The totality of evidence from randomized clinical trials
The totality of evidence from randomized clinical trials supports the premise that worsening Losartan failure is a class effect of DPP-4 inhibitors. A meta-analysis by Verma et al. (54) of 100 randomized controlled clinical trials reported that the use of DPP-4 inhibitors was accompanied a significant 13% increase in the risk of blindly adjudicated heart failure hospitalizations, with no significant heterogeneity across members of the drug class. This estimate was confirmed by Li et al. (55) in their meta-analysis of 5 randomized controlled trials. Monami et al. (56) observed a 19% significant increase in the risk of events classified as acute heart failure that were observed in 84 randomized clinical trials, again without evidence of heterogeneity among members of the drug class. Finally, a meta-analysis by Clifton (57) reported a 24% increase in the risk of heart failure endpoints in DPP-4 inhibitor–treated patients, and the estimate remained nearly significant in its own right even when the results of SAVOR-TIMI 53 were removed from the analysis. None of these meta-analyses were carried out using patient-level data, and thus, they could not determine if the reported risks were modulated by the concurrent use of other antidiabetic medications (i.e., insulin and metformin). Concerns that DPP-4 inhibitor can increase the risk of heart failure have been reinforced by the results of nonrandomized studies carried out in the community. Post-marketing analyses by the Food and Drug Administration have suggested a disproportionate reporting of adverse heart failure events among users of DPP-4 inhibitors across all members of the drug class (58), and an increased risk of hospitalization for heart failure has been observed early following the initiation of treatment in a nonrandomized cohort of patients receiving these drugs (59), a pattern similar to that seen in the SAVOR-TIMI 53 trial (44). Other observational studies have also reported an increase in risk 60, 61, 62. Several retrospective population-based studies have concluded that DPP-4 inhibitors do not precipitate or worsen heart failure; however, these reports have been difficult to interpret, either because they did not focus on new users or because they showed no difference with comparator groups that are known to increase the risk of heart failure in their own right 63, 64. If the incidence of heart failure in patients receiving DPP-4 inhibitors is comparable with that seen with rosiglitazone and pioglitazone, the study implies an increased risk, rather than a neutral effect. Interestingly, in the only observational study that used SGLT2 inhibitors as a comparator, the risk of hospitalization for heart failure in users of DPP-4 inhibitors was increased (65). The totality of evidence from meta-analyses of randomized trials and observational studies is consistent with an increased risk and supports the premise that worsening heart failure represents a class effect. It is important to note that concerns about an increased risk of worsening heart failure with DPP-4 inhibitors have been based on evidence from trials that were carried out not in patients with established heart failure but in patients who largely had clinically stable type 2 diabetes, who typically did not have clinically overt evidence of cardiac dysfunction. If DPP-4 inhibitors adversely affect the pathophysiological mechanisms that can lead to heart failure, this finding might be most apparent in patients with existing diagnoses. This possibility is supported by experience with other incretin-based drugs. Whereas GLP-1 receptor agonists did not increase the risk of heart failure in large-scale trials of patients without clinically apparent cardiac dysfunction (35), the use of liraglutide in patients with moderate to severe heart failure was accompanied by clinically important deleterious effects 66, 67. This observation suggests that the risks of DPP-4 inhibitors in patients with established heart failure, although poorly investigated, are being underestimated.