Glycemic-Lowering Treatments: Balancing Risk for Heart Failure With Certain Therapies Against Overall Benefits | Journal Scan

Study Questions:

What is the risk of heart failure with glucose-lowering drugs or strategies, compared with standard care, and is this risk countered by any reduction in atherothrombotic events?


This was a meta-analysis, which included randomized controlled trials that compared experimental glucose-lowering drugs or strategies with placebo or standard care. Eligible trials enrolled 1,000 or more individuals with or at risk for type 2 diabetes. The primary endpoint was incidence of heart failure.


The authors included 14 trials with an aggregate of 95,502 patients; 3,907 (4%) patients developed a heart failure event and 9,378 (10%) patients had a major adverse cardiovascular event. Compared to standard care, glucose-lowering drugs or strategies increased the risk of heart failure (relative risk [RR], 1.14; 95% confidence interval [CI], 1.01-1.30; p = 0.041). The magnitude of this effect varied dependent on the method of glucose lowering. The risk was highest for peroxisome proliferator-activated receptor (PPAR) agonists (thiazolidinediones) with a relative risk of 1.42 (95% CI, 1.15-1.76). With removal of the entire PPAR class of trials, the effect of other glucose-lowering drugs or strategies was nonsignificant. Glucose-lowering drugs or strategies overall modestly lowered the risk of major adverse cardiovascular events, driven primarily by a reduction in myocardial infarction (p = 0.017). Heart failure was associated with weight gain (p = 0.022) with each 1.0 kg relative increase in weight between treatments associated with a 7.1% (95% CI, 1.0-13.6) relative increase in the risk of heart failure; however, removal of the entire PPAR class of trials eliminated weight gain as a significant modifier.


Compared to standard care, glucose-lowering therapies are associated with an increase in risk for heart failure, a relationship that is countered by a reduction in major adverse cardiac events (MACE) and attenuated after eliminating thiazolidinediones from the meta-analysis.


This is a well-conducted meta-analysis that draws attention to the risk for heart failure associated with glycemic-lowering therapy. This relationship seems to be dependent on the method of glucose lowering (and the impact of glucose-lowering therapy on risk for heart failure is no longer significant after eliminating the thiazolidinediones from analysis) and may be mediated by weight gain. The beneficial effects of glycemic lowering cannot be discounted, and should be countered against the risks demonstrated in this analysis.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Diabetes Mellitus, Type 2, Blood Glucose, Heart Failure, Incidence, Myocardial Infarction, Thiazolidinediones, PPAR gamma, Peroxisome Proliferator-Activated Receptors, Risk, Weight Gain, Metabolic Syndrome X

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