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.