Current antihyperglycemic treatment strategies for patients with type 2 diabetes mellitus

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The current epidemics of excessive weight and type 2 diabetes mellitus (T2DM) cause significant morbidity and mortality. T2DM frequently coexists with excess weight as well as hypertension and dyslipidemia, placing a significant percentage of the population at an elevated risk of cardiovascular disease. Maintaining effective glycemic control is linked with a diminished risk of developing microvascular complications, and recent studies have shown it may also reduce overall macro­vascular complications. Reduction of associated risk factors, including those related to excessive weight, high blood pressure, and dyslipidemia, are also necessary to meaningfully decrease cardiovascular risk. Agents that can improve glycemia with weight neutrality or weight loss could offer additional benefit to overweight patients with T2DM. Although the major pathophysiologic defects in T2DM are recognized to be beta-cell dysfunction and peripheral insulin resistance, derangements in the incretin system may contribute as well. Antidiabetes agents targeting this system include dipeptidyl peptidase–4 (DPP-4) inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists. Both classes have been shown to significantly reduce hyperglycemia. GLP-1 receptor agonists also promote significant weight loss and have potentially beneficial effects on cardiovascular risk markers.


  • Up to 65% of deaths among people with diabetes are caused by cardiovascular disease.
  • Glycemic control can delay or slow the progression of microvascular complications.
  • In addition to hyperglycemia, comprehensive diabetes therapy must target cardiovascular disease–related risk factors, including excess weight/obesity, elevated blood pressure, and abnormal lipid concentrations.
  • Diminished incretin hormonal activity contributes to the pathophysiology of diabetes.



Data from the Centers for Disease Control and Prevention indicate that almost 24 million Americans, or 7.8% of the population, have diabetes; 90% to 95% of these have type 2 diabetes mellitus (T2DM). 1 Diabetes and excessive weight often coexist. An analysis of data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES) showed that among individuals with diabetes, 85% were overweight or obese and 55% were obese. 2

Gaps remain in the management of T2DM between the goals for clinical parameters of care (eg, control of glucose, blood pressure [BP], and lipids) and actual clinical practice. 3 NHANES data reveal that glycemic control improved from a mean glycosylated hemoglobin A1c (HbA1c) of 7.82% in 1999–2000 to 7.18% in 2003–2004. 4 Hazard models based on the United Kingdom Prospective Diabetes Study (UKPDS) 10-year outcomes data in 4,320 newly diagnosed T2DM patients suggest that a sustained decrease in HbA1c of 0.511 percentage points could reduce diabetes complications by 10.7%. 4,5

Additional analysis of NHANES data showed that in 2003–2004, about 57% of individuals achieved glycemic control, 48% reached BP targets, and 50% achieved target cholesterol goals.Only about 13% of diabetes patients achieved their target goals for all three parameters concurrently. 6

This article reviews the association between cardiometabolic risk and the current antihyperglycemic treatments for patients with T2DM, with a focus on the role of incretin-related therapies.


Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among people with diabetes and is the reported cause of mortality in up to 65% of deaths in persons with diabetes in the United States. 7 The risk of CVD is two- to fourfold greater among adults with diabetes than among adults who do not have diabetes. 8 The risk of CVD in patients with T2DM was evident in the UKPDS 17, where macrovascular complications, including CVD, were about twice as common as microvascular complications (20% vs 9%) after 9 years of follow-up. 9 A study that involved more than 44,000 patients showed an almost double rate of mortality from all causes among individuals with T2DM compared with those with no diabetes (hazard ratio, 1.93; 95% confidence interval, 1.89 to 1.97). 10 Current guidelines recommend aggressive management of CV risk factors, including BP control, correction of atherogenic dyslipidemia, glycemic control, weight reduction for those who are overweight or obese, and smoking cessation for those who smoke. 3,11 Lifestyle interventions, including weight reduction and appropriately prescribed physical activity, result in reduced CV risk factors, which can help slow the progression of T2DM. 12


Several studies have demonstrated that glycemic control can delay or prevent the development and progression of microvascular complications. 13,14 UKPDS 33 showed that more intensive blood glucose control (median HbA1c 7.0%) in patients with T2DM followed over 10 years significantly ( P = .029) reduced the risk for any diabetes-related end point by 12% compared with conventional therapy (median HbA1c 7.9%). Most of the risk reduction was accounted for by a 25% risk reduction in microvascular end points ( P = .0099). 13 Another report (UKPDS 35) demonstrated that HbA1c was strongly related to microvascular effects, with a 1% reduction in HbA1c associated with a 37% reduction in microvascular complications. 14


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Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus

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