13.20 – Mechanisms of Drug-Induced Cardiovascular Toxicity: Cardiotoxicity Associated With Diabetes Medications☆

Diabetes mellitus (DM) affects over 135 million individuals worldwide and is associated with a number of serious complications that include cardiovascular disease (CVD). The majority of cases of DM are DM type 2 (DM2), which is a disorder of carbohydrate metabolism that is a result of both insulin resistance and pancreatic islet β-cell dysfunction. Over the past decade several new classes of diabetes medications have been developed for the management of DM2. The thiazolidinediones (rosiglitazone and pioglitazone) activate peroxisome proliferator-activated receptor-γ (PPARγ). PPAR-γ regulates transcription and gene expression for several elements involved in glucose and lipid metabolism. Through activation of PPAR-γ, thiazolidinediones improve insulin sensitivity and are therefore used in the treatment of DM2. Rosiglitazone and pioglitazone are comparable in their ability to improve glycemic control; however, they differ in their effects on lipid metabolism. The safety profile of the thiazolidinediones was called into question by two meta-analyses of clinical trials with rosiglitazone that suggested an increased risk of myocardial infarction or death. In addition, multiple clinical trials and meta-analyses have demonstrated that both rosiglitazone and pioglitazone are associated with an increased risk of heart failure (HF) exacerbation. In 2010, implemented a Risk Evaluation and Mitigation Strategy (REMS) in order to restrict access to rosiglitazone in response to the increased risk of myocardial infarction. The final results of the prospective, placebo-controlled RECORD trial with rosiglitazone did not demonstrate an increased risk of myocardial infarction (MI). Based on this trial and several additional meta-analyses that found no increased risk of MI with rosiglitazone, the FDA in 2015 removed the REMS requirement for rosiglitazone. The available evidence does not support a causal role for the thiazolidinediones in the development of heart failure. However, these agents may exacerbate HF symptoms in patients with underlying left ventricular systolic dysfunction. The mechanism is likely a result of PPAR-γ activation of epithelial sodium channels (ENaCs) in the collecting duct leading to sodium and water retention with a resultant increase in edema. Therefore, neither agent should be used in patients with symptomatic HF and should be used with extreme caution, if used at all, in individuals with asymptomatic left ventricular dysfunction. A second class of medication has raised concerns regarding heart failure. The dipeptidyl peptidase 4 inhibitors (DPP4-Is), saxagliptin and alogliptin, have been found to increase hospitalizations due to heart failure. The DPP4-Is, by inhibiting DPP4, result in increased concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These actions have the effect of increasing pancreatic β-cell insulin production and release in response to elevated serum glucose concentrations (glucose dependent) and decreasing glucagon secretion as well as delaying gastric emptying. DPP4 has multiple cardiovascular substrates, such as b-type natriuretic peptide (BNP), stromal cell-derived factor-1α (SDF-1α), neuropeptide Y (NPY), glucagon-like peptide-2 (GLP-2), substance P, and bradykinin. It is relatively unknown what effects DPP4 inhibition has on these substrates and importantly what are the cardiovascular consequences. Future research is needed to determine potential mechanisms for the increase in HF hospitalizations with saxagliptin and alogliptin as well as to determine the cardiovascular safety of the additional classes of diabetes medications.