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In 2008, the Food and Drug Administration proposed a 2-step process for the approval of oral glucose-lowering therapies for type 2 diabetes that included an initial approval contingent on effective hemoglobin A1c reduction and then a postmarketing cardiovascular outcomes trial with predefined end points, longer follow-up, and a higher risk population to demonstrate “noninferiority” to placebo. Incretin-based therapies were the first drugs to be evaluated under the new guidance policy. Glucagon-like peptide (GLP)–1 and glucose-dependent insulinotropic polypeptide are incretin hormones secreted from the small intestine after meals and lower glucose levels by increasing β-cell insulin secretion, decreasing glucagon release, improving satiety, and slowing gut motility. Glucagon-like peptide–1 is rapidly deactivated by the enzyme dipeptidyl peptidase 4 (DPP4). The incretin axis can be pharmacologically enhanced either through injections of GLP-1 mimetics to achieve supraphysiologic levels or by inhibition of DPP4, which prolongs the half-life of physiologic levels of GLP-1, thus prolonging its action, although to a lesser extent than exogenous GLP-1 agonist. In preclinical experiments, both GLP-1 agonists and DPP4 inhibitors promoted nonglycemic-mediated cardioprotective actions.1 There were no signals of any cardiovascular harm in any of the incretin-based clinical development programs and, in fact, there were data to suggest direct cardioprotective and vasculoprotective benefits.2
Scirica BM. The Safety of Dipeptidyl Peptidase 4 Inhibitors and the Risk for Heart Failure. JAMA Cardiol. 2016;1(2):123–125. doi:10.1001/jamacardio.2016.0184
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