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

Does intensive glucose control reduce CV risk?

To resolve the ongoing question of whether intensive glucose control can lead to a reduction in CV risk in patients with T2DM, three large, long-term trials were conducted within the last decade.15–18 Two of these, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials, each enrolled more than 10,000 previously treated patients with long-standing T2DM. Patients were randomized to standard or intensive glycemic control for 3.5 years in the ACCORD trial and for 5 years in the ADVANCE trial.15,16

The ACCORD and ADVANCE trials, along with the smaller Veterans Administration Diabetes Trial (VADT) (N = 1,791), failed to show that more intensive glycemic control significantly reduced CVD.15–17 Additionally, the glycemic control component of ACCORD was halted because of increased mortality in the intensive arm compared with the standard arm.15 Further analyses of ACCORD data presented at the 69th Scientific Sessions of the American Diabetes Association (ADA) showed that HbA1c values lower than 7.0% did not explain the increased mortality. The 20% higher risk of death for every 1.0% increase in HbA1c greater than 6.0% suggests that glucose concentrations even lower than the general HbA1c goal of less than 7.0% may be appropriate in some patients.18 The most recent finding from VADT was that CV risk was dependent on disease duration and presence of comorbidities. Intensive therapy seemed to work best in patients with diabetes of less than 15 years’ duration, while risk of a CV event was more than doubled with intensive therapy in patients having diabetes for more than 21 years.

Clarification of treatment goals

A position statement of the ADA and a scientific statement of the American College of Cardiology Foundation and the American Heart Association19 concluded that the “evidence obtained from ACCORD, ADVANCE, and VADT does not suggest the need for major changes in glycemic control targets but, rather, additional clarification of the language that has consistently stressed individualization.” They state that while the general HbA1c goal of less than 7.0% seems reasonable, even lower HbA1c goals may be appropriate for some patients if they can be achieved without significant hypoglycemia or other adverse effects. Such patients might include those with diabetes of short duration, long life expectancy, or no significant CVD or hypoglycemia. Conversely, higher HbA1c goals may be appropriate for patients with limited life expectancy, a history of severe hypoglycemia, established microvascular or macrovascular complications, significant other comorbid conditions, or longstanding diabetes in whom an HbA1c of less than 7.0% has been difficult to attain despite optimal treatment and diabetes self-management education.19

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

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