Diabetes Mellitus

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DIABETES MELLITUS TIPE 2
INTRODUCTION Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Miscellaneous Pictures Bibliography
Background: Type 2 diabetes mellitus is a group of disorders characterized by hyperglycemia and associated
with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular),
and neuropathic (ie, autonomic, peripheral) complications. Unlike type 1 diabetes mellitus, the patients are not
absolutely dependent upon insulin for life, even though many of these patients ultimately are treated with
insulin.
Pathophysiology: Hyperglycemia is produced by lack of endogenous insulin, which is either absolute, as in

type 1 diabetes mellitus, or relative, as in type 2 diabetes mellitus. Relative insulin deficiency usually occurs
because of resistance to the actions of insulin in muscle, fat, and the liver and an inadequate response by the
pancreatic beta cell. This pathophysiologic abnormality results in decreased glucose transport in muscle,
elevated hepatic glucose production, and increased breakdown of fat.
The genetics of type 2 diabetes are complex and not completely understood, but presumably this disease is
related to multiple genes (with the exception of maturity-onset diabetes of the young [MODY]). Evidence
supports inherited components for both pancreatic beta cell failure and insulin resistance. Considerable debate
exists regarding the primary defect in type 2 diabetes mellitus. Most patients have both insulin resistance and
some degree of insulin deficiency. However, insulin resistance per se is not the sine qua non for type 2 diabetes
mellitus because many people with insulin resistance (particularly patients who are obese) do not develop
glucose intolerance. Therefore, insulin deficiency is necessary for the development of hyperglycemia. Patients
may have high insulin levels, but the insulin concentrations are inappropriately low for the level of glycemia.
MODY is associated with autosomal dominant inheritance and is characterized by onset in at least 1 family
member younger than 25 years, correction of fasting hyperglycemia without insulin for at least 2 years, and
absence of ketosis. At least 6 genetically different types of MODY have been described. Some patients
ultimately require insulin to control glycemia.
Recent work has suggested that elevated free fatty acids may be the driving force behind insulin resistance and
perhaps even beta cell dysfunction. If this defect is more proximal than defects specifically related to glycemia,
then therapies aimed at correcting this phenomenon would be highly beneficial.
Presumably, the defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories,
inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype. The extent of excess
weight may vary with different groups. For example, overweight patients from Asia may not be overweight by
Western standards, but excess weight is often much more pronounced in these ethnic groups. Recent work
suggests that in utero environment resulting in low birth weight may predispose some individuals to develop
type 2 diabetes mellitus. The pathophysiology of abnormal glucose metabolism in type 2 diabetes mellitus is
simply depicted in Image 1.
Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However,

glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small
dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels,
elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator
inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventional atherosclerotic risk factors (eg,
family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C),
determine cardiovascular risk.
Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably
because of the effects of insulin resistance. Stern in 1996 and Haffner and D'Agostino in 1999 developed the
“ticking clock” hypothesis of complications, asserting that the clock starts ticking for microvascular risk at the
onset of hyperglycemia, while the clock starts ticking for macrovascular risk at some antecedent point,
presumably with the onset of insulin resistance.
Frequency:
• In the US: In 2002, the estimated prevalence of diabetes in the United States was 6.3% (18.2 million
people); approximately one quarter of cases were undiagnosed. More than 90% of cases of diabetes are
type 2 diabetes mellitus. With increasing obesity in the population, an older population, and an increase
in the population of higher-risk minority groups (see Race), prevalence is increasing.
• Internationally: Type 2 diabetes mellitus is less common in non-Western countries where the diet
contains fewer calories and caloric expenditure on a daily basis is higher. However, as people in these
countries adopt Western lifestyles, weight gain and type 2 diabetes mellitus are becoming virtually
epidemic.
Mortality/Morbidity: Diabetes mellitus is one of the leading causes of morbidity and mortality in the United
States because of its role in the development of optic, renal, neuropathic, and cardiovascular disease. These
complications, particularly cardiovascular disease (~50-75% of medical expenditures), are the major sources of
expenses for patients with diabetes mellitus. Approximately two thirds of people with diabetes die from heart
disease or stroke. Men with diabetes face a 2-fold increased risk for coronary heart disease, and women have a
3- to 4-fold increased risk. In 1994, 1 of every 7 health care dollars in the United States was spent on patients
with diabetes mellitus. The 2002 estimate for direct medical costs due to diabetes in the United States was $92
billion, with another $40 billion in indirect costs. Approximately 20% of Medicare funds are spent on these
patients.
• Diabetes is the leading cause of blindness in working-age adults in the United States, accounting for
12,000-24,000 newly blind persons every year. The National Eye Institute estimates that 90% of cases
of lost vision are preventable.
• Diabetes mellitus is the leading cause of end-stage renal disease (ESRD) accounting for 44% of new
cases according to the Centers for Disease Control and Prevention (CDC). In 2001, 42,813 people
began renal replacement therapy, and 142,963 people with diabetes were on dialysis or had received a
kidney transplant.
• Diabetes mellitus is the leading cause of nontraumatic lower limb amputations in the United States,
with a 15- to 40-fold increase in risk compared to that of the nondiabetic population. In 2000-2001,
about 82,000 nontraumatic lower limb amputations were performed related to neuropathy and
vasculopathy.
Race: The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups. Image 2
shows data for various groups. Type 2 diabetes mellitus is becoming virtually pandemic in some groups of
Native Americans and Hispanic people. Recent work suggests more retinopathy and nephropathy in blacks,
Native Americans, and Hispanic groups.
Sex: Type 2 diabetes mellitus is slightly more common in older women than men.
Age: While type 2 diabetes mellitus traditionally has been thought to affect individuals older than 40 years, it is
being recognized increasingly in younger persons, particularly in highly susceptible racial and ethnic groups. In
some areas, more type 2 than type 1 diabetes mellitus is being diagnosed in prepubertal children, teenagers, and
young adults. Type 2 diabetes mellitus is observed even in some obese children. The effects of age on the
prevalence of diabetes mellitus are shown in Image 3. Virtually all cases of the disease in older individuals are
type 2 diabetes mellitus.
CLINICAL Section 3 of 11

History:
• While a diagnosis of diabetes mellitus is readily entertained when a patient presents with classic
symptoms (ie, polyuria, polydipsia, polyphagia, weight loss), most patients with type 2 diabetes
mellitus are asymptomatic for years. Other symptoms that might suggest hyperglycemia include
blurred vision, lower extremity paresthesias, or yeast infections, particularly balanitis in men. However,
the asymptomatic state does not mean that hyperglycemia is not affecting the individual.
• The possible presence of diabetes mellitus should be considered in obese patients, patients with a first-
degree relative with type 2 diabetes mellitus, members of high-risk ethnic groups (ie, black, Hispanic,
Native American, Asian American, Pacific Islander), women with a previous delivery of a large infant
(>9 lb) or with a history of gestational diabetes mellitus, patients with hypertension, or patients with
high triglycerides (>250 mg/dL) or low HDL-C (<35 mg/dL). While the United States Public Health
Service and the American College of Physicians do not recommend routine screening for diabetes,
targeted screening may be useful.
• Because polycystic ovary disease is an insulin-resistant state, screening these women may be
warranted.
• Whether at-risk persons should be screened for prediabetes is unclear at present. The therapy would
generally be lifestyle changes to facilitate weight loss and improve cardiovascular fitness, and in
virtually all cases, this would be the recommendation for such patients without a measured glucose
value.
Physical: Early in the course of diabetes mellitus, the physical examination findings are likely to be
unrevealing. However, ultimately, end-organ damage may be observed. Potential findings are listed in Image 4.
Causes:
• Superimposition of caloric excess (usually in the form of a high-fat diet accompanied by minimal
excess caloric expenditure) upon a susceptible genotype appears to cause type 2 diabetes mellitus.
• Diabetes mellitus may be caused by other conditions. Secondary diabetes may occur in patients taking
glucocorticoids or when patients have conditions that antagonize the actions of insulin (eg, Cushing
syndrome, acromegaly, pheochromocytoma).
DIFFERENTIALS Section 4 of 11

Diabetes Mellitus, Type 1

Insulin Resistance
Obesity
Other Problems to be Considered:

Latent autoimmune diabetes of adults (LADA)

Stein-Leventhal syndrome
WORKUP Section 5 of 11

Lab Studies:
• The American Diabetes Association adopted new diagnostic criteria for diabetes mellitus in late 1997.
The criteria for the diagnosis of diabetes are listed in Image 5. Most commonly, the diagnosis is made
when the health care provider discovers either fasting plasma glucose (FPG) greater than or equal to
126 mg/dL on 2 occasions or random glucose greater than or equal to 200 mg/dL and classic symptoms
of diabetes mellitus (ie, polyuria, polydipsia, polyphagia, weight loss).
o Plasma glucose is determined in a grey top (sodium fluoride) tube, which inhibits red blood
cell glycolysis immediately. A serum glucose measurement (commonly obtained on
multiphasic panels using a red or speckled top tube) may have significantly lower results than
plasma glucose measurements. Capillary whole blood measurements are not recommended to
diagnose diabetes mellitus.
o The noted values for fasting glucose measurements are based on the level of glycemia at
which retinopathy, a fairly pathonomic diabetic complication, appears. Fasting glucose
measurements are not as predictive for indicating macrovascular risk. The World Health
Organization criteria for impaired glucose tolerance (IGT) are as follows:
§ FPG <140 mg/dL at 2 hours after a 75-g glucose load
§ Plasma glucose >140 mg/dL to <200 mg/dL with 1 intervening plasma glucose value
>200 mg/dL
o These criteria are a better predictor of increased macrovascular risk than the current
intermediate category of impaired fasting glucose (IFG) or prediabetes of the American
Diabetes Association. Presumably, patients with IFG are at increased risk for development of
diabetes mellitus, but their risk for macrovascular disease does not appear to be the same as
for patients with IGT (which is about the same as patients with frank type 2 diabetes mellitus).
• Hemoglobin A1c (HbA1c or A1c) or glycosylated hemoglobin (GHb) measurements are not useful for
the diagnosis of diabetes mellitus because they are not standardized nationally and are insensitive for
detecting milder forms of glucose intolerance. Present changes in standardization may also affect the
actual values that individual laboratories generate. However, these measurements are the criterion
standard for monitoring long-term glycemic control and reflect glycemia for the previous 3 months.
Whether HbA1c or GHb assays are superior for measuring glycemic control is debatable.
Hemoglobinopathies can affect both measurements.
Because the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective
Diabetes Study (UKPDS), as well as the American Diabetes Association Standards of Care, refer to
HbA1c measurements, this article refers to HbA1c as the standard for glycemic control. Utilizing GHb
measurements is acceptable, but these values are 1-2% higher than HbA1c concentrations. When using
GHb, an available conversion factor to HbA1c for the assay utilized is helpful.
• Screening urine microalbumin measurements is recommended yearly in all patients with diabetes.
Performing an albumin-to-creatinine ratio probably is easiest. If abnormal (ie, >30 mg/g), a
quantitation on a timed urine specimen (ie, overnight, 10 hours, or 24 hours) should be performed.
Normal urine albumin excretion is defined as less than 30 mg/d. Microalbuminuria is defined as 30-300
mg/d (20-200 mcg/min). Because of wide variability among patients, confirm persistent
microalbuminuria on at least 2 of 3 samples over 3-6 months. Greater values can be detected by
standard protein dipstick screening and are considered macroproteinuria.
• Unlike type 1 diabetes mellitus, in which microalbuminuria is a good indicator of early kidney damage,
microalbuminuria is a common finding (even at diagnosis) in type 2 diabetes mellitus and is a risk
factor for macrovascular (especially coronary heart) disease. It is a weaker predictor for future kidney
disease in type 2 diabetes mellitus.
• Measuring insulin or C-peptide concentrations rarely is necessary to diagnose type 2 diabetes mellitus
or differentiate type 2 diabetes from type 1 diabetes mellitus. Insulin levels generally are high early in
the course of type 2 diabetes mellitus and gradually wane over time. Stimulated C-peptide
concentrations (after a standard meal challenge such as Sustacal or after glucagon) are somewhat
preserved until late in the course of type 2 diabetes mellitus. Absence of a C-peptide response to
carbohydrate ingestion may indicate total beta cell failure.
• Antibodies to insulin, islet cells, or glutamic acid decarboxylase (GAD) are absent in type 2 diabetes
mellitus.
• LADA is a form of slow-onset type 1 diabetes that occurs in middle-aged (usually white) adults. It can
be differentiated from type 2 diabetes by measuring antiGAD65 antibodies. Such patients may respond
to insulin secretagogues for a brief period (months) of time.
TREATMENT Section 6 of 11

Medical Care: The goals in caring for patients with diabetes mellitus include the elimination of symptoms;
microvascular (ie, eye and kidney disease) risk reduction through control of glycemia and blood pressure (BP);
macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk reduction through control of lipids and
hypertension, smoking cessation, and utilizing aspirin therapy; and metabolic risk reduction through control of
glycemia. Such care requires appropriate goal setting, regular complications monitoring, dietary and exercise
modifications, medications, appropriate self-monitoring of blood glucose (SMBG), and laboratory assessment.
Focus on glucose alone does not provide adequate treatment for patients with diabetes mellitus. Treatment
involves multiple goals (ie, glycemia, lipids, BP).
• Implications of the UKPDS: The UKPDS was a landmark study for the care of patients with type 2
diabetes mellitus, confirming the importance of glycemic control in reducing the risk for microvascular
complications and refuting previous data implicating increased macrovascular disease risk with
sulfonylureas or insulin. Major findings of the study are displayed in Images 6-8. Significant
implications include the following:
o Microvascular complications (predominantly the need for laser photocoagulation on retinal

lesions) are reduced by 25% when median HbA1c is 7% compared to 7.9%.
o A continuous relationship exists between glycemia and microvascular complications, with a
35% reduction in risk for each 1% decrement in HbA1c. A glycemic threshold (above the
upper limit of normal for HbA1c) below which risk for microvascular disease is eliminated
does not appear to exist.
o Glycemic control has minimal effect on macrovascular disease risk. Excess macrovascular
risk appears to be related to conventional risk factors such as dyslipidemia and hypertension.
o Sulfonylureas and insulin therapy do not increase macrovascular disease risk.
o Metformin reduces macrovascular risk in patients who are obese.
o Vigorous BP control reduces microvascular and macrovascular events. Beta-blockers and
angiotensin-converting enzyme (ACE) inhibitors appear to be equally efficacious.
• Glycemic goal setting and achieving glycemic goals: Both the DCCT and UKPDS provide ample
evidence that glycemic control is paramount in reducing microvascular complications. Unless the risk
outweighs the benefit, an HbA1c target of less than 7% is appropriate. Some organizations (eg, the
American Association of Clinical Endocrinologists, the International Diabetes Federation) recommend
a glycemic target of HbA1c less than 6.5%.
o The author thinks that practitioners should aim for the lowest possible HbA1c that does not
cause undue harm. The limiting factor is almost always risk for hypoglycemia. Unfortunately,
some physicians and their patients pursue a particular HbA1c value despite uncertain benefit
(eg, patients with advanced complications) or unacceptable risk (eg, hypoglycemia
unawareness, elderly patients, patients with other major systemic disease with significant risk
for side effects [eg, coma, seizures, falling and breaking a hip]). Situations with an
unfavorable risk-benefit ratio for intensive blood glucose lowering include advanced age,
significant concomitant disease, and advanced complications.
o Decisions about glycemic management generally are made on the basis of HbA1c
measurements performed quarterly (possibly less often in patients with adequate control
through lifestyle measures alone) and the results of SMBG. If a total GHb measurement is
utilized, the actual number is 1-2% higher, but the laboratory should provide a correlation
with actual HbA1c values.
• Complications monitoring: The American Diabetes Association recommends initiation of
complications monitoring at the time of diagnosis of diabetes mellitus. This regimen should include
yearly dilated eye examinations, yearly microalbumin checks, and foot examinations at each visit.
• SMBG: Daily SMBG is important for patients treated with insulin or insulin secretagogues to monitor
for and prevent hypoglycemia and optimize the treatment regimen. The optimal frequency of SMBG
for patients with type 2 diabetes is unresolved, but it should be sufficient to facilitate reaching glucose
goals. The author often utilizes no or minimal SMBG in patients using lifestyle changes alone or agents
that do not cause hypoglycemia (eg, metformin, glitazones, glucosidase inhibitors).
• Laboratory monitoring: Because diabetes mellitus is a multisystem disease, focusing solely on blood
sugar is inadequate. Image 9 lists appropriate laboratory parameters in the global assessment of patients
with type 2 diabetes mellitus. Obviously, patients with abnormalities need more frequent monitoring to
guide therapeutic interventions. Drug-specific monitoring also is necessary (eg, serum creatinine for
metformin, serum transaminases for glitazones).
• Intercurrent medical illness: Patients with intercurrent illness become more insulin resistant because of
the effects of increased counter-regulatory (ie, anti-insulin) hormones. Therefore, despite decreased
nutritional intake, glycemia may worsen. Patients on oral agents may need transient therapy with
insulin to achieve adequate glycemic control. In patients requiring insulin, scheduled doses of insulin,
as opposed to sliding scale insulin, are far more effective in achieving glycemic control.
o Recent work (ie, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction
[DIGAMI] trial) suggests improved outcomes in patients with type 2 diabetes with acute
myocardial infarctions or strokes who receive constant intravenous insulin during the acute
phase of the event to maintain blood glucose values of approximately 100-150 mg/dL.
However, this work has not been confirmed in a recently published study (ie, DIGAMI-2).
o In the case of cardiac ischemia, the beneficial effects may be due to reducing free fatty acids
with insulin therapy.
o In patients treated with metformin, any illness leading to dehydration or hypoperfusion should
lead to temporary discontinuation of the drug because of possible increased risk of lactic
acidosis.
• Surgery: Surgical patients may experience worsening of glycemia for reasons similar to those listed
above for intercurrent medical illness. Patients on oral agents may need transient therapy with insulin
to maintain blood glucose at approximately 100-180 mg/dL. In patients requiring insulin, scheduled
doses of insulin, as opposed to sliding scale insulin, are far more effective in controlling glucose.
Intensive regulation of glucose (ie, maintaining glucose approximately <110 mg/dL) in surgical ICU
patients on ventilators appears to improve survival and reduce complications.
o For patients who can eat soon after surgery: The time-honored approach of administering one
half of the usual morning neutral protamine Hagedorn (NPH) insulin dose with 5% dextrose in
the IV is acceptable, with resumption of scheduled insulin (perhaps at reduced doses) within
the first 1-2 days. Patients receiving insulin glargine can often receive their usual dose if they
are given intravenous glucose during surgery with appropriate intraoperative and
postoperative monitoring of glucose.
o For patients requiring more prolonged periods without oral nutrition and for major surgery,
such as coronary artery bypass grafting and major abdominal surgery: Constant infusion
intravenous insulin is preferred. Discontinue metformin temporarily after any major surgery
until the patient clearly is hemodynamically stable and normal renal function is documented.
The practice of discontinuing metformin for at least 48 hours in this situation until proof of
normal renal function is established is sound.
• Women of reproductive age: An increasing prevalence of type 2 diabetes mellitus has been noted in
women of reproductive age. Prepregnancy planning is becoming necessary. Insulin is the only
generally accepted pharmacologic therapy for women contemplating pregnancy who previously have
been diagnosed with diabetes mellitus. For women with diabetes mellitus controlled by lifestyle
measures alone, conversion to insulin as soon as the pregnancy is confirmed is appropriate. For women
with polycystic ovary disease who ovulate and become pregnant with insulin sensitizer therapy,
conversion to insulin is often mandatory as soon as pregnancy is confirmed. While metformin has been
used during pregnancy in other countries, it is not so used in the United States.
• Pregnancy: Insulin is the only acceptable pharmacologic therapy during pregnancy for women with
established diabetes mellitus. (Glyburide has been used for gestational diabetes mellitus patients late in
the second and third trimesters, but this is not appropriate therapy for patients with established diabetes.
Its safety during early gestation is not established.) For a complete discussion of this topic, see
Diabetes Mellitus and Pregnancy.
• Hypertension: The role of hypertension in increasing microvascular and macrovascular risk in patients
with diabetes mellitus has been confirmed in the UKPDS and Hypertension Optimization Treatment
(HOT) trials. The American Diabetes Association suggests that the BP goal be less than 130/80 mm
Hg. In patients with greater than 1 g/d proteinuria and renal insufficiency, a more aggressive
therapeutic goal (ie, <125/75 mm Hg) is advocated. While ACE inhibitors, angiotensin receptor
blockers (ARB), diuretics, beta-blockers, and calcium channel blocker are all considered acceptable
initial therapy, the author prefers inhibitors of the renin-angiotensin system (ie, ACE inhibitors, ARB)
because of their proven renal protection effects in patients with diabetes. Many patients require
multiple agents. Diuretics or calcium channel blockers frequently are useful as second and third agents.
• Dyslipidemia: Dyslipidemia, particularly high triglycerides and low HDL-C, is more common in
patients with type 2 diabetes mellitus. Data from statin trials (see coronary heart disease [CHD]) show
that event reduction is achievable in secondary prevention (ie, patients with diabetes and known CHD
and LDL-C elevation). Fibrates may reduce CHD events in patients with isolated low HDL-C. Primary
prevention studies have also now shown that statin therapy reduces CHD events. Whether therapy
aimed more at triglyceride reduction and HDL-C elevation (ie, fibrates, niacin) is effective in CHD
event reduction in primary prevention remains to be determined. The American Diabetes Association
guidelines for therapy of LDL-C are presented in Image 10.
Surgical Care: Bariatric surgery has been shown to improve diabetes control and, in some situations, normalize
glucose tolerance in morbidly obese patients. It is certainly a reasonable alternative in carefully selected patients
if an experienced team (providing appropriate preoperative evaluation as well as technical surgical expertise) is
available.
Consultations: Primary care physicians can care for patients with type 2 diabetes mellitus adequately. The
multiple facets of disease treatment (eg, nutrition, exercise, smoking cessation, medications, complications
monitoring) and data management (eg, glucose levels, BP, lipids, complications monitoring) must be
continually noted. Inability to achieve adequate glycemic (or BP or lipid) control usually should be a clear
indication to consult a diabetes specialist. When a patient has developed advanced complications, a diabetes
specialist cannot be expected to be able to lessen the burden of these complications.
Diet: For most patients, the best diet is less than they are currently eating. Time honored attachments to a
precise macronutrient composition of the diet to control diabetes are generally not supported by the research.
Caloric restriction is of first importance. After that, individual preference is reasonable. Modest restriction of
some saturated fats and simple sugars is probably reasonable. However, some patients have remarkable short-
term success with high-fat low-carbohydrate diets of various sorts. Therefore, the author always stresses weight
management in general and is flexible regarding the actual diet that the patient consumes. Also, the practitioner
should advocate a diet using foods that are within the financial reach and cultural milieu of the patient.
Activity: In general, most patients with type 2 diabetes mellitus can benefit from increased activity. Aerobic
exercise improves insulin sensitivity and may improve glycemia markedly in some patients.
• The patient should choose an activity that she or he is likely to continue. Walking is accessible to most
patients in terms of time and money expenditure.
• A previously sedentary patient should start activities slowly.
• Older patients, patients with long-standing disease, patients with multiple risk factors, and patients with
previous evidence of atherosclerotic disease should have a cardiovascular evaluation, probably
including an imaging study, prior to beginning a significant exercise regime.
MEDICATION Section 7 of 11

Pharmacologic therapy has changed dramatically in the last 10 years. New drug classes and new drugs
effectively treat type 2 diabetes mellitus, allowing glycemic control previously beyond the reach of medical
therapy. Traditionally, diet modification has been the cornerstone of diabetes management. Weight loss is more
likely to control glycemia in patients with recent onset of the disease than in patients who are significantly
insulinopenic. Medications that induce weight loss such as orlistat may be effective in highly selected patients
but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus. At
presentation, patients who are symptomatic may require transient treatment with insulin to reduce glucose
toxicity (which may reduce beta cell insulin secretion and worsen insulin resistance) or an insulin secretagogue
to rapidly relieve symptoms such as polyuria and polydipsia.
Patients with HbA1c less than 8% usually are treated initially with single oral agents. Patients with initial
HbA1c greater than 9-10% may benefit from initial therapy with 2 oral agents.
Various categories of therapeutic agents effectively treat type 2 diabetes mellitus. Comparisons of studies
looking at glycemic efficacy of individual agents are highly affected by 2 study conditions: level of glycemia
prior to treatment and percent of study population previously untreated with drugs. These 2 factors make
comparison of drug studies quite difficult because all agents are more effective in a population of patients with
poor glycemic control at baseline (a large decrease in glucose concentrations occurs, but the treatment often
leaves the patients with poorly controlled glucose levels).
Sulfonylureas are time-honored insulin secretagogues (ie, oral hypoglycemic agents) and probably have the
greatest efficacy for glycemic lowering of any of the oral agents. The UKPDS confirmed their safety after years
of suspicion from the University Group Diabetes Program (UGDP).
Meglitinides are much more short-acting insulin secretagogues than sulfonylureas, with preprandial dosing
potentially achieving more physiologic insulin release and less risk for hypoglycemia. Their glycemic efficacy is
probably less than sulfonylureas.
Biguanides are old agents that reduce hepatic glucose production and may have a minor effect on glucose
utilization in the periphery (ie, antihyperglycemics, hepatic insulin sensitizers). Insulin must be present for
biguanides to work. Phenformin was taken off the market in the United States in the 1970s because of its risk of
causing lactic acidosis and associated mortality (rate of approximately 50%). Metformin has been used
successfully for the last few years with very low risk. It is the only oral diabetes drug that reliably facilitates
modest weight loss. It was used in the UKPDS and was successful at reducing macrovascular disease endpoints
in patients who are obese. The results with concomitant sulfonylureas in a heterogeneous population were
conflicting, but overall, this drug probably improves macrovascular risk.
Alpha-glucosidase inhibitors prolong the absorption of carbohydrates. Their induction of flatulence greatly
limits their use. These agents should be titrated slowly to reduce gastrointestinal intolerance. Their effect on
glycemic control is modest, affecting primarily postprandial glycemic excursions.
Thiazolidinediones (glitazones) are a new class of drugs that reduce insulin resistance in the periphery (ie,
sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (ie, insulin
sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a
nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism. Their major
action is probably actually fat redistribution. These drugs may have beta cell preservation properties. Their
glycemic efficacy is probably moderate, between alpha-glucosidase inhibitors and sulfonylureas. They are the
most expensive oral agents.
Glitazones require the presence of insulin to work. They generally decrease triglycerides and increase HDL-C,
but they increase LDL-C (perhaps large buoyant LDL, which may be less atherogenic). While these drugs have
many desirable effects on inflammation and the vasculature, edema and weight gain may be problematic adverse
effects in patients taking glitazones, especially when administered with insulin or insulin secretagogues. These
effects may induce or worsen congestive heart failure in patients with left ventricular compromise and
occasionally in patients with normal left ventricular function. These agents have not been tested in patients with
New York Heart Association class III or IV heart failure. A recently recognized possible side effect of these
agents is macular edema.
The recently approved incretin-mimetic, exenatide, has a novel mechanism of action. It stimulates glucose-
dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent
insulin release and hypoglycemia), as well as reducing glucagon and slowing gastric emptying. Animal data
suggest that this drug prevents beta cell apoptosis and may in time restore beta cell mass. This latter property, if
proven in humans, would have tremendous therapeutic potential. This drug requires twice daily injections and is
comparable in expense to high-dose glitazone therapy.
Ultimately, many patients with type 2 diabetes mellitus become markedly insulinopenic. The only therapy that
corrects this defect is insulin. Because most patients are insulin resistant, small changes in insulin dosage may
make no difference in glycemia in some patients. Furthermore, because insulin resistance is variable from
patient to patient, therapy must be individualized in each patient.
Considerable debate exists regarding the best initial oral therapy for patients with type 2 diabetes mellitus.
Based on the results of the UKPDS and safety record, patients who are obese (>120% ideal body weight) should
be started on metformin initially, titrated to at least 1500-2000 mg/d administered in divided doses (during or
after meals to reduce gastrointestinal side effects). Patients who are markedly symptomatic may be treated with
an insulin secretagogue initially to rapidly alleviate symptoms and then perhaps switched to other agents.
Patients with near-normal weight may be treated with sulfonylureas or metformin initially. Short-acting insulin
secretagogues (eg, repaglinide, nateglinide) can be used in patients unusually predisposed to hypoglycemia.
Failure of initial therapy usually should result in addition of another class of drug rather than substitution
(reserve substitution for intolerance to a drug due to adverse effects). Considerable debate exists regarding
second agents added to (or used initially in conjunction with) metformin. The time-honored approach is to add
an insulin secretagogue (usually titrated to no more than the half-maximal approved dose to reduce risk for
hypoglycemia). However, some experts recommend a glitazone because of the positive effects of these drugs on
inflammation and the vasculature. If this strategy is used, a moderate dose of glitazone (as opposed to the
highest approved dose) should be used. A therapeutic scheme utilized by the author is listed in Image 11.
The author usually only uses glitazones in cases of metformin intolerance or contraindication because of the side
effects of weight gain and edema seen not infrequently with glitazones. Exceptions to the practice might include
patients with marked insulin resistance of relatively normal weight, such as patients of Asian heritage. If an
insulin secretagogue is being taken by the patient prior to adding a second agent, the physician should warn the
patient about the possibility of inducing hypoglycemia when another agent is added. In such cases, the insulin
secretagogue, not the newly added agent, should be reduced.
If 2 drugs are unsuccessful, the practitioner may consider adding a third class of oral agents. An alternative
would be to add bedtime insulin, usually NPH or glargine, to the initial oral agent or 2-drug combination, or add
the new drug exenatide. The expense and side effect profile of glitazones make the oral triple therapy approach
less of an option for the author. The new approach of adding exenatide twice daily to 1 or 2 oral agents (eg,
metformin and/or sulfonylureas) is attractive because of its simplicity (ie, only 2 possible doses with easy
titration compared to insulin), but its expense may be prohibitive. If insulin is used, the insulin dose is titrated to
the fasting sugar concentration, which the patient can measure at home (usually with titration to a maximum
bedtime insulin dose of approximately 60 units). Some patients need reduction of their insulin secretagogue to
prevent daytime hypoglycemia as the bedtime insulin is initiated or increased and the fasting glucose
concentration is decreased.
Glucose patterns in patients with type 2 diabetes, particularly if they have central obesity and hepatic steatosis,
often reveal that the highest preprandial glucose of the day is the fasting sugar (because of disordered hepatic
glucose production overnight), with a "stair-step" decrease during the day (after the usual postmeal rise).
Therefore, the physician should not necessarily be deterred from his or her present therapy by higher-than-
desired morning glucose values if the HbA1c level is at target. For patients who primarily have fasting
hyperglycemia, bedtime insulin is the easiest way to correct this abnormality.
When the previous approaches are unsuccessful, the patient should be switched to conventional twice daily or
multiple daily dose insulin with or without an insulin sensitizer. The author prefers metformin in this scenario if
there are no problems with tolerability or contraindications. If a glitazone is used, a moderate dose should be
administered to minimize fluid retention and weight gain.
A necessary condition for twice daily insulin to succeed in a regimented lifestyle, with meal times regularly
spaced and insulin injections taken at essentially the same time every day including weekends and holidays.
Lack of regularity in the schedule is self-defeating for this approach to therapy. The author only uses premixed
insulin in patients who might have trouble mixing their insulins. The author also prefers premix containing
regular insulin if a premix is administered to maintain better midday coverage. Premix with rapid-acting
medications can be used if the midday meal is small. All insulin injections should be administered in the
abdomen.
Conventional multiple daily doses of insulin gives the patient the greatest flexibility. In this approach, glargine
or ultralente are generally given as the basal insulin, and rapid-acting insulin (eg, aspart, glulisine, lispro) are
administered just before each meal. Glargine generally has a more stable profile. The basal component can be
administered any time of day as long as it is given at the same time each day. Interpreting glucose patterns is
probably easiest if the basal insulin is administered at or near bedtime. The basal insulin can then be titrated to
the morning sugar, and the bolus pre-meal insulin can be titrated to the next pre-meal sugar and, in some cases, a
postprandial (~2 h) value.
For patients trying to achieve near euglycemia, pre-meal glucose values of 80-120 mg/dL are the goal, with the
patient going to sleep at night with a value at least 100 mg/dL. In patients with less stringent glycemic goals (eg,
advanced age, advanced complications, severe concomitant disease), preprandial glucose values of 100-140
mg/dL are desired. Because of the limitations of therapies, essentially no patient is able to achieve these goals
all the time if, in fact, insulin is needed to treat their disease.
Unlike in long-standing type 1 diabetes mellitus, patients with type 2 diabetes mellitus usually maintain
adequate warning symptoms and signs of hypoglycemia. This situation greatly facilitates hypoglycemic therapy
(ie, insulin secretagogues, insulin) in patients with type 2 diabetes.
Recent work has reminded practitioners that glycemic control is a function of fasting and preprandial glucose
values and postprandial glycemic excursions. Postprandial glucose measurements may need more emphasis.
This change in emphasis is fueled to some degree by the availability of short-acting insulin secretagogues, very
short-acting insulin, and alpha-glucosidase inhibitors, all of which target postprandial glycemia. While
postprandial sugars are a better predictor of macrovascular disease risk early in the course of loss of glucose
tolerance, whether targeting after-meal glucose excursions has more of an effect on complications risk than
more conventional strategies remains to be seen.
Intuitively, one would assume that therapies that normalize both preprandial and postprandial glycemia (or come
close to normalization) would be optimal. Whether such a strategy can be achieved without untoward adverse
effects and with further reductions in microvascular and macrovascular disease risk (compared to regimens used
in the UKPDS) with newly available therapies is open to question. Practically speaking, most patients are fully
occupied trying to do conventional glucose monitoring and insulin dose adjustment.
An outline of the therapeutic approach generally used by the author is presented in Image 11. An idealized
scheme for glucose and insulin patterns is presented in Image 14. The author finds keeping such an idealized
scheme in mind is helpful in treating and educating patients, even if the patient is trying to replicate it with less-
intensive insulin therapy.
Drug Category: Sulfonylureas -- Stimulate insulin release from pancreatic beta cells.
Glyburide (Micronase, DiaBeta, Glynase) -- Second-

generation agent. More potent and exhibits fewer drug
Drug Name
interactions than first-generation agents. Was used in the
UKPDS.
Original formulation (Micronase, DiaBeta): 2.5-20 mg PO
qd ac breakfast or bid ac; optimal dose often does not
exceed 10 mg qd
Adult Dose
Elderly patients: 1.25 mg PO qd ac breakfast
Newer formulation (Glynase): 3-12 mg PO qd ac
breakfast; optimal dose often does not exceed 6 mg qd
Pediatric Dose Not established
Documented hypersensitivity; diabetic ketoacidosis; type
Contraindications
1 diabetes mellitus
NSAIDs, sulfonamides, chloramphenicol, probenecid,
warfarin, MAOIs, beta-blockers, and miconazole may
produce increased hypoglycemic effects; thiazides,
hydantoins, oral contraceptives, corticosteroids,
phenothiazines, thyroid hormones, estrogen, nicotinic
Interactions acid, sympathomimetics, calcium channel blockers, and
isoniazid produce decreased hypoglycemic effects; may
rarely cause disulfiramlike alcohol reactions; increases
warfarin effects (the author doubts the significance of
most these interactions--ACE inhibitors may also rarely
potentiate hypoglycemic effects)
C - Safety for use during pregnancy has not been
Pregnancy
established.
Caution in patients predisposed to hypoglycemia, such as
patients with liver disease or renal disease and elderly
patients; black box warning on cardiovascular mortality
from the UGDP probably is irrelevant; trauma, infection,
Precautions
surgery, and stress may require use of insulin; although
the drug has been used in gestational diabetes during the
third trimester, it should not be used in women
considering pregnancy or early in pregnancy
Glipizide (Glucotrol, Glucotrol XL) -- Second-generation
agent. More potent and exhibits fewer drug interactions
Drug Name than first-generation agents. May cause more physiologic
insulin release with less risk for hypoglycemia and weight
gain than other sulfonylureas.
Original formulation: 2.5-40 mg/d PO; optimal dose often
does not exceed 15-20 mg/d divided bid ac
Adult Dose ER formulation: 5-20 mg qd ac breakfast (2.5 mg in
patients at high risk for hypoglycemia); maximum
effective dose is often 10 mg ac breakfast
Documented hypersensitivity; type 1 diabetes; diabetic
Contraindications
ketoacidosis
Beta-blockers, phenytoin, corticosteroids, and thiazides
Interactions decrease hypoglycemic effects; cimetidine may increase
hypoglycemic effects; ACE inhibitors enhance
hypoglycemic activity
Pregnancy
established.
Caution in renal or liver dysfunction; trauma, infection,
surgery, and stress may require use of insulin; black box
Precautions
warning on cardiovascular mortality from the UGDP
probably is irrelevant
Glimepiride (Amaryl) -- Third-generation sulfonylurea
that may cause more physiologic insulin release than
some of the older agents. Its interaction with cardiac
potassium channels is different from that of other
Drug Name sulfonylureas, suggesting greater potential safety in
patients with ischemic heart disease. However, this has
never been verified in a clinical endpoint trial. Only
sulfonylurea approved for concomitant use with
metformin or insulin.
1-8 mg PO qd with breakfast; 4 mg PO qd is often
Adult Dose
maximum effective dose
Contraindications Documented hypersensitivity; diabetic ketoacidosis
NSAIDs, sulfonamides, chloramphenicol, probenecid,
warfarin, MAOIs, beta-blockers, and miconazole produce
increased hypoglycemic effects; thiazides, hydantoins,
oral contraceptives, corticosteroids, phenothiazines,
thyroid hormones, estrogen, nicotinic acid,
Interactions sympathomimetics, calcium channel blockers, and
isoniazid produce decreased hypoglycemic effects;
increases alcohol-related disulfiram reactions; increases
warfarin effects (the author doubts the significance of
most these interactions); ACE inhibitors may also rarely
potentiate hypoglycemic effects
Pregnancy
established.
patients with liver disease or renal disease and elderly
Precautions patients; black box warning on cardiovascular mortality
from the UGDP probably is irrelevant; trauma, infection,
surgery, and stress may require use of insulin
Drug Category: Meglitinides -- Short-acting insulin secretagogues with preprandial dosing, potentially achieving
more physiologic insulin release and less risk for hypoglycemia.
Repaglinide (Prandin) -- Probably most useful in patients

at increased risk for hypoglycemia who still need an
insulin secretagogue. Better control of postprandial
Drug Name
glycemic excursions also may be achieved with
repaglinide. FDA approved for monotherapy and in
conjunction with metformin or glitazones.
Adult Dose 0.5-4 mg PO up to qid ac; not to exceed 16 mg qd
Documented hypersensitivity; diabetic ketoacidosis; type
Contraindications
1 diabetes mellitus
Interactions CYP3A4 inhibitors (eg, clarithromycin, ketoconazole,
miconazole, erythromycin) decrease metabolism, thus

increasing serum levels and effects; NSAIDs,
sulfonamides, chloramphenicol, probenecid, warfarin,
MAOIs, or beta-blockers produce increased
hypoglycemic effects; thiazides, hydantoins, oral
contraceptives, estrogens, corticosteroids, phenothiazines,
thyroid products, nicotinic acid, sympathomimetics,
calcium channel blockers, and isoniazid produce
decreased hypoglycemic effects; increases alcohol-related
disulfiram reactions; increases warfarin effects
Pregnancy
established.
Precautions patients with liver disease and elderly patients; trauma,
infection, surgery, and stress may require use of insulin
Nateglinide (Starlix) -- Mimics endogenous insulin
patterns, restores early insulin secretion, and controls
mealtime glucose surges. Indicated as monotherapy for
Drug Name
type 2 diabetes or combination therapy with metformin or
glitazones.
Available as 60-, 120-, and 180-mg tablets.
Usual dose: 120 mg PO 1-30 min ac
Adult Dose Elderly patients or patients at higher risk of
hypoglycemia: may use 60 mg ac
Documented hypersensitivity; type 1 diabetes mellitus;
Contraindications
ketoacidosis
NSAIDs, MAOIs, and beta-blockers produce increased
hypoglycemic effects; thiazides, hydantoins,
Interactions
corticosteroids, thyroid products, and sympathomimetics
produce decreased hypoglycemic effects
Pregnancy
established.
Hypoglycemia may occur (take prior to meals to reduce
Precautions
incidence); caution in moderate-to-severe hepatic disease
Drug Category: Biguanides -- Decrease the amount of glucose produced by the liver and may help improve
insulin sensitivity.
Metformin (generic, Glucophage, Glucophage XR,

Metformin XR) -- Use of this drug frequently results in
weight loss and mild improvement of all aspects of the
lipid profile. Cannot be used in renal or significant hepatic
insufficiency or decompensated congestive heart failure
requiring pharmacological therapy (increased risk for
lactic acidosis). Because of GI adverse effects, titrate
slowly and take during or after (rather than before) meals.
Drug Name
Can be used as monotherapy or with sulfonylureas,
glitazones, or insulin. Reduces hepatic glucose output,
may decrease intestinal absorption of glucose, and may
increase glucose uptake in the peripheral tissues. Major
drug used in patients who are obese with type 2 diabetes.
Many patients tolerate metformin better if administered in
the middle or at the end of the meal.
ER preparations are given in 1 dose after an evening meal
and should be titrated up slowly from 500 mg daily.

ER preparations may not be as efficacious for glucose or
lipid control and have not been used in any clinical end-
point trials.
IR: 500 mg PO bid during or with or after meal for 1 wk
initially, then increase weekly by 500 mg; 1000 mg PO
bid to 850 mg PO tid with or after meals maintenance
Adult Dose
ER: 500 mg PO after evening meal for 1 wk, then
increase by 500 mg qwk up to 2000 mg qd administered
after evening meal
Documented hypersensitivity; acute myocardial
Contraindications infarction; septicemia; renal insufficiency; decompensated
congestive heart failure; decompensated liver disease
Diuretics, thyroid products, oral contraceptives,
phenytoin, calcium channel blockers, and phenothiazines
Interactions may decrease effects of metformin; cimetidine may
increase metformin levels (the author is doubtful of the
significance of these effects)
Pregnancy B - Usually safe but benefits must outweigh the risks.
Caution in elderly patients (>80 y), renal insufficiency
(serum Cr in males >1.4 mg/dL, serum Cr in females >1.3
mg/dL), decompensated heart failure, and hypoperfusion;
Precautions hold for 2 days after a radiocontrast procedure and make
sure renal function has returned to baseline; discontinue
therapy before performing any surgical procedures;
markedly impaired liver function
Drug Category: Thiazolidinediones (glitazones) -- Improve target cell response (ie, muscle, fat) to insulin
without increasing insulin secretion. Redistribute adipose tissue.
Rosiglitazone (Avandia) -- Indicated as monotherapy and

in conjunction with sulfonylureas and/or metformin and
insulin. Insulin sensitizer with major effect on stimulation
of glucose uptake in skeletal muscle and adipose tissue.
Drug Name
Lowers plasma insulin levels. Used for treatment of type
2 diabetes associated with insulin resistance. May
preserve beta cell function. Positive effects on vasculature
and inflammation. Changes LDL and HDL particle size.
4-8 mg/d PO qd or divided bid (starting with lower dose
Adult Dose may reduce side effects); may require 2-3 mo to observe
full effect
Documented hypersensitivity; active liver disease;
Contraindications ketoacidosis; type 1 diabetes mellitus; class III or IV
CHF; macular edema
In combination with insulin or oral hypoglycemics (eg,
Interactions sulfonylureas, meglitinides) may increase risk for
hypoglycemia
Pregnancy
established.
Monitor transaminases; discontinue if ALT rises above
Precautions 3X upper limit of reference range; caution in edema and
congestive heart failure; may decrease hemoglobin,
hematocrit, and white blood cell counts; weight gain (both

edema and adiposity) problematic in some patients,
particularly if coadministered with insulin or insulin
secretagogues
Pioglitazone (Actos) -- Indicated as monotherapy and in
conjunction with sulfonylureas, metformin, and insulin.
Improves target cell response to insulin without
Drug Name increasing insulin secretion from pancreas. Increases
insulin-dependent glucose use in skeletal muscle and
adipose tissue. Lowers triglycerides more than
rosiglitazone, probably related to PPAR alpha effect.
15-30 mg PO qd; may increase; not to exceed 45 mg/d
Adult Dose
(15-mg dose often of little efficacy)
Documented hypersensitivity; active liver disease;
Contraindications ketoacidosis; type 1 diabetes mellitus; class III or IV
CHF; macular edema
May reduce plasma concentrations of contraceptives
containing ethinyl estradiol and norethindrone; laboratory
studies suggest ketoconazole may inhibit metabolism of
Interactions pioglitazone (monitor blood glucose levels closely);
pioglitazone in combination with insulin or oral
hypoglycemics (eg, sulfonylureas) may increase risk for
hypoglycemia
Monitor transaminases; discontinue if ALT rises above
3X upper limit of reference range; caution in edema and
congestive heart failure; may decrease hemoglobin,
Precautions hematocrit, and white blood cell counts; weight gain (both
edema and adiposity) problematic in some patients,
particularly if coadministered with insulin or insulin
secretagogues
Drug Category: Alpha-glucosidase inhibitors -- These agents delay sugar absorption and help prevent
postprandial glucose surges.
Acarbose (Precose), Miglitol (Glyset) -- Acarbose was

first of the alpha-glucosidase inhibitors. Absorbed to a
small degree, so liver function abnormalities can occur
rarely. Can be used as monotherapy or in combination
Drug Name
with other treatment modalities. Its modest effect on
glycemia and high degree of GI adverse effects
(flatulence) limit use. Miglitol is not absorbed, so liver
function abnormalities do not occur.
Acarbose: 12.5 mg PO qd with first bite of meal, titrate
dose slowly to 25-50 mg PO tid with first bite of meal;
Adult Dose may administer 100 mg tid in patients >60 kg
Miglitol: 12.5-25 mg PO qd with first bite of meal, titrate
slowly to 25-100 mg PO tid
Documented hypersensitivity; cirrhosis; severe bowel
Contraindications
disease; renal failure
Decreases absorption and bioavailability of digoxin,
Interactions
propranolol, and ranitidine; digestive enzymes reduce
effects; diuretics (ie, thiazide), corticosteroids,

phenothiazines, thyroid, estrogen, oral contraceptives,
phenytoin, nicotinic acid, sympathomimetics, calcium
channel blockers, isoniazid, intestinal absorbents, and
digestive enzymes produce decreased hypoglycemic
effects
In patients who develop hypoglycemia while taking
acarbose or miglitol with sulfonylureas, meglitinides, or
insulin, administer pure glucose rather than sucrose PO
Precautions
because acarbose slows breakdown of sucrose; abnormal
liver function test results may occur; trauma, infection,
surgery, and stress may require use of insulin
Drug Category: Combination oral products -- Approved combinations of drugs for therapy of type 2 diabetes
mellitus. No advantage except convenience and reduced number of copayments for patients.
Combination tablets -- Indicated for initial therapy or

Drug Name second line. Targets dual physiologic defects, but main
utility may be one of convenience.
Glucovance: available as 1.25-mg glyburide/250-mg
metformin tab, 2.5-mg glyburide/500-mg metformin tab,
and 5-mg glyburide/500-mg metformin tab; not to exceed
20 mg glyburide and 2000 mg metformin; glyburide in
these pills may be more bioavailable than conventional
glyburide tab
Metaglip: available as 2.5-mg glipizide/250-mg
metformin tab, 2.5-mg glipizide/500-mg metformin tab,
Adult Dose
and 5-mg glipizide/500-mg metformin tab; not to exceed
2 tab bid
Avandamet: available as 1-mg rosiglitazone/500-mg
metformin tab, 2-mg rosiglitazone/500-mg metformin tab,
4-mg rosiglitazone/500-mg metformin tab, 2-mg
rosiglitazone/1000-mg metformin tab, and 4-mg
rosiglitazone/1000-mg metformin tab; not to exceed 4-mg
rosiglitazone/1000-mg metformin bid
Contraindications See individual component drugs
Interactions See individual component drugs
Pregnancy
established.
Precautions See individual component drugs
Drug Category: Incretin mimetics -- Mimics glucose-dependent insulin secretion, suppresses elevated glucagon
secretion, and delays gastric emptying.
Exenatide (Byetta) -- Incretin mimetic agent that mimics

glucose-dependent insulin secretion and several other
antihyperglycemic actions of incretins. Improves
glycemic control in patients with type 2 diabetes mellitus
Drug Name
by enhancing glucose-dependent insulin secretion by
pancreatic beta cells, suppresses inappropriately elevated
glucagon secretion, and slows gastric emptying. The
drug's 39–amino acid sequence partially overlaps that of
the human incretin, glucagonlike peptide-1. Indicated as

adjunctive therapy to improve glycemic control in
patients with type 2 diabetes who are taking metformin or
a sulfonylurea but have not achieved glycemic control.
5 mcg SC bid within 1 h ac in morning and evening;
Adult Dose based on response, may increase to 10 mcg SC bid after 1
mo
Contraindications Documented hypersensitivity
Data limited; coadministration decreases digoxin Cmax and
delays Tmax, decreases lovastatin AUC and Cmax, delays
lisinopril Tmax, and decreases acetaminophen AUC and
Cmax, but these pharmacokinetic alterations do not appear
Interactions
to be clinically significant; may decrease absorption of
orally administered drugs (take drugs requiring rapid
absorption, eg, oral contraceptives, antibiotics, at least 1 h
before exenatide)
Pregnancy
established.
Administer in thigh, abdomen, or upper arm; may cause
hypoglycemia, nausea, vomiting, diarrhea, jittery feeling,
Precautions
dizziness, headache, or dyspepsia; may develop
antibodies to protein contents
Drug Category: Insulin agents -- Stimulate proper utilization of glucose by the cells and reduce blood sugar
levels.
Insulin (Humulin multiple types, Novolin multiple types,

Lantus, Apidra) -- Insulin is a vital therapy in many
patients with type 2 diabetes mellitus because the
pancreas ultimately fails to produce enough insulin, even
in the setting of insulin secretagogues, to maintain
glycemic control. Types of insulin and their
characteristics are listed in Image 12. Therapy is largely
empiric, with multiple choices available to achieve
glycemic control (see Image 13). Idealized glucose and
Drug Name insulin patterns with MDI (multiple daily injections) are
shown in Image 14. The DIGAMI trial and the UKPDS
largely have exonerated insulin therapy as atherogenic in
patients with type 2 diabetes mellitus.
Aspart, glargine, glulisine, and lispro are all insulin

analogs (modifications of the insulin molecule to change
absorption characteristics, dissociation in subcutaneous
tissue, and time course of action). All but glargine are
rapid-acting insulins.
Insulin injections should generally be taken in the
abdomen; insulin analogs may be administered in the
limbs if absolutely necessary; pen devices facilitate
convenience and may improve compliance but increase
expense
Adult Dose
Bedtime NPH or glargine: approximately 10-15 U initial
dose, titrate to fasting glucose; not to exceed 60 U bid
Insulin: initiate with approximately 0.5 U/kg with two
thirds in morning and two thirds as NPH, titrate by
SMBG results; for this therapy to be successful, the
injections and meals should be taken at about the same

time every day
Multiple daily injections: 50% as basal insulin (glargine
or ultralente) and preprandial insulin (aspart, glulisine, or
lispro) 20% ac breakfast, 15% ac lunch, and 15% ac
supper; titrate by SMBG results; add metformin or
glitazone if total insulin dose >1-2 U/kg; rapid-acting
insulins should be injected immediately ac; regular insulin
should be injected 20-30 min ac; the timing of other
insulin preparations is variable
Premixed insulins: Novolin and Humulin 70/30 with 70%
NPH and 30% regular insulin; NovoMix 70/30 with NPH-
like profile 70% and 30% aspart; Humalog mix 75/25
with NPH-like profile 75% and 25% lispro
Pediatric Dose Administer as in adults
Documented hypersensitivity (may require desensitization
Contraindications
in some patients); hypoglycemia
Acetazolamide, AIDS antivirals, asparaginase, phenytoin,
nicotine isoniazid, diltiazem, diuretics, corticosteroids,
thiazide diuretics, thyroid products, estrogens, ethacrynic
acid, calcitonin, oral contraceptives, diazoxide,
dobutamine, phenothiazines, cyclophosphamide,
dextrothyroxine, lithium carbonate, epinephrine,
Interactions morphine sulfate, and niacin may decrease hypoglycemic
effects; calcium, ACE inhibitors, alcohol, tetracyclines,
beta-blockers, lithium carbonate, anabolic steroids,
pyridoxine, salicylates, MAOIs, mebendazole,
sulfonamides, phenylbutazone, chloroquine, clofibrate,
fenfluramine, guanethidine, octreotide, pentamidine, and
sulfinpyrazone may increase hypoglycemic effects
Monitor glucose carefully; dose adjustments of insulin
may be necessary in patients diagnosed with renal and
Precautions
hepatic dysfunction; safety of analogs in pregnancy is less
well established
Insulin detemir (Levemir) -- Indicated for qd or bid SC
administration for individuals with type 1 or 2 diabetes
mellitus who require long-acting basal insulin for
hyperglycemia control. Duration of action ranges from
5.7 h (low dose) to 23.2 h (high dose). Prolonged action is
a result of slow systemic absorption of detemir molecules
Drug Name
from injection site. Primary activity is regulation of
glucose metabolism. Binds to insulin receptors and lowers
blood glucose by facilitating cellular uptake of glucose
into skeletal muscle and fat; also inhibits glucose output
from liver. Inhibits lipolysis in adipocytes, inhibits
proteolysis, and enhances protein synthesis.
Administer individualized dose SC qd or bid
Once-daily dosage: Administer with evening meal or hs
Twice-daily dosage: Administer second dose with
evening meal, hs, or 12 h after morning dose
Persons currently receiving only basal insulin can switch
Adult Dose
to insulin detemir on unit-to-unit basis
For insulin-naive patients with type 2 diabetes
inadequately controlled with oral antidiabetic drugs,
initiate at 0.1-0.2 U/kg qd in evening, then adjust to
achieve glycemic control

Contraindications Documented hypersensitivity
Numerous drugs may affect glucose metabolism,
requiring dose adjustment
Drugs that may reduce blood glucose–lowering effect of
insulin are corticosteroids, danazol, diuretics,
sympathomimetic agents (eg, epinephrine, albuterol,
terbutaline), isoniazid, phenothiazine derivatives,
somatropin, thyroid hormones, estrogens, and
progestogens (eg, oral contraceptives)
Drugs that may increase blood glucose–lowering effect of
insulin and susceptibility to hypoglycemia are oral
Interactions antidiabetic drugs, ACE inhibitors, disopyramide,
fibrates, fluoxetine, MAOIs, propoxyphene, salicylates,
somatostatin analog (eg, octreotide), and sulfonamide
antibiotics
Beta-blockers, clonidine, lithium salts, and alcohol may
either potentiate or weaken blood glucose–lowering effect
of insulin; pentamidine may cause hypoglycemia, which
may sometimes be followed by hyperglycemia;
sympatholytics (eg, beta-blockers, clonidine,
guanethidine, reserpine) may reduce signs of
hypoglycemia
Pregnancy
established.
Administer in thigh, abdominal wall, or upper arm; rotate
injection site within same region; most common adverse
effect is hypoglycemia (glucose monitoring required); do
Precautions
not dilute or mix with any other insulin; caution with
renal or hepatic impairment (dose adjustment may be
needed); injection site allergy or lipodystrophy may occur
Drug Category: Amylin analogs -- Mimic endogenous amylin effects by delaying gastric emptying, decreasing
postprandial glucagon release, and modulating appetite.
Pramlintide acetate (Symlin) -- Synthetic analogue of

human amylin, a naturally occurring hormone made in
pancreatic beta cells. Slows gastric emptying, suppresses
postprandial glucagon secretion, and regulates food intake
because of centrally mediated appetite modulation.
Indicated to treat type 1 or type 2 diabetes in combination
with insulin. Administered before mealtime for patients
Drug Name
who have not achieved desired glucose control despite
optimal insulin therapy. Helps achieve lower blood
glucose levels after meals, less fluctuation of blood
glucose levels during the day, and improvement of long-
term control of glucose levels (ie, HbA1C levels)
compared with insulin alone. Additionally, less insulin
use and a reduction in body weight observed.
60 mcg SC ac initially; titrate upward (if no significant
nausea occurs for at least 3 d) to 120 mcg/dose
maintenance; insulin dose must initially be decreased by
Adult Dose
as much as 50% during initiation phase; once target
pramlintide dose achieved, optimize insulin to maintain
glycemic control
Documented hypersensitivity; documented

Contraindications hypersensitivity to metacresol; gastroparesis;
hypoglycemia unawareness
Do not use with other drugs that slow gastric emptying
(eg, anticholinergic agents such as atropine) or drugs that
slow intestinal nutrient absorption (eg, alpha-
Interactions
glucosidase); may delay absorption of concomitantly
administered oral drugs; to avoid this effect, administer
other drug 1 h before or 2 h after pramlintide
Pregnancy
established.
Increases risk of insulin-induced severe hypoglycemia,
especially with type 1 diabetes or gastroparesis; reduce
insulin dose in all patients (either type 2 or type 1
diabetes) when initiating therapy (monitor blood glucose
and adjust insulin dose during initiation phase); common
adverse effects include GI complaints, especially nausea
Precautions
(risk decreased when dose increased gradually); always
use separate insulin syringe to measure and administer, do
not mix in same syringe as insulin (insulin alters
pharmacokinetics); may cause local redness, swelling, or
itching at injection site; do not administer unless ingesting
major meal (ie, >250 calories or 30 g of carbohydrates)
FOLLOW-UP Section 8 of 11

Further Inpatient Care:
• Hospitalization often is necessary in patients with decompensated diabetes mellitus, ie, extreme
hyperglycemia (>600 mg/dL), diabetic ketoacidosis, or nonketotic hyperglycemia (usually present in
type 2 diabetes mellitus in conjunction with intercurrent illness, often infection).
o Therapy with intravenous fluids, electrolyte replacement, intravenous insulin, and treatment of
any concurrent illness is mandatory to correct metabolic disturbance.
o In patients with extreme hyperglycemia, free water deficits are several liters, requiring
massive administrations of free water. The serum osmolality should not be lowered too
quickly. Modest doses of insulin (approximately 2 U/h) should be initiated because dramatic
reductions in the blood glucose concentration may occur with hydration and small doses of
insulin.
Further Outpatient Care:
• The health care provider must consider multiple aspects of the patient's condition at regular visits (eg,
glycemic, blood pressure, and lipid goals; foot care; complications monitoring).
Deterrence/Prevention:
• The Diabetes Primary Prevention trial (DPP) has shown that modest lifestyle changes (eg, 4-5%
sustained weight reduction for approximately 3 y) reduce risk for diabetes in patients at high risk by
58%. Metformin 1700 mg daily was about half as effective.
o The thiazolidinedione, troglitazone, initially was used in the study but was withdrawn in 1999
after a participant taking the drug developed hepatic failure and died. Analysis of available
data from the DPP suggests that the drug was effective in preventing diabetes. This effect was
also seen in the Troglitazone in Prevention of Diabetes (TRIPOD) study of women with a
history of gestational diabetes.
o The experience with troglitazone calls for considerable circumspection before testing a
relatively new drug to prevent a disease.
• Acarbose was shown in the Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-
NIDDM) to reduce diabetes rates by ~25% in patients at high risk for the development of type 2
diabetes.
Complications:
• Coronary heart disease
o The risk for CHD is 2-4 times greater in patients with diabetes than in individuals without
diabetes. Conventional risk factors remain relevant and probably are more important in event
reduction than glycemic control. Control of hypertension, aspirin therapy, and LDL-C
lowering are vitally important in reducing CHD risk.
o The Scandinavian Simvastatin Survival Study (4S) showed a 42% reduction in CHD events in
patients with diabetes with known CHD and very high LDL-C levels with simvastatin therapy
(mean dose 27 mg/d with LDL-C reduction approximately 35%). A smaller reduction was
seen in the Heart Protection Study (HPS) in patients with CHD or other vascular disease and
diabetes. Lesser degrees of risk reduction have been shown in other secondary prevention
studies in patients treated with pravastatin with mild-to-moderate LDL-C elevation at
baseline.
o The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) of patients with hypertension and
no previous CHD enrolled a considerable number of patients with diabetes. However,
atorvastatin 10 mg daily did not reduce CHD risk. The Collaborative Atorvastatin Diabetes
Study (CARDS) did show a significant reduction in CHD risk in patients with type 2 diabetes
mellitus and one other risk factor when treated with atorvastatin 10 mg daily. The diabetic
subgroup of HPS without previous vascular disease also showed a significant reduction in
events when treated with simvastatin 40 mg daily compared to placebo.
o Epidemiologic studies suggest that the LDL-C goal in patients with type 2 diabetes mellitus
should be less than or equal to 100 mg/dL. There is contradictory epidemiologic evidence as
to whether diabetes is in fact a CHD risk equivalent, but for the moment, that is the dogma
adopted by most groups such as the National Cholesterol Education Program (NCEP) and
American Diabetes Association. Recent studies contacting small numbers of patients with
diabetes have led to a suggestion that a lower LDL-C goal of less than 70 mg/dL be
considered in patients at very high risk, including patients with diabetes. However, the NCEP
lists this as a therapeutic option rather than a formal recommendation as of this writing. The
American Diabetes Association guidelines for LDL-C are listed in Image 10. Whether therapy
to reduce triglycerides, a common abnormality in type 2 diabetes mellitus, is efficacious in
reducing events has not been determined from clinical end-point trials.
o The diabetic subgroup in the Veterans Administration HDL Intervention Trial (VA-HIT)
showed approximately 22% reduction in CHD events in patients with diabetes and known
CHD when HDL-C was increased by approximately 6% by gemfibrozil. This was a low LDL-
C population, so whether these same benefits would accrue in patients with elevated LDL-C
who are treated with a statin before addressing their low HDL-C is unclear. Some of the statin
trials suggest that statin therapy eliminates some of the excess risk for low HDL-C in patients
with LDL-C elevation at baseline. For further discussion, see information on
Hypercholesterolemia, Polygenic.
• Retinopathy
o Patients with established retinopathy should see an ophthalmologist every 6-12 months or
more often as necessary.
o Early background retinopathy may reverse with improved glycemic control. More advanced
retinopathy does not regress with improved glycemia and may worsen, rarely, with short-term
marked improvements in glycemia. Hypertension control is of paramount importance in these
latter patients.
o Laser photocoagulation has improved markedly the ability of ophthalmologists to preserve
sight in patients with diabetes and proliferative retinopathy or macular edema.
o While only noticed anecdotally at this point, therapy with glitazones appears to be associated
with refractory macular edema in rare cases.
• Neuropathy
o Peripheral neuropathy is the most common complication observed in patients with type 2
diabetes in outpatient clinics. Patients may have paresthesias, numbness, or pain. The feet are
involved more often than the hands.
o Improved glycemic control early may alleviate some of the symptoms, although sometimes
symptoms actually worsen with lowering blood glucose levels. Later symptomatic therapy
largely is empiric, including low-dose tricyclic antidepressants, duloxetine, anticonvulsants
(eg, phenytoin, gabapentin, carbamazepine), topical capsaicin, and various pain medications,
including nonsteroidal anti-inflammatory drugs.
o Protection of the feet by applying lubricating agents (but not between the toes) and wearing
appropriate footwear (shoes and socks or stockings) is important. Rarely is prescription
footwear needed, but shoes must be comfortable and fit well. Daily inspection of the feet after
bathing is mandatory. In patients with advanced neuropathy, water temperature must be
checked by a companion or with a thermometer. Soaking the feet generally is not
recommended and may be harmful.
o Examination of the feet at regular visits to the health care provider also is important.
Symptoms usually are indicative of disease. Screening can be carried out using a 10-gauge
monofilament. Early lesions often can be treated with local care (eg, file or otherwise partially
remove calluses and debride shallow ulcers), preventing them from becoming major problems
that lead to amputations. More advanced lesions require the attention of a foot care specialist.
Nonhealing ulcers often are neuropathic and vasculogenic. Revascularization, local foot care,
and antibiotics are valuable modalities in treating advanced lesions. The role of hyperbaric
oxygen and platelet growth factor extracts is debatable.
o Gastroparesis usually is less of a problem in patients with type 2 diabetes mellitus. Improved
glycemic control, discontinuation of medications that slow gastric motility, and the use of
metoclopramide (preferably for only a few days at a time) may be helpful.
o Autonomic neuropathy may manifest as orthostatic hypotension. Such patients may require
volume expanders or adrenergic agents.
o Cystopathy may benefit from cholinergic agents.
o Erectile dysfunction often is neuropathic and vasculogenic. Hormonal deficiencies should be
ruled out. Decreased testicular pain sensation and diminished cremasteric reflexes suggest
neuropathic problems. Sildenafil and similar agents are effective in about one half of patients
with diabetes and erectile dysfunction.
• Nephropathy
o Diabetes mellitus, and particularly type 2 diabetes mellitus, is the biggest contributor
numerically to the development of ESRD in the United States.
o Glycemic and BP control are most important for prevention of nephropathy, and BP control is
most important for retarding the progression of established nephropathy. Inhibitors of the
renin angiotensin system are the first recommended treatment modality. (The clinical trial data
are more compelling for ACE inhibitors for type 1 diabetes and angiotensin receptor blockers
for type 2 diabetes.) Diuretics frequently are necessary because of the volume-expanded state
of the patient. Loop diuretics administered at least twice daily are necessary once the
creatinine clearance is less than 30 mL/min.
o The National Kidney Foundation and Sixth Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)
recommend that patients with greater than 1 g proteinuria/d have their BP goal be less than
120/75 mm Hg. This goal often is difficult to achieve. For further information, see
Hypertension and Nephrotic Syndrome.
• Peripheral vascular disease
o Claudication and nonhealing foot ulcers are common in patients with type 2 diabetes mellitus.
For the latter problem, see the neuropathy discussion.
o Smoking cessation, correction of lipid abnormalities, and antiplatelet therapy are important
strategies in treating claudication. Pentoxifylline or cilostazol may be useful in selected
patients. Revascularization is vital in selected patients.
Prognosis:
• Cardiovascular disease is the major source of mortality in patients with type 2 diabetes mellitus.
• Recent studies suggest that broad-based focus in treatment (eg, glycemia, nutrition, exercise, lipids,
hypertension, smoking cessation) is much more likely to reduce the burden of excess microvascular
and macrovascular events.
Patient Education:
• No longer is it satisfactory to provide patients who have diabetes with brief instructions and a few
pamphlets and expect them to manage their disease adequately. An apt sports analogy would be the
patient as the player on the field and the physician, nutritionist, diabetes educator, and other health
professionals as spectators on the sidelines instructing and cheering on the patient.
• Nonphysician health professionals usually are much more proficient at diabetes education and have
much more time for this very important activity. Believing that diabetes education is limited to 1 or 2
encounters is misguided; it is a lifetime exercise.
• For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's
patient education article Diabetes.
MISCELLANEOUS Section 9 of 11

Medical/Legal Pitfalls:
• Failure to examine the feet of patients with diabetes probably is the most dangerous medicolegal pitfall
for the health care provider. Most amputations are preventable.
Special Concerns:
• Type 2 diabetes mellitus usually can be differentiated from type 1 diabetes mellitus by history and
physical examination findings and simple laboratory tests. Obesity (present or a previous history),
being a member of a high-risk minority group, family history of type 2 diabetes mellitus, history of
gestational diabetes mellitus, having acanthosis nigricans, history of response to oral agents for more
than a few months, and having a characteristic diabetic dyslipidemia (ie, high triglycerides and low
HDL-C) suggest individually, as well in the aggregate, that the patient has type 2 diabetes mellitus.

Diabetes Mellitus

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DIABETES MELLITUS TIPE 2

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Pathophysiology: Hyperglycemia is produced by lack of endogenous insulin, which is either absolute, as in

Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However,

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Diabetes Mellitus, Type 1

Other Problems to be Considered:

Latent autoimmune diabetes of adults (LADA)

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

o Microvascular complications (predominantly the need for laser photocoagulation on retinal

• A previously sedentary patient should start activities slowly.

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Glyburide (Micronase, DiaBeta, Glynase) -- Second-

Repaglinide (Prandin) -- Probably most useful in patients

miconazole, erythromycin) decrease metabolism, thus

Metformin (generic, Glucophage, Glucophage XR,

and should be titrated up slowly from 500 mg daily.

Rosiglitazone (Avandia) -- Indicated as monotherapy and

hematocrit, and white blood cell counts; weight gain (both

Acarbose (Precose), Miglitol (Glyset) -- Acarbose was

effects; diuretics (ie, thiazide), corticosteroids,

Combination tablets -- Indicated for initial therapy or

Exenatide (Byetta) -- Incretin mimetic agent that mimics

the human incretin, glucagonlike peptide-1. Indicated as

Insulin (Humulin multiple types, Novolin multiple types,

Aspart, glargine, glulisine, and lispro are all insulin

injections and meals should be taken at about the same

Pediatric Dose Not established

Pramlintide acetate (Symlin) -- Synthetic analogue of

Documented hypersensitivity; documented

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Further Inpatient Care:

Further Outpatient Care:

• Coronary heart disease

• Peripheral vascular disease

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

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