Pharmacologic Therapy for Type 2 Diabetes Mellitus

In the United States, approximately 15.6 million persons have type 2 diabetes mellitus, and about 13.4 million have impaired glucose tolerance (1). Throughout the world, the prevalence of type 2 diabetes mellitus has increased dramatically in the past two decades (1). Decreased physical activity, increasing obesity, and changes in food consumption have been implicated in this epidemic (2). Patients with diabetes experience significant morbidity and mortality from microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (heart attacks, stroke, and peripheral vascular disease) complications. Proliferative retinopathy, macular edema, or both occur in 40% to 50% of patients with type 2 diabetes, and diabetes is the leading cause of blindness in the United States (3). The prevalence of renal disease varies considerably among ethnic populations, from 5% to 10% in white persons to 50% in Native Americans (4). Diabetes is the leading cause of end-stage renal failure, accounting for one of every three patients who enter dialysis or transplantation programs (4). Peripheral and autonomic neuropathy occur in 50% to 60% of patients with type 2 diabetes, whereas heart attacks and stroke occur two to four times more frequently in persons with diabetes than in those without the disease (5). The cost of treating diabetes and associated microvascular and macrovascular complications exceeds $100 billion per year (6). I briefly review the pathogenesis of type 2 diabetes mellitus; provide a rationale for the importance of good glycemic control in this disease; and provide a therapeutic strategy, with a focus on oral agents alone and in combination with each other and with insulin. Indications for insulin are discussed briefly, but the major emphasis is on therapy with oral agents. This review primarily relies on evidence-based medicine. Wherever possible, the results of large, prospective, double-blind, placebo-controlled studies published in peer-reviewed journals have been used. For several of the recently approved oral agents, I used information filed by the drug company with the U.S. Food and Drug Administration (FDA). Where controversy exists, I delineate both points of view and offer commentary that attempts to synthesize and reconcile published results. Statements that are not founded on evidence-based medicine are clearly indicated. Pathogenesis of Type 2 Diabetes Mellitus The appropriate treatment of any disease is based on an understanding of its pathophysiology (7). The mechanisms responsible for impaired glucose homeostasis in type 2 diabetes mellitus (Figure 1) are discussed briefly to provide the foundation for discussion of currently available oral agents, including their mechanism of action, efficacy, and side effects. Figure 1. Pathogenesis of type 2 diabetes mellitus. After ingestion of glucose, maintenance of normal glucose tolerance depends on three events that must occur in a tightly coordinated fashion: 1) stimulation of insulin secretion; 2) insulin-mediated suppression of endogenous [primarily hepatic] glucose production by the resultant hyperinsulinemia; and 3) insulin-mediated stimulation of glucose uptake by peripheral tissues, primarily muscle. Hyperglycemia also has its own independent effect of suppressing hepatic glucose production and enhancing muscle glucose uptake, but these effects are modest compared to those of insulin. In patients with type 2 diabetes and established fasting hyperglycemia, the rate of basal hepatic glucose production is excessive, despite plasma insulin concentrations that are increased twofold to fourfold (8) (Figure 1). These findings provide unequivocal evidence for hepatic resistance to insulin, and this evidence is substantiated by an impaired ability of insulin to suppress hepatic glucose production (9). Accelerated gluconeogenesis is the major abnormality responsible for the increased rate of basal hepatic glucose production (10). The increased rate of basal hepatic glucose production is closely correlated with the increase in fasting plasma glucose level (7-10). Because the fasting plasma glucose level is the major determinant of the mean day-long blood glucose level (which clinically is reflected by the hemoglobin A1c [HbA1c] value), it follows that agents that reduce the elevated basal rate of hepatic glucose production will be especially effective in improving glycemic control (Figure 1). Muscle tissue in patients with type 2 diabetes is resistant to insulin (7, 9, 11) (Figure 1). Defects in insulin receptor function, insulin receptor-signal transduction pathway, glucose transport and phosphorylation, glycogen synthesis, and glucose oxidation contribute to muscle insulin resistance (7). In response to a meal, the ability of endogenously secreted insulin to augment muscle glucose uptake is markedly impaired (12, 13), and muscle insulin resistance and impaired suppression of hepatic glucose production contribute approximately equally to the excessive postprandial increase in the plasma glucose level (13). It follows that drugs that improve muscle insulin sensitivity will be effective in decreasing the excessive increase in plasma glucose level after carbohydrate ingestion (Figure 1). From a quantitative standpoint, however, in diabetic patients with established fasting hyperglycemia (glucose level>7.8 mmol/L [>140 mg/dL]), the excessive increase in the plasma glucose level above baseline after a meal plays a much smaller role in determining the mean day-long plasma glucose concentration than does the elevated fasting plasma glucose level. This is clear from studies that have examined the mean day-long glycemic excursions in diabetic patients who consume typical mixed meals. For example, in a study by Jeppesen and colleagues (14), the fasting glucose level in diabetic patients was (10.6 mmol/L [190 mg/dL]), indicating an increase in basal glucose level of 5.6 mmol/L (100 mg/dL) above that in nondiabetic controls (5 mmol/L [90 mg/dL]). This increase above baseline was present 24 hours per day, giving a hyperglycemic index of 2400 (100 mg/dL 24 hours). After each of three daily meals, the increase in plasma glucose concentration was greater in diabetic patients than in controls by about 1.9 mmol/L (35 mg/dL) but returned to the baseline value by 4 to 6 hours. The hyperglycemic index accounted for by the excessive increase in plasma glucose level during each meal is 525 (35 mg/dL 3 meals 5 hours). Thus, the contribution of postprandial hyperglycemia to day-long hyperglycemia is only 22% (525/2400). Impaired insulin secretion also plays a major role in the pathogenesis of glucose intolerance in patients with type 2 diabetes (15). Although debate still continues about which defectinsulin resistance or impaired insulin secretioninitiates the cascade of events leading to overt diabetes mellitus , essentially all patients who have type 2 diabetes with elevated fasting plasma glucose levels have a defect in insulin secretion (15). In diabetic patients with mild fasting hyperglycemia (glucose level<7.8 mmol/L [<140 mg/dL]), plasma insulin levels during an oral glucose tolerance test or a mixed meal usually are elevated in absolute terms (16). However, relative to the severity of insulin resistance and prevailing hyperglycemia, even these elevated plasma insulin levels are deficient (16, 17). As the fasting plasma glucose level increases to more than 7.8 mmol/L (>140 mg/dL), insulin secretion decreases progressively, and essentially all diabetic patients with a fasting plasma glucose level that exceeds 10.0 to 11.1 mmol/L (180 to 200 mg/dL) have a plasma insulin response that is deficient in absolute terms (16, 17). It follows, therefore, that drugs that improve insulin secretion will be effective in treating type 2 diabetes (Figure 1). In summary, patients with type 2 diabetes mellitus are characterized by defects in both insulin secretion and insulin action. A recent extensive review (7) provides more detailed discussion about the pathogenesis of type 2 diabetes mellitus. Glycemic Control and Complications The Diabetes Control and Complications Trial (DCCT) (18) established that in type 1 diabetes mellitus, the risk for microvascular complications could be reduced by maintaining near-normal blood glucose levels with intensive insulin therapy. No glycemic threshold for the development of long-term microvascular complications was observed in the DCCT (19). As the HbA1c value was reduced to less than 8.0%, the risk for microvascular complications continued to decrease (19). Until recently, no large prospective long-term study had demonstrated that improved glycemic control in patients with type 2 diabetes can prevent microvascular complications. Nonetheless, convincing arguments suggested that the DCCT results could be extrapolated to type 2 diabetes. First, retinal, renal, and neurologic anatomical lesions seem to be identical in type 1 and type 2 diabetes mellitus (3, 20, 21). Second, epidemiologic studies have shown a close association between glycemic control and microvascular complications (3, 22-24). Third, a randomized clinical trial in Japanese patients with type 2 diabetes (15) showed that attainment of near-normal glycemia with intensive insulin therapy resulted in improvements in retinopathy, nephropathy, and neuropathy similar to those observed in the DCCT. Finally, short-term prospective studies (25, 26) have shown that reduction of the plasma glucose level reduces microalbuminuria and improves nerve conduction velocity in patients with type 2 diabetes. On the basis of these arguments, most diabetes experts have concluded that the DCCT results are applicable to type 2 diabetes mellitus (27). More definitive information on the relation between improved glycemic control and prevention of complications was recently provided by the United Kingdom Prospective Diabetes Study (UKPDS) (28, 29). In the main randomization group of the UKPDS (28), after a diet