CME
Lipoprotein abnormalities in patients with
type 2 diabetes and metabolic syndrome
Tania Dickson-Humphries, MPAS, PA-C; B. Bottenberg, DO, FACOI, FNLA; Susan Kuntz, PhD
Tania Dickson-Humphries is a PA in vascular surgery for Carson
Surgical Group in Carson City, Nevada, and a recent graduate of the
University of North Dakota PA program. B. Bottenberg practices
internal medicine and lipidology in Carson City, Nevada, and is
president-elect of the Pacific Lipid Association. Susan Kuntz is
an assistant professor in the department of family and community
medicine in the PA program at the University of North Dakota at Grand
Forks. The authors have indicated no relationships to disclose relating to
the content of this article.
DOI: 10.1097/01.JAA.0000431506.00627.be
Copyright 2013 American Academy of Physician Assistants
JAAPA Journal of the American Academy of Physician Assistants
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
ABSTRACT
Cardiovascular disease remains the leading cause of death in
men and women in the United States. Aggressive treatment
of insulin resistance and its associated lipid abnormalities
remains a top priority for preventing cardiovascular morbid-
ity and mortality.
Keywords: type 2 diabetes, metabolic syndrome, cardiovas-
cular disease, atherogenic dyslipidemia, insulin resistance
Learning objectives
Describe the pathophysiology of lipoprotein metabolism.
Identify the 2012 ADA criteria for screening for diabetes
and dyslipidemia in adults.
Discuss strategies to aggressively treat lipoprotein abnor-
malities in patients with type 2 diabetes and metabolic
syndrome.
In 2010, according to the Centers for Disease Control and
Prevention, 25.6 million people (11.3% of the US adult
population) had type 2 diabetes. About 79 million adults
(35% of the adult population) had insulin resistance or
pre-diabetes. Patients with pre-diabetes have an impaired
fasting glucose or impaired glucose tolerance but do not meet
the clinical criteria for diabetes. The total annual estimated
cost of treatment for these conditions exceeds $174 billion.1
Diabetes is an independent risk factor for cardiovascular
disease (CVD). Diabetic dyslipidemia is a well-recognized
and modifiable risk factor that must be identified and treated
aggressively to reduce the associated cardiovascular risk
in this population. Key diagnostic findings include lipid
abnormalities commonly seen in patients with metabolic
syndrome: triglycerides of 150 mg/dL or higher; small, dense
low-density lipoprotein (LDL); and reduced high-density
lipoprotein (HDL) levels (less than 40 mg/dL in men and less
than 50 mg/dL in women).2,3 This triad of lipid abnormali-
ties is commonly referred to as atherogenic dyslipidemia.
According to the American Diabetes Association (ADA)
2012 guidelines, LDL cholesterol remains the primary
target of therapy.4
In patients with triglycerides over 200 mg/dL, non-HDL
cholesterol becomes a secondary target of therapy. When
www.JAAPA.com 13
CME
Key points
Cardiovascular disease is the leading cause of death
in men and women in the United States. Aggressive
treatment of insulin resistance and dyslipidemia can
reduce patients risk of cardiovascular morbidity and
mortality.
Asymptomatic adults who are overweight and have one or
more risk factors should be screened for diabetes.
Therapeutic lifestyle changes are first-line therapy for type
2 diabetes, insulin resistance, and dyslipidemia, followed
by phamacologic therapy if indicated.
A small, dense LDL phenotype is found in patients with
insulin resistance, metabolic syndrome, or type 2 diabetes.
triglycerides exceed 500 mg/dL, they become a primary
target of therapy in order to prevent pancreatitis.3
Healthcare providers should aggressively treat blood
glucose levels to the ADA goals in order to facilitate the
management of atherogenic dyslipidemia and decrease
the risk of CVD and pancreatitis in patients with type
2 diabetes or insulin resistance/metabolic syndrome.
Therapeutic lifestyle changes remain the primary treat-
ment option in nearly all cases. Pharmacologic therapy
is often required.
PATHOPHYSIOLOGY OF LIPOPROTEIN METABOLISM
Lipids are carried by lipoprotein particles categorized by
their individual densities. The outer portion of a lipoprotein
particle contains various proteins enabling it to carry hydro-
phobic lipid particles through the bloodstream. In general,
lipoprotein particles include triglyceride-rich chylomicrons,
very-low-density lipoprotein (VLDL), intermediate-density
lipoprotein (IDL), LDL, and HDL. Each particle has a dis-
tinct chemical composition that determines its atherogenic
or anti-atherogenic properties. Lipoprotein particles that are
atherogenic include chylomicrons, VLDL, IDL, LDL, and
their metabolic remnants. HDL is the only anti-atherogenic
TABLE 1. Function, chemical composition, and density of lipoproteins5,7,16
Lipoprotein Composition
Triglyceride (%) Cholesterol (%)
Chylomicrons 80-90 2-7
HDL 5-12 15-25
IDL 20-50 20-40
VLDL 55-80 5-15
LDL 5-15 40-50
14 www.JAAPA.com
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
particle.5 The function and chemical composition of lipo-
proteins are shown in Table 1.
The membranes surrounding lipoprotein particles include
a number of proteins that attach to specific uptake recep-
tors, affecting the solubility and transport properties of
the particles as well as their effect on enzyme activation
and inhibition.
Apo A1 is the major apolipoprotein of HDL. The primary
functions of Apo A1 are to promote cholesterol efflux from
peripheral tissues and to facilitate lecithin-cholesterol acyl-
transferase (LCAT), an enzyme involved in the metabolism
of cholesterol.
Apo B is primarily found in chylomicrons from intes-
tinal absorption and VLDL produced by the liver. Apo
B-100 is a structural component of VLDL, IDL, and LDL
particles.5 Apo B-48 is formed from Apo B-100 and is
required for the synthesis of chylomicrons in the small
intestine. Chylomicrons transport exogenous lipids from
the intestines to other body tissues such as the liver, muscle,
and adipose tissue.
Apo C is a component of chylomicrons, VLDL, IDL,
and HDL particles. Functions include the inhibition of
the uptake of chylomicrons and VLDL remnants by the
liver and activation/inhibition of lipoprotein lipase (LPL).
Apo E is found on chylomicrons, VLDL, IDL, and HDL
particles, and functions as a ligand to bind various lipo-
proteins to the LDL receptor.6
Lipoprotein particles are metabolized by various enzymes
including LPL, LCAT, hepatic lipase, and cholesterol ester
transfer protein (CETP). Three major pathways of lipid
metabolism have been identified: the endogenous and
exogenous pathways, and reverse cholesterol transport.5
The exogenous pathway begins with the digestion and
absorption of dietary fats, triglycerides, and cholesterol.
These products are placed into chylomicrons and are trans-
ported through the lymphatic system into the blood. In
adipose tissue, heart, and skeletal muscle, LPL breaks down
chylomicrons to liberate the free fatty acids, apolipoprotein,
phospholipids, and free cholesterol, leaving a chylomicron
Density(g/mL) Function
Apoproteins
Apo B, A, C, E < 0.95 Transports exogenous
triglyceride
Apo A,C,E 1.063-1.210 Transports cholesterol
from the cells to the liver
Apo B,C,E 1.006-1.019 Transports triglyceride
and cholesterol
Apo B,C,E <1.006 Transports exogenous
triglyceride
Apo B 1.019-1.063 Transports cholesterol to
the cells
Volume 26 Number 7 July 2013
 Lipoprotein abnormalities in patients with type 2 diabetes and metabolic syndrome

remnant. These free fatty acids can then be used as an

energy source by peripheral tissue or stored by peripheral
cells as triglyceride. They also may be transported to the
liver and prepackaged as VLDL. Chylomicron remnants
containing large amounts of cholesterol esters and Apo
E bind to the LDL receptor and are removed by the liver.
The endogenous pathway, also called the hepatic path-
way, is active during the fasting state, and involves the
production of VLDL particles by the liver. During normal
cholesterol metabolism, VLDL particles are metabolized by
LPL and hepatic lipase into free fatty acids, apolipoproteins,
phospholipids, and free cholesterol (Figure 1). The VLDL
particles then become IDL and eventually LDL particles.5
During this process, CETP increases the cholesterol con-
tent of IDL. HDL particles pick up cholesterol from the
peripheral tissue and deliver it to the liver for removal. This
uptake of cholesterol by the liver from the HDL particle
is part of the HDL reverse cholesterol transport system.
Because HDL has the ability to transport cholesterol from
FIGURE 1. Normal cholesterol metabolism
the cells back to the liver, higher HDL cholesterol levels
decrease a persons risk of CVD.5
In patients with insulin resistance, the normal metabolism
of LDL is inhibited, LPL becomes inhibited, and CETP is
more active. In this situation, triglycerides and cholesterol
are exchanged between the HDL and VLDL particles by the
enzyme CETP. Triglyceride-rich VLDL become triglyceride-
depleted and cholesterol-enriched. In turn, the cholesterol-
rich HDL and LDL particles become cholesterol-depleted
and triglyceride-enriched. The result is a large number of
small, dense, atherogenic LDL particles.7
The triglyceride-rich and cholesterol-depleted HDL par-
ticles lose Apo A1 and are unable to participate in reverse
cholesterol transport. Apo A1 is eventually excreted by
the kidneys and lost (Figure 2).

SCREENING
The 2012 ADA guidelines include criteria for screening
asymptomatic adults for diabetes and pre-diabetes. The
ADA recommends that healthcare providers consider
testing asymptomatic adults who are overweight (defined
as a BMI of 25 kg/m2 or greater) and have one or more of
these risk factors:
physical inactivity
first-degree relative with diabetes
high-risk race or ethnicity (African American, Latino,
Native American, Asian American, Pacific Islander)
delivering a baby weighing more than 9 lbs or a diagnosis
of gestational diabetes (women)
hypertension (defined as a BP of 140/90 mm Hg or greater,
or taking antihypertensive medication)
HDL cholesterol of 35 mg/dL or less, and/or a triglyceride
level greater than 250 mg/dL
polycystic ovary syndrome (in women)
A1C of 5.7% or greater, impaired glucose tolerance, or
impaired fasting glucose on previous testing
FIGURE 2. Cholesterol metabolism in patients with insulin
resistance and dyslipidemia
other clinical conditions that may indicate insulin resis-
tance, such as morbid obesity or acanthosis nigricans
history of CVD.4
Overweight patients without any of the above risk
factors should begin diabetes testing at age 45. Patients
who dont meet the definition of pre-diabetes should be
monitored every 3 years; those with pre-diabetes should
be monitored annually.3
DIAGNOSING METABOLIC SYNDROME AND
TYPE 2 DIABETES
Metabolic syndrome is recognized and defined by the Adult
Treatment Panel (ATP) III guidelines from the National

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CME
Cholesterol Education Program (NCEP) as a cluster of
risk factors. Three of these risk factors are required for
the diagnosis of metabolic syndrome:
abdominal obesity, defined as a waist circumference of
more than 40 inches (102 cm) in men and more than 35
inches (88 cm) in women
elevated triglycerides, defined as 150 mg/dL or greater
low HDL, defined as less than 40 mg/dL in men and less
than 50 mg/dL in women
BP of 130/85 mm Hg or higher
fasting glucose of 110 mg/dL or higher.3
According to the ADA guidelines, type 2 diabetes can be
diagnosed using the classic symptoms of hyperglycemia,
or using an A1C, fasting blood glucose, or an oral glucose
tolerance test (Table 2). The ADA also has added a category
of increased risk for diabetes or pre-diabetes (Table 3).3
Patients with insulin resistance, metabolic syndrome,
or type 2 diabetes have the following lipid abnormalities:
triglycerides of 150 mg/dL or greater, and HDL choles-
terol of less than 40 mg/dL in men and less than 50 mg/
dL in women. This is associated with a small, dense LDL
phenotype.2
DYSLIPIDEMIA SCREENING AND DIAGNOSIS
The ADA guidelines recommend that most adults be screened
annually using a fasting lipid profile. If the lipid profile is
normal, patients may be monitored every two years.4
LDL cholesterol is calculated using Friedwalds for-
mula. In patients with elevated triglycerides, this formula
becomes less accurate, and may grossly underestimate
LDL cholesterol.8
Triglycerides are classified as borderline high (150 to
199 mg/dL), high (200 to 499 mg/dL), and very high
(500 mg/dL and greater).9
TREATMENT OPTIONS: LIFESTYLE CHANGES
Therapeutic lifestyle changes are considered first-line
therapy in nearly all cases of type 2 diabetes, metabolic
syndrome or insulin resistance, and atherogenic dyslipid-
emia. Lifestyle changes include smoking cessation, increased
physical activity, weight loss, decreased alcohol intake,
and dietary modification. The patient will need intensive
nutritional counseling focusing on decreasing high-glycemic
carbohydrates and foods high in fructose. Increasing soluble
fiber and plant sterols or stanols may also be beneficial.10
Patients can decrease their triglyceride levels by as much
as 20% with a modest weight loss of 5% to 10%.9
Moderate physical activity is known to provide beneficial
health effects. In patients with diabetes or insulin-resistant
dyslipidemia, moderate to intensive activity in addition to
dietary modification and caloric reduction provides the
greatest benefit.9
Patients with triglyceride levels of 150 to 199 mg/dL do
not need pharmacological therapy unless they also have
elevated LDL cholesterol. If the patients triglycerides remain
16 www.JAAPA.com
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TABLE 2. Criteria for the diagnosis of diabetes4
The patient must have one of the following criteria:
A1C of 6.5% or greater. The test should be performed in a
laboratory using a method that is National Glycohemoglobin
Standardization Program-certified and standardized to the
Diabetes Control and Complications Trial assay.
Fasting plasma glucose of 126 mg/dL or greater. Fasting is
defined as no caloric intake for at least 8 hours.
Two-hour plasma glucose of 200 mg/dL or greater during
an oral glucose tolerance test. Per WHO, the recommended
glucose load is 75 grams of anhydrous glucose dissolved
in water.
Random plasma glucose of 200 mg/dL or greater in a pa-
tient with classic symptoms of hyperglycemia or hypergly-
cemic crisis.
If the patient does not have unequivocal hyperglycemia,
confirm the first three criteria with repeat testing.
TABLE 3. Category of increased risk of diabetes4
The patient must have one of these criteria:
Fasting plasma glucose of 100 to 125 mg/dL. Fasting is
defined as no caloric intake for at least 8 hours.
Two-hour plasma glucose of 140 to 199 mg/dL following
the 75-gram oral glucose tolerance test.
A1C of 5.7% to 6.4%.
at 200 to 499 mg/dL despite lifestyle changes, consider
adding pharmacologic treatment.10
TREATMENT OPTIONS: DRUGS
Metformin Unless contraindicated, metformin is initiated
when the patient is diagnosed with type 2 diabetes, and
can be continued when basal insulin is started.4 Metformin
is considered weight-neutral without high risk of hypo-
glycemia even with long-term therapy. Gastrointestinal
adverse reactions are most common; the drug carries
a black-box warning about avoiding use in patients at
risk for lactic acidosis. Metformin is less effective than
fenofibrate or diet-controlled reduction of triglycerides,
but it may be safer and more tolerable in patients with
insulin resistance. In the randomized control trial by Wan
and colleagues, metformin showed a 40.6% reduction in
hypertriglyceridemia.11
Insulin If blood glucose control is not achieved with life-
style changes and metformin, insulin may be prescribed.4
Insulin activates insulin receptors, increasing glucose uptake
and decreasing hepatic glucose production. Therapy carries
a risk of hypoglycemia and weight gain, and some patients
are extremely reluctant to use insulin. Most patients with
type 2 diabetes who need insulin can be successfully treated
with basal insulin alone. Those who continue to remain
uncontrolled may also need rapid-acting prandial glucose.12
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 Lipoprotein abnormalities in patients with type 2 diabetes and metabolic syndrome
Omega-3 fatty acids The beneficial effect of EPA/DHA
in lowering triglycerides has only been demonstrated using
omega-3 derived from marine sources. The AHA recom-
mends 2 to 4 grams of EPA plus DHA per day for triglycer-
ide reduction. For every 1 gram of EPA/DHA, triglycerides
are reduced 5% to 10%. The accompanying effects are
increased LDL and HDL cholesterol.9 Supplementation
often is required, because achieving the required 2 to 4
grams solely from dietary intake is difficult.9
Fibrates Fenofibrate inhibits the synthesis of triglyc-
erides and stimulates the catabolism of triglyceride-rich
lipoproteins. The FIELD trial showed a 22% reduction in
triglycerides but also reported an increase in pancreatitis.13
Wan and colleagues found that fenofibrate decreased
triglycerides by 63% but caused significant adverse
reactions, including liver damage, GI intolerance, and
rhabdomyolysis.11 A 2010 review by Moutzouri and col-
leagues found that fenofibrate as monotherapy decreased
triglycerides by 20% to 50% and also increased HDL
cholesterol.14
The most common adverse reactions to fenofibrate are
nausea, diarrhea, myalgia, and moderate increases in cre-
atinine kinase. Patients who also are taking a statin during
fenofibrate therapy are at increased risk for myalgia and
rhabdomyolysis.14
Niacin This drug is most effective when used to raise
HDL cholesterol. At high doses, niacin can make blood
glucose control more difficult by increasing blood glucose
levels. At modest doses (750 to 2,000 mg/day), niacin can
improve LDL, HDL, and triglyceride levels with minimal
effects on blood glucose.4
Statins HMG-CoA reductase inhibitors have been shown
to reduce LDL cholesterol by 30% to 40%.4 Higher initial
triglyceride levels respond well to statin therapy, provid-
ing a 10% to 52% reduction. Numerous studies support
the use of statins for hypertriglyceridemia, but few trials
address the effect of statins on severe hypertriglyceridemia.10
The most common adverse reactions to statin therapy are
pain, pharyngitis, myalgia, and headache. The STELLAR
trial reported that patients on higher statin doses were at
the greatest risk for myalgia.15
Combination therapy To achieve optimal glycemic control,
combination therapy may be required.4 Statins in combi-
nation with niacin or fibrate may be beneficial in treating
LDL, HDL, and triglycerides, but can potentially increase
transaminase levels and increase the risk of myositis and
rhabdomyolysis. The risk of rhabdomyolysis is greater
with higher statin doses and in patients with poor renal
function. This risk decreases when a statin is combined
with fenofibrate instead of gemfibrozil.
CURRENT TREATMENT GUIDELINES
The ADA recommends the following glycemic goals for
patients with diabetes: A1C of less than 7%, preprandial
plasma glucose of 70 to 130 mg/dL, and peak postprandial
JAAPA Journal of the American Academy of Physician Assistants
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plasma glucose (1 to 2 hours after beginning a meal) of
less than 180 mg/dL.4
The ADA-recommended medical nutrition therapy should
begin with consultation with a registered dietitian, and
may include:
weight loss for patients who are overweight or obese
a low-carbohydrate, low-fat, calorie-restricted, or
Mediterranean diet for short-term (2 years) weight loss.
Monitor lipid profiles, renal function, and protein intake
for patients on low-carbohydrate diets.
Most patients with type 2
diabetes who need insulin can
be successfully treated with
basal insulin alone.
primary prevention steps including a 7% weight loss, 150
minutes per week of moderate physical activity (50%-70%
of maximum heart rate) over 3 days per week, resistance
training, diet containing 14 grams of fiber per 1,000 kcal,
and limiting sugar-sweetened beverages.
management including an individualized macronutrient
prescription, diet containing less than 7% saturated fat,
and minimizing trans-fat intake.
limiting daily alcohol intake to 1 drink (adult women)
and 2 drinks (adult men).4
The goal of the ADAs recommended dyslipidemia/lipid
management is an LDL cholesterol level less than 100 mg/
dL (less than 70 mg/dL in patients with CVD). If those
targets are unsuccessful, an alternative goal is a 30% to
40% reduction in LDL cholesterol. The goal of glycemic
control is an A1C of less than 7%. Recommended lifestyle
modifications include weight loss; physical activity; limiting
alcohol intake; decreasing intake of saturated fat, trans-fat,
and cholesterol; and increasing intake of omega-3 fatty
acids, viscous fiber, and plant stanols/sterols.
Statin therapy is recommended for the following patients
without consideration of lipid profile:
patients with diagnosed CVD
patients without CVD who are over age 40 and have one
or more risk factors for CVD
patients at lower risk and under age 40 whose LDL
cholesterol is more than 100 mg/dL.
Little evidence-based data supports treating low HDL and
elevated triglycerides. For patients with severe hypertriglyc-
eridemia, treat with lifestyle changes and pharmacologic
therapy to decrease the risk of acute pancreatitis. Treatment
options include fibric acid derivative, niacin, and fish oil.4
The American Heart Association (AHA) recommends
these intensive therapeutic lifestyle changes:
www.JAAPA.com 17
CME
A Mediterranean-style diet; 5% to 10% weight loss;
increase in dietary fiber and omega-3 fatty acids; elimina-
tion of trans-fats; and reduction of simple carbohydrates,
fructose, saturated fats, and alcohol.
Moderate physical activity, which can decrease triglyceride
levels 20% to 30%.9
In patients with very
high triglycerides,
consider adding
pharmacological therapy
to prevent acute
pancreatitis.
The AHA states that clinical trials to support specific
guidelines for pharmacologic therapy are lacking.9 Review
patient medications for oral contraceptives or hormone
replacement therapy that may influence triglyceride lev-
els. In patients with very high triglycerides (500 mg/dL
or greater), consider adding pharmacological therapy to
prevent acute pancreatitis.
The primary goal of the NCEPs ATP III guidelines is
to reduce LDL cholesterol to 100 mg/dL or less via drug
therapy.2 If LDL cholesterol is less than 100 mg/dL, the
goal is to reduce the level by 30%. A secondary goal is to
keep non-HDL cholesterol below 100 mg/dL if the patients
triglyceride level is above 200 mg/dL.2
Recommendations from the National Lipid Association
(NLA) for managing lipids in patients with diabetes and
metabolic syndrome has a primary treatment goal of reduc-
ing LDL cholesterol to below 70 mg/dL, and non-HDL
cholesterol to less than 100 mg/dL.8 Initiate therapeutic
lifestyle changes, and follow the ADA recommendations
for statin therapy and the NCEP primary goal recommen-
dations as described earlier.
The secondary treatment goal of the NLA recommenda-
tions is to reduce HDL cholesterol to less than 40 mg/dL in
men and less than 50 mg/dL in women, and triglycerides to
less than 150 mg/dL (in line with the ADA recommenda-
tions). Non-HDL cholesterol should be kept below 100 mg/
dL if the patients triglycerides are more than 200 mg/dL,
in line with the NCEP recommendations. Recommended
therapy is to intensify statin therapy, administer niacin (less
than 2 grams per day) and fibrates, maintain intensive gly-
cemic control, and intensify therapeutic lifestyle changes.8
CONCLUSION
The aggressive diagnosis and treatment of patients with
type 2 diabetes, metabolic syndrome or insulin resistance,
18 www.JAAPA.com
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and atherogenic dyslipidemia has been advocated by the
ADA, AHA, NCEP, and NLA. By diagnosing and aggres-
sively treating patients at increased risk for cardiovascular
disease, clinicians can reduce the burden these diseases
place on patients and society. JAAPA
Earn Category I CME credit by reading this article and the article begin-
ning on page 20 and successfully completing the posttest on page 28.
Successful completion is defined as a cumulative score of at least 70%
correct. This material has been reviewed and is approved for 1 hour of
clinical Category I (Preapproved) CME credit by the AAPA. The term of
approval is for 1 year from the publication date of July 2013.
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Volume 26 Number 7 July 2013