Effect of glucose-lowering therapies on heart failure

Key Points

  • Heart failure is now the most common cardiovascular complication of type 2 diabetes mellitus (T2DM), with its incidence exceeding that of myocardial infarction or stroke

  • Since 2008, the FDA and the European Medicines Agency require proof of cardiovascular safety for all glucose-lowering agents, resulting in an increase in trials focusing on the cardiovascular effects of T2DM drugs

  • No large randomized, controlled trials have been conducted to examine the effects of insulin, metformin, or sulfonylureas in patients with established heart failure

  • Use of thiazolidinediones is cautioned in all patients with signs and symptoms of heart failure, and they are contraindicated in patients with established heart failure

  • Different types of dipeptidyl peptidase 4 inhibitors are associated with varying levels of heart failure risk, possibly owing to different selectivity for glucagon-like peptide 1 receptor agonists

  • Sodium/glucose cotransporter 2 inhibitors (specifically empagliflozin) are associated with significant reductions in heart failure hospitalization and prevention of heart failure-related and arrhythmia-related deaths

Abstract

Heart failure is one of the most common comorbidities of diabetes mellitus. Glucose-lowering therapies that can prevent heart failure or improve outcomes in patients with established heart failure are of critical importance among those with type 2 diabetes. Several types of glucose-lowering drugs have been assessed in this setting. Metformin has been shown to modestly improve the outcomes of patients with heart failure, whereas the effect of insulin in those with established heart failure is less clear. The effect of sulfonylureas on improving heart failure is controversial; observational reports have suggested that they are harmful in these patients, but these data have not been confirmed in randomized, controlled trials. Thiazolidinediones are contraindicated in patients with established heart failure and have also been known to cause heart failure. Furthermore, certain dipeptidyl peptidase 4 inhibitors seem to increase heart failure hospitalization. The effects of glucagon-like peptide 1 receptor agonists might differ in patients with or without established heart failure, particularly those with decompensated heart failure with a reduced ejection fraction. However, perhaps the most important finding has been that sodium/glucose cotransporter 2 (SGLT2; also known as SLC5A2) inhibitors reduce heart failure hospitalizations and, in the case of empagliflozin, markedly reduce the rate of cardiovascular death. Given the known neutral (or even harmful) effects of other glucose-lowering drugs on heart failure outcomes, SGLT2 inhibitors might well be considered the drug class of choice in patients with diabetes and heart failure, or in those at high risk of developing heart failure.

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Figure 1: HF outcomes with different sSGLT2 inhibitors.

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Both authors researched data for the article, discussed the content, wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Mikhail Kosiborod.

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M.K. declares that he is on the advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Merck, Novo Nordisk, Sanofi, and ZS Pharma; is a consultant for AstraZeneca, Sanofi, and ZS Pharma; and has received research grants from AstraZeneca and Boehringer Ingelheim. M.N. declares no competing interests.

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Nassif, M., Kosiborod, M. Effect of glucose-lowering therapies on heart failure. Nat Rev Cardiol 15, 282–291 (2018). https://doi.org/10.1038/nrcardio.2017.211

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