Worsening Heart Failure During the Use of DPP-4 Inhibitors Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications

Milton Packer

Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.