Diabetes medications and heart failure: recognizing the risk.

T he diabetes pandemic is currently among the most challenging noncommunicable disease threats to public health. It is estimated that 382 million people worldwide have diabetes mellitus, and the majority will likely die of cardio-vascular disease. Diabetes mellitus is an independent risk factor for atherosclerotic cardiovascular disease and heart failure, with a 5-fold increased risk of heart failure in women with diabetes mellitus and a 2.4-fold increased risk in men. 1–3 In patients with diabetes mellitus, the prevalence of heart failure is between 10% and 22%, 4 times higher than that of the general population. 2 The degree of glycemic control in patients with diabetes mellitus has been demonstrated to be associated with the risk of atherosclerotic cardiovascular disease and new-onset heart failure. It has been a widely held belief that lowering hemoglobin A 1c levels with glucose-lowering medications in patients with diabetes mellitus would result in clinical benefits, including a reduction in atherosclerotic car-diovascular events. Lowering of the hemoglobin A 1c levels by glucose-lowering medications in patients with diabetes mel-litus has been used as a surrogate measure of their benefit, including the potential to reduce cardiovascular risk, by clini-cians, guideline writing groups, and regulators. There is, however, little evidence from randomized, clinical trials of substantial cardiovascular risk reduction with improved glycemic control in patients with type 2 diabetes mel-litus. Trials of individual glucose-lowering medications and trials comparing more intensive and standard glucose-lowering strategies, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Veterans Administration Diabetes Trial (VADT), and Action in Diabetes and Vascular Disease (ADVANCE) trials, have, despite their large sample sizes and follow-up for up to 5 years, demonstrated no or very modest reductions in cardiovascular events. After the publication of a meta-analysis suggesting that one of the thiazolidinedione medications may have increased the risk of myocardial infarction and the resulting controversy, regulatory agencies revised the process for approval of new medications to treat diabetes mellitus and require demonstration that cardiovascular risk is not above certain specified levels. The US Food and Drug Administration now requires that clinical trials done before the approval of a diabetes drug show a 2-sided 95% confidence interval upper boundary of 1.8 for the risk ratio for major adverse cardiovascular events compared with the placebo/usual-care control group, with subsequent outcomes trials having an upper boundary of 1.3 for major adverse cardiovascular events. 10 The focus of the US Food and Drug Administration …