Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition.

BACKGROUND

Cardiovascular (CV) disease is the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial and involves direct and indirect injury to the vasculature and heart. The impact of intensive glucose-lowering therapy with antihyperglycemic agents on CV outcomes is not clear, and questions remain as to which glucose-lowering agents may be beneficial to CV health in patients with T2DM.

PURPOSE

This review discusses findings regarding the known mechanisms of CV injury in T2DM and current knowledge regarding the potential cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors.

CONCLUSIONS

Dipeptidyl peptidase-4 inhibitors are relatively new antihyperglycemic agents. Their main mechanism of action is to inhibit the degradation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide by DPP-4. By increasing levels of glucagon-like peptide-1, glucose-dependent insulin secretion is enhanced, glucagon secretion is suppressed, and the rate of gastric emptying is decreased. Dipeptidyl peptidase-4 also degrades other substances that are important in the regulation of CV function and inflammation. Animal studies, small observational studies in humans, and analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Recent prospectively designed CV outcomes trials with saxagliptin and alogliptin in patients with T2DM and high CV risk presented evidence that these DPP-4 inhibitors neither increased nor decreased adverse CV outcomes in this select patient population.

CLINICAL IMPLICATIONS

Dipeptidyl peptidase-4 inhibitors are promising therapies for the treatment of T2DM. Able to improve glycemic control without the risk of weight gain or hypoglycemia, they provide a safe alternative to sulfonylureas and are an effective adjunct to metformin. To date, this class of drugs seems to be at least neutral in terms of CV effects. Time will tell if these findings translate into a benefit for our patients.