AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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, patients are not absolutely dependent upon insulin for life, even though many of these patients are ultimately 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.¹

Frequency

United States

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.

International

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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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  

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Other Problems to be Considered

Latent autoimmune diabetes of adults (LADA)
Stein-Leventhal syndrome

WORKUP

Section 5 of 11  

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• Introduction
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• Follow-up
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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).

• 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 chemistry 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.
• The noted values for fasting glucose measurements are based on the level of glycemia at which retinopathy, a fairly pathognomic diabetic complication, appears. (However, recent evidence suggests that retinopathy may even occur in prediabetes.) Fasting glucose measurements are not as predictive for indicating macrovascular risk as post-glucose load values. However, there are no formal recommendations for using glucose tolerance tests for this purpose.
• The World Health Organization criteria for impaired glucose tolerance (IGT) are below. 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).
• • 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

Hemoglobin A1c (HbA1c or A1c) or glycosylated hemoglobin (GHb) measurements are not useful for the diagnosis of diabetes mellitus because they are not standardized internationally 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. Using 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 is probably 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.
• Latent autoimmune diabetes of adults, or 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.

CME/CE is available for recent guidelines for screening for and treating diabetes. See Practice Guidelines Issued for Screening, Diagnosing, and Treating Diabetes.

TREATMENT

Section 6 of 11  

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• Introduction
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• Follow-up
• Miscellaneous
• Multimedia
• References

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:
• • Microvascular complications (predominantly the need for laser photocoagulation on retinal lesions) are reduced by 25% when median HbA1c is 7% compared to 7.9%.
  • 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.
  • 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.
  • Sulfonylureas and insulin therapy do not increase macrovascular disease risk.
  • Metformin reduces macrovascular risk in patients who are obese.
  • 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%.
• • 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 practitioners 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.
  • Decisions about glycemic management are generally 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 used, 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. For additional resources, please see Diabetic Microvascular Complications.
• 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 is also 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 who require insulin, scheduled doses of insulin, as opposed to sliding scale insulin, are far more effective in achieving glycemic control.
• • 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).
  • In the case of cardiac ischemia, the beneficial effects may be due to reducing free fatty acids with insulin therapy.
  • 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 who require 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.
• • 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. Oral antidiabetic agents can be restarted when the patient is stable and eating. Insulin secretagogues should be used with caution in the hospital since food intake may be interrupted by diagnostic tests and procedures. Metformin may have to be started at a lower dose and gradually titrated to full dose due to gastrointestinal side effects. Since glitazones have such a long biologic effect, their omission in the hospital is usually inconsequential. The role of incretins in the hospital has not yet been defined.
  • For patients who require 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 is clearly 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 pregnant 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 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.

CME/CE is available for revised guidelines on the management of type 2 diabetes. See Guidelines Revised for Management of Type 2 Diabetes Mellitus.

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 providers 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 of what 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 saturated fats and simple sugars is 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.

CME/CE is available for recently released nutritional guidelines. See American Diabetes Association Updates Guidelines for Medical Nutrition Therapy.

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 financial 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 regimen.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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% are usually 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), and in previously diabetes drug-naive patients.

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 possibly 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 were 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 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. Recent animal work suggests that concomitant therapy with the diuretic amiloride may reduce fluid retention related to glitazone therapy.

A recently published study (PROactive) assessed the effect of pioglitazone titrated to 45 mg/d versus placebo added to existing diabetes therapy on macrovascular outcomes. No statistically significant difference was noted between the two groups at 3 years. A later developed main secondary endpoint (all cause mortality, nonfatal myocardial infarction, and stroke) not mentioned in the original study design was reduced 16% (p=0.027). Treated patients gained 4 kg on average and had a much higher rate of heart failure and edema than patients treated with placebo. The author views this study as primarily a confirmation of concerns over weight gain, edema, and congestive heart failure with these drugs and thinks their potential antiatherosclerotic effects are still unproven.

The incretin-mimetic, exenatide, has a novel mechanism of action. Mimicking the endogenous incretin, glucagon-like peptide-1 (GLP-1), 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. Studies have used exenatide in addition to metformin and/or a sulfonylurea. Patients may attain modest weight loss. 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 more expensive than high-dose glitazone therapy. It does have the advantage of ease of titration (only two possible doses, with most patients progressing to the higher dose) than insulin.

The newest addition to available oral hypoglycemic agents is the dipeptidyl peptidase IV (DPP-4) inhibitor, sitagliptin, which gained FDA approval in October 2006. DPP-4 degrades numerous biologically active peptides including the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). Sitagliptin can be used as a monotherapy or in combination with metformin or the thiazolidinediones. It is a once daily drug and is weight neutral. Another DPP-4 inhibitor, vildagliptin, is currently under review at the FDA. Exenatide exhibits resistance to DPP-4 and, thus, has a longer half life than GLP-1.

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 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 patient should be warned 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 injectable 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 of exenatide 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. If exenatide is used, the author monitors fasting and postprandial sugars, expecting a marked flattening of the postprandial rise in glucose concentrations.

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 clinician 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 dosing of insulin gives the patient the greatest flexibility. In this approach, insulin glargine or twice daily insulin detemir is generally given as the basal insulin, and rapid-acting insulin (eg, aspart, glulisine, lispro) are administered just before each meal. 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 premeal insulin can be titrated to the next premeal sugar and, in some cases, a postprandial (~2 h) value.

For patients trying to achieve near euglycemia, premeal 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.

In January 2006, the first inhaled insulin (Exubera) was approved by the FDA as a rapid-acting prandial insulin. It does not produce better glycemic control than conventionally injected insulins and requires a mildly cumbersome device, skill to deliver an accurate dose (up to a few min to deliver 1 dose), and pulmonary function monitoring due to concerns about lung toxicity over time. The powder insulin comes in a 1 mg and a 3 mg packet approximately converted to 3 units and 8 units of subcutaneous aqueous insulin, respectively. Dose titration requires certain combinations of the available preparations and, thus, multiple deliveries at a time. In the author's opinion, inhaled insulin offers no advantage except convenience, but highly needle-phobic patients may find it useful. On October 18, 2007, Pfizer Inc announced that it was no longer making inhaled insulin (Exubera). The decision was not based on any safety concerns but was due to economic feasibility resulting from too few patients taking the inhaled insulin. Pfizer indicated that it would work with clinicians over a period of several months to transition patients from inhaled insulin to other treatment options.

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 and Image 13. 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.

Drug Category: Meglitinides

Short-acting insulin secretagogues with preprandial dosing, potentially achieving more physiologic insulin release and less risk for hypoglycemia.

Drug Category: Biguanides

Decrease the amount of glucose produced by the liver and may help improve insulin sensitivity.

Drug Category: Thiazolidinediones (glitazones)

Improve target cell response (ie, muscle, fat) to insulin without increasing insulin secretion. Redistribute adipose tissue.

The US Food and Drug Administration issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
 
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD) including the following articles: 1) Rosiglitazone increases MI and CV death in meta-analysis, 2) The rosiglitazone aftermath: Legitimate concerns or hype? and 3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers.

Drug Category: Alpha-glucosidase inhibitors

These agents delay sugar absorption and help prevent postprandial glucose surges.

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.

Drug Category: Incretin mimetics

Mimic glucose-dependent insulin secretion, suppresses elevated glucagon secretion, and delays gastric emptying.

Drug Category: Insulin agents

Stimulate proper utilization of glucose by the cells and reduce blood sugar levels.