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Am Fam Physician. 2003;67(3):639-643

The prevalence of diabetes mellitus is increasing in the United States, along with the resultant morbidities of blindness, end-stage renal disease, myocardial infarction, stroke, and amputations. Improved glycemic control clearly decreases the incidence and progression of retinopathy, nephropathy, microalbuminuria, and microvascular and macrovascular disease, and lowers the costs of diabetes management as well. Insulin resistance, increased hepatic glucose production, and decreased ability to secrete insulin are the pathologies that cause type 2 diabetes. Lifestyle modification has been found effective in delaying or preventing the onset of diabetes, but these steps rarely control hyperglycemia once the disease is overt. Weissman reviewed the management of type 2 diabetes mellitus with special attention to the issue of insulin resistance.

Early intervention is recommended because complications—usually macrovascular—often begin in the prediabetic phase. Treatment with sulfonylureas, metformin, or insulin reduces the incidence or progression of microvascular complications, and reducing the mean glycosylated hemoglobin (HbA1c) level may lower the risk of myocardial infarction and stroke.

Pharmacologic management options include thiazolidinediones, biguanides, insulin secretogogues, and alpha-glucosidase inhibitors. The thiazolidinediones increase insulin sensitivity in the peripheral organs, including muscle, liver, and adipose tissue, and improve glucose disposal. The two available agents, rosiglitazone and pioglitazone, improve glycemic control and circulating insulin. There may also be an improvement in pancreatic beta-cell function. Thiazolidinediones can decrease HbA1c levels by as much as 1.5 percent, with greater reductions possible in obese patients. Thiazolidinediones also can be combined with metformin or sulfonylureas to get greater reductions in circulating glucose and HbA1c levels. The adverse-effect profile is minimal, with low risk for hypoglycemia, although idiosyncratic liver inflammations can occur. Biguanides decrease gluconeogenesis in the liver. Metformin, the only biguanide currently available in the United States, can be used alone or in combination with sulfonylureas. Decreases in HbA1c level of 1 to 2 percent (with a linear dosing efficacy up to 2,000 mg per day) can be obtained without stimulating insulin secretion. Lactic acidosis is the most serious adverse effect and is more common in patients with renal disease or advanced age because of drug accumulation.

Insulin secretogogues increase basal and postprandial insulin secretion and can lower HbA1c levels by 1 to 2 percent. These medications often do not achieve glucose control when used alone. Hypoglycemia is a more common adverse event among older patients, patients who restrict carbohydrate intake or use alcohol or drugs, and patients with renal or hepatic disease. The alpha-glucosidase inhibitors, acarbose and miglitol, delay carbohydrate absorption, resulting in lower postprandial glucose levels and an HbA1c decrease of 0.5 to 1 percent. These drugs can be used with diet alone or with other oral hypoglycemic agents. Acarbose has been used with insulin to decrease glucose levels. Adverse effects include gastrointestinal symptoms. Insulin is useful when patients have not normalized their HbA1c levels with maximal dosages of oral medications, or at other times, as noted inthe accompanying table. Many patients eventually require insulin therapy because of the natural progression of type 2 diabetes.

Hyperglycemia with maximal oral therapy
Decompensation periods (acute injury, stress, infection, severe weight loss)
Renal disease
Serious reaction to oral agents

Combination therapies are probably best to control glucose levels, especially as the disease progresses. Thiazolidinediones are probably useful early in the disease because of their effect on lowering insulin resistance and their documented synergistic benefits with other oral preparations. Other considerations in determining the type of oral therapy for type 2 diabetes include mechanism of action, safety profile, urgency for glucose normalization, and other effects of the medications. Other components of type 2 diabetes treatment include management of nonglycemic risk factors, including dyslipidemia, hypertension, and, possibly, hormone replacement.

The author concludes that aggressive treatment of type 2 diabetes will decrease the incidence of complications. Thiazolidinediones appear to be particularly useful because of their association with increased insulin sensitivity and improved lipid profiles and vascular response in patients with type 2 diabetes.

editor's note:Thiazolidinediones are the newest family of antidiabetic medications. They target insulin receptors, which play a major role in the associated metabolic syndrome characterized by obesity, dyslipidemia, hypertension, and endothelial dysfunction. This syndrome is strongly associated with increased cardiovascular risk. Because thiazolidinediones activate peroxisome proliferator-activated receptors (PPARs) implicated in other functions besides lipid and glucose metabolism, these medications may be effective in treating other conditions associated with insulin resistance, including polycystic ovary syndrome and human immunodeficiency virus–associated lipodystrophy. PPARs also regulate gene expression, affecting vascular tone and inflammation. Modulation of PPAR-gamma agonist activity may improve endothelial function, decrease inflammatory conditions, decrease serum free fatty acids, and lower blood pressure. More study is needed to evaluate the positive potential, as well as to look at adverse effects such as hepatotoxicity, increased low-density lipoprotein cholesterol levels, and increased edema introduced by thiazolidinediones. Long-term trials of the effect of thiazolidinediones on cardiovascular mortality are currently in progress.—R.S.

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