Muscle

Fig. 2. Antidiabetic agents and their mechanisms of action. The variety of antidiabetic agents for the treatment of type 2 diabetes target different mechanisms in the underlying pathogenesis of the disease. Sulfonylureas and the glitinides (repaglinide, nateglinide) are insulin secretagogues that stimulate release of insulin from the pancreas. Metformin, a biguanide, improves insulin sensitivity chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. The thiazolidinediones (rosiglita-zone, pioglitazone) improve insulin sensitivity primarily in the muscle, thereby increasing peripheral uptake and utilization of glucose. The a-glucosidase inhibitors (acarbose, precose) prevent the breakdown of carbohydrates to glucose in the gut, by inhibiting the enzymes that catalyze this process, thereby delaying carbohydrate absorption. Insulin and insulin analogs increase insulin levels in the presence of declining P-cell function and diminished endogenous insulin secretion. Exenatide and the synthetic amylin, pram-lintide exploit novel mechanisms related to effects on glucagon secretion, gastric emptying, and satiety. (From DeFronzo (53). Reprinted from Annals of Internal Medicine with permission from American College of Physicians.)

inhibiting the enzymes that catalyze this process, thereby delaying carbohydrate absorption. Sitagliptin, a dipeptidyl-peptidase (DPP)-IV inhibitor, is an agent that reduces blood glucose with less risk of hypoglycemia. Met-formin is recommended as first choice for pharmacologic treatment and has good efficacy to lower HbA1c by approximately 1-1.5% as monotherapy (57). However, most patients will eventually require treatment with combinations of oral medications with different mechanisms of action simultaneously in order to attain adequate glycemic control. Table 3 lists the available classes of oral antidiabetic medications, their mechanisms of action, and side effects.

Table 3

Available oral antidiabetic agents

Drug class

Mechanism of action

Major side effects

Sulfonylureas

Meglitinides

Metformin

Thiazolidinediones a-Glucosidase inhibitors

Stimulate insulin secretion Suppress hepatic glucose production (major) Improve insulin sensitivity in target tissues (minor) Improve insulin sensitivity in target tissues (major) Suppress hepatic glucose production (minor) Delay carbohydrate absorption from the intestine

Weight gain Hypoglycemia GI side effects Lactic acidosis (rare)

Weight gain

Edema Congestive heart failure

Flatulence or abdominal discomfort

Adapted and summarized from Florez et al. (56).

Injectable Therapy

Injectable agents for treatment of insulin-deficient T2D include traditional insulin preparations, newer insulin analogs, amylin, and incretin mimetics (see Fig. 2). Insulin and the insulin analogs increase circulating insulin levels in the presence of declining |-cell function and diminished endogenous insulin secretion. Insulin and analogs, available in both long-acting and rapid-acting formulations, can be used in combination with oral agents in T2D or as insulin replacement therapy in long-standing, insulin-deficient T2D (56). Therecent additions to the market, the incretin mimetic exenatide and the synthetic amylin, pramlintide, exploit novel mechanisms related to effects on glucagon secretion, gastric emptying, and satiety to improve glycemic control (58, 59).

Other Strategies for Reduction of Comorbidities and Complications

In addition to hyperglycemia, individuals with T2D often have a constellation of other metabolic abnormalities which increase their CVD risk (60-64). Risk determinants of CVD include the presence or absence of coronary heart disease (CHD), other clinical forms of atherosclerotic disease, and the major risk factors: high LDL cholesterol, cigarette smoking, hypertension, low HDL cholesterol, family history of premature CHD (defined as a relative with CHD younger than 65 years for women and 55

years for men), and age (men > 45 years, women > 55 years). It is important to point out that diabetes is considered to be a CHD equivalent, so the goal for LDL cholesterol is <100mg/dl. Based on these risk determinants, the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) identifies three categories of risk that modify the goals and modalities of LDL-lowering therapy (65) (Tables 4 and 5). In very high-risk persons, an LDL-C goal of <70 mg/dl is a therapeutic option on the basis of available clinical trial evidence (66). The justification for the more aggressive LDL targets in patients with diabetes with CVD is based on three large statin-outcome trials: the Heart Protection Study (HPS), the Treating to New Targets (TNT) Study, and the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) Study, which also identified the diabetic subgroup as a cohort of patients with high residual risk even on statin therapy (67-69).

Table 4

ATP III classification of LDL, total, and HDL cholesterol (mg/dl).*

Table 4

ATP III classification of LDL, total, and HDL cholesterol (mg/dl).*

LDL cholesterol

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