirms a previous study that also did not demonstrate an
increased cancer risk in the three largest ezetimibe trials [103].

Thus, over many years of use ezetimibe has been shown to be a very safe drug without major side effects.

Contraindications

Ezetimibe is contraindicated in patients with active liver disease. The use of ezetimibe during pregnancy and lactation has not been
studied.

Summary
Ezetimibe has a modest ability to lower LDL cholesterol levels and can be a very useful adjunct to statin therapy. When added to
statin therapy it will lower the LDL cholesterol by an additional 15-20% which is equivalent to three titrations of the statin dose (for
example adding ezetimibe is equivalent to increasing atorvastatin from 10mg to 80mg per day). Additionally, the combination of a
high dose of a potent statin (rosuvastatin 40mg per day) with ezetimibe was able to lower the LDL by approximately 70%, which will
allow many patients to reach their LDL goal [91]. In patients intolerant of statins who either cannot take a statin or can only take low
doses of a statin, ezetimibe is extremely useful in further lowering LDL cholesterol. The ease of taking ezetimibe and the lack of
serious side effects make it an obvious second choice drug after statins to lower LDL.

Go to:

BILE ACID SEQUESTRANTS

Introduction

There are three bile acid sequestrants approved for use in the United States. The first bile acid sequestrant, cholestyramine (Questran),
was developed in the 1950s and was the second drug available to lower cholesterol levels (niacin was the first drug). Colestipol
(Colestid) was developed in the 1970s and is very similar to cholestyramine. In 2000, Colesevelam was approved. Colesevelam has
enhanced binding and affinity for bile acids compared to cholestyramine and colestipol and therefore can be given in much lower
doses reducing some side effects [104]. Because these drugs work by binding bile acids they are most effective when taken with
meals.

Effect of Bile Acid Sequestrants on Lipid and Lipoprotein Levels

The major effect of bile acid sequestrants is to lower LDL cholesterol levels in a dose dependent fashion. Depending upon the specific
drug and dose the decrease in LDL ranges from approximately 5 to 30% [104-106]. The effect of monotherapy with bile acid
sequestrants on LDL levels observed in various studies is shown in table 6.

Table 6Effect of bile acid sequestrants on LDL cholesterol

Drug LDL lowering

Cholestyramine 4g/day 7% decrease
Cholestyramine 24g/day 28% decrease
Colestipol 4g/day 12% decrease
Colestipol 16g/day 24% decrease
Colesevelam 3.8g/day 15% decrease
Colesevelam 4.3g/day 18% decrease

Bile acid sequestrants are typically used in combination with statins and the addition of bile acid sequestrants to statin therapy will
result in a further 10% to 25% decrease in LDL cholesterol levels [104-106]. Combination therapy can result in a 60% reduction in
LDL levels when high doses of potent statins are combined with high doses of bile acid sequestrants. Bile acid sequestrants will also
further lower LDL cholesterol levels by as much as 18% when added to statins and ezetimibe [107]. This is particularly useful in
patients with Heterozygous Familial Hypercholesterolemia who can have very high LDL levels at baseline. Additionally, in patients
who are statin intolerant, the combination of a bile acid sequestrant and ezetimibe resulted in an additional 10-20% decrease in LDL
cholesterol compared to either drug alone [108, 109]. Thus both in monotherapy and in combination with other drugs that lower LDL
levels, bile acid sequestrants are very effective in lowering LDL levels

Bile acid sequestrants have a very modest effect on HDL levels, typically resulting in a 3-9% increase [104-106]. The effect of bile
acid sequestrants on triglyceride levels varies [104-106]. In patients with normal triglyceride levels, bile acid sequestrants increase
triglyceride levels by a small amount. However, as baseline triglyceride levels increase, the effect of bile acid sequestrants on plasma
triglyceride levels becomes greater, and can result in substantial increases in triglyceride levels. In patients with triglycerides >
400mg/dl the use of bile acid sequestrants is contraindicated.

Non-Lipid Effects of Bile Acid Sequestrants

Bile acid sequestrants have been shown to reduce fasting glucose and hemoglobin A1c levels [110]. Colesevelam has been most
intensively studied and in a number of different studies colesevelam has decreased A1c levels by approximately 0.5-1.0% in patients
also treated with a variety of glucose lowering drugs including metformin, sulfonylureas, and insulin. The Food and Drug
Administration (FDA) has approved colesevelam for improving glycemic control in patients with type 2 diabetes.

Bile acid sequestrants decrease CRP. For example, Devaraj et al have shown that colesevelam decreases hs-CRP by 18% compared to
placebo [111]. In combination with a statin, colesevelam reduced hs-CRP levels by 23% compared to statin alone [112].

Mechanisms Accounting for Bile Acid Sequestrants Induced Lipid Effects

Bile acid sequestrants bind bile acids in the intestine, preventing their reabsorption in the terminal ileum leading to the increased fecal
excretion of bile acids [113]. This decrease in bile acid reabsorption reduces the size of the bile acid pool, which stimulates the
conversion of cholesterol into bile acids in the liver [113]. This increase in bile acid synthesis decreases hepatic cholesterol levels
leading to the activation of SREBPs that up-regulate the expression of the enzymes required for the synthesis of cholesterol and the
expression of LDL receptors [113]. The increase in hepatic LDL receptors results in the increased clearance of LDL from the
circulation leading to a decrease in serum LDL levels (Figure 1). Thus similar to statins and ezetimibe, bile acids lower plasma LDL
cholesterol levels by decreasing hepatic cholesterol levels, which stimulates LDL receptor production and thereby accelerates the
clearance of LDL from the blood.

The key regulator of bile acid synthesis is FXR (farnesoid X receptor), a nuclear hormone receptor that forms a heterodimer with RXR
to regulate gene transcription [114, 115]. Bile acids down-regulate cholesterol 7α hydroxylase, the first enzyme in the bile acid
synthetic pathway by several FXR mediated mechanisms. In the ileum, bile acids via FXR stimulate the production of FGF19, which
is secreted into the portal vein and inhibits cholesterol 7α hydroxylase expression in the liver [114]. Additionally, in the liver, bile
acids activate FXR leading to the increased expression of SHP (small heterodimer partner), which inhibits the transcription of
cholesterol 7α hydroxylase [115]. Thus, a decrease in bile acids will lead to the decreased activation of FXR in the liver and intestines
and thereby result in an increase in cholesterol 7α hydroxylase expression and the increased conversion of cholesterol to bile acids
resulting in a decrease in hepatic cholesterol content.

Decreased activation of FXR can also explain the adverse effects of bile acid sequestrants on triglyceride levels [116, 117]. Activation
of FXR increases the expression of apolipoprotein C-II, apolipoprotein A-V, and the VLDL receptor, proteins that decrease plasma
triglyceride levels while decreasing the expression of apolipoprotein C-III, a protein that is associated with increases in plasma
triglycerides [116, 117]. Thus, activation of FXR would be expected to decrease triglyceride levels as increases in apolipoprotein C-II,
apolipoprotein A-V, and the VLDL receptor and decreases in apolipoprotein C-III would reduce plasma triglyceride levels. With bile
acid sequestrants the activation of FXR would be reduced and decreases in the expression of apolipoprotein C-II, apolipoprotein A-V,
and the VLDL receptor and increased expression of apolipoprotein C-III would increase plasma triglyceride levels.

The mechanism by which treatment with bile acid sequestrants improves glycemic control is unclear.

Pharmacokinetics and Drug Interactions

Bile acid sequestrants are not absorbed and not altered by digestive enzymes and thus their primary effects are localized to the
intestine [104-106]. It should be noted that bile acid sequestrants can indirectly have systemic effects by decreasing the reabsorption of
bile acids and thereby reducing the exposure of cells to bile acids, which are biologically active compounds.
Unfortunately, in the intestine bile acid sequestrants can impede the absorption of many other drugs [104-106]. This is particularly
true for cholestyramine and colestipol which are used in large quantities (maximum doses- cholestyramine 24 grams per day;
colestipol 30 grams per day). In contrast, colesevelam, which requires a much lower quantity of drug because of its high affinity and
binding capacity for bile salts, has less of an effect on the absorption of other drugs (recommended dose of colesevelam 3.75
grams/day). Of particular note colesevelam does not interfere with absorption of statins, fenofibrate, or ezetimbe. A list of some of the
drugs whose absorption is affected by cholestyramine or colestipol is shown in table 7 and a list of drugs whose absorption is affected
by colesevelam is shown in table 8.

Table 7Some of the Drugs Affected by Cholestyramine/Colestipol

Statins Ezetimibe Gemfibrozil Fenofibrate

Thiazides Furosemide Spironolactone Digoxin
Warfarin L-thyroxine Corticosteroids Vitamin K
Cyclosporine Raloxifine NSAIDs Sulfonylureas
Aspirin Beta blockers Tricyclic

Table 8Some of the Drugs Affected by Colesevelam

L-thyroxine Cyclosporine Glimepiride Glipizide

Glyburide Phenytoin Olmesartan Warfarin
Oral contraceptives

It is currently recommended that medications should be taken either 4 hours before or 4 hours after taking bile acid sequestrants. This
is particularly important with drugs that have a narrow toxic/therapeutic window, such as thyroid hormone, digoxin, or warfarin. It can
be very difficult for many patients, particularly those on multiple medications, to take bile acid sequestrants given the need to separate
pill ingestion.

Cholestyramine and colestipol may also interfere with the absorption of fat soluble vitamins. Taking a multivitamin 4 hours before or
after these drugs can reduce the likelihood of a vitamin deficiency.

Effect of Bile Acid Sequestrants on Clinical Outcomes

The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) of cholestyramine vs. placebo was the first large drug
study to explore the effect of specifically lowering LDL cholesterol on cardiovascular outcomes [118]. LRC-CPPT was a multicenter,
randomized, double-blind study in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia. The treatment group
received cholestyramine 24 grams per day and the control group received a placebo for an average of 7.4 years. In the cholestyramine
group total and LDL cholesterol was decreased by 8.5% and 12.6% as compared to the placebo group. In the cholestyramine group
there was a 19% reduction in risk (p < 0.05) of the primary end point accounted for by a 24% reduction in definite CHD death and a
19% reduction in nonfatal myocardial infarction. In addition, the incidence rates for new positive exercise tests, angina, and coronary
bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The reduction in events correlated
with the decrease in LDL cholesterol levels [119]. Of note, compliance with cholestyramine 24 grams per day was limited with many
patients taking much less than the prescribed doses. These results indicate that lowering LDL cholesterol with bile acid sequestrant
monotherapy will reduce cardiovascular disease.

In addition to the LRC-CPPT clinical outcome study, two studies have examined the effect of cholestyramine monotherapy on
angiographic changes in the coronary arteries. The National Heart, Lung, and Blood Institute Type II Coronary Intervention Study and
the St Thomas Atherosclerosis Regression Study reported that cholestyramine decreased the progression of atherosclerosis [120, 121].
There are a number of studies that have employed bile acid sequestrants in combination with other drugs and have shown a reduction
in the progression of atherosclerosis or an increase in the regression of atherosclerosis but given the use of multiple drugs it is difficult
to attribute the beneficial effects to the bile acid sequestrants [122-124]. Unfortunately there are no clinical outcome studies
comparing statins alone vs. statins plus bile acid sequestrants.

Side Effects

Bile acid sequestrants do not have major systemic side effects as they are not absorbed and remain in the intestinal tract. However,
they do cause gastrointestinal (GI) side effects [104-106]. Constipation is a very common side effect and can be severe. In addition,
patients will often complain of bloating, abdominal discomfort, and aggravation of hemorrhoids. Because of GI distress, a significant
number of patients will discontinue therapy with bile acid sequestrants. These GI side effects are much more common with
cholestyramine and colestipol compared to colesevelam, which is much better tolerated. One can reduce or ameliorate these GI side
effects by increasing hydration, adding fiber to the diet (psyllium), and using stool softeners. Notably, bile acid sequestrants do not
cause liver or muscle problems.

One should also be aware that bile acid sequestrants can be difficult for many patients to take. Colestipol and colesevelam pills are
large and can be difficult for some patients to swallow. Additionally, patients need to take a large number of these pills (colesevelam-
6 pills per day; colestipol- as many as 16 pills per day). The granular forms of cholestyramine and colestipol do not dissolve and are
ingested as a suspension in liquid. Many patients find mixing with water leads to an unpalatable mixture that is difficult to take.
Sometimes mixing with fruit juice, apple sauce, mash potatoes, etc. make the mixture more palatable. The suspension form of
colesevelam with either 1.875 or 3.75 grams is preferred by many patients.

Contraindications

Bile acid sequestrants usually should be avoided in patients with pre-existing GI disorders. Bile acid sequestrants are contraindicated
in patients with recent or repeated intestinal obstruction and patients with plasma triglyceride levels > 400mg/dl. In contradistinction
from other lipid lowering drugs, bile acid sequestrants are not contraindicated during pregnancy or lactation (category B) [125]. In
women of child bearing age who are planning to become pregnant bile acid sequestrants can be a good choice to lower LDL levels.

Summary

Bile acid sequestrants are useful secondary drugs for the treatment of elevated LDL cholesterol levels. They are typically used in
combination with statin therapy as a second line drug or as an addition to statin plus ezetimibe therapy as a third line drug. In statin
intolerant patients the combination of ezetimibe and a bile acid sequestrant is frequently employed. Bile acid sequestrants can be
difficult drugs for patients to take due to GI side effects, difficulty taking the medication, and the need to avoid taking these drugs with
other medications. To improve compliance with these drugs the clinician needs to spend time educating the patient on how to take
these drugs and how to avoid side effects.

Go to:

PCSK9 INHIBITORS
Introduction

In 2015 two monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin kexin type 9) were approved for the lowering
of LDL cholesterol levels. Alirocumab (Praluent) is produced by Regeneron/Sanofi and evolocumab (Repatha) is produced by Amgen
[126, 127]. Alirocumab is administered as either 75mg or 150mg subcutaneously every 2 weeks while evolocumab is administered as
either 70mg subcutaneously every 2 weeks or 420mg subcutaneously once a month. Other monoclonal antibodies that inhibit PCSK9
are under development so it is likely that in the future there will be several monoclonal antibodies available for clinical use [126, 127].
Effect of PCSK inhibitors on Lipid and Lipoprotein Levels

There are a large number of studies that have examined the effect of PCSK9 inhibitors on lipid and lipoprotein levels. A meta-analysis
of 24 studies comprising 10,159 patients reported a reduction in LDL cholesterol levels of approximately 50% and in an increase in
HDL of 5-8% [128]. Notably, in 12 RCTs with 6,566 patients, Lp(a) levels were reduced by 25-30% [128]. It should be recognized
that most LDL cholesterol lowering drugs (statins, ezetimibe, and bile acid sequestrants) do not lower Lp(a) levels. PCSK9 inhibitors
have not been shown to decrease hs-CRP levels [129].

Monotherapy:

Both alirocumab and evolocumab have been studied as monotherapy vs. ezetimibe. In the Mendel-2 study patients were randomly
assigned to evolocumab, placebo, or ezetimibe [130]. In the evolocumab group, LDL cholesterol levels decreased by 57% while in the
ezetimibe group LDL cholesterol levels decreased by 18% compared to placebo. Additionally, non-HDL cholesterol was decreased by
49%, apolipoprotein B by 47%, triglycerides by 5.3% (NS), and Lp(a) by 18.5% while HDL levels increased by 5.5% in the
evolocumab treated subjects. In a study of alirocumab vs. exetimibe LDL cholesterol levels were reduced by 47% in the alirocumab
group and 16% in the ezetimibe group [131]. In addition alirocumab decreased non-HDL cholesterol by 41%, apolipoprotein B by
37%, triglycerides by 12%, and Lp(a) by 17% and increased HDL by 6%. Thus PCSK9 monoclonal antibodies are very effective in
lowering pro-atherogenic lipoproteins when used in monotherapy and have a more robust effect than ezetimibe.

In Combination with Statins:

In the Odyssey Combo I study, patients on maximally tolerated statin therapy were randomized to alirocumab or placebo [132].
Similar to monotherapy results, when alirocumab was added to statin therapy there was a further decrease in LDL cholesterol levels
by 46%, non-HDL cholesterol by 38%, apolipoprotein B by 36%, and Lp(a) by 15% with an increase in HDL of 7% and no change in
triglyceride levels. In the Odyssey Combo II study, patients on maximally tolerated statin therapy were randomized to alirocumab vs.
ezetimibe [133]. Alirocumab reduced LDL levels by 51% while ezetimibe reduced LDL by 21%, demonstrating that even when added
to statin therapy, alirocumab has a significantly greater ability to reduce LDL cholesterol levels than ezetimibe. In Odyssey Combo II,
non-HDL cholesterol levels were decreased by 42%, apolipoprotein B by 41%, triglycerides by 13%, and Lp(a) by 28% while HDL
increased by 9% in the alirocumab treated group. In the Laplace-2 study, evolocumab was added to various statins used at different
doses [134]. It didn’t make any difference which statin was being used (atorvastatin, rosuvastatin, or simvastatin) or what dose
(atorvastatin 10mg or 80mg; rosuvastatin 5mg or 40mg); the addition of evolocumab resulted in an approximately 60% further
decrease in LDL cholesterol levels beyond statin alone. Additionally, the Laplace-2 trial also showed that evolocumab was much more
potent than ezetimibe when added to statin therapy (evolocumab resulted in an approximately 60% decrease in LDL vs. while
ezetimibe resulted in an approximately 20-25% reduction).

In Combination with a Statin and Ezetimibe:

When evolocumab was added to patients receiving atorvastatin 80mg and ezetimibe 10mg there was 48% further reduction in LDL
cholesterol levels indicating that even in patients on very aggressive lipid lowering therapy the addition of a PCSK9 inhibitor can still
result in a marked reduction in LDL [135]. In addition to decreasing LDL there was also a 41% decrease in non-HDL cholesterol, a
38% decrease in apolipoprotein B, and a 19% decrease in Lp(a) when evolocumab was added to statin plus ezetimibe therapy.

Patients with Heterozygous Familial Hypercholesterolemia:

Both alirocumab and evolocumab have been tested in patients with Heterozygous Familial Hypercholesterolemia [136, 137]. In the
Rutherford-2 trial, evolocumab lowered LDL cholesterol by 60%, non-HDL cholesterol by 56%, apolipoprotein B by 49%, Lp(a) by
31%, and triglycerides by 22% while increasing HDL by 8% [136]. In the Odyssey FH I and FH II studies, alirocumab lowered LDL
cholesterol by approximately 55%, non-HDL cholesterol by ~50%, apolipoprotein B by ~43%, Lp(a) by ~19% and triglycerides by
~14% while increasing HDL by ~7% [137]. Thus, in these difficult to treat patients PCSK9 monoclonal antibodies were still very
effective at lowering pro-atherogenic lipoproteins.

Patients with Homozygous Familial Hypercholesterolemia:

Evolocumab resulted in a 31% decrease in LDL levels compared to placebo in patients with Homozygous Familial
Hypercholesterolemia [138]. The response to therapy appears to be dependent on the underlying genetic cause. Patients with
mutations in the LDL receptor leading to the expression of defective receptors respond to therapy whereas patients with mutations
leading to negative receptors have a poor response [138, 139]. Given the mechanism by which PCSK9 inhibitors lower LDL
cholesterol levels it is not surprising that patients that do not have any functional LDL receptors will not respond to therapy (see
section on Mechanism of Lipid Lowering)

Statin Intolerant Patients:

A number of studies have examined the effect of PCSK9 monoclonal antibodies in statin intolerant patients (myalgias) and compared
the response to ezetimibe treatment [77, 140, 141]. As expected treatment with a PCSK9 inhibitor was more effective in lowering
LDL cholesterol levels than ezetimibe. Importantly, muscle symptoms were less frequent in the pCSK9 treated patients than those
treated with ezetimibe, indicating that PCSK9 monoclonal antibodies will be an effective treatment choice in statin intolerant patients
with myalgias.

Patients with Diabetes:

A meta-analysis of three trials with 413 patients with type 2 diabetes found that in patients with type 2 diabetes evolocumab caused a
60% decrease in LDL cholesterol compared to placebo and a 39% decrease in LDL compared to ezetimibe treatment [142]. In
addition, in patients with type 2 diabetes, evolocumab decreased non-HDL cholesterol 55% vs. placebo and 34% vs. ezetimibe) and
Lp(a) (31% vs. placebo and 26% vs. ezetimibe). These beneficial effects were not affected by glycemic control, insulin use, renal
function, and cardiovascular disease status. Thus, PCSK9 inhibitors are effective therapy in patients with type 2 diabetes and the
beneficial effects on pro-atherogenic lipoproteins is similar to what is observed in non-diabetic patients.

Patients with Hypertriglyceridemia:

There are no studies that have examined the effect of PCSK9 monoclonal antibodies in patients with marked elevations in triglyceride
levels (>400mg/dl).

Mechanism Accounting for the PCSK9 Inhibitor Induced Lipid Effects

The linkage of PCSK9 with lipoprotein metabolism was first identified by Abifadel and colleagues in 2003, when they demonstrated
that certain mutations in PCSK9 could result in the phenotypic appearance of Familiar Hypercholesterolemia [143]. Subsequent
studies demonstrated that gain of function mutations in PCSK9 are an uncommon cause of Familiar Hypercholesterolemia [126, 127,
144]. In 2005 it was shown that loss of function mutations in PCSK9 resulted in lower LDL cholesterol levels and this decrease in
LDL cholesterol levels is associated with a reduction in the risk of cardiovascular events [145, 146].

The main route of clearance of clearance of plasma LDL is via LDL receptors in the liver [147]. When the LDL particle binds to the
LDL receptor the LDL particle- LDL receptor complex is taken into the liver by endocytosis [147]. The LDL particle and the LDL
receptor then disassociate and the LDL lipoprotein particle is delivered to lysosomes where it is degraded and the LDL receptor
returns to the plasma membrane (Figure 2) [147]. After endocytosis LDL receptors recirculate back to the plasma membrane over 100
times.

PCSK9 is predominantly expressed in the liver and secreted into the circulation. Once extracellular, PCSK9 can bind to the LDL
receptor and alter the metabolism of the LDL receptor [148, 149]. Instead of the LDL receptor recycling to the plasma membrane the
LDL receptor bound to PCSK9 remains associated with the LDL particle and is delivered to the lysosomes where it is also degraded
(Figure 2) [148, 149]. This results in a decrease in the number of plasma membrane LDL receptors resulting in the decreased
clearance of circulating LDL leading to elevations in plasma LDL cholesterol levels.

The PCSK9 monoclonal antibodies bind PCSK9 preventing the PCSK9 from interacting with LDL receptors and thereby preventing
PCSK9 from inducing LDL receptor degradation [148, 149]. The decreased LDL receptor degradation results in an increase in hepatic
LDL receptors on the plasma membrane leading to decreases in plasma LDL cholesterol levels. Thus, similar to statins, ezetimibe, and
bile acid sequestrants, PCSK9 inhibitors are reducing plasma LDL levels by up-regulating hepatic LDL receptors. The difference is
that PCSK9 inhibitors are decreasing the degradation of LDL receptors while statins, ezetimibe, and bile acid sequestrants stimulate
the production of LDL receptors.
The expression of PCSK9 is stimulated by SREBP-2 [148, 149]. Statins and other drugs that lower hepatic cholesterol levels lead to
the activation of SREBP-2 and thereby increase plasma PCSK9 levels [148, 149]. Inhibition of PCSK9 with monoclonal antibodies is
more effective in lowering plasma LDL cholesterol levels in patients on statin therapy due to the higher levels of plasma PCSK9 in
these individuals.

The mechanism by which PCSK9 inhibitors reduce Lp(a) levels is unclear. It has recently been postulated that increasing hepatic LDL
receptor levels in the setting of marked reductions in circulating LDL levels will result in the clearance of Lp(a) by liver LDL
receptors [150]. Whether this entirely explains the decrease in Lp(a) is unclear given that in patients with Homozygous Familiar
Hypercholesterolemia the absolute LDL cholesterol levels are not profoundly reduced but Lp(a) levels still decrease.

Pharmacokinetics and Drug Interactions

PCSK9 monoclonal antibodies are eliminated primarily by cellular endocytosis, phagocytosis, and target-mediated clearance. They are
not metabolized or cleared by the liver or kidneys and therefore there is no need to adjust the dose in patients with either liver or
kidney disease. There are no interactions with the cytochrome P450 system or transport proteins and thus the risk of drug-drug
interactions is minimal. Currently there are no reported drug-drug interactions with PCSK9 monoclonal antibodies.

Effect of PCSK9 Inhibitors on Clinical Outcomes

There are four large outcome trials with > 70,000 patients that are expected to be completed in 2017/2018 (Table 9) [126, 127]. There
are two studies that provide preliminary data addressing cardiovascular outcomes. In the Osler study, 4465 patients who had
completed phase 2 or 3 studies with evolocumab .were randomly assigned in to receive either evolocumab plus standard therapy or
standard therapy alone [151]. Patients were followed for a median of 11.1 months. Evolocumab treatment reduced LDL cholesterol
levels by 61% and the rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the
evolocumab group (hazard ratio 0.47; P=0.003). In the Odyssey long term trial, 2341 patients on statin therapy and at high risk for
cardiovascular events who had LDL cholesterol levels > 70 mg/dl despite therapy were randomly assigned to receive alirocumab or
placebo [152]. LDL cholesterol levels were decreased by 62% and the rate of major adverse cardiovascular events at 78 weeks was
decreased with alirocumab compared to placebo (1.7% vs. 3.3%; hazard ratio, 0.52; P=0.02). These two trials provide preliminary data
supporting that lowering LDL cholesterol levels with PCSK9 inhibitors will have beneficial effects on cardiovascular outcomes.

Table 9PCSK9 Outcome Trials

Number Drug Patient Population

ODYSSEY 18,000 Alirocumab Post-acute coronary syndrome
FOURIER 27,500 Evolocumab Stable cardiovascular disease
SPIRE-1 17,000 Bococizumab High risk patients; LDL 70-100
SPIRE-2 9,000 Bococizumab High risk patients; LDL > 100

Side Effects

The major side effect of PCSK9 monoclonal antibodies has been injection site reactions including erythema, itching, swelling, pain,
and tenderness. Allergic reactions have been reported and as with any protein there is potential immunogenicity. In general side
effects have been minimal, which is not surprising, as monoclonal antibodies do not typically have off target side effects. Since
PCSK9 does not appear to have important functions other than regulating LDL receptor degradation, it is not surprising that inhibiting
PCSK9 function has not resulted in major side effects. One must recognize that these PCSK9 monoclonal antibodies have only been in
use for a relatively short time in a small number of patients and it of course possible that unexpected side effects will be revealed with
longer use in a larger number of subjects. The large cardiovascular outcome studies described above should provide further insights
into potential side effects (Table 9).

An issue of concern is whether lowering LDL to very low levels has the potential to cause toxicity. In a number of the PCSK9 studies
a significant number of patients have had LDL cholesterol levels < 25mg/dl. For example, in the Odyssey long term study 37% of
patients on alirocumab had two consecutive LDL cholesterol levels below 25mg/dl and in the Osler long term study in patients treated
with evolocumab 13% had values below 25mg/dl [152, 153]. In these short term PCSK9 studies, toxicity from very low LDL
cholesterol levels has not been observed. Additionally, in patients with Familial Hypobetalipoproteinemia LDL levels can be very low
and these patients do not have any major disorders [85]. Similarly, there are rare individuals who are homozygous for loss of function
mutations in the PCSK9 gene and they also do not appear to have major medical issues [127]. Finally, in a number of statin trials there
have been patients with very low LDL cholesterol levels and an increased risk of side effects has not been consistently observed in
those patients [154-156]. Thus, with the limited data available there does not appear to be a major risk of markedly lowering LDL
cholesterol levels. However, the large outcome studies that are in progress will shed further light on this important issue.

Contraindications

Other than a history of a hypersensitivity to these drugs there are currently no contraindications.

Summary

PCSK9 monoclonal antibodies robustly reduce LDL cholesterol levels when used as monotherapy or when used in combination with
statins. In distinction to most other cholesterol lowering drugs the PCSK9 inhibitors also decrease Lp(a) levels. The side effect profile
appears to be very favorable and there are no drug-drug interactions. Crucial studies are underway to determine whether PCSK9
inhibitors will reduce cardiovascular events and whether significant side effects will occur.

Go to:

LOMITAPIDE
Introduction

Lomitapide (Juxtapid), a selective microsomal triglyceride transfer protein inhibitor, was approved in December 2012 for lowering
LDL cholesterol levels in adults with Homozygous Familial Hypercholesterolemia [157-159]. As will be discussed below it lowers
LDL cholesterol levels by an LDL receptor independent mechanism.

Effect on Lomitapide on Lipid and Lipoprotein Levels

The effect of lomitapide on lipid and lipoprotein levels has been studied in patients with Homozygous Familial Hypercholesterolemia.
The pivotal study was a 78 week single arm open label study in 29 patients receiving treatment for Homozygous Familial
Hypercholesterolemia [160]. Lomitapide was initiated at 5mg per day and was up-titrated to 60mg per day based on tolerability and
liver function tests. On an intention to treat basis, LDL was decreased by 40% and apolipoprotein B by 39%. In patients who were
taking lomitapide, LDL levels were reduced by 50%. In addition to decreasing LDL cholesterol levels, non-HDL cholesterol levels
were decreased by 50%, Lp(a) by 15%, and triglycerides by 45%. Interestingly HDL and apolipoprotein A-I levels were decreased by
12% and 14% respectively in this study.

The effect of lomitapide has also been studied in patients without Homozygous Familial Hypercholesterolemia. A study by Samaha
and colleagues compared the effect of ezetimibe and lomitapide in patients with elevated cholesterol levels [161]. Patients were
treated with ezetimibe alone, lomitapide alone, or the combination of ezetimibe and lomitapide. Ezetimibe monotherapy led to a 20–
22% decrease in LDL cholesterol levels, lomitapide monotherapy led to a dose dependent decrease in LDL-cholesterol levels (19% at
5.0 mg, 26% at 7.5 mg and 30% at 10 mg). Combined therapy produced a larger dose-dependent decrease in LDL cholesterol levels
(35%, 38% and 46%, respectively). Additionally, lomitapide decreased triglycerides by 10%, non-HDL cholesterol by 27%,
apolipoprotein B by 24%, and Lp(a) by 17%.

The above studies demonstrate that lomitapide decreases LDL cholesterol, non-HDL cholesterol, triglycerides, and Lp(a) levels.
Mechanism Accounting for the Lomitapide Induced Lipid Effects

Lomitapide is a selective inhibitor of microsomal triglyceride transfer protein (MTP) [157-159]. MTP is located in the endoplasmic
reticulum of hepatocytes and enterocytes where it plays a key role in transferring triglycerides onto newly synthesized apolipoprotein
B leading to the formation of VLDL and chylomicrons [162]. Loss of function mutations in both alleles of MTP results in
abetalipoproteinemia, which is characterized by the virtual absence of apolipoprotein B, VLDL, and LDL in the plasma due to the
failure of the liver to produce VLDL [85]. Lomitapide by inhibiting MTP activity reduces the secretion of chylomicrons by the
intestine and VLDL by the liver leading to a decrease in LDL, apolipoprotein B, triglycerides, non-HDL cholesterol, and Lp(a) [157-
159].

Pharmacokinetics and Drug Interactions

Lomitapide is extensively metabolized in the liver by the CYP3A4 pathway [157, 158]. Therefore lomitapide is contraindicated in
patients on strong CYP3A4 inhibitors and lower doses should be used in patients on weak inhibitors. Of particular note, in patients on
atorvastatin the maximal dose of lomitapide is 30mg per day and lomitapide should not be used in patients taking more than 20mg of
simvastatin [157, 158]. Lomitapide can increase warfarin levels and therefore close monitoring is required. Finally, given the risk of
liver abnormalities (see side effect section) the avoidance of alcohol or a reduction in alcohol intake is prudent.

Effect of Lomitapide on Clinical Outcomes

There are no clinical outcome trials but it is presumed that lowering LDL cholesterol levels in patients with Homozygous Familial
Hypercholesterolemia will reduce cardiovascular events.

Side Effects

As expected from its mechanism of action lomitapide causes side effects in the GI tract and liver. In the GI tract diarrhea, nausea,
vomiting, and dyspepsia occur very commonly [157-159]. In the pivotal study in patients with Homozygous Familial
Hypercholesterolemia, 90% of the patients developed GI symptoms during drug titration[160]. GI side effects are potentiated by high
fat meals and it is therefore recommended that dietary fat be limited. Approximately 10% of patients will discontinue lomitapide
mostly from diarrhea. Lomitapide also reduces the absorption of fat soluble vitamins and therefore patients need to take vitamin
supplements [157, 158]. Additionally, it may also block the absorption of essential fatty acids and it is therefore recommended that
supplements of essential fatty acids also be provided (at least 200 mg linoleic acid, 210 mg alpha-linolenic acid (ALA), 110 mg
eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA) [157, 158].
Blocking the formation of VLDL in the liver can lead to fatty liver with elevated liver enzymes [157-159]. Approximately 30% of
patients will develop increased transaminase levels but in the small number of patients studied this has not resulted in liver failure.
After stopping the drug the transaminases have returned to normal. Whether long term treatment with lomitapide will lead to an
increase in liver disease is unknown. There is a single case of a patient with lipoprotein lipase deficiency who was treated for 13 years
with lomitapide who developed steatohepatitis and fibrosis [163].

Because of the high potential risk of serious complications the FDA has mandated several measures to ensure that patients are closely
followed and monitored for liver toxicity ((Risk Evaluation and Mitigation Strategy (REMS) Program) [157, 158]. ALT, AST,
alkaline phosphatase, and total bilirubin should be measured before initiating treatment. During the first year, liver function tests
should be measured prior to each increase in dose or monthly, whichever occurs first. After the first year, liver function tests should be
measured at least every 3 months and before any increase in dose.

Contraindications

Lomitapide should not be used during pregnancy and in patients with moderate or severe liver disease. In addition, it should not be
used in patients on strong CYP3A4 inhibitors.

Summary

Lomitapide is approved only for the treatment of lipid disorders in patients with Homozygous Familiar Hypercholesterolemia. The
frequent GI side effects and the potential risk of serious liver disease greatly limit the use of this drug and it should be reserved for the
small number of patients in which more benign therapies are not sufficient in lowering LDL cholesterol into a reasonable range. It is
used as an adjunct to other lipid lowering therapies in patients with Homozygous Familiar Hypercholesterolemia.

Go to:

MIPOMERSEN
Introduction

Mipomersen (Kynamro) is a second generation apolipoprotein B antisense oligonucleotide that was approved in January 2013 for the
treatment of patients older than 12 years with Homozygous Familiar Hypercholesterolemia [158, 159, 164]. It is administered as a
200mg subcutaneous injection once a week [158, 159, 164]. As will be discussed below, it lowers LDL cholesterol levels by an LDL
receptor independent mechanism.

Effect on Mipomersen on Lipid and Lipoprotein Levels

In the pivotal trial, 51 patients with Homozygote Familial Hypercholesterolemia on treatment were randomized to additional treatment
with mipomersen (n= 34) or placebo (n=17) and followed for 26 weeks [165]. Mipomersen lowered LDL cholesterol levels by 21%
and apolipoprotein B levels by 24% compared to placebo. In addition, non-HDL cholesterol was decreased by 21.6%, triglycerides by
17%, and Lp(a) by 23% while HDL and apolipoprotein A-I were increased by 11.2% and 3.9% respectively.

Mipomersen has also been studied in patients with Heterozygous Familial Hypercholesterolemia. In a double-blind, placebo-
controlled, randomized trial patients on maximally tolerated statin therapy were treated weekly with subcutaneous mipomersen 200
mg or placebo for 26 weeks [166]. LDL cholesterol levels decreased by 33% in the mipomersen group compared to placebo.
Additionally, mipomersen significantly reduced apolipoprotein B by 26%, triglycerides by 14%, and Lp(a) by 21% compared to
placebo with no significant changes in HDL cholesterol levels. In an extension follow-up study the beneficial effects of mipomersen
were maintained for at least 2 years [167].

In a meta-analysis of 8 randomized studies with 462 subjects with either non-specified hypercholesterolemia or Heterozygous Familial
Hypercholesterolemia, Panta and colleagues reported that mipomersen decreased LDL cholesterol levels by 32% compared to placebo
[168]. Additionally, non-HDL cholesterol was decreased by 31%, apolipoprotein B by 33%, triglycerides by 36%, and Lp(a) by 26%
with no effect on HDL levels.

Mechanism Accounting for the Mipomersen Induced Lipid Effects

Apolipoprotein B 100 is the main structural protein of VLDL and LDL and is required for the formation of VLDL and LDL [147].
Familiar Hypobetalipoproteinemia is a genetic disorder due to a mutation of one apolipoprotein B allele that is characterized by very
low concentrations of LDL and apolipoprotein B due to the decreased production of lipoproteins by the liver [85]. Mipomersin, an
apolipoprotein B antisense oligonucleotide, mimics Familiar Hypobetalipoproteinemia by inhibiting apolipoprotein B 100 production
in the liver by pairing with apolipoprotein B mRNA preventing its translation [158, 159, 164]. This decrease in apolipoprotein B
synthesis results in a decrease in hepatic VLDL production leading to a decrease in LDL levels.

Pharmacokinetics and Drug Interactions

No significant drug interactions have been reported. Given the risk of liver abnormalities (see side effect section) the avoidance of
alcohol or a reduction in alcohol intake would be prudent.

Effect of Mipomersen on Clinical Outcomes

There are no clinical outcome trials but it is presumed that lowering LDL cholesterol levels in patients with Homozygous Familial
Hypercholesterolemia will reduce cardiovascular events.

Side Effects

The most common side effect is injection site reactions, which occur in 75-98% of patients and typically consist of one or more of the
following: erythema, pain, tenderness, pruritus and local swelling [158, 159, 164]. Additional, influenza like symptoms, which
typically occur within 2 days after an injection, occur in 30-50% of patients and include one or more of the following: influenza-like
illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue which result in a substantial percentage of patients discontinuing therapy
[158, 159, 164].

A major safety concern is liver toxicity [158, 159, 164]. By inhibiting VLDL formation and secretion the risk of fatty liver is
increased. Fatty liver has been observed in 5-20% of patients treated with mipomersen [158, 159, 164]. In 10-15% treated with
mipomersen increases in transaminases occur [158, 159, 164]. Additionally, liver biopsies from 7 patients after a minimum of 6
months of mipomersen therapy have demonstrated the presence of fatty liver although there was no inflammation despite elevations in
liver enzymes [169]. Fortunately when treatment is discontinued liver function tests and fatty liver return to normal.

Because of the high potential risk of serious complications the FDA has mandated several measures to ensure that patients are closely
followed and monitored for liver toxicity (Risk Evaluation and Mitigation Strategy (REMS) Program) [158, 159, 164]. Liver function
should be measured prior to initiating therapy and monthly during the first year and every 3 months after the first year.

Contraindications

Mipomersen is contraindicated in patients in patients with liver disease or severe renal disease. Mipomersen is not recommended for
use during pregnancy or lactation. In animal studies mipomersen has not resulted in fetal abnormalities.

Summary
Mipomersen is approved only for the treatment of lipid disorders in patients with Homozygous Familiar Hypercholesterolemia. The
potential risk of serious liver disease greatly limits the use of this drug and therefore it should be reserved for the small number of
patients in which more benign therapies are not sufficient in lowering LDL cholesterol into a reasonable range. It is used as an adjunct
to other lipid lowering therapies in patients with Homozygous Familiar Hypercholesterolemia.

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APPROACH TO TREATING PATIENTS WITH HYPERCHOLESTEROLEMIA

Introduction

The issues of deciding who to treat, how aggressive to treat, and the goals of therapy are discussed in detail in Chapter 4 and therefore
will not be addressed in this chapter [2]. Additionally, the role of life style changes to lower LDL cholesterol is discussed in great
depth in chapter 23 and therefore will also not be addressed here [1]. Rather we will focus on how to use the drugs discussed in this
chapter to treat various categories of patients. The factors to consider when deciding which drugs are appropriate to use for lowering
plasma LDL cholesterol levels are; the efficacy in lowering LDL cholesterol levels, the effect on other lipid and lipoprotein levels, the
ability to reduce cardiovascular events, the side effects of drug therapy, the ease of complying with the drug regimen, and the cost of
the drugs. The approximate monthly cost of various cholesterol lowering drugs is shown in table 10.

Table 10Monthly Cost of Cholesterol Lowering Drugs

Simvastatin 40mg per day $3.69*

Pravastatin 40mg per day $9.03*
Atorvastatin 10mg per day $10.26
Atorvastatin 80mg per day $19.50*
Rosuvastatin 40mg per day $260.83*
Pitavastatin 4mg per day $232.65*
Ezetimibe 10mg per day $272.41*
Colesevelam 3.75g packet (1 per day) $643.36*
Colesevelam 625mg (6 per day) $641.52*
Colestipol 1g (10 per day) $367.12*
Alirocumab twice a month Approx. $1166
Evolocumab twice a month Approx. $1166
Lomitapide (dose varies) Approx. $20,000
Mipomersen 200mg q 2weeks Approx. $14,000-15,000

*Costco prices May 18, 2016

Isolated Hypercholesterolemia

In patients with isolated hypercholesterolemia (LDL cholesterol < 190mg/dl), initial drug therapy should be a generic statin such as
atorvastatin. The dose should be chosen based on the percent reduction in LDL required to lower the LDL level to below the target
goal. As discussed earlier, the side effects of statin therapy increase with higher doses so one should not routinely use high doses, but
instead should choose a dose balancing the benefits and risks. Generic statins are inexpensive drugs and are very effective in both
lowering LDL cholesterol levels and reducing cardiovascular events. Additionally, they have an excellent safety profile. If the initial
statin dose does not lower LCL cholesterol to goal, one can then increase the dose. If the maximal statin dose does not lower LDL
cholesterol sufficiently adding ezetimibe is a reasonable next step. Ezetimibe is easy to take, has few side effects, will modestly lower
LDL cholesterol, and has been shown in combination with statins to further reduce cardiovascular events. High dose statin and
ezetimibe will lower LDL cholesterol by as much as 70%, which will lower LDL to goal in the vast majority of patients who do not
have a genetic basis for their elevated LDL levels. If the combination of statin plus ezetimibe does not lower the LDL to goal one can
add a third drug. If the LDL is close to goal one could add a bile acid sequestrant such as colesevelam. If the LDL is not very close to
goal one could instead use a statin plus a PCSK9 inhibitor, which together will result in marked reductions in LDL cholesterol levels.
If the patient has diabetes with a moderately elevated A1c level using a bile acid sequestrant such as colesevelam instead of ezetimibe
or in combination with ezetimibe could improve both glycemic control and further lower LDL levels.

Mixed Hyperlipidemia

In patients with mixed hyperlipidemia (elevated LDL cholesterol and triglyceride levels) Initial drug therapy should also be a generic
statin unless triglyceride levels are greater than 500-1000mg/dl. In addition to lowering LDL cholesterol levels, statins are also very
effective in lowering triglyceride levels particularly when the triglycerides are elevated. If LDL is not lowered sufficiently ezetimibe is
a reasonable next step. Bile acid sequestrants are not appropriate drugs in patients with hypertriglyceridemia. The great uncertainty is
what to do when the LDL levels are at goal but the triglycerides and non-HDL cholesterol are still elevated. Should one add a fibrate,
niacin, or fish oil to lower triglycerides and non-HDL cholesterol levels? At this time it is uncertain as there are no randomized
outcome studies demonstrating benefit of adding triglyceride lowering drugs to statins and therefore experts have diverse opinions.
Hopefully, future studies will clarify the appropriate approach.

Heterozygous Familial Hypercholesterolemia

In patients with Heterozygous Familial Hypercholesterolemia or other disorders with very elevated LDL cholesterol levels
(>190mg/dl), high doses of a potent statin such as atorvastatin or rosuvastatin are the first step to lower LDL cholesterol levels. In
many patients this will not be sufficient. If the LDL cholesterol levels are close to goal then adding ezetimibe is a reasonable next step.
However, if the LDL cholesterol still needs to be markedly reduced a PCSK9 inhibitor may be a better choice as these drugs can
markedly lower LDL cholesterol levels.

Statin Intolerantance

Statin intolerance is almost always due to myalgias but on occasion can be due other issues, such as increased liver or muscle
enzymes, cognitive dysfunction, or other neurological disorders. The percentage of patients who are “statin intolerant” varies greatly
but in clinical practice a significant number of patients have difficulty taking statins.

As discussed earlier it can be difficult to determine if the muscle symptoms that occur when a patient is taking a statin are actually due
to the statin or are unrelated to statin use. The first step in a “statin intolerant patient” is to take a careful history of the nature and
location of the muscle symptoms and the timing of onset in relation to statin use to determine whether the presentation fits the typical
picture for statin induced myalgias. The characteristic findings with a statin induced myalgia are shown in table 11 and findings that
are not typical for statin induced myalgia are shown in table 12.

Table 11Characteristic Findings with Statin Induced Myalgia

Symmetric
Proximal muscles
Muscle pain, tenderness, weakness, cramps
Symptom onset < 4 weeks
Improves within 2-4 weeks of stopping statin
Same symptoms occur with re-challenge within 4 weeks
Table 12Symptoms Atypical in Statin Induced Myalgia

Unilateral
Asymmetric
Small muscles
Joint or tendon pain
Shooting pain, muscle twitching or tingling
Symptom onset > 12 weeks
No improvement after discontinuing statin

One should also check a CK level but this is almost always in the normal range. If the CK is not elevated and the symptoms do not
suggest a statin induced myalgia one can often reassure the patient and continue statin therapy. This is often successful and studies
have shown that many patients that stop taking statins due to “statin induced myalgia” can be successfully treated with a statin. If the
CK is elevated it should be repeated after instructing the patient to avoid exercise for 48 hours. Also the CK levels should be
compared to CK levels prior to starting therapy. If the CK remains elevated (3x upper limit of normal) the statin should be
discontinued. Similarly if the CK is normal but the symptoms are suggestive of a statin induced myalgia the statin should also be
discontinued. The next step is to determine if one can identify reversible factors that could be increasing statin toxicity
(hypothyroidism, vitamin D deficiency, drug interactions). If none are identified the next step after the myalgias have resolved is to try
a low dose of a different statin that is metabolized by a different pathway (for example instead of atorvastatin, which is metabolized by
the CYP3A4 pathway, rosuvastatin, which has a different pathway of metabolism). Because statin side effects are dose related, a low
dose of a statin may often be tolerated. One can also try several different statins as sometimes a patient may tolerate one statin and not
others. In some instances using a long acting statin (rosuvastatin or atorvastatin) 1-3 times per week can work (we usually start with
once per week and then slowly increase frequency as tolerated). In these circumstances (low doses or 1-3 times per week) the
reduction in LDL cholesterol may not be sufficient but one can use combination therapy with other drugs such as ezetimibe, bile acid
sequestrants, or PCSK9 inhibitors to achieve LDL target goals.

Many providers have combined Coenzyme Q10 with statins to prevent statin induced myalgias. However, randomized trials with
Coenzyme Q10 supplementation have not consistently shown benefit. A recent trial, which carefully screened patients to make sure
they actually had statin induced myalgias, failed to show a benefit from Coenzyme Q10 supplementation. It has also been
recommended that vitamin D supplementation be used to prevent statin induced myalgias but there are no randomized trials
demonstrating benefit.
If after trying various approaches a patient still has myalgias and is unable to tolerate statin therapy one needs to utilize other
approaches to lower LDL levels. Similarly, if there are other reasons why a patient cannot take a statin, such as developing muscle
pathology, one will also need to utilize other approaches to lower LDL levels. These patients can be treated with ezetimibe, bile acid
sequestrants, or PCSK 9 inhibitors either as monotherapy or in combination to achieve LDL goals.

There are patients who will refuse statins and other drug therapy because they do not believe in taking pharmaceuticals but will take
natural products. In these patients we have employed red yeast rice, which decreases LDL cholesterol because it contains a form of
lovastatin. It is effective but one should recognize that the quality control is not similar to the standards of pharmaceutical products
and that there can be batch to batch variations. Furthermore there is a risk of drug-drug interactions if used with inhibitors of CYP3A4.
However, in this particular patient population, who refuses to take statins or other drugs, this can be a reasonable alternative. If a
patient just refuses statins (usually based on a belief that statins are toxic) we will employ other cholesterol lowering drugs.

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CONCLUSIONS
With currently available drugs to lower LDL cholesterol levels we are now able to markedly reduce LDL cholesterol levels and
achieve our LDL goals in the vast majority of patients and thereby reduce the risk of cardiovascular disease. Patients with
Homozygous Familial Hypercholesterolemia and some patients with Heterozygous Familial Hypercholesterolemia still present major
clinical challenges and it can be very difficult in these patients to achieve LDL goals.

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Triglyceride Lowering Drugs
Kenneth Feingold, MD and Carl Grunfeld, MD, PhD.

Author Information

Last Update: January 20, 2017.

Go to:

ABSTRACT
The two major goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and pancreatitis. Here we
discuss the drugs currently available for the treatment of hypertriglyceridemia: (niacin, fibrates, omega-3-fatty acids, and lipoprotein
lipase gene therapy (alipogene tiparvovec)). Statins, ezetimibe, PCSK9 inhibitors, lomitapide, and mipomersen, which are primarily
used to lower LDL cholesterol, also lower plasma triglyceride levels and are discussed in detail in Chapter 25 “Cholesterol Lowering
Drugs”. Niacin decreases all the pro-atherogenic lipid and lipoprotein particles including total cholesterol, triglycerides (20-50%
decrease), LDL cholesterol, and Lp(a) levels. Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant
LDL particles. Moreover, niacin increases HDL cholesterol levels. Skin flushing, insulin resistance, and other side effects have limited
the use of niacin. Moreover, the enthusiasm for the use of niacin has decreased with the failure of AIM-HIGH and HPS-2 Thrive to
show a decrease in cardiovascular events when niacin was added to statin therapy. The lipid lowering effects of fish oil are mediated
by two omega-3-fatty acids: eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA). Omega-3-fatty
acids lower triglycerides by 10-50% but do not effect total cholesterol, HDL cholesterol, or Lp(a) levels. LDL cholesterol levels may
increase with EPA + DHA treatment when the triglyceride levels are markedly elevated (>500mg/dl). EPA alone does not increase
LDL cholesterol levels. Omega-3-fatty acids have few side effects, drug interactions, or contraindications. Despite numerous studies
the effect of omega-3-fatty acids on cardiovascular outcomes is uncertain but additional studies are underway. Fibrates reduce
triglyceride levels by 25-50% and increase HDL cholesterol levels by 5-20%. The effect on LDL cholesterol is variable. If the
triglyceride levels are very high (>400-500mg/dl), fibrate therapy may result in an increase in LDL cholesterol levels, whereas if
triglycerides are not markedly elevated fibrates decrease LDL cholesterol by 10-30%. Fibrates also reduce apolipoprotein B, LDL
particle number, and non-HDL cholesterol levels and there may be a shift from small dense LDL towards large LDL particles. Fibrates
do not have any major effects on Lp(a) levels. Due to increased myopathy the combination of gemfibrozil and statins should be
avoided but fenofibrate can be used safely with statins. Monotherapy with fibrates appears to reduce cardiovascular events particularly
in patients with high triglyceride and low HDL cholesterol levels. Whether the addition of fibrates to statin therapy will reduce
cardiovascular disease is uncertain. In patients with diabetes fibrates appear to slow the progression of microvascular disease.
Alipogene tiparvovec is a gene therapy approved in Europe for adult patients with Familial Lipoprotein Lipase deficiency and a
history of multiple or severe episodes of pancreatitis who have failed dietary therapy. Therapy with alipogene tiparvovec results in the
expression of lipoprotein lipase in muscle, which accelerates the clearance of triglyceride rich lipoproteins. Studies have suggested a
decrease in episodes of pancreatitis. Thus, a number of drugs are available for the treatment of hypertriglyceridemia and maybe
employed when lifestyle changes are not sufficient.

Go to:

INTRODUCTION
The two primary goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and the prevention of
pancreatitis. The evaluation and guidelines for the management of hypertriglyceridemia are discussed in detail in Chapter 5 “Risk
Assessment and Guidelines for the Management of High Triglycerides [1] and the approach to evaluating a patient with
hypertriglyceridemia is discussed in Chapter 22 “Approach to the Patient with Dyslipidemia” [2]. The treatment of
hypertriglyceridemia by lifestyle changes such as diet, exercise, and weight loss are discussed in detail in Chapter 23 “Lifestyle
Changes: Effect of Diet, Exercise, Functional Food, and Obesity Treatment on Lipids and Lipoproteins” [3]. Lifestyle changes are
recommended as the first line for therapy of hypertriglyceridemia, but drug therapy is often required. In this chapter we will discuss
the four classes of drugs currently available for the treatment of elevated plasma triglyceride levels (niacin, fibrates, omega 3 fatty
acids, and lipoprotein lipase gene therapy (alipogene tiparvovec, Glybera)). Statins, ezetimibe, PCSK9 inhibitors, lomitapide, and
mipomersen, which are primarily used to lower LDL cholesterol, also lower plasma triglyceride levels and are discussed in detail in
Chapter 25 Cholesterol Lowering Drugs [4].

Go to:

NIACIN
Introduction

Niacin was the first drug approved to treat dyslipidemia. In 1955, Altschul et al showed that pharmacologic doses of niacin decreased
plasma cholesterol levels [5]. Several forms of niacin are available for clinical use. Immediate release niacin has a short duration of
action and is typically given two or three times per day with meals, whereas sustained release niacin and extended release niacin are
once a day drugs usually given at bedtime. The extended release form of niacin exhibits release rates that are intermediate between
immediate release niacin and sustained release niacin [6]. While the effects of the various forms of niacin on plasma lipid levels are
similar, the side effect profiles are different. Because of an increased risk of serious liver toxicity with sustained release niacin this
preparation is no longer widely used to treat dyslipidemia. Over-the- counter “No flush” niacin is also available but is generally
ineffective as a lipid-modifying agent because most of these preparations do not contain active nicotinic acid.

Effect of Niacin on Lipid and Lipoprotein Levels

Table 1Effect of Niacin on Lipid and Lipoproteins

Decreases Total Cholesterol

Decreases LDL cholesterol
Decreases Triglycerides
Decreases Non-HDL Cholesterol
Decreases Lp(a)
Increases HDL cholesterol
Decreases Apolipoprotein B
Shifts Small Dense LDL to Large Buoyant LDL

Niacin decreases all the pro-atherogenic lipid and lipoprotein particles including total cholesterol, triglycerides, LDL cholesterol, and
Lp(a) levels (Table 1) [7, 8]. Additionally, niacin has been shown to decrease small dense LDL resulting in a shift to large, buoyant
LDL particles [9]. Moreover, niacin increases HDL cholesterol levels [7, 8].

In a meta-analysis of 30 trials with 4,749 subjects treatment with immediate release, sustained release, or extended release niacin
decreased total cholesterol by 10%, decreased triglycerides by 20%, decreased LDL cholesterol by 14%, and increased HDL
cholesterol by 16% [10]. All three niacin preparations were effective in decreasing total cholesterol, triglycerides, and LDL cholesterol
levels and increasing HDL cholesterol levels [10]. At a dose of 1.5 grams per day, immediate release niacin and extended release
niacin produced similar decreases in total cholesterol, triglycerides, and LDL cholesterol and a similar increase in HDL cholesterol
[11]. A meta-analysis of 14 studies with 9,013 subjects reported a 23% decrease in Lp(a) with extended release niacin treatment [12].
A small meta-analysis of 5 trials in 432 subjects compared the response to extended release niacin in men and women [13]. The effect
of niacin on LDL cholesterol was greater in women than men at all niacin doses (1,000mg 6.8% decrease in women vs 0.2% in men, p
= 0.006; 1,500mg 11.3% decrease vs 5.6% decrease, p = 0.013; 2,000 mg 14.8% decrease vs 6.9% decrease, p = 0.010; 3,000mg
28.7% decrease vs 17.7% decrease, p = 0.006). The effect of niacin on plasma triglyceride levels also tended to be greater in women
but the difference only reached statistical significance at the 1,500mg dose (28.6% vs 20.4%, p = 0.040). The mechanism for the more
robust decrease in LDL cholesterol and triglycerides is unknown but might be due to a smaller body mass in women leading to
increased circulating niacin levels and hence a greater response. However, the effect of niacin on HDL cholesterol and Lp(a) levels
were similar in males and females. Not unexpectedly the effect of niacin is dose dependent with higher doses having a greater effect
on plasma lipid and lipoprotein levels (Table 2) [13].

Table 2Effect of Niacin Dose on Lipid and Lipoprotein Response in Women (percent change)

Niacin Dose LDLc TG HDLc Lp(a)

500mg -5.2 -9.5 7.7 -2.6
1000mg -6.8 -14.5 17.6 -11.5
1500mg -11.3 -28.6 21.1 -4.0
2000mg -14.8 -37.3 25.2 -24.7
2500mg -28.7 -45.6 34.5 -28.6
3000mg -28.7 -51.0 28.7 -29.9

Numerous studies have examined the effect of the addition of niacin to statin therapy. Combination therapy typically results in further
reductions in atherogenic lipoprotein particles and an increase in HDL cholesterol levels. An example of such a study is shown in
Table 3 [14].

Table 3Effect of the Addition of Niacin to Statin Therapy on Lipid and Lipoprotein Levels

Change in Lipids with Addition of Extended Release Niacin 2000mg/day to Simvastatin 20mg/day
LDL-C 7.1% Decrease
HDL-C 18.2% Increase
TG 22.7% Decrease
Non-HDL-C 15.1% Decrease
Lp(a) 17.4% Decrease
A number of patients cannot tolerate statins and therefore it is of interest to determine the effect of niacin in combination with non-
statin drugs that lower LDL cholesterol levels on the lipid profile. The combination of niacin + bile acid sequestrants has been utilized
in statin intolerant patients. The addition of colesevelam to niacin therapy results in a further decrease in LDL cholesterol (7.8%
decrease; p<0.001) and non-HDL cholesterol (4.9% decrease; p=0.098) [15]. This combination is of interest as the increases in plasma
triglyceride levels induced by colesevelam are often reversed by niacin treatment.

While a literature search did not find any studies comparing the combination of ezetimibe + niacin vs. monotherapy there is a large
trial that has examined the effect of adding 2 grams niacin to ezetimibe/simvastatin 10/20 [16]. In this study the addition of niacin
improved the lipid profile with a marked decrease in triglycerides and an increase in HDL cholesterol levels (table 4).

Table 4Effect of the Addition of Niacin to Ezetimibe/Statin Therapy on Lipid and Lipoprotein Levels

Change in Lipids with Addition of Niacin 2000mg/day to Ezetimibe/Simvastatin 10/20mg/day

LDL-C 4.8% Decrease
HDL-C 21.5% Increase
TG 17.6% Decrease
Non-HDL-C 7.3% Decrease

In patients with marked hypertriglyceridemia combining niacin with other drugs that also lower plasma triglycerides can be
considered. Sixty patients with the metabolic syndrome were randomized to 16 weeks of treatment with placebo, omega-3-fatty acids
(Lovaza 4 g/day), extended release niacin (2 g/day), or both drugs in combination [17]. In the niacin group triglycerides were
decreased by 30%, in the omega-3-fatty acids group by 22%, and in the combination group by 42% compared to the placebo group. Of
note the beneficial effects of niacin on decreasing LDL and non-HDL cholesterol levels were blunted by omega-3-fatty acids, which
are known to raise LDL cholesterol levels in patients with marked hypertriglyceridemia (see below). These results show that the
combination of niacin and fish oil will lower triglyceride levels more than either drug individually but at the expense of diminishing
the effect of niacin on LDL and non-HDL cholesterol levels.

Surprisingly there are few large randomized trials examining the effect of combination therapy with niacin + fibrate vs. monotherapy.
One very small trial did report that while both niacin monotherapy and bezafibrate monotherapy were effective in lowering serum
triglycerides there was no statistically significant added benefit of combination therapy in reducing serum triglyceride levels [18].
However, a larger trial in HIV+ patients reported that the combination of niacin and fenofibrate was better at lowering triglycerides
and non-HDL cholesterol and increasing HDL cholesterol levels than monotherapy with either niacin or fenofibrate [19]. It would be
informative if additional trials of combination therapy were carried out in patients with marked hypertriglyceridemia that can often be
difficult to control with lifestyle changes and monotherapy.

Mechanisms Accounting for the Niacin Induced Lipid Effects

Triglycerides: Early studies demonstrated that niacin inhibited the release of free fatty acids from cultured adipocytes and decreased
circulating free fatty acid levels [20-22]. The ability of niacin to inhibit adipose tissue lipolysis is mediated by the activation of
GPR109A (hydroxycarboxylic acid 2 receptor), a G protein-coupled receptor that is highly expressed in adipose tissue [22-24]. It was
initially thought that the decrease in plasma triglycerides induced by niacin therapy was due to niacin inhibiting lipolysis in adipose
tissue resulting in a decrease in the transport of fatty acids to the liver leading to the decreased availability of fatty acids for hepatic
triglyceride synthesis. However, studies have shown that while niacin acutely decreases plasma free fatty acid levels this inhibition is
not sustained [25]. Additionally, studies in mice lacking GPR109A have shown that niacin does not inhibit lipolysis but still decreases
plasma triglyceride and LDL cholesterol levels [26]. Moreover, studies in humans using GPR109A agonists lowered plasma free fatty
acid levels but did not cause the expected effects on plasma triglycerides and LDL cholesterol [26]. Thus, the effects of niacin on
adipose tissue lipolysis are no longer thought to mediate the niacin induced decrease in plasma triglyceride levels.

Niacin has been shown to inhibit diglycerol acyltransferase 2 (DGAT2) activity in the liver [22, 27]. DGAT2 is the key enzyme that
catalyzes the final step in triglyceride synthesis. Inhibition of DGAT2 will reduce hepatic triglyceride synthesis and the availability of
triglyceride for VLDL assembly and secretion [22]. A decrease in triglyceride will result in an increase in apolipoprotein B
degradation in the liver. Kinetic studies in humans have shown that treatment with niacin decreases VLDL triglyceride production [28,
29].

In addition, in animal models, niacin reduces the hepatic expression of apolipoprotein C-III, which could result in the accelerated
clearance of triglyceride rich lipoproteins [30]. Whether this plays a significant role in mediating the decrease in plasma triglyceride
levels induced by niacin therapy remains to be determined.

LDL: The decrease in plasma LDL cholesterol with niacin therapy is thought to be secondary to a reduction in VLDL and LDL
formation and secretion by the liver [22].

HDL: There are multiple potential mechanisms by which niacin may increase HDL cholesterol levels. Some of these changes may be
anti-atherogenic while others may be pro-atherogenic. One hypothesis for the increase in HDL induced by niacin therapy is a decrease
in the surface expression of hepatocyte beta chain ATP synthase, a receptor that has been proposed to be involved in the uptake of
HDL particles by the liver [31]. Studies have further shown that niacin inhibits HDL protein degradation by cultured hepatocytes but
does not inhibit the selective uptake of cholesterol esters carried in HDL [22, 32].

Kinetic studies have shown that niacin decreases HDL and apolipoprotein A1 fractional catabolic rate [33, 34]. In contrast, other
kinetic studies have shown that niacin increase apolipoprotein AI production [35].

In addition, in monocytes, niacin also increased the expression of ABCA1 and CD36 resulting in an increase in cholesterol efflux to
HDL, which would increase HDL cholesterol levels and likely have anti-atherogenic effects [36]. Similarly, in vitro studies suggest
that niacin may increase the transport of cholesterol and phospholipids via ABCA1 from the liver to lipid poor apolipoprotein A1
particles thereby decreasing the clearance of apolipoprotein A1, which might not be anti-atherogenic [22, 37].

Finally, decreasing plasma triglyceride levels may result in a reduction in CETP mediated exchange of triglycerides on VLDL for
cholesterol on HDL leading to an increase in HDL cholesterol levels. Additionally studies have shown that niacin decreases the
expression of CETP [38].

Lp(a): Niacin decreases the synthetic rate of Lp(a) but does not increase Lp(a) catabolism [39, 40]. In cell culture and animal studies
niacin has been shown to decrease the expression of apo (a) [41].

Pharmacokinetics

Oral niacin is well absorbed with immediate release niacin resulting in a rapid increase in plasma levels while extended release and
sustained release niacin result in a delayed peak in plasma levels. Niacin undergoes metabolism in the liver by two primary pathways;
conjugation or amidation [6, 42]. The conjugative pathway is low affinity and high capacity that metabolizes niacin to nicotinuric acid
while the amidation pathway is high affinity and low capacity that converts niacin into several oxidative-reductive intermediates,
which can induce hepatic toxicity [6, 42] (Figure 1). The clinical importance is that immediate release niacin results in high levels of
niacin and therefore is primarily metabolized by the conjugative pathway (low affinity, high capacity), which does not result in toxic
intermediates that can cause liver damage. In contrast, sustained release niacin results in lower levels of niacin for a longer period and
therefore metabolism via the amidation pathway (high affinity, low capacity) is dominant leading to an increase in the formation of
toxic intermediates that can induce hepatic injury [6, 42]. Extended release niacin would be metabolized midway between immediate
release and sustained release niacin [42].
Figure 1Pathways of Niacin Metabolism

Effect of Niacin on Cardiovascular Outcomes

Monotherapy: The Coronary Drug Project, conducted between 1966 and 1975, was the first large randomized, double-blind clinical
trial to show that lowering lipids reduced cardiovascular disease [43]. This trial determined the effect of clofibrate (1.8g/day),
dextrothyroxine (6mg/day), two doses of oral estrogen (2.5 or 5mg per day), or immediate release niacin (3 grams/day) vs. placebo in
8,341 men 30 to 64 years of age with an electrocardiogram documented myocardial infarction. The mean baseline total cholesterol
level was 251mg/dl and the triglyceride level was 183mg/dl. The two estrogen regimens and dextrothyroxine treatment groups were
discontinued early because of increased adverse effects. Clofibrate treatment did not demonstrate clinical benefit. In the niacin treated
patients there was average 10% decrease in serum cholesterol and 26% decrease in serum triglycerides despite modest compliance
with the study medication. Moreover, niacin treatment (n=1119) decreased recurrent myocardial infarctions by 26%, stroke by 24%,
and revascularization by 67% compared to placebo (n=2789) but did not decrease total mortality, which was the primary endpoint.
Long term follow-up (6.2 years during the study and 8.8 years post study after niacin was discontinued in most participants)
demonstrated an 11% decrease in mortality in the niacin group vs. the placebo group (52.0 versus 58.2%; p = 0.0004) [44]. The
majority of this difference in mortality was accounted for by a decrease in coronary heart disease mortality (36.5% vs. 41.3%;
p=0.005). Further analysis revealed that niacin reduced the risk of 6-year recurrent myocardial infarction and coronary heart disease
death and 15-year total mortality similarly in patients at all levels of baseline fasting plasma glucose, including those with glucose
levels ≥126mg/dl (i.e. patients with diabetes) [45]. Additionally, the beneficial effect of niacin on cardiovascular events and total
mortality was not diminished, even among those with one hour plasma glucose levels > 220mg/dl [45]. Moreover, the beneficial
effects of niacin on recurrent myocardial infarction and total mortality were similar in patients with or without the metabolic syndrome
at baseline [46]. These results demonstrate that niacin monotherapy decreases recurrent atherosclerotic cardiovascular events in a
broad spectrum of patients with pre-existing cardiovascular disease (secondary prevention).

Combination with Fibrate: In the Stockholm Ischemic Heart Disease Secondary Prevention Study survivors of a myocardial
infarction below 70 years of age were randomized to a control group (n = 276) (no placebo) and a group treated with clofibrate (2
grams) and immediate release nicotinic acid (up to 3 grams) (n = 279) [47]. Serum cholesterol and triglyceride was lowered by 13%
and 19%, respectively, in the treatment group compared to the control group. Recurrent myocardial infarction was reduced by 50%
within one year [48]. Total mortality was decreased by 26% in the group treated with clofibrate + niacin (p< 0.05) while ischemic
heart disease mortality was decreased by 36% (p< 0.01). Notably, the benefit of clofibrate + niacin was only observed in patients with
a baseline triglyceride level > 143mg/dl. In the age of statins the clinical implications of this early study are unclear.

Combination with Statins: The AIM-HIGH trial was designed to determine if the addition of Niaspan, an extended release form of
niacin, to aggressive statin therapy would result in a further reduction in cardiovascular events in patients with pre-existing
cardiovascular disease [49]. In this trial 3,314 patients were randomized to extended release Niaspan (1500-2000mg/day) vs. placebo
that contained 100-150mg of immediate release niacin. On trial, LDL cholesterol levels were in the 60-70mg/dl range in both groups.
As expected, HDL cholesterol levels were increased in the Niaspan treated group (approximately 44mg/dl vs. 38mg/dl), while
triglycerides were decreased (approximately 121mg/dl vs. 155mg/dl). However, there were no differences in the primary endpoint
between the control and Niaspan treated groups (Primary endpoint consisted of the first event of death from coronary heart disease,
nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or
cerebral revascularization). There were also no differences in secondary endpoints except for a possible increase in strokes in the
Niaspan treated group. The addition of Niaspan to statin therapy did not result in a significant increase in either muscle or liver
toxicity. Thus, this study does not provide support for the addition of niacin to statins. However, most of the patients included in this
study did not have a lipid profile that one would typically consider treating with niacin therapy. In the subset of patients with TG >
198mg/dl and HDL cholesterol < 33mg/dl Niaspan treatment showed a trend towards benefit (hazard ratio 0.74; p=0.073) in this
study, suggesting that if the appropriate patient population was studied the results may have been different [50].

HPS 2 Thrive also studied the effect of niacin added to statin therapy [51]. This trial utilized extended release niacin (2000mg/day)
combined with laropiprant, a prostaglandin D2 receptor antagonist, which reduces the flushing side effect of niacin treatment. HPS 2
Thrive was a very large trial with over 25,000 patients randomized to either niacin therapy or placebo. As in the AIM HIGH study, the
baseline LDL cholesterol levels were low at 63mg/dl, the HDL cholesterol levels were 44mg/dl, and the triglycerides were 125mg/dl
at baseline. As expected, niacin therapy resulted in a modest reduction in LDL cholesterol (10mg/dl), a modest increase in HDL
cholesterol (6mg/dl), and a marked reduction in triglycerides (33mg/dl) compared to placebo. However, despite these lipid changes
there were no significant differences in major cardiovascular events between the niacin and control group (risk ratio 0.96 CI 0.90-
1.03). It is unknown whether laropiprant, the prostaglandin D2 receptor antagonist, might have effects that worsen atherosclerosis and
increase event rates. Mice deficient in the prostaglandin D2 receptor have been noted to have an increase in atherogenesis in response
to angiotensin II [52]. Similar to the AIM-HIGH study, the group of patients included in the HPS 2 Thrive trial may not have been the
ideal patient population to test for the beneficial effects of niacin treatment added to statin therapy. Ideally, patients with high
triglycerides and high non-HDL cholesterol levels coupled with low HDL cholesterol levels should be studied.

Thus, these two studies have failed to demonstrate that adding niacin to statin therapy results in a decrease in cardiovascular events. It
should be recognized that both the AIM-HIGH study and the HPS-2 Thrive study had limitations. First, the patient populations that
were included in these studies were not ideal as the triglyceride and non-HDL cholesterol levels were not elevated in a range that one
would usually consider adding niacin therapy. Second, in both trials a significant percentage of patients stopped niacin therapy (AIM-
HIGH 25.4% discontinued niacin; HPS-2 Thrive 25.4% discontinued niacin). Third, the duration of these studies was relatively short
and it is possible that the beneficial effects of niacin take longer to occur (AIM-HIGH 3 years; HPS-2 Thrive 3.9 years). Fourth, in the
HPS-2 Thrive it is possible, as noted earlier, that laropiprant had adverse effects that increased the risk of cardiovascular events. Fifth,
in the AIM-HIGH study the placebo contained a low dose of niacin, which may have resulted in beneficial effects. Finally, both of
these trials used extended release niacin, whereas the Coronary Drug Project and the Stockholm Ischemic Heart Disease Secondary
Prevention Study used immediate release niacin. It is possible that these different formulations of niacin have different effects on
cardiovascular events. Additional studies are required to definitively determine the effect of niacin added to a statin therapy on
cardiovascular events.

Effect of Niacin on Atherosclerosis:

Many of the initial niacin therapy imaging studies combined niacin with other drugs and compared these combinations vs. placebo.
These studies showed that niacin in combination with other drugs reduced the progression and/or increased the regression of
atherosclerosis. However, because of the use of other drugs it is impossible to determine if niacin therapy per se was beneficial (Table
5).

Table 5Niacin Coronary Angiography Imaging Studies

Combination Studies Drugs

Cholesterol Lowering Atherosclerosis Study (CLAS) [53] Niacin + colestipol vs. placebo
Familial Atherosclerosis Treatment Study (FATS) [54] Niacin + colestipol or lovastatin + colestipol vs. placebo
UCSF-SCORE [55] Niacin + colestipol +/- lovastatin vs. placebo +/- low dose colestipol
HDL Atherosclerosis Study (HATS) [56] Niacin + simvastatin vs. placebo
Armed Forces Regression Study [57] Niacin + gemfibrozil + cholestyramine vs. placebo
Harvard Atherosclerosis Reversibility Project (HARP) Niacin + pravastatin + cholestyramine + gemfibrozil as needed vs.
[58] placebo

However, there are studies that compared niacin to placebo or other drugs added to standard statin therapy that do provide useful
insights (Table 6).

Table 6Effect of Niacin Added to Statin Therapy on Atherosclerosis

ARBITER 2/3 ER niacin vs. placebo Decrease in CIMT vs. placebo

[59, 60]
ARBITER 6 [61] ER niacin vs. ezetimbe Decrease in CIMT vs. ezetimibe
Thoenes [62] ER niacin vs. placebo Decrease in CIMT vs. placebo
Lee [63] Modified release niacin vs. placebo Decrease in carotid wall area on MRI vs. placebo

The ARBITER 2 Trial was a double-blind randomized study of extended-release niacin (1000mg) vs. placebo added to background
statin therapy in 167 patients with coronary heart disease and low HDL cholesterol levels (<45mg/dl) [60]. At the initiation of the
study mean LDL cholesterol levels were < 100mg/dl. The primary end point was the change in common carotid intima-media
thickness (CIMT). As expected plasma triglycerides decreased and HDL cholesterol levels increased with niacin therapy. LDL
cholesterol levels were unchanged. After 12 months, mean CIMT increased significantly in the placebo group (P<0.001) and was
unchanged in the niacin group (P=0.23). The overall difference in CIMT progression between the niacin and placebo groups was
almost statistically significant (P=0.08). Cardiovascular events occurred in 3 patients treated with niacin (3.8%) and 7 patients treated
with placebo (9.6%; P=0.20). ARBITER 3 was a 12 month extension and in the 57 patients that continued on niacin therapy there was
an additional regression of CIMT (p = 0.001 vs. placebo) [59].

In ARBITER 6, patients with coronary heart disease or a coronary heart disease risk equivalent on long-term statin therapy with LDL
cholesterol level < 100mg/dl and an HDL cholesterol level < 50mg/dl for men or 55mg/dl for women were randomly assigned to
receive either extended-release niacin (target dose, 2000mg per day) or ezetimibe (10mg per day) [61]. The primary end point was the
change from baseline in the mean CIMT. LDL cholesterol levels decreased in the ezetimibe group by −18mg/dl (~ 20%) and by
−10.0mgdl (~ 12%) in the niacin group (P=0.01) while HDL cholesterol levels were slightly decreased in the ezetimibe group
−2.8mg/dl and increased by 7.5mg/dl (~18%) in the niacin group (P<0.001). Triglyceride levels were not markedly altered in the
ezetimibe group but decreased by ~ 15-20% in the niacin group. Notably niacin therapy resulted in a significant reduction of both
mean (P = 0.001) and maximal CIMT (P < 0.001) while ezetimibe therapy significantly increased CIMT (P < 0.001). The incidence of
major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04).

In a trial by Thoenes and colleagues fifty patients with the metabolic syndrome not on statin therapy were randomized to either
extended-release niacin (1000mg/day) or placebo [62]. Treatment with niacin decreased LDL cholesterol by 17% and triglycerides by
23% and increased HDL cholesterol levels by 24% without significant changes in the placebo group. After 52 weeks of treatment,
there was an increase in CIMT of +0.009 +/- 0.003 mm in the placebo group and a decrease in CIMT of -0.005 +/- 0.002 mm in the
niacin group (p = 0.021 between groups).

Finally, Lee and colleagues performed a double-blind, randomized study of 2 g daily modified-release niacin or placebo added to
statin therapy in 71 patients with low HDL cholesterol (<40mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2)
carotid/peripheral atherosclerosis [63]. The primary end point was the change in carotid artery wall area, quantified by magnetic
resonance imaging, after 1 year. Treatment with niacin increased HDL cholesterol by 23% and decreased LDL cholesterol by 19% and
triglycerides by 11%. At 12 months, niacin significantly reduced carotid wall area compared with placebo (Mean change in carotid
wall area was -1.1 +/- 2.6 mm2 for niacin vs +1.2 +/- 3.0 mm2 for placebo).

While these imaging studies provide data suggesting that niacin therapy when added to statin therapy may reduce atherosclerotic
cardiovascular disease, one must recognize that the studies described above were relatively small studies and that decreases or the lack
of progression in CIMT or carotid wall area are surrogate markers, which may not necessarily indicate that cardiovascular events will
be decreased.

Side Effects

Treatment with niacin frequently results in side effects and these side effects are a major limitation of niacin therapy.

Skin Flushing: This is a very common side effect and is characterized by redness and warmth due to vasodilation of the blood vessels
in the skin [7, 64]. It is often most apparent in the head and neck region. Itching can occur and a tingling and burning sensation may
also be noted. Niacin induced flushing is usually not accompanied by diaphoresis. The cutaneous flushing usually lasts for
approximately one hour and in some patients is extremely annoying. In a review of 30 studies, it was noted that flushing occurred in
85% of participants treated with immediate release niacin, 66% of participants treated with extended release niacin, and 26% of
participants treated with slow release niacin [10]. The occurrence of flushing is related to a rapid increase in plasma nicotinic acid
levels, which differs depending upon the niacin preparation. Flushing was the primary reason that subjects discontinued niacin therapy
during studies and with either immediate release or extended release niacin approximately 20% of study participants discontinue
niacin, which is twice the rate of discontinuation observed in the placebo groups [10]. Continuous administration of niacin for
approximately one week results in tachyphylaxis and the flushing decreases. Unfortunately if a patient skips taking niacin for a few
days this tachyphylaxis is lost and the flushing returns.

The mechanism for the niacin induced skin flushing has been partially elucidated [7, 64]. Niacin activates GPR109A in dermal
Langerhan cells (macrophages in the skin), which leads to the increased production of prostaglandin D2. Additionally, niacin activates
GPR 109A in keratinocytes, which leads to the production of prostaglandin E2. The prostaglandins then interact with prostaglandin
receptors on blood vessels resulting in vasodilation and the flushing phenomena. Aspirin and nonsteroidal anti-inflammatory drugs
(NSAIDS) taken prior to niacin administration can decrease flushing by inhibiting the synthesis of prostaglandins [7, 65]. Laropiprant
decreases flushing by blocking the D prostanoid receptor [7]. Since flushing is related to rapid increases in plasma nicotinamide levels
taking immediate release niacin with food slows absorption and thereby reduces flushing. Extended release niacin is typically taken at
bedtime so that the flushing will occur when the patient is asleep. Conditions that predispose to cutaneous vasodilatation such as
alcohol intake, hot liquids, spicy foods, or hot showers should be avoided. One should increase the dose of niacin slowly to reduce the
severity of flushing reactions and allow tolerance to develop.

Hepatic Toxicity: Sustained release niacin has a much greater propensity to induce hepatic toxicity than other niacin preparations and
therefore is no longer widely used [6, 42, 66]. The explanation for this difference is due to the increased metabolism of sustained
release niacin by the amidation pathway described in the pharmacokinetics section, which results in toxic compounds that injure the
liver [6, 42]. Patients who have developed signs of liver toxicity on sustained release niacin can often be treated with immediate
release niacin without developing liver problems [67]. Extended release niacin can induce liver dysfunction but the rate is much lower
than sustained release niacin. Because of the potential for liver disease, serum transaminase levels (SGOT and SGPT) should be
monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6-month
intervals).

Muscle Symptoms: Myalgias and myopathy have not been a significant adverse effect with niacin monotherapy [10]. In combination
with statins, an increased risk of muscle symptoms has been observed in some studies. In the HPS-2 Thrive study the combination of
simvastatin and extended release niacin increased the risk of myopathy four-fold (1.2% of patients on combined therapy) [51]. Of
note, this increase occurred predominantly in Chinese participants. In contrast, in the AIM-HIGH trial muscle related symptoms were
not increased with the simvastatin + niacin combination [49, 68].

Hyperglycemia: It has been recognized for many years that niacin induces insulin resistance [69]. The mechanisms by which niacin
induces insulin resistance are unknown but possible mechanisms include a rebound increase in free fatty acids with niacin therapy or
the accumulation of diacylglycerol [29, 70]. A recent analysis of the AIM-HIGH trial demonstrated that in subjects with normal
glucose metabolism, subjects with impaired fasting glucose, and subjects with diabetes, treatment with extended release niacin
resulted in only small increases in fasting glucose levels but increased serum insulin levels due to an increase in insulin resistance
[71]. Additionally, there was an increased risk of progressing from normal to impaired fasting glucose in subjects treated with niacin
in the AIM-HIGH trial (niacin 58.6% vs placebo 41.5%; P < .001) [71]. A recent meta-analysis examined the effect of niacin therapy
on the development of new onset diabetes [72]. In 11 trials with 26,340 non-diabetic participants, niacin therapy was associated with a
34% increased risk of developing diabetes (RR of 1.34; 95% CIs 1.21 to 1.49). This increased risk results in one additional case of
diabetes per 43 initially non-diabetic individuals who are treated with niacin for 5 years (0.47% ten year risk or 4.7 per 1000 patient
years). Results were similar in patients who were receiving niacin therapy in combination with statin therapy.

Studies have shown that niacin is usually well tolerated in diabetic subjects who are in good glycemic control [73, 74]. In patients with
poor glycemic control, niacin is more likely to adversely impact glucose levels. A recent meta-analysis of 7 studies with 838 patients
with diabetes found that niacin therapy did not result in a significant increase in fasting glucose levels in short term studies but in long
term studies there was a very small increase in fasting glucose levels (1.5mg/dl) that was not clinically significant [75]. An important
caveat is that in most of these trials adjustments in diabetes therapy was permitted, which could blunt worsening of glycemic control.
In contrast to these findings, the HPS-2 Thrive Trial reported that in the 8299 participants who had diabetes at the time of
randomization, treatment with niacin–laropiprant was associated with a 55% increase in serious disturbances in diabetes control, most
of which led to hospitalization (11.1% vs. 7.5%, P<0.001) [51]. The extent to which the latter was due to laropiprant is unknown.
Thus, care must be used in treating patients with diabetes with niacin. In patients in whom adjustments in diabetic therapy can easily
be carried out the risk of adverse effects will likely be limited whereas in patients in whom adjustments in diabetic therapy will be
difficult the risks of niacin therapy are likely to be increased. Careful patient selection and education are important steps to reduce the
risks of niacin therapy in patients with diabetes.

Thus, while niacin therapy may adversely affect glucose homeostasis one needs to balance these adverse effects with the benefits of
niacin therapy. One should note that in the Coronary Drug Project participants with abnormal glucose metabolism also demonstrated a
decrease in cardiovascular events with niacin therapy [45].

Uric Acid: Niacin may increase uric acid levels by inhibiting the secretion of uric acid [7, 76]. In susceptible patients niacin therapy
can precipitate gouty attacks [7].

Gastrointestinal Symptoms: Niacin therapy can induce heartburn, indigestion, nausea, diarrhea, and abdominal discomfort [7]. High
dose niacin is more likely to cause these gastrointestinal disturbances. The mechanism for these symptoms is not clear.
Miscellaneous: Recent trials have reported an increased incidence of infections with niacin therapy [51, 68]. A trial of niacin in
combination with laropiprant found increased bleeding [51]. The increased bleeding could be due to the approximately 10% decrease
in platelet levels that can occur with niacin (see Niaspan Package Insert). Niacin has been reported to induce cystoid macular edema,
which resolves when the drug is stopped [77].

Contraindications

There are a number of contraindications to niacin therapy (Table 7).

Table 7Contraindications for Niacin Therapy

Active gastritis or peptic ulcer disease

Impaired liver function (elevated transaminases 2-3X the upper limit or cholestasis)
Uncontrolled gout
Pregnancy
Lactation
Poorly controlled diabetes
Active bleeding

Summary

The enthusiasm for the use of niacin has decreased with the failure of AIM-HIGH and HPS-2 Thrive to show a decrease in
cardiovascular events when niacin was added to statin therapy. In the absence of definitive data showing benefits from niacin therapy
when added to a statin it is hard to justify the use of this drug given the frequent side effects. However, in statin intolerant patients,
niacin can be useful to help lower LDL cholesterol levels in combination with other drugs. The availability of ezetimibe and PCSK9
inhibitors has reduced the need to use niacin to lower LDL cholesterol levels. Additionally, in patients with markedly elevated
triglyceride levels (>500mg/dl), niacin can also be employed either as monotherapy or in combination with other drugs to reduce the
risk of pancreatitis.

Go to:

FISH OIL
Introduction

The lipid lowering effects of fish oil are mediated by two omega-3-fatty acids; eicosapentaenoic acid (C20:5n-3) (EPA) and
docosahexaenoic acid (C22:6n-3) (DHA). There are four prescription products approved by the FDA which contain various amounts
of EPA and DHA (Table 8). Lovaza and Omacor contain a mixture of EPA and DHA fatty acid esters (ethyl esters), Vascepa contains
only EPA fatty acid esters (ethyl esters), and Epanova contains a mixture of EPA and DHA free fatty acids.

Table 8Prescription Omega-3-fatty acid products (data from package inserts)

Generic Name Omega-3-ethyl esters Icosapent ethyl Omega-3-carboxylic acid

Brand Name Lovaza or Omacor Vascepa Epanova
EPA/capsule 0.465g 1.0g See below
DHA/capsule 0.375g --- See below
Daily Dose 4 capsules/day 4 capsules/day 2-4 capsules/day

1 gram capsules of Epanova contain at least 850mg of fish oil derived fatty acids including multiple omega-3-fatty acids with EPA
and DHA being the most abundant

Fish oil is also sold as a food supplement. It should be recognized that dietary fish oil supplements are not approved by the FDA and
quality control will not meet the same rigorous standards as prescription or over the counter drugs. The amount of EPA and DHA can
vary greatly in these supplements and one needs to read the labels carefully, as products can contain less than 100mg of EPA/DHA per
1 gram capsule [78]. It is helpful to have the patient bring their fish oil supplements to the clinic for verification of the actual amount
of EPA and DHA in the product. Moreover, the amount of EPA and DHA indicated on the label may not be accurate [79]. One needs
to take a sufficient number of capsules to provide 2-4 grams of EPA/DHA per day to effectively lower plasma triglyceride levels.
Depending upon the fish oil supplement, the patient may be required to take a large number of capsules to obtain 2-4 grams of
EPA/DHA per day. Furthermore, these supplements may contain other compounds in addition to omega-3-fatty acids, such as
cholesterol, oxidized lipids, and saturated fatty acids. The major advantage of fish oil supplements is that they are much less expensive
than prescription omega-3-fatty acid drugs. If one elects to use fish oil supplements, one should have the patient use a single brand to
try to ensure as much consistency as possible.

Some omega-3 supplements contain alpha linolenic acid (C18:3n-3) (ALA), a plant omega-3-fatty acid rather than EPA/DHA. ALA
can be converted to EPA and DHA but the conversion is limited and hence it is ineffective in lowering plasma triglyceride levels or
altering other lipid or lipoprotein levels [80].
Effect of Fish Oil on Lipid and Lipoprotein Levels

Table 9Effect of Fish Oil Supplements on Lipids and Lipoproteins

Decreases Triglycerides
No Change in Total Cholesterol
No Change in LDL Cholesterol; if Triglycerides very high may increase LDL Cholesterol
No Change in HDL Cholesterol
No Change in Lp(a)
Shift from Small Dense LDL to Large Buoyant LDL

Several meta-analyses have examined the effect of fish oil supplements on lipid and lipoprotein levels. A meta-analysis by Eslick and
colleagues of 47 studies with 16,511 participants found that fish oil supplements significantly decreased plasma triglyceride levels by
approximately 14% without resulting in clinically significant changes in total, LDL, or HDL cholesterol levels [81]. These authors
also reported that the reduction in plasma triglyceride levels was directly related to baseline plasma triglyceride levels (i.e. the higher
the baseline triglyceride level the greater the reduction in triglycerides with fish oil). Additionally, the higher the dose of EPA/DHA,
the greater the reduction in plasma triglycerides, with clinically significant reductions occurring with approximately 3.25 grams per
day. A meta-analysis by Balk and colleagues of 21 studies also found minimal effects of fish oil supplements on total, LDL, and HDL
cholesterol levels (< 5% change) with significant decreases in plasma triglyceride levels (most of the studies in this meta-analysis has
at least a 15% decrease) [82]. Similar to the meta-analysis by Eslick et al, the higher the baseline triglyceride levels the greater the
reduction in triglyceride levels.

Several meta-analyses have focused on specific patient populations. In a meta-analysis of patients with diabetes, twenty three trials
with1075 participants were analyzed and similar to patients without diabetes the major effect of fish oil supplements was a reduction
in plasma triglyceride levels with no change in total or HDL cholesterol [83]. A small increase in LDL cholesterol was observed
(4.3mg/dl). Of note, fish oil supplementation did not alter fasting glucose or glycated hemoglobin levels indicating that fish oil
supplementation does not adversely affect glycemic control. In a meta-analysis that included patients with type 2 diabetes or impaired
glucose metabolism a decrease in triglycerides was observed without significant changes in total, LDL, or HDL cholesterol levels
[84]. Again no adverse effects on glycemic control were observed.

In patients with end stage renal disease several meta-analyses have consistently shown a decrease in plasma triglycerides with fish oil
administration but the effect on total, LDL, and HDL cholesterol has been variable [85-87]. This variability was likely due to the small
changes that were observed. In patients with nephrotic syndrome a study has shown a reduction in plasma triglycerides and an
increase in LDL cholesterol levels without a change in total or HDL cholesterol levels [88]. In patients with non-alcoholic fatty liver
disease, omega-3-fatty acids have also been shown to decrease plasma triglyceride levels [89]. Finally, In HIV infected subjects, fish
oil supplementation was also effective in lowering plasma triglyceride levels [90, 91].

Thus, fish oil supplementation in a variety of different patient populations lowers plasma triglyceride levels. In patients with elevated
triglyceride levels treated with 3-4 grams of EPA/DHA one can expect an approximate 25% decrease. Total plasma cholesterol levels
are usually not altered by fish oil supplementation. The exceptions are patients with high chylomicron and/or VLDL levels where a
substantial portion of the plasma cholesterol is carried on these triglyceride rich lipoproteins. Fish oil supplementation will decrease
the levels of these triglyceride rich lipoproteins and thereby result in a decrease in total plasma cholesterol levels. LDL cholesterol
levels are not markedly affected by fish oil supplementation except in patients with very high triglyceride levels (>500mg/dl) where
increases in LDL cholesterol levels have been observed [92-94]. If there are sufficient reductions in plasma triglyceride levels a shift
from small dense LDL to large buoyant LDL may be observed [95, 96]. The effect of fish oil supplements on HDL cholesterol levels
is minimal except if the patient has very high triglyceride levels where significant elevations (>10%) have been reported [92-94].
Finally, some but not all studies have shown that the administration of fish oil modestly lowers Lp(a) levels [97-101]

During the development of pharmacological omega-3-fatty acid drugs for approval by the FDA, extensive clinical trials were carried
out and will be reviewed below (Tables 10 and 11). It should be noted that these studies are not directly comparable as they studied
different patient populations at different times.

EPA + DHA fatty acid esters (Lovaza): In patients with marked elevations in plasma triglyceride levels (500-2000mg/dl) a 6 week
trial of EPA + DHA esters resulted in a 31% decrease in plasma triglycerides, a 21% increase in LDL cholesterol levels, and a 12%
increase in HDL cholesterol levels compared to the placebo group [94]. In a 16 week trial triglyceride concentrations were decreased
by 45% and LDL and HDL cholesterol were increased by 31% and 13%, respectively [92]. Studies have also been carried out in
patients with moderate hypertriglyceridemia (200-500mg/dl) who were on statin therapy [102]. EPA + DHA esters resulted in a 23%
decrease in plasma triglycerides and a 7% decrease in non-HDL cholesterol levels, and a 4.6% increase in HDL cholesterol levels
[102].

EPA fatty acid ester alone (Vascepa): In patients with marked elevations in plasma triglycerides (500-2000mg/dl), 4 grams of EPA
ester alone significantly decreased triglyceride levels by 33.1% and non-HDL cholesterol levels by 17.7% [103]. In contrast to EPA
and DHA fatty acid esters, LDL cholesterol and HDL cholesterol levels were not significantly altered by EPA fatty acid esters alone
[103]. Studies have also been carried out in patients with moderate hypertriglyceridemia (200-500mg/dl) who were on statin therapy.
EPA esters resulted in a 21.5% decrease in plasma triglycerides, 13.6% decrease in non-HDL cholesterol, 6.2% decrease in LDL
cholesterol, and a 4.5% decrease in HDL cholesterol levels [104]

EPA + DHA fatty acids: In patients with marked elevations in plasma triglycerides (500-2000mg/dl), 4 grams of EPA + DHA fatty
acids decreased plasma triglycerides by 31% and non-HDL cholesterol by 9.6% and increased LDL cholesterol by 19% and HDL
cholesterol by 5.8% [105]. Studies have also been carried out in patients with moderate hypertriglyceridemia (200-500mg/dl) who
were on statin therapy. EPA + DHA fatty acids resulted in a 20.6% decrease in plasma triglycerides, 6.9% decrease in non-HDL
cholesterol with no significant changes in LDL cholesterol or HDL cholesterol levels [93].

These studies demonstrate that in patients on statin therapy with moderate elevations in plasma triglyceride levels the effects of these
three pharmaceutical products on lipids and lipoprotein levels are similar. However, in patients with marked elevations in plasma
triglyceride levels EPA ethyl esters alone do not increase LDL cholesterol levels whereas products containing EPA and DHA result in
a substantial increase in LDL cholesterol levels. It should also be noted that the ability of omega-3-fatty acids to reduce plasma
triglycerides and increase HDL cholesterol levels is enhanced if baseline triglyceride levels are markedly elevated.

Table 10Effect of Omega-3-Fatty Acids on Lipids and Lipoprotein in Patients with Marked
Hypertriglyceridemia (500-2000mg/dl)

Triglycerides Non-HDLc LDLc HDLc

EPA+DHA ethyl esters- 31% decrease ND 21% increase 12% increase

6 weeks
EPA+DHA ethyl esters 45% decrease ND 31% increase 13% increase
12 weeks
EPA ethyl esters 33% decrease 18% decrease NS NS
EPA+DHA fatty acids 31% decrease 9.6% decrease 19% increase 5.8% increase

ND- not determined; NS- no significant change

Table 11Effect of Omega-3-Fatty Acids on Lipids and Lipoprotein in Patients with Moderate
Hypertriglyceridemia (200-500mg/dl) on Statin Therapy
 Triglycerides Non-HDLc LDLc HDLc
EPA+DHA ethyl esters 23% decrease 7% decrease __ 4.6% increase
EPA ethyl esters 22% decrease 14% decrease 6.2% increase 4.5% decrease
EPA+DHA fatty acids 21% decrease 6.9% decrease NS NS

NS- no significant change

Head to Head Comparisons: A meta-analysis of six studies has compared the effect of EPA alone vs. DHA alone on plasma lipids
and lipoproteins [106]. Administration of DHA increased LDL cholesterol by 4.6mg/dl compared to EPA (95% CI 2.2- 7.1). In
contrast, DHA reduced plasma triglyceride levels to a greater extent than EPA (6.1mg/dl; 95% CI 2.5- 9.8). Finally, DHA increased
HDL cholesterol levels more than EPA (3.7mg/dl; 95% CI: 2.4- 5.1). Whether these modest differences are clinical significant is
unknown.

Tatsuno et al compared the effect of DHA + EPA ethyl esters vs. EPA ethyl esters alone on lipid and lipoprotein levels in patients with
mean baseline plasma triglyceride of 250-270mg/dl and mean LDL cholesterol levels of 125- 135mg/dl [107, 108]. These authors
found that at equivalent doses there were no differences in effect on plasma triglyceride, LDL cholesterol, or HDL cholesterol levels
between DHA + EPA ethyl ester or EPA ethyl ester treatment.

These head-to-head studies indicate that in subjects with moderate hypertriglyceridemia the effects of EPA and DHA on lipid and
lipoprotein levels are similar. Perhaps if the baseline triglycerides were markedly elevated differences in response might have been
observed.

In Combination with Fenofibrate: In patients with marked hypertriglyceridemia a single drug is often not sufficient to lower
triglycerides into the desired range. In patients with triglyceride levels > 500mg/dl the combination of fenofibrate 130mg per day and
4 grams of Lovaza reduced triglyceride levels to a greater extent than monotherapy with fenofibrate alone (7% decrease; P = 0.059)
[109]. Not unexpectedly, LDL levels were increased to a greater extent with combination therapy (9% increase; p= 0.03). When
subjects who had received 8 weeks of fenofibrate monotherapy were treated with Lovaza during the 8-week, open-label extension
study, triglyceride levels were reduced by an additional 17.5% (P = 0.003). These results indicate that the addition of omega-3-fatty
acids to fenofibrate will further decrease triglyceride levels.

In Combination with Niacin: Sixty patients with the metabolic syndrome were randomized to 16 weeks of treatment with placebo,
Lovaza (4 g/day), extended release niacin (2 g/day), or both drugs in combination [17]. In the niacin group triglycerides were
decreased by 30%, in the omega-3-fatty acids group by 22%, and in the combination group by 42% compared to the placebo group. Of
note, the beneficial effects of niacin on decreasing LDL and non-HDL cholesterol were blunted by omega-3-fatty acids. These results
show that the combination of niacin and fish oil will lower triglyceride levels more than either drug individually but at the expense of
diminishing the effect of niacin on LDL and non-HDL cholesterol levels.

Mechanism Accounting for the Fish Oil Induced Lipid Effects

As noted above, the major effect of fish oil is to lower plasma triglyceride levels. The predominant cause of the reduction in plasma
triglyceride levels is a decrease in the hepatic production and secretion of triglyceride rich lipoproteins [110-113]. In cultured
hepatocytes, omega-3-fatty acids inhibit the assembly and secretion of VLDL and apolipoprotein B 100 [111, 113-115]. The
incorporation of triglycerides into VLDL is a key regulatory step in determining the rate of formation and secretion of VLDL and
there are a number of mechanisms by which omega-3 fatty acids reduce the level of hepatic triglycerides available for VLDL
formation [110, 111, 113]. Studies in animal models have demonstrated that omega-3-fatty acids inhibit fatty acid synthesis and
stimulate fatty acid oxidation in the liver, which would reduce the availability of fatty acids for triglyceride synthesis [110-113]. The
increase in fatty acid oxidation is due to omega-3-fatty acids activating PPAR alpha, which stimulates fatty acid oxidation in the liver
and other tissues [110, 112, 113, 116]. The decrease in fatty acid synthesis is due to omega-3-fatty acids inhibiting the expression of
SREBP-1c, a key transcription factor that regulates fatty acid synthesis [112, 113, 116]. In addition, omega-3-fatty acids decrease
triglyceride synthesis, which may be due to the decreased availability of fatty acids and an inhibition of the activity of DGAT, a key
enzyme required for triglyceride synthesis [110, 112, 113]. Finally, omega-3-fatty acids also decrease the flux of free fatty acids from
adipose tissue to the liver, which will lead to a decreased quantity of fatty acids available for triglyceride synthesis in the liver [110].
This decrease in flux of free fatty acids is due to omega-3-fatty acids reducing hormone sensitive lipase mediated intracellular
lipolysis in adipose tissue [110]. It is likely that these and perhaps other factors lead to the decreased availability of triglycerides
resulting in a reduction in VLDL formation and secretion. In addition, the peroxidation of omega-3-fatty acids may stimulate the
degradation of apolipoprotein B-100, which would provide another pathway that could contribute to a decrease in VLDL formation
and secretion [113].

While not the primary mechanism for the decrease in plasma triglycerides, studies have shown that omega-3-fatty acids may increase
the clearance of triglyceride rich lipoproteins [110, 117]. Post heparin lipoprotein lipase activity is not increased by omega-3-fatty acid
administration but the lipolytic activity of non-stimulated plasma is enhanced [110, 117]. Additionally, apolipoprotein C-III levels are
decreased with omega-3-fatty acid administration which could also contribute to an increase in the clearance of triglyceride rich
lipoproteins [118-120].

The increase in LDL cholesterol levels that occurs in patients with marked hypertriglyceridemia treated with omega-3-fatty acids is
thought to be due to the enhanced conversion of VLDL to LDL [112].
Pharmacokinetics and Drug Interactions

Omega-3 ethyl esters and fatty acids are absorbed by the GI tract similar to other dietary lipids. It is worth noting that omega-3-free
fatty acids (Epanova) are directly absorbed by the small intestine and are not dependent on pancreatic lipases for absorption. Thus,
absorption of omega-3-fatty acids is not decreased in patients with pancreatic insufficiency and therefore may be preferred in patients
with pancreatic disease. Additionally, the bioavailability of omega-3-fatty acids with a low fat diet was greater than omega-3-ethyl
esters while there was little difference between these different formulations with a high fat diet [121, 122].

Drug interactions have not been seen with omega-3-fatty acids (Package Inserts for Lovaza, Vascepa, and Epanova).

Effect of Fish Oil on Clinical Outcomes

Initial studies of the effect of fish oil administration on cardiovascular outcomes were favorable, demonstrating a reduction in events
including all-cause mortality. However, more recent studies have failed to confirm these favorable results. In these more recent studies
the use of other drugs, such as statins, that reduce cardiovascular disease were more intensively utilized. The outcomes studies that
will be described below were carried out with doses of EPA and DHA that are lower than the doses used to lower plasma triglycerides.
We will limit our discussion to the administration of fish oil as a drug and not discuss diet studies, such as DART, which had patients
increase fatty fish intake [123, 124].

 GISSI-Prevenzione trial was a randomized trial of 850-882mg of EPA and DHA ethyl esters per day in 11,323 participants
with a recent myocardial infarction (< 3 months) for 3.5 years [125]. The primary endpoint was death, non-fatal myocardial
infarction, and stroke. No change in total cholesterol, LDL cholesterol, or HDL cholesterol was observed but plasma
triglyceride levels were decreased by 5%. Patients treated with EPA/DHA had a significant decreased risk of major
cardiovascular events (RR 0.90), cardiac death (RR 0.78), and sudden death (RR 0.74). The decrease in sudden death occurred
very quickly and was noted as early as 4 months after initiation of therapy. Interestingly, non-fatal cardiovascular events were
not affected by EPA/DHA treatment (RR 0.98). The decrease in total mortality was driven by a reduction in sudden death
suggesting an anti-arrhythmic effect of EPA/DHA.

 GISSI-Heart Failure (GISSI-HF) trial was a randomized, double-blind, placebo-controlled trial in patients with chronic heart
failure who were randomly assigned to 850-882mg of EPA and DHA ethyl esters per day (n=3494) or placebo (n=3481) [126].
Patients were followed for a median of 3.9 years. Primary endpoints were time to death, and time to death or admission to the
hospital for cardiovascular reasons. Omega-3-fatty acid treatment at these low doses resulted in a slight decrease in plasma
triglyceride levels with no change in total, LDL or HDL cholesterol levels. In the omega-3-fatty acid group 27% patients died
 from any cause vs. 29% in the placebo group (HR 0.91; p=0.041). In the omega-3-fatty acid group 57% of patients died or
were admitted to hospital for cardiovascular reasons vs. 59% in the placebo group (HR 0.92; p=0.009). No significant
differences were observed in fatal or non-fatal myocardial infarctions or strokes. In this trial, similar to the GISSI-Prevenzione
trial, the benefit was primarily due to a reduction in arrhythmic events and little benefit on atherothrombotic events was noted.

 Japan EPA Lipid Intervention Study (JELIS) was an open label study in patients with total cholesterol levels > 254mg/dl
with (n= 3664) or without cardiovascular disease (n=14,981) who were randomly assigned to be treated with 1800 mg of EPA
+ statin (n=9326) or statin alone (n= 9319) with a 5 year follow-up [127]. The primary endpoint was any major coronary event,
including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina
pectoris, angioplasty, stenting, or coronary artery bypass grafting. Total, LDL, and HDL cholesterol levels were similar in the
two groups but plasma triglycerides were modestly decreased in the EPA treated group (5% decrease in EPA group compared
to controls; p = 0.0001). In the EPA group the primary endpoint occurred in 2.8% of the patients vs. 3.5% of the patients in the
statin alone group (19% decrease; p = 0.011). Unstable angina and non-fatal coronary events were also significantly reduced in
the EPA group but in this study sudden cardiac death and coronary death did not differ between groups. Unstable angina was
the main component contributing to the primary endpoint and this is a more subjective endpoint than other endpoints such as a
myocardial infarction, stroke, or cardiovascular death. A subjective endpoint has the potential to be an unreliable endpoint in
an open label study and is a major limitation of the JELIS Study.

 OMEGA was a randomized, placebo-controlled, double-blind, trial in 3851 survivors of an acute myocardial infarction [128].
Patients were randomized 3 to 14 days after an acute myocardial infarction to omega-3-acid ethyl esters, 1 gram/day (460mg
EPA and 380mg DHA) or placebo capsules containing 1 gram of olive oil and followed for one year. The primary endpoint
was rate of sudden death and secondary end points were total mortality and nonfatal clinical events. No significant differences
were seen in the primary or secondary endpoints.

 Alpha Omega was a double-blind, placebo-controlled trial in 4837 patients between 60 through 80 years of age (78% men)
who had had a myocardial infarction [129]. Patients were randomized to receive for 40 months one of four trial margarines: a
margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400mg of EPA-DHA;
actual intake 226mg EPA and 150mg DHA), a margarine supplemented with alpha-linolenic acid (ALA) (with a targeted
additional daily intake of 2g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The
primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and
cardiac interventions. Low dose EPA-DHA, ALA, or the combination of EPA/DHA and ALA did not significantly reduce the
rate of major cardiovascular events or cardiac interventions.
  FOL.OM3 Study was a double blind, randomized, placebo controlled trial in 2501 patients with a history of a myocardial
infarction, unstable angina, or ischemic stroke in the past 12 months [130]. Patients were randomized to a daily dietary
supplement containing 5-methyltetrahydrofolate (560μg), vitamin B-6 (3mg), and vitamin B-12 (20μg) or placebo; and a
dietary supplement containing omega 3 fatty acids (600mg of EPA and DHA) or placebo. Median duration of treatment was
4.7 years. The primary outcome was a composite of non-fatal myocardial infarction, stroke, or death from cardiovascular
disease. Treatment with B vitamins or omega 3 fatty acids had no significant effect on major vascular events.

 Origin was a double-blind study in 12,536 patients at high risk for cardiovascular disease who had impaired fasting glucose,
impaired glucose tolerance, or diabetes [131]. Patients were randomized to receive a 1 gram capsule containing at least 900mg
of ethyl esters of omega-3 fatty acids (EPA 465mg and DHA 375mg) or placebo for approximately 6 years. The primary
outcome was death from cardiovascular causes. Triglyceride levels were reduced by 14.5mg/dl in the group receiving omega-
3-fatty acids compared to the placebo group (P<0.001), without a significant effect on other lipids. The incidence of the
primary outcome was not significantly decreased among patients receiving omega-3-fatty acids as compared with those
receiving placebo. The use of omega-3-fatty acids also had no significant effect on the rates of major vascular events, death
from any cause, or death from arrhythmia.

 Risk and Prevention Study was a double-blind, placebo-controlled trial in 12,513 men and women with multiple
cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarctions [132]. Patients were randomly
assigned to 1 gram daily omega-3 fatty acids (EPA and DHA content not <85 %,) or placebo (olive oil) for 5 years. The
initially specified primary end point was the rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after
the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular
causes or admission to the hospital for cardiovascular causes. Plasma triglyceride levels decreased slightly more in the
omega−3-fatty acid group than in those who received placebo (−28.2±1.3mg/dl vs. −20.1±1.3mg/dl; P<0.001). Total, LDL,
and HDL cholesterol levels were similar in the omega-3-fatty acid and placebo groups. No significant differences were
observed between the omega-3-fatty acid group and placebo group for the primary endpoint or any of the secondary endpoints.

 Meta-analyses: There have been a number of meta-analyses of the effect of omega-3-fatty acid treatment on cardiovascular
disease and as one would suspect the results have varied with some meta-analyses suggesting that omega-3-fatty acids
decrease death and cardiovascular events [133-135] and others showing no significant benefits [136-141].

It is thus apparent that the effect of fish oil on cardiovascular outcomes is uncertain at this time. As will be described below there are
four large studies in progress that will provide additional data addressing this issue. Of note, two of the studies in progress will be
employing pharmacological doses of omega-3-fatty acids in patients with hypertriglyceridemia and it will be interesting to see the
results of these studies.

Outcome Studies in Progress

 A Study of Cardiovascular Events in Diabetes (ASCEND) - a randomized, placebo controlled, double blind trial of 1 gram
omega-3-fattys acids (400mg EPA and 300mg DHA ethyl esters) vs. olive oil placebo in 15,480 patients with diabetes without
a history of cardiovascular disease (primary prevention trial).The primary end point is non-fatal myocardial infarction, non-
fatal stroke, transient ischemic attack, or vascular death. The estimated completion date is September 2017. (ClinicalTrials.gov
Identifier NCT00135226)

 The Vitamin D and Omega-3 Trial (Vital) – a randomized, double blind, placebo controlled trial of 1 gram omega-3 fatty
acids (465mg EPA and 375mg DHA ethyl esters) vs. placebo in 25,875 men and women that have not been selected on the
basis of an elevated risk. The primary outcomes are cancer and major cardiovascular events (non-fatal myocardial infarction,
non-fatal stroke, or vascular death). The estimated completion date is December 2017. (ClinicalTrials.gov Identifier
NCT01169259)

 The Reduction of Cardiovascular Events with EPA – Intervention Trial- a randomized, double blind trial of 4 grams per
day of EPA ethyl ester (Vascepa) vs. placebo in 8000 patients with hypertriglyceridemia and established cardiovascular
disease or high cardiovascular disease risk who are on statin therapy. The primary outcome will be major atherosclerotic
cardiovascular events. The estimated completion date is late 2017/early 2018. (ClinicalTrials.gov Identifier NCT01492361)

 Statin Residual Risk Reduction with Epanova in High Risk Patients with Hypertriglyceridemia (Strength) - a
randomized, placebo controlled, double blind trial of 4 grams per day of omega-3-fatty acids (Epanova) vs. corn oil placebo in
13,000 patients on statins with hypertriglyceridemia, optimal LDL levels, low HDL, and high risk of cardiovascular disease.
The primary outcome will be major atherosclerotic cardiovascular events. The estimated completion date is 2019.
(ClinicalTrials.gov Identifier NCT02104817)

Side Effects

Gastrointestinal side effects such as diarrhea, nausea, dyspepsia, abdominal discomfort, and eructation have been observed with fish
oil therapy (Package Inserts for Lovaza, Vascepa, and Epanova).
At very high doses, omega-3-fatty acids can inhibit platelets and prolong bleeding time. However, at the recommended doses this has
not been a clinical problem but nevertheless when patients are on anti-platelet drugs one should be alert for the possibility of bleeding
problems (Package Inserts for Lovaza, Vascepa, and Epanova). A recent review found no evidence for discontinuing the use of
omega-3 fatty acid treatment before invasive procedures or when given in combination with other agents that affect bleeding [142].

Contraindications

There are no contraindications to the use of omega-3-fatty acids. Lovaza, Omacor, and Vascepa are pregnancy category C drugs and
they should only be used if the benefits to the mother outweigh the potential risks to the fetus.

Conclusions

Omega-3-fatty acids are effective drugs in reducing triglyceride levels with few significant side effects, drug interactions, or
contraindications. Whether the addition of omega-3-fatty acids to statin therapy will reduce cardiovascular disease is uncertain but the
studies in progress will hopefully provide a definitive answer to this question. Finally, omega-3-fatty acids are effective in lowering
triglycerides in patients with marked hypertriglyceridemia and while not proven will likely reduce the risk of development of
pancreatitis.

Go to:

FIBRATES
Introduction

The fibrate drug class includes clofibrate, gemfibrozil, fenofibrate, bezafibrate, and `ciprofibrate. Clofibrate was developed in the
1960s and was the first member of this class. Clofibrate is no longer available because of an increased risk of adverse effects.
Gemfibrozil and fenofibrate are available in the United States while gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate are
available in Europe. All of the fibrates work via activation of the nuclear hormone receptor PPAR alpha.

Effect of Fibrates on Lipid and Lipoprotein Levels

Table 12Effect of Fibrates on Lipids and Lipoproteins

Decreases Triglyceride
Increases HDL Cholesterol
Decreases LDL cholesterol; if Triglycerides Very High can Increase LDL Cholesterol
Decreases Non-HDL Cholesterol
Decreases Apolipoprotein B
Decreases LDL Particle Number
Shift Small Dense LDL to Large Buoyant LDL
No Effect on Lp(a)

Fibrates reduce fasting triglyceride levels by 25-50% [143-145]. The magnitude of the reduction in triglycerides is dependent on the
baseline triglyceride levels. Patients with marked elevations in triglycerides have a greater reduction in triglyceride levels [143, 145,
146]. In addition, fibrates increase HDL cholesterol levels by 5-20% [144, 145]. The increase in HDL cholesterol levels is more robust
if the triglyceride levels are elevated and/or if the HDL cholesterol levels are low [146]. The effect on LDL cholesterol is more
variable [145]. If the triglyceride levels are very high (>400-500mg/dl), fibrate therapy may result in an increase in LDL cholesterol
levels whereas if triglycerides are not elevated fibrates decrease LDL cholesterol by 10-30% [143]. Given the decrease in plasma
triglycerides and LDL cholesterol levels, fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL cholesterol levels
[145]. Depending upon the triglyceride level there may be a shift from small dense LDL towards large LDL particles [145]. Fibrates
do not have any major or consistent effects on Lp(a) levels [147]. Table 13 below shows the effect of fenofibrate on lipid and
lipoprotein levels in patients with different lipid profiles and illustrates some of the principles outlined above.

Table 13Effect of Fenofibrate on Lipid and Lipoprotein Levels

Elevated Triglyceride Levels Triglycerides LDL-C HDL-C

Baseline Levels ~404mg/dl ~125mg/dl ~35mg/dl

Change with Fenofibrate 45% Decrease 2.5% Increase 16% Increase

Elevated LDL Cholesterol and Triglyceride Levels Triglycerides LDL-C HDL-C

Baseline Levels 232mg/dl 220mg/dl 46.7mg/dl
Change with Fenofibrate 37% Decrease 13% Decrease 12% Increase
Elevated LDL Cholesterol and Normal Triglyceride Levels Triglycerides LDL-C HDL-C
Baseline Levels 102mg/dl 228mg/dl 58.1mg/dl
Change with Fenofibrate 35% Decrease 29% Decrease 7% Increase

The values are adjusted for changes in the placebo group. Data modified from Tricor Package Insert.

In large, randomized, fibrate outcome trials similar changes in lipid and lipoprotein levels were noted (Table 14). These trials are
discussed in detail in the effect of fibrates on cardiovascular outcomes section presented below.

Table 14Effect of Fibrates on Lipid and Lipoprotein Levels in Large Outcome Studies*

Triglycerides LDL-C HDL-C

Helsinki Heart Study- Gemfibrozil [148] 35% Decrease 11% Decrease 10% Increase
VA-HIT Study 31% Decrease No Change 6% Increase
Gemfibrozil [149]
BIP Study 21% Decrease 7% Decrease 18% Increase
Bezafibrate [150]
Leader Study 23% Decrease 8% Decrease 8% Increase
Bezafibrate [151]
Field Study 29% Decrease 12% Decrease 5% Increase
Fenofibrate [152]

*The values are adjusted for changes in the placebo group.

The different fibrates in general cause similar changes in lipid and lipoprotein levels. There are only a few comparative trials of
fibrates comparing their effects on lipid and lipoprotein levels and these trials have been very small. Comparisons of ciprofibrate and
gemfibrozil have not shown any major differences between these two fibrates [153, 154]. In contrast, two very small trials have
compared gemfibrozil vs. fenofibrate and reported that fenofibrate was more efficacious in lowering LDL levels than gemfibrozil
[155, 156].

In very rare instances fibrates can cause a paradoxical marked decrease in HDL cholesterol levels [157-160]. This rare paradoxical
decrease in HDL cholesterol typically occurs when fibrates are used in combination with a thiazolidinedione (rosiglitazone and
piuoglitazone) but can occur when fibrates are used alone [157-160]. The decrease in HDL cholesterol can be extreme with decreases
of 50% to 88% reported and recovery to normal can take weeks after the fibrate is discontinued [158]. The mechanism for this
paradoxical effect is unknown.

Effect of Fibrates in Combination with Other Lipid Lowering Drugs on Lipid and Lipoprotein Levels

Statins: Statins are the primary drugs used to treat most patients with dyslipidemia. Statin are very effective in lowering LDL
cholesterol levels but have only modest effects on triglyceride and HDL cholesterol levels. Therefore it is appealing to add a fibrate to
patients who on statin therapy have LDL cholesterol levels at goal but still have elevated non-HDL cholesterol and triglyceride levels
and decreased HDL cholesterol levels. Therefore, there have been numerous studies examining the effect of the combination of statins
and fibrates on lipid and lipoprotein levels. An example is the Safari Trial which compared the effect of simvastatin only (n=207) vs.
simvastatin + fenofibrate (n=411) in patients with combined hyperlipidemia [161]. The results of this trial are shown in table 15. As
anticipated, adding a fibrate results in a further lowering of LDL cholesterol, non-HDL cholesterol and triglyceride levels with a
further increase in HDL cholesterol.

Table 15

Effect of Simvastatin Alone vs. Simvastatin + Fenofibrate on Lipid and Lipoprotein Levels

LDL TG Non-HDLC HDL

Simvastatin -26% -20% -26% +10%
Simvastatin + Fenofibrate -31% -43% -35% +19%

A recent meta-analysis of 9 studies with over 1200 participants compared the effect of statin alone vs. statin + fibrate on lipid and
lipoprotein levels [162]. The combination of statins and fibrates provided significantly greater reductions in total cholesterol, LDL
cholesterol and triglycerides, and a significantly greater increase in HDL cholesterol than treatment with statins alone. A larger meta-
analysis of 13 randomized controlled trials, involving 7712 patients, similarly demonstrated significant decreases in LDL cholesterol
(8.8mg/dl), triglycerides (58mg/dl) and total cholesterol (11.2mg/dl), and increases in HDL cholesterol (4.65mg/dl) in patients
receiving the combination of statins + fibrates compared with statin therapy alone [163]. The combination of statins + fibrates also
results in a shift of LDL particles from small dense particles to large buoyant particles whereas no change in LDL particle size was
observed with statin monotherapy [164].

A recent meta-analysis of 6 studies with over 400 participants compared the effect of fibrate alone vs. fibrate + statin and showed
similar changes [165]. The fibrate-statin combination produced significantly greater reductions in the levels of total cholesterol, LDL
cholesterol, and triglycerides compared to fibrate alone. In contrast there was no significant difference in HDL cholesterol levels in the
fibrate vs. fibrate + statins group.

Ezetimibe: In patients unable to tolerate statin therapy one needs to use other drugs to treat dyslipidemia. In a study comparing the
effect of ezetimibe 10mg alone, fenofibrate 145mg alone, or ezetimibe + fenofibrate the combination had a better effect on the lipid
profile resulting in a greater decrease in LDL cholesterol levels and increase in HDL cholesterol levels than either drug alone (Table
16) [166].

Table 16Effect of the Combination of Ezetimibe and Fenofibrate on Lipid and Lipoprotein Levels

LDL-C HDL-C TG
Ezetimibe 23% Decrease 2.2% Increase 10% Decrease
Fenofibrate 22% Decrease 7.5% Increase 38% Decrease
Ezetimibe + Fenofibrate 34% Decrease 11.5% Increase 38% Decrease

Similar results were observed in another randomized trial of ezetimibe 10mg and fenofibrate 160mg [167]. Moreover, both fibrate
therapy and the combination of ezetimibe and fenofibrate results in a shift of LDL particles from small dense LDL particles to large
buoyant particles [167].

Ezetimibe + Statin: A large randomized trial has compared the effect of ezetimibe /simvastatin 10mg/20mg, fenofibrate 160mg, or
ezetimibe/simvastatin + fenofibrate on lipid and lipoprotein levels. As one would expect triple drug therapy had a better effect on the
lipid profile (Table 17) [168]. While ezetimibe/simvastatin was very effective in lowering LDL cholesterol levels and fenofibrate was
very effective in lowering triglycerides and raising HDL cholesterol levels the combination resulted in more favorable changes in
triglycerides. In a similar study the addition of fenofibrate 135mg to atorvastatin 40 mg + ezetimibe 10 mg resulted in a greater
reduction in triglycerides (-57% vs. 40%; p<0.001) and a greater increase in HDL (13% vs. 4.2%; p<0.001) than placebo [169].
Fibrate therapy and ezetimibe/simvastatin + fenofibrate also resulted in a shift of LDL particles from small dense LDL particles to
large buoyant particles [168].

Table 17Effect of the Combination of Ezetimibe/Simvastatin and Fenofibrate on Lipid and Lipoprotein Levels

LDL-C HDL-C TG
Placebo -3.5% +1.1 -3.1%
Ezetimibe/Simvastatin -47% +9.3% -29%
Fenofibrate -16% +18.2 -41
Eze/Simva + Fenofibrate -46% +18.7 -50%

Bile Acid Sequestrant: Studies have examined the effect of fibrates in combination with bile acid sequestrants. Participants receiving
fenofibrate 160 mg/day were randomized to receive either colesevelam HCl 3.75 g/day or placebo [170]. No significant differences in
triglyceride or HDL cholesterol levels were observed between the two groups. However, LDL cholesterol levels were decreased in the
fenofibrate + colesevelam group compared to the fenofibrate + placebo group (12.4% greater decrease: p<0.001). A study of the
combination of fenofibrate and colestipol also demonstrated a more marked decrease in LDL cholesterol with that combination
compared to either drug alone (colestipol -18%; fenofibrate -17%, colestipol + fenofibrate 37%) [171]. The combination of both drugs
did not blunt the effects of fenofibrate on VLDL and HDL. Other studies of the combination of a fibrate with a bile acid sequestrant
have also demonstrated an enhanced effect in lowering LDL cholesterol levels [172-174].

Niacin: Surprisingly there are few large randomized trials examining the effect of combination therapy with niacin + fibrate vs.
monotherapy. One very small trial did report that while both niacin monotherapy and bezafibrate monotherapy were effective in
lowering serum triglycerides there was no added benefit of combination therapy in reducing serum triglyceride level although a large
variance may have reduced the ability to detect statistically significant results [16]. A larger trial in HIV+ patients reported that the
combination of niacin and fenofibrate was better at lowering triglycerides and non-HDL cholesterol and increasing HDL cholesterol
levels than monotherapy with either niacin or fenofibrate [17]. It would be informative if additional trials of fibrate + niacin
combination therapy were carried out in patients with marked hypertriglyceridemia that can often be difficult to control with lifestyle
changes and monotherapy.

Fish Oil: In patients with triglyceride levels > 500mg/dl the combination of fenofibrate 130mg per day and 4 grams of Lovaza
reduced triglyceride levels to a greater extent than monotherapy with fenofibrate alone (7% decrease; P = 0.059) [103]. Not
unexpectedly, LDL levels were increased to a greater extent with combination therapy (9% increase; p= 0.03). When subjects who had
received 8 weeks of fenofibrate monotherapy were treated with Lovaza during the 8-week, open-label extension study triglyceride
levels were reduced by an additional 17.5% (P = 0.003). These results indicate that the addition of omega-3-fatty acids to fenofibrate
will further decrease triglyceride levels.

Mechanisms Accounting for the Fibrate Induced Lipid Effects

Fibrates are ligands that bind and activate PPAR alpha, a member of the family of nuclear hormone receptors that are activated by
lipids [175, 176]. PPAR alpha is highly expressed in the liver and other tissues important in fatty acid metabolism. PPAR alpha forms
a heterodimer with RXR and together the PPAR alpha:RXR complex when activated binds to the PPAR response elements in a large
number of genes and regulates the expression of these genes [175, 176]. The natural ligands of PPAR alpha are fatty acid derivatives
formed during lipolysis, lipogenesis, of fatty acid catabolism [175, 176].

Triglycerides: Fibrates lower plasma triglyceride levels by decreasing VLDL production and by increasing the clearance of
triglyceride rich lipoproteins [177, 178]. The decrease in VLDL production is primarily due to PPAR alpha activation of the beta
oxidation of fatty acids, which reduces the substrate available for the synthesis of triglycerides and the formation of VLDL [175, 178].
Additionally, a decrease in hepatic fatty acid synthesis may also contribute to the decrease in fatty acids [175, 178]. The increased
clearance of triglyceride rich lipoproteins is due to PPAR alpha stimulating the transcription of lipoprotein lipase, the key enzyme that
catabolizes the triglycerides carried by VLDL and chylomicrons [175, 178]. In addition, activation of PPAR alpha also inhibits the
transcription of apolipoprotein C-III, which inhibits lipoprotein lipase activity [175, 178]. A decrease in apolipoprotein C-III enhances
the clearance of triglyceride rich lipoproteins by increasing lipoprotein lipase activity. Notably, a decrease in apolipoprotein C-III also
decreases triglyceride levels in patients deficient in lipoprotein lipase indicating that there are multiple mechanisms for its effects on
triglyceride metabolism [179]. Recent studies suggest that apolipoprotein C-III inhibits the uptake of triglyceride rich lipoproteins into
the liver by the LDL receptors/ LDLR-related protein 1 axis .[180]. PPAR alpha activation also increases the transcription of
apolipoprotein A-V, which would also facilitate the activity of lipoprotein lipase [175].

HDL: The increase in HDL induced by fibrates is due to PPAR alpha activation stimulating apolipoprotein A-I and A-II transcription
[175, 178]. This leads to the increased production of HDL [177]. In addition, a decrease in triglyceride rich lipoproteins may result in
a reduction in CETP mediated transfer of cholesterol from HDL to VLDL and of triglyceride from VLDL to HDL [178]. This would
lead to less triglyceride enrichment of HDL and a decrease in the opportunity of hepatic lipase to remove triglyceride leading to small
HDL particles that may be rapidly catabolized.

LDL: As noted above the effect of fibrates on LDL cholesterol levels is variable with increases in LDL seen in patients with high
triglyceride levels (>400mg/dl) and decreases in LDL cholesterol levels in patients with lower triglyceride levels. In patients with
modest elevations in plasma triglyceride levels the clearance of LDL is enhanced [177]. The mechanism for this enhanced clearance
could be due to a decrease in apolipoprotein C-III, as increased levels of this protein inhibits LDL receptor activity [180, 181].
Additionally, the shift from small dense LDL to large buoyant LDL would enhance the uptake of LDL by the LDL receptor [182]. In
patients with triglyceride levels > 400mg/dl fibrate therapy decreases LDL clearance [177]. Prior to treatment, patients with marked
hypertriglyceridemia have hypercatabolism of LDL, which is likely due to increased uptake by the reticuloendothelial system [177].
This increased clearance is LDL receptor independent. Treatment with fibrates lowers the plasma triglycerides leading to
normalization of reticuloendothelial cell function and a decrease in LDL clearance resulting in an increase in LDL cholesterol levels
with fibrate therapy [177]. In addition, the metabolism of VLDL to LDL may be enhanced by fibrates when the triglyceride levels are
markedly elevated.

Effect of Fibrates on Cardiovascular Outcomes

There have been a number of studies that have examined the effect of a variety of different fibrates on cardiovascular disease. We will
describe the major studies below.

 Coronary Drug Project (CDP): CDP conducted between 1966 and 1975, was a randomized, double-blind clinical trial that
determined the effect of clofibrate (1.8g/day), dextrothyroxine (6mg/day), two doses of oral estrogen (2.5 or 5mg per day), or
immediate release niacin (3 grams/day) vs. placebo in 8,341 men aged 30 to 64 years of age with an electrocardiogram
documented myocardial infarction on cardiovascular events and mortality [43]. The mean baseline total cholesterol level was
251mg/dl and triglyceride level was 183mg/dl. The two estrogen regimens and dextrothyroxine treatment groups were
discontinued early because of increased adverse effects. Clofibrate treatment (n= 1051) compared to placebo (n= 2680) also
did not demonstrate clinical benefit. The five-year mortality in subjects treated with clofibrate was 20.0% as compared with
20.9% in subjects on placebo therapy (P = 0.55).

 WHO: WHO was a double-blind trial in middle-aged men, age 30-59 years of age, without evidence of heart or other major
disease, who were treated with 1.6 grams/day clofibrate (n=5000) or placebo (n=5000) for an average of 5.3 years [183].
Average serum cholesterol levels were approximately 248mg/dl and a mean reduction of approximately 9 per cent occurred in
the clofibrate group. The incidence of ischemic heart disease was decreased by 20% in the clofibrate group compared to the
control group (P <0.05). This decrease was confined to non-fatal myocardial infarcts which were reduced by 25 per cent while
the incidence of fatal heart attacks and angina was similar in the clofibrate and placebo groups. Importantly, the numbers of
deaths and crude mortality rates from all causes were increased in the clofibrate-treated group compared to the control group
(P < 0.05). The excess deaths were partially accounted for by increased deaths due to liver, biliary tract, and intestinal disease.
There was also an increase in cholecystectomies in subjects treated with clofibrate. Because of increased toxicity clofibrate is
no longer available.

 Helsinki Heart Study (HHS): HSS was a randomized double-blind trial in middle aged men age 40-55 years of age without
cardiovascular who had non-HDL cholesterol levels greater than or equal to 200mg/dl [148]. Subjects were randomized to
receive 600mg gemfibrozil twice a day (n=2051) or placebo (n=2030) for five years. At initiation of the study total cholesterol
was 289mg/dl, HDL cholesterol 47mg/dl, non-HDL cholesterol 242mg/dl, and triglycerides 176mg/dl. Gemfibrozil caused an
increase in HDL cholesterol (approximately 10%) and reductions in total (~10%), LDL (~11%), and non-HDL cholesterol
 (~14%) and triglyceride levels (~35%). There were minimal changes in serum lipid levels in the placebo group. Fatal and non-
fatal myocardial infarctions and cardiac death were the principle end points and the cumulative rate of these cardiac end points
were reduced 34% in the gemfibrozil group (27.3 per 1,000 in the gemfibrozil group vs. 41.4 per 1,000 in the placebo group;
P< 0.02). The decrease in cardiovascular disease in the gemfibrozil group became evident in the second year and continued
throughout the remainder of the study. There was no difference in mortality between the gemfibrozil and placebo groups. The
benefit of gemfibrozil therapy was greatest in participants with elevated triglycerides and decreased HDL cholesterol levels
[184, 185]. Risk reduction with gemfibrozil was 78% (P = .002) among those with BMI > 26 kg/m2 and dyslipidemia
(triglycerides > ~200mg/dl and HDL cholesterol < 42mg/dl) suggesting that certain types of patients are likely to derive greater
benefit from fibrate treatment [186].

 Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT): VA-HIT was a double-blind trial in
men with coronary heart disease who had an HDL cholesterol level <40mg/dl and LDL cholesterol level <140mg/dl [149].
Subjects were randomized to gemfibrozil 1200mg per day (n=1264) or placebo (n=1267) for 5.1 years. Mean lipid levels at
study initiation were HDL cholesterol 32mg/dl, LDL cholesterol 111mg/dl, total cholesterol 175mg/dl, and triglycerides
160mg/dl. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent
lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL
cholesterol levels did not differ significantly between the groups. The primary study outcome was nonfatal myocardial
infarction or death from coronary causes. The primary outcome occurred in 21.7% of patients in the placebo group and 17.3%
of patients in the gemfibrozil group (22 percent decrease; P=0.006). A 24% reduction in the combined outcome of death from
coronary heart disease, nonfatal myocardial infarction, and stroke was observed in the gemfibrozil group (P< 0.001). There
were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any
cause, and cancer. Similar to HHS the beneficial effect of gemfibrozil did not become apparent until approximately two years
after treatment. A low HDL cholesterol (<33.5mg/dl) and high triglycerides (>180mg/dl) at baseline predicted a beneficial
response to gemfibrozil therapy [187].

 Bezafibrate Infarction Prevention Study (BIP): BIP was a double blind study in male and female patients aged 45-74 with a
previous myocardial infarction or stable angina [150]. Patients were randomized to receive either 400 mg of bezafibrate per
day (n=1548) or a placebo (n=1542) and were followed for 6.2 years. At the initiation of the study total cholesterol was
212mg/dl, LDL cholesterol was 148mg/dl, HDL cholesterol was 34.6mg/dl, and triglycerides were145mg/dl. Bezafibrate
increased HDL cholesterol by 18% and reduced triglycerides by 21%. There was a small 7% decrease in LDL cholesterol. The
primary end point was fatal or nonfatal myocardial infarction or sudden death. The primary end point occurred in 13. 6% of the
bezafibrate group vs. 15.0% of the placebo (9.4% reduction; P=0.26). Total and non-cardiac mortality rates were similar and
thus significant reductions in cardiovascular events were not observed in this study. However, in a post hoc analysis in the
 subgroup with high baseline triglycerides (> or =200 mg/dL), the reduction in the primary end point in the bezafibrate group
was 39.5% (P=0.02). Additionally, bezafibrate reduced cardiovascular events in patients with the metabolic syndrome [188].
These results again suggest that patients with high triglycerides are likely to derive benefit from fibrate therapy.

 Leader Trial: The Leader trial was a double blind placebo controlled randomized trial in 1568 men age 35 to 92 with lower
extremity arterial disease [189, 190]. Subjects were randomized to bezafibrate 400mg per day (n=783) or placebo (n=785). At
baseline total cholesterol levels were 218mg/dl, LDL cholesterol levels 132mg/dl, HDL cholesterol levels 44mg/dl, and
triglycerides 187mg/dl. Bezafibrate therapy reduced total cholesterol levels by 7.6%, LDL cholesterol by 8.1%, and
triglycerides by 23% and increased HDL cholesterol levels by 8%. The primary endpoint of coronary heart disease and strokes
was not reduced by bezafibrate treatment. Neither major coronary events nor strokes were significantly reduced.

 Fenofibrate Intervention and Event Lowering in Diabetes Trial (FIELD): In the FIELD Trial 9795 patients with Type 2
diabetes between the ages of 50 and 75 with or without pre-existing cardiovascular disease not taking statin therapy were
randomized to fenofibrate 200 mg daily (n=4895) or placebo (n=4900) and followed for approximately 5 years [152]. At
initiation of the study total cholesterol was 196mg/dl, LDL cholesterol was 120mg/dl, HDL cholesterol was 43mg/dl, and
triglycerides were 152mg/dl. Fenofibrate therapy resulted in an 11% decrease in total cholesterol, a 12% decrease in LDL
cholesterol, a 29% decrease in triglycerides, and a 5% increase in HDL cholesterol levels. The primary outcome was coronary
events (coronary heart disease death and non-fatal MI), which were reduced by 11% in the fenofibrate group but this difference
did not reach statistical significance (p= 0.16). However, there was a 24% decrease in non-fatal MI in the fenofibrate treated
group (p=0.01) and a non-significant increase in coronary heart disease mortality. Total cardiovascular disease events
(coronary events plus stroke and coronary or carotid revascularization) were reduced 11% (p=0.035). These beneficial effects
of fenofibrate therapy on cardiovascular disease were observed in patients without a previous history of cardiovascular disease.
In patients with a previous history of cardiovascular disease no benefits were observed. Additionally, the beneficial effect of
fenofibrate therapy was seen only in those subjects less than 65 years of age. The beneficial effects of fenofibrate in this study
may have been blunted by the increased use of statins in the placebo group, which reduced the differences in lipid levels
between the placebo and fenofibrate groups. If one adjusted for the addition of lipid-lowering therapy, fenofibrate reduced the
risk of coronary heart disease events by 19% (p=0·01) and of total cardiovascular disease events by 15% (p=0·004).
Additionally, many patients in the Field trial did not have elevations in triglycerides and decreased HDL cholesterol levels. In
a post hoc analysis, patients with high triglycerides 200mg/dl) and low HDL levels (40mg for men and <50mg/dl for women)
derived greater benefit from fenofibrate therapy [191].
  ACCORD LIPID Trial: The ACCORD-LIPID Trial was designed to determine if the addition of fenofibrate to aggressive
statin therapy would result in a further reduction in cardiovascular disease in patients with Type 2 diabetes [192]. In this trial,
5,518 patients on statin therapy were randomized to placebo or fenofibrate therapy. The patients had diabetes for
approximately 10 years and either had pre-existing cardiovascular disease or were at high risk for developing cardiovascular
disease. During the trial, LDL cholesterol levels were approximately 80mg/dl. There was only a small difference in HDL
cholesterol with the fenofibrate groups having a mean HDL cholesterol of 41.2mg/dl while the control group had an HDL
cholesterol of 40.5mg/dl. Differences in triglyceride levels were somewhat more impressive with the fenofibrate group having
a mean triglyceride level of 122mg/dl while the control group had a triglyceride level of 144mg/dl. First occurrence of nonfatal
myocardial infarction, nonfatal stroke, or death from cardiovascular causes was the primary outcome and there was no
statistical difference between the fenofibrate treated group and the placebo group. Additionally, there were also no statistically
significant differences between the groups with regards to any of the secondary outcome measures of cardiovascular disease.
Of note, the addition of fenofibrate to statin therapy did not result in an increase in either muscle or liver side effects. On
further analysis there was a suggestion of benefit with fenofibrate therapy in the patients in whom the baseline triglyceride
levels were elevated (>204mg/dl) and HDL cholesterol levels decreased (<34mg/dl). While this was a negative study, it must
be recognized that most of the patients included in this study did not have the lipid profile that would typically lead to
treatment with fibrates.

 Meta-Analyses: There have been two recent meta-analyses that have analyzed the effect of fibrates in the above studies and a
number of smaller studies on cardiovascular outcomes. Focusing on primary prevention patients, a meta-analysis identified six
studies with 16,135 individuals [193]. The mean treatment duration and follow-up of participants across trials was 4.8 years
and four trials included only individuals with Type 2 diabetes. Patients treated with fibrates had a significantly reduced risk for
the combined primary outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke compared to
patients on placebo (risk ratio (RR) 0.84, 95% CI 0.74 to 0.96). For secondary outcomes RRs for fibrate therapy compared
with placebo were 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92);
1.01 for overall mortality (95% CI 0.81 to 1.26), and 1.01 for non-CVD mortality (95% CI 0.76 to 1.35). Two studies that
evaluated fibrates combined with statin therapy showed no benefits in preventing cardiovascular events.

A separate meta-analysis has focused on the effect of fibrates on cardiovascular disease in patients with pre-existing disease
(secondary prevention) [194]. It included 13 trials involving a total of 16,112 participants. For the primary composite outcome of non-
fatal stroke, non-fatal myocardial infarction, and vascular death, fibrate therapy significantly decreased risk by 12% (risk ratio (RR)
0.88, 95% (CI) 0.83 to 0.94). Fibrates were moderately effective for preventing myocardial infarction (RR 0.86, 95% CI 0.80 to 0.93).
Fibrates were not effective in lowering all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06), death from vascular causes (RR 0.95, 95%
CI 0.86 to 1.05), or stroke events (RR 1.03, 95% CI 0.91 to 1.16). Since clofibrate has been discontinued due to safety concerns, the
data were reanalyzed excluding clofibrate trials. Without clofibrate, fibrates no longer significantly reduced the primary outcome (RR
0.90, 95% CI 0.79 to 1.03) but were still effective in preventing myocardial infarctions (RR 0.85, 95% CI 0.76 to 0.94). Subgroup
analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes
mellitus.

A meta-analysis of five fibrate trials analyzed patients who had both low HDL cholesterol levels (<35mg/dl) and elevated triglycerides
(>200mg/dl) [195]. In these five trials 4671 patients, (2401 treated with fibrates and 2270 in the placebo group) were included in this
analysis. In these patients with high triglyceride and low HDL cholesterol levels (atherogenic dyslipidemia phenotype) fibrates
reduced cardiovascular risk by 30% (P < 0.0001). In contrast in patients without dyslipidemia there was a non-significant 6% decrease
in cardiovascular risk (P = 0.13). These results strongly suggest that patients with elevated triglyceride levels and decreased HDL
cholesterol levels are more likely to benefit from fibrate therapy.

Summary: In reviewing this data certain conclusions can be reached. First, fibrate therapy has not been shown to markedly reduce
cardiovascular events either as monotherapy or when combined with statins. Second, many of the fibrate studies have not focused on
patients with the lipid profiles most likely to benefit from fibrate therapy. Third, when subgroup analyses were carried out, the patients
with high triglycerides and low HDL cholesterol levels appeared to benefit from fibrate therapy when used as monotherapy or when
combined with statins. Clearly additional studies are required that specifically focus on patients with high triglycerides and low HDL
cholesterol levels.

Effect of Fibrates on Non- Cardiovascular Outcomes

Diabetic Retinopathy: Small studies in the 1960’s presented evidence that treatment with clofibrate improved diabetic retinopathy
[196, 197]. Two large randomized have confirmed these observations.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a randomized trial in patients with Type 2 diabetes
mellitus. Patients were randomly assigned to receive either fenofibrate 200 mg/day (n=4895) or placebo (n=4900). Laser treatment for
retinopathy was significantly lower in the fenofibrate group than in the placebo group (3.4% patients on fenofibrate vs 4.9% on
placebo; p=0.0002) [198]. Fenofibrate therapy reduced the need for laser therapy to a similar extent for maculopathy (31% decrease)
and for proliferative retinopathy (30% decrease). In the ophthalmology sub-study (n=1012), the primary endpoint of 2-step
progression of retinopathy grade did not differ significantly between the fenofibrate and control groups (9.6% patients on fenofibrate
vs 12.3% on placebo; p=0.19). In patients without pre-existing retinopathy there was no difference in progression (11.4% vs 11.7%;
p=0.87). However, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than
did those on placebo (3.1% patients vs 14.6%; p=0.004). A composite endpoint of 2-step progression of retinopathy grade, macular
edema, or laser treatments was significantly reduced in the fenofibrate group (HR 0.66, 95% CI 0.47-0.94; p=0.022).

In the ACCORD Study a subgroup of participants were evaluated for the progression of diabetic retinopathy by 3 or more steps on the
Early Treatment Diabetic Retinopathy Study Severity Scale or the development of diabetic retinopathy necessitating laser
photocoagulation or vitrectomy over a four year period [199]. At 4 years, the rates of progression of diabetic retinopathy were 6.5%
with fenofibrate therapy (n=806) vs. 10.2% with placebo (n=787) (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P = 0.006). Of
note, this reduction in the progression of diabetic retinopathy was of a similar magnitude as intensive glycemic treatment vs. standard
therapy.

Taken together these results indicate that fibrates have beneficial effects on the progression of diabetic retinopathy [200]. The
mechanisms by which fibrates decrease diabetic retinopathy are unknown.

Diabetic Kidney Disease: The Diabetes Atherosclerosis Intervention Study (DAIS) evaluated the effect of fenofibrate therapy (n=
155) vs. placebo (n=159) on changes in urinary albumin excretion in patients with Type 2 diabetes [201]. Fenofibrate significantly
reduced the worsening of albumin excretion (fenofibrate 8% vs. placebo 18%; P < 0.05). This effect was primarily due to reduced
progression from normal albumin excretion to microalbuminuria (fenofibrate 3% vs. 18% placebo; P < 0.001).

In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, Type 2 diabetic patients (n = 9,795) aged 50 to 75 years
were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years [202]. Fenofibrate reduced urine
albumin/creatinine ratio by 24% vs 11% in placebo group (p < 0.001), with 14% less progression and 18% more albuminuria
regression (p < 0.001) in the fenofibrate group than in participants on placebo. As expected, fenofibrate therapy acutely increased
plasma creatinine levels and decreased eGFR [203]. However, over the long term, plasma creatinine rise was decreased in the
fenofibrate group compared to the placebo group (14% decrease; p=0.01). Similarly, there was a slower annual decrease in eGFR in
the fenofibrate group (1.19 vs 2.03 ml min(-1) 1.73 m(-2) annually, p < 0.001). End-stage renal disease, dialysis, renal transplant, and
renal death were similar in the fenofibrate and placebo groups.

In the ACCORD-LIPID trial, 5,518 patients on statin therapy were randomized to placebo or fenofibrate therapy [192]. The patients
had diabetes for approximately 10 years and either had pre-existing cardiovascular disease or were at high risk for developing
cardiovascular disease. The post-randomization incidence of microalbuminuria was 38.2% in the fenofibrate group and 41.6% in the
placebo group (p=0.01) and post-randomization incidence of macroalbumuria was 10.5% in the fibrate group and 12.3% in the
placebo group (p=0.04) indicating a modest reduction in the development of proteinuria in patients treated with fenofibrate [192].
There was no significant difference
in the incidence of end-stage renal disease or need for dialysis between the fenofibrate group and the placebo group.

These studies suggest that fibrates may have a beneficial effect on diabetic kidney disease [204]. One should recognize that reducing
proteinuria is a surrogate marker and may not indicate a reduction in the development of end stage renal disease. The mechanisms
accounting for decreased in proteinuria are unknown.

Amputations: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients aged 50-75 years with Type 2
diabetes were randomly assigned to receive fenofibrate 200 mg per day (n=4895) or matching placebo (n=4900) for 5 years' duration
[205]. The risks of first amputation was decreased by 36% (p=0.02) and minor amputation events without known large-vessel disease
by 47% (p=0.027) in the fenofibrate treated group [205]. The reduction in amputations was independent of glucose control or
dyslipidemia. No difference between the risks of major amputations was seen in the placebo and fenofibrate groups. The basis for this
reduction in amputations is unknown.

Summary: The above studies provide substantial evidence that fibrates have a favorable effect on diabetic microvascular disease
[151]. While fibrates are not approved specifically for the prevention or treatment of diabetic microvascular disease one should
consider these potential beneficial effects when deciding on treatment choices. For example, in a patient with diabetes and
microvascular disease and hypertriglyceridemia one might elect to use fibrates to lower plasma triglycerides given their potential
beneficial effects on slowing the progression of microvascular disease.

Side Effects

Renal: Fibrate therapy leads to an increase in serum creatinine levels [206]. For example, in the Field Trial serum creatinine levels
increased from 0.88mg/dl to 0.99mg/dl, a 12% increase [152]. This increase has been seen with all fibrates but appears to be less
profound with gemfibrozil [206]. It must be recognized that this increase in creatinine is reversible on stopping fibrate therapy and
does not reflect kidney damage [206]. In fact, careful measurements of renal function have not demonstrated a decrease in glomerular
filtration rate despite the increase in serum creatinine [203, 207, 208]. As discussed above, studies of renal function in patients with
diabetes actually suggests that treatment with fibrates may be protective. The precise mechanism by which fibrates increase serum
creatinine levels is unknown.

In patients with chronic renal disease fibrates should be used with caution and at lower doses [206]. Fibrates are all excreted by the
kidneys and thus the excretion of fibrates is decreased in patients with renal dysfunction [206]. Therefore one needs to adjust the
fibrate dose depending upon renal function. The National Kidney Foundation recommends the dose adjustments shown in Table 18
[209].
Table 18Fibrate Dose Adjustments in Renal Disease

No Kidney Disease GFR 30-60 GFR < 30 Kidney Transplant

Bezafibrate 400-600mg 200mg Avoid Avoid
Ciprofibrate 1000-2000mg ? Avoid Avoid
Fenofibrate 150-200mg 40-60mg Avoid Avoid
Gemfibrozil 1200mg 1200mg 600mg 600mg

Gallbladder Disease: It is clear that clofibrate increases the risk of gallbladder disease. In both the WHO trial and the Coronary Drug
Project, cholecystectomies occurred two to three times more often in the patients treated with clofibrate compared to placebo [43, 183,
210]. Whether gemfibrozil, fenofibrate, or other fibrates increases the risk of gallbladder disease is uncertain. In the large randomized
outcome studies presented earlier (Effect of fibrates on cardiovascular outcomes section) a statistically significant increase in either
gallbladder disease or cholecystectomies were not observed. However, in a sub-study of 450 Helsinki Heart Study participants a trend
toward a greater prevalence of gallstones during the study in the gemfibrozil group was observed (7.5% versus 4.9% for the placebo
group, a 55% excess for the gemfibrozil group) (Lopid Package Insert). A trend toward a greater incidence of gallbladder surgery was
also observed in the gemfibrozil group (17 versus 11 subjects, a 54% excess) (Lopid Package Insert). In a single epidemiological trial
fibrate treatment independently correlated with the presence of gallstones with a relative risk of 1.7 (p=0.04) [211].

All fibrates alter the composition of bile resulting in an increase in the concentration of cholesterol, which will predispose to the
formation of cholesterol gallstones [206]. In a comparison of clofibrate and gemfibrozil it was observed that clofibrate resulted in
changes in bile composition that would be more lithogenic than gemfibrozil [212].

The effect of combining fibrates with statins on the risk of gallbladder disease is unknown. An increased risk of gallbladder disease or
cholecystectomies was not reported in the ACCORD-LIPID trial where fenofibrate was added to statin therapy [192].

While it is clear that clofibrate increases the risk of gallbladder disease the effect of other fibrates either as monotherapy or in
combination with other drugs is less well defined.

Pancreatitis: In a meta-analysis of 7 fibrate trials involving 40,162 participants conducted over 5.3 years, 144 participants developed
pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P = .053) [213]. These observations
raise the possibility that fibrates may increase the risk of pancreatitis perhaps via increasing gallstone formation.
Cancer: A large meta-analysis of 17 randomized controlled trials, involving 44,929 participants, with an average follow-up of 5.2
years has examined if fibrates lead to an increased risk of cancer. No increase in either cancer incidence (RR = 1.02, 95% CI 0.92-
1.12) or cancer death (RR = 1.06, 95% CI: 0.92-1.22) was noted with fibrate treatment [214].

Muscle Disorders: Fibrate monotherapy has been reported to cause myopathy [206]. In a large epidemiological study the incidence of
hospitalization for rhabdomyolysis per 10,000 person-years for monotherapy with a fibrate was 2.82 (95% CI, 0.58-8.24) while in
patients not exposed to lipid lowering drugs the incidence was 0 (95% CI, 0-0.48) [215]. The risk of rhabdomyolysis was greater with
gemfibrozil therapy than with fenofibrate. Interestingly the incidence of rhabdomyolysis was greater for patients treated with fibrate
monotherapy than for patients treated with statin monotherapy (incidence for atorvastatin, pravastatin, or simvastatin was only 0.44
per 10,000 person-years). In an epidemiological study focusing on myopathy similar results were observed [216]. The relative risks of
myopathy in current users of fibrates and statins compared with nonusers were 42.4 (95% CI = 11.6-170.5) and 7.6 (95% CI = 1.4-
41.3), respectively. It should be recognized though that in large randomized clinical trials the risk of muscle symptoms was low in
patients treated with fibrates and not dissimilar to that seen in the patients treated with placebo [206]. For example, in the Helsinki
Heart Study over 2000 patients were treated and in the VA-HIT over 1000 patients were treated with gemfibrozil for five years and no
cases of myopathy were reported in either trial [148, 149]. In the Bezafibrate Infarction Prevention Study, seven patients in the
placebo group and five patients in the bezafibrate group reported muscle pain, while CPK levels greater than 2x the upper range of
normal was seen in four patients in the bezafibrate group and one patient in the placebo group [150]. Finally, in the Field Trial,
patients with diabetes were treated with fenofibrate (n=4895) or placebo (n=4900) [152]. Myositis was observed in one patient treated
with placebo and two patients treated with fenofibrate while rhabdomyolysis was observed in one patient treated with placebo and
three patients treated with fenofibrate. Elevations in CPK levels values > 10x the upper range of normal were seen in three patients on
placebo and 4 patients treated with fenofibrate. Thus, while fibrates can lead to significant muscle dysfunction this is a relatively rare
event and appears to occur only slightly more often in patients treated with a fibrate than in patients treated with a placebo. The risk of
serious muscle disease appears to be increased in patients with renal failure, hypothyroidism, and in the elderly [206]. The mechanism
by which fibrates predispose to muscle disorders is unknown.

The effect of fibrates in combination with statins on muscle disorders will be discussed in detail in the section on drug interactions.

Drug Interactions

Statins: The combination a fibrate and a statin may increase the risk of developing muscle symptoms [206]. The degree of risk is
dependent on both the specific statin and the specific fibrate that is being used in combination [206]. For example, the average
incidence per 10,000 person-years for hospitalization for rhabdomyolysis with monotherapy with atorvastatin, pravastatin, or
simvastatin was 0.44 (95 % CI, 0.20-0.84); with fibrate alone was 2.82 (95% CI, 0.58-8.24); and with combined therapy of
atorvastatin, pravastatin, or simvastatin with a fibrate was 5.98 (95% CI, 0.72-216.0) [215]. Of note, the average incidence per 10,000
person-years for hospitalization for rhabdomyolysis with the combination of cerivastatin with a fibrate was 1035 (95% CI, 389-2117),
clearly demonstrating an increased risk of the cerivastatin-fibrate combination compared to other statin-fibrate combinations [215]. A
study by Alsheikh-Ali and colleagues looking at cases of rhabdomyolysis reported to the FDA relative to the total number of
prescriptions reached the conclusion that the combination of cerivastatin with a fibrate markedly increased the risk of this
complication [217]. Additionally, it was noted that the risk of rhabdomyolysis was greater with gemfibrozil compared to fenofibrate
and that the combination of cerivastatin and gemfibrozil was particularly toxic [217]. Other studies have also noted a marked risk with
the combination of cerivastatin and gemfibrozil [218]. Cerivastatin is no longer available.

Studies comparing the risk of rhabdomyolysis with gemfibrozil-statin combination therapy compared to fenofibrate-statin combination
therapy have shown an increased risk with gemfibrozil [206]. For example, the number of cases of rhabdomyolysis reported with
fenofibrate and statins other than cerivastatin was 0.58 per million prescriptions whereas with gemfibrozil and statins other than
cerivastatin was 8.6 per million prescriptions [219]. Reviews of the FDA’s adverse events reporting system database have estimated
that the risk of myopathy for the combination of gemfibrozil with a statin was much greater than the risk with the combination of
fenofibrate with a statin [217, 219]. Additionally, studies that employed the combination of gemfibrozil and statins have reported a
significant occurrence of muscle related symptoms whereas studies of fenofibrate in combination with statins have not shown an
increase in muscle related symptoms [206]. For example, the rate of myopathy in over 4000 patients taking lovastatin was only 0.4%
but in patients on the combination of lovastatin and gemfibrozil the frequency increased to 5% [220]. In contrast, in the ACCORD-
LIPID Trial over 5000 patients on statin therapy were randomized to fenofibrate or placebo for 4.7 years and no increase in the
incidence of muscle related symptoms was observed with fenofibrate therapy [192]. Similarly, in the Field Trial approximately 1000
patients were taking fenofibrate and a statin and with 5 years of follow-up no cases of rhabdomyolysis were reported [152]. Finally, a
meta-analysis by Geng and colleagues identified 13 randomized trials with 7,712 patients receiving combination fenofibrate-statin
therapy compared with statin therapy alone [163]. The incidence of elevated creatine kinase levels, muscle-associated adverse events,
or withdrawals attributed to muscle dysfunction did not differ significantly between the fenofibrate + statin patients vs. the statin alone
patients [163]. The American College of Cardiology and American Heart Association Guidelines recommend against using the
combination of a statin and gemfibrozil but recognize that the use of a statin and fenofibrate is appropriate under certain circumstances
[221].

The increased risk of combining gemfibrozil with statins is due to alterations in statin metabolism leading to increases in the serum
levels of statins and hence an increased risk of myopathy [206, 222]. In contrast, fenofibrate does not alter statin metabolism and
therefore can be safely combined with statins (Table 19) [222].

Table 19Effect of Fibrates on Statin Pharmacokinetics [206, 222, 223]

 Statin Gemfibrozil Fenofibrate
Atorvastatin Increase in C-Max by 1.5 Fold No Change
Simvastatin Increase in C-Max by 2 Fold No Change
Pravastatin Increase in C-Max by 2 Fold No Change
Rosuvastatin Increase in C-Max by 2 Fold No Change
Lovastatin Increase in C-Max by 2.8 Fold No Change
Pitavastatin Increase in C-Max by 41% Unknown
Fluvastatin No Change No Change

The explanation for the difference between gemfibrozil and fenofibrate is that gemfibrozil uses the same family of glucuronidation
enzymes as the statins thereby inhibiting statin metabolism [206, 224]. In contrast, fenofibrate uses a different family of
glucuronidation enzymes and does not inhibit statin metabolism [206].

Coumadin Anti-Coagulants: Gemfibrozil and fenofibrate can potentiate the effect of coumadin anti-coagulants leading to a
prolongation of prothrombin time and an increased risk of bleeding. When starting a fibrate in patients on coumadin therapy the dose
of coumadin should be decreased and prothrombin times should be closely monitored (Lopid and Tricor Package Inserts).

Repaglinide: Gemfibrozil in combination with rapaglinide increases blood levels of rapaglinide and therefore this combination should
not be used because of the increased risk of hypoglycemia (Lopid Package Insert).

Contraindications

Fibrates are contraindicated in patients with severe hepatic dysfunction. Additionally, patients with pre-existing gallstones should not
be treated with fibrates. Fenofibrate and gemfibrozil are pregnancy category C drugs and should only be used if the potential benefit
justifies the potential risk to the fetus.

Conclusions

Fibrates are effective drugs in reducing triglyceride levels and modestly increase HDL cholesterol levels. Additionally, they also
reduce LDL cholesterol and non-HDL cholesterol levels. Fibrates have a number of side effects and one should avoid using
gemfibrozil in combination with statins. In contrast, fenofibrate can be used in combination with statins. Monotherapy with fibrates
appears to reduce cardiovascular events particularly in patients with high triglyceride and low HDL cholesterol levels. Whether the
addition of fibrates to statin therapy will reduce cardiovascular disease is uncertain. In patients with diabetes fibrates appear to slow
the progression of microvascular disease. Finally, fibrates are effective in lowering triglycerides in patients with marked
hypertriglyceridemia and while not proven will likely reduce the risk of the development of pancreatitis.

Go to:

ALIPOGENE TIPARVOVEC (GLYBERA)

Introduction

Alipogene tiparvovec is a gene therapy approved in Europe for adult patients with Familial Lipoprotein Lipase deficiency and a
history of multiple or severe episodes of pancreatitis who have failed dietary therapy [225]. The diagnosis of Familial Lipoprotein
Lipase with loss of function mutations must be confirmed by genetic testing but patients need to have detectable levels of lipoprotein
lipase protein (to avoid immunological reactions) [225]. Alipogene tiparvovec is an adeno-associated virus gene therapy that results in
the expression of the naturally occurring S447X variant of the human lipoprotein lipase gene that has increased lipoprotein lipase
activity compared to “normal” lipoprotein lipase [225]. Approximately 20% of Caucasians express this gene variant and these
individuals have lower plasma triglyceride levels and an increase in HDL cholesterol levels [226, 227].

Effect of Alipogene Tiparvovec on Lipid and Lipoprotein Levels

In patients with plasma triglyceride levels > 880mg/d, treatment with alipogene tiparvovec resulted in an approximately 40% decrease
in fasting plasma triglycerides with half of the patients having > 40% decrease in fasting plasma triglyceride levels at 3-12 weeks post
treatment [228]. By week 16-26, fasting triglyceride levels returned to baseline values but chylomicron levels were reduced [228].
While fasting triglyceride levels returned to baseline, postprandial triglyceride levels were reduced by approximately 60% suggesting
that there are long term effects that are not reflected by fasting triglyceride levels [229]. In fact, in some patients treated with
alipogene tiparvovec, lipoprotein lipase expression was demonstrated in muscle biopsies at 26 weeks [228].

Mechanisms Accounting for the Alipogene Tiparvovec Induced Lipid Effects

Gene therapy with alipogene tiparvovec results in the expression of lipoprotein lipase in muscle, which accelerates the clearance of
chylomicrons [225, 228]. Studies have demonstrated a reduced peak level and a reduced area under the curve for postprandial
chylomicrons [229].
Drug Administration and Pharmacokinetics

Alipogene tiparvovec is administered by multiple intramuscularly injections in the legs given at a single visit [225]. The number of
injections is > 40 and therefore the injections are given under spinal anesthesia [228]. From 3 days before administration until 12
weeks after administration patients may be treated with cyclosporine (3mg/kg/day) and mycophenolate (2g/day) and on the day of
administration methylprednisolone 1mg/kg) may be administered IV [225, 228].

Effect on Clinical Outcomes

In patients with Familial Lipoprotein Lipase Deficiency the outcome of interest is pancreatitis. In a retrospective study of 19 patients
treated with alipogene tiparvovec an approximate 50% decrease in pancreatitis was observed [230]. In addition, patients treated with
alipogene tiparvovec have reported benefits including increased energy and the ability to liberalize their diet, which is difficult to
comply with due to the marked limitation in dietary fat [228].

Conclusions

Alipogene tiparvovec may be useful treatment for the rare patient with Familial Lipoprotein Lipase deficiency. Because of the rarity of
this disorder the information on patients treated with this drug is limited and randomized trials are impossible.

Go to:

CLINICAL USE OF TRIGLYCERIDE LOWERING DRUGS

Marked Hypertriglyceridemia (>500mg/dl); Prevention of Pancreatitis

In patients with marked elevations in triglyceride levels (>500-1000mg/dl) the major concern is an increased risk of pancreatitis [231,
232]. Because of this increased risk it is imperative to lower triglyceride levels. The initial steps are to 1) treat any disease states that
could be leading to an elevation in plasma triglyceride levels, 2) if possible discontinue any drugs that could be leading to an elevation
in plasma triglycerides, and 3) initiate lifestyle changes (Table 19).

Table 19Causes of Secondary Hypertriglyceridemia

 Lifestyle Diseases Medications
Excess calories Poorly controlled diabetes Corticosteroids
Excess dietary fat intake Hypothyroidism Oral estrogen
Excess simple sugars Renal disease Retinoic acid derivatives
Overweight/Obesity HIV infection Beta adrenergic blockers
Alcohol intake Cushing’s syndrome Thiazide diuretics
Pregnancy Acromegaly Protease inhibitors
Growth hormone deficiency Bile acid sequestrants
Lipodystrophy Anti-psychotic drugs
Paraproteinemia Cyclosporine/tacrolimus
Nephrotic Syndrome L-asparaginase
Interferon alpha 2b
Cyclophosphamide

These initial steps are often sufficient to result in marked reductions in plasma triglyceride levels eliminating the need for triglyceride
lowering medications. For example, in patients with diabetes in very poor glycemic control, treatment that results in good glycemic
control can markedly lower triglyceride levels [233]. Similarly, the restoration of euthyroidism in a hypothyroid patient can also
markedly lower lipid levels [234]. If these initial steps do not result in a lowering of triglycerides into an acceptable range then the use
of drugs to lower plasma triglyceride levels is indicated. There have been no randomized controlled trials demonstrating that treatment
diminishes pancreatitis but most experienced clinicians believe that lowering triglyceride levels to below 500-1000mg/dl reduces the
risk of developing pancreatitis [231, 232]. The addition of either fibrates or fish oil to lifestyle changes are commonly used to lower
markedly elevated triglyceride levels. In some patients combination therapy is required to lower plasma triglycerides to an acceptable
range.

Moderate Hypertriglyceridemia (150-500mg/dl); Prevention of Cardiovascular Disease

In the era of statin therapy it is uncertain whether adding triglyceride lowering drugs to statins will further reduce cardiovascular
events. As discussed in detail in the sections on individual drugs, the studies carried out so far have not clearly shown that adding
niacin, fish oil, or fibrates to statin therapy is beneficial with regards to cardiovascular disease. As also discussed the available studies
have major limitations because many of the patients in these outcome studies did not have substantial elevations in triglycerides and
therefore the issue is an open question that requires additional studies. Some guidelines use non-HDL cholesterol as a therapeutic goal
and thus the use of niacin, fish oil, and fibrates will often be required to lower triglyceride levels to achieve these non-HDL cholesterol
goals [232]. In contrast, other guidelines focus on LDL cholesterol levels and the use of statins and thus de-emphasize the use of
niacin, fish oil, and fibrates [235]. Given the absence of definitive data one needs to use ones clinical judgement. We will often add
either fenofibrate or fish oil in high risk patients when statins have lowered the LDL cholesterol levels to goal but the non-HDL
cholesterol levels are well above goal due to elevated triglyceride levels (>200mg/dl). We are more likely to add fibrates and fish oil
when the HDL cholesterol levels are also low. Consideration should also be given to the use of fenofibrate in hypertriglyceridemic
patients with diabetes at high risk for microvascular disease given the studies that have shown that fibrates reduce the microvascular
complication of diabetes. Because of the side effects of niacin our use of niacin to lower triglyceride levels has diminished. In the past
we used to use niacin to lower both LDL cholesterol levels and triglycerides but with the availability of ezetimibe and PCSK9
inhibitors the need to use niacin to lower LDL cholesterol levels has decreased.

Go to:

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