• Myocardial Infarction
• Heart Failure
• Hyperglycemia/Hypoglycemia

The most common treatments for diabetes include lifestyle changes (diet and exercise); oral medications, such as the sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors; and parenteral insulin therapy. Silvio E. Inzucchi, MD, Yale University School of Medicine, New Haven, Connecticut, USA, discussed a new line of therapy using incretins. The incretin system regulates postprandial glucose control through effects on the pancreas, gastric motility, and appetite. Incretin therapy has also demonstrated cardiovascular (CV) effects, including improved left ventricular (LV) function in patients with LV dysfunction after acute myocardial infarction [Nikolaidis N et al. Circulation 2004] and in patients with chronic heart failure [Sokos GG et al. J Card Fail 2006]. Following incretin treatment, studies have demonstrated less need for insulin and inotropic support in coronary artery bypass graft (CABG) patients after surgery [Sokos GG et al. Am J Cardiol 2007].

There are two types of incretin-based drugs that improve the effects of glucagon-like peptide-1 (GLP-1): the GLP-1 receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors (Table 1). Either can be used alone or in combination with other antidiabetes medications. An important safety advantage of incretin-based therapy for type 2 diabetes mellitus is the essential absence of hypoglycemia.

The GLP-1 receptor agonists are relatively new, injectable agents that mimic the actions of endogenous GLP-1. They have several mild beneficial effects on CV risk factors (weight, glucose, cholesterol, blood pressure) and may also have direct actions on the heart. Currently marketed GLP-1 products include exenatide and liraglutide. A recent meta-analysis of exenatide clinical trials showed no increased risk of CV events versus pooled comparators (RR, 0.69; 95% CI, 0.46 to 1.04) [Shen L et al. Diabetes 2009; Best JH et al. ADA 2010]. An FDA analysis of clinical trial data on liraglutide identified no excess risk of CV events versus comparators [http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf]. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER; NCT01179048) trial, which is currently recruiting, aims to assess and confirm the CV safety of liraglutide. The trial satisfies the draft guidance for industry that was released by the FDA in 2008 regarding the development of drugs and therapeutic biologics for the treatment and prevention of diabetes (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf). Several other agents (eg, exenatide LAR, taspoglutide, and albiglutide) also are under investigation.

DPP-4 inhibitors are newer, generally well-tolerated oral antihyperglycemic agents of modest effectiveness. They enhance endogenous postprandial incretin levels. The CV safety of these agents is currently being studied. Currently marketed products include sitagliptin, saxagliptin, and vildagliptin. Sitagliptin has been studied in more than 10,000 type 2 diabetes patients for up to 2 years, with no CV signals of concern [Williams-Herman D et al. BMC Endocr Disord 2010]. The Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS; NCT00790205), a large (expected enrollment 14,000) postmarketing trial to further evaluate the long-term (4 to 5 years) CV profile of sitagliptin, is expected to be complete in 2014. Saxagliptin has had more than 5000 patient-years of exposure with no increase in CV events when used as monotherapy or in combination with other oral antidiabetes agents (HR, 0.44; 95% CI, 0.24 to 0.82). The CV outcomes with saxagliptin are being evaluated in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) trial, a 5-year multicenter, randomized, placebo-controlled Phase 4 study that will follow ∼12,000 patients with type 2 diabetes who have either a history of previous CV events or multiple risk factors for vascular disease, The study also includes patients with renal impairment. Other products that are still under investigation include linagliptin and alogliptin.

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