New Drugs for the Treatment of Diabetes Mellitus

The cardiovascular disease (CVD) risk associated with diabetes mellitus (DM) has become increasingly evident, accounting for ≈80% of deaths among patients with this disease1 and making CVD risk modification a key therapeutic objective in diabetic patients. Indeed, in some clinical contexts, DM has been elevated to a coronary heart disease risk equivalent for risk reduction strategies.1–4 The rapidly increasing global burden of DM,5 coupled with the associated CVD risk, underscores the imperative for continued generation and application of evidence-based therapies to reduce CVD risk in this high-risk cohort.In this 2-part series, we first review the CVD effects of the thiazolidinedione medications, the most broadly investigated class of antihyperglycemic drugs evaluated in the context of CVD risk. In the second part, we review the modulators of the incretin axis that have most recently achieved US Food and Drug Administration approval, with a focus on CVD considerations; introduce selected drugs in advanced development; summarize glucose control strategies for cardiovascular patients; and discuss the regulatory review of glucose-lowering medications.Ciglitazone, the first thiazolidinedione, was discovered in a compound-screening program for lipid-lowering agents and serendipitously observed to lower glucose in experimental animals, but it failed in clinical testing as a result of toxicities.6 Troglitazone became the first thiazolidinedione approved to treat type 2 DM (T2DM) in 1997, with little understanding of its mechanism of action. Subsequently, the peroxisome proliferator–activated (PPAR)-γ receptor, a nuclear receptor that regulates gene transcription, was identified as the thiazolidinedione target of action.7 PPAR-γ is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors8 that, when activated, dimerizes with the retinoid X receptor and binds to DNA (PPAR-response element) to regulate gene transcription through coordinate transactivation and transrepression.9 PPAR-γ is expressed most prominently in adipocytes, regulating adipogenesis10 and glucose …