Spotlight on heart failure

The risk of heart failure in patients taking medication for type 2 diabetes was analyzed by 2 recent studies.

The first study, published in The Lancet on March 9, was a follow-up analysis of the EXAMINE trial. The EXAMINE trial included 5,380 patients with type 2 diabetes and a recent (prior 15-90 days) acute coronary syndrome event, who were randomly assigned to alogliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor) or placebo plus standard treatment and followed for a median of 533 days. The original trial showed non-inferiority of alogliptin to placebo on major adverse cardiac event (MACE) rates, defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. For the new analysis the authors' prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularization due to unstable angina, and hospital admission for heart failure. Alogliptin and placebo patients had similar rates of this composite endpoint (16.0% vs. 16.5%). Alogliptin had no effect on a composite outcome of cardiovascular death and hospital admission for heart failure in the post-hoc analysis. Study authors concluded that alogliptin did not increase the risk of heart failure.

An accompanying comment noted that patients without heart failure at baseline actually did have a slightly higher risk of hospitalization for the condition if they were taking alogliptin (which the study authors said could be due to chance) and the comment authors cautioned physicians “to look out for the signs and symptoms of emerging heart failure in all patients with diabetes at all times,” particularly in patients taking DPP-4 inhibitors.

The other study, a meta-analysis published by The Lancet Diabetes and Endocrinology on March 17, compared rates of heart failure among patients assigned to various glucose-lowering drugs or strategies. Overall, the analysis found an increased risk of heart failure associated with the interventions (risk ratio [RR], 1.14; P=0.041). Peroxisome proliferator-activated receptor (PPAR) agonists were associated with the highest risk (RR, 1.42; 6 trials), followed by DPP-4 inhibitors (RR, 1.25; 2 trials). Insulin glargine had a neutral association with heart failure, as did target-based intensive control strategies and intensive weight loss. The risk seen with PPAR agonists may relate to the weight gain seen in patients taking them, speculated the authors, who encouraged clinicians to “consider the trade-off between [ischemic] and [hemodynamic] cardiovascular events when choosing between different drugs or strategies for lowering blood glucose.”

An accompanying comment noted the multiple types of errors that can occur in systematic reviews and also pointed out the potential problem of heterogeneity of the included trials, particularly the variations in baseline cardiovascular risk, from patients with newly diagnosed type 2 diabetes to patients needing acute intervention for symptomatic coronary artery disease. Due these concerns, the authors of the comment cautioned against “concluding that all glucose-lowering drugs and strategies in general are associated with an increased risk of heart failure.”