5.6.0.0 Antihyperglycemic Therapies and Heart Failure
As many as 50% of patients with type 2 diabetes may develop heart failure (164). Data on the effects of glucose-lowering agents on heart failure outcomes have demonstrated that thiazolidinediones have a strong and consistent relationship with increased risk of heart failure (165-167). Therefore, thiazolidinedione use should be avoided in patients with symptomatic heart failure.
Recent studies have also examined the relationship between DPP-4 inhibitors and heart failure and have had mixed results. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study showed that patients treated with saxagliptin (a DPP-4 inhibitor) were more likely to be hospitalized for heart failure than those given placebo (3.5% vs. 2.8%, respectively) (168). Two other recent multicenter, randomized, double-blind, noninferiority trials, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) and Trial Evaluating Cardiovascular Out-comes with Sitagliptin (TECOS), did not show associations between DPP-4 inhibitor use and heart failure. The FDA reported that the hospital admission rate for heart failure in EXAMINE was 3.9% for patients randomly assigned to alogliptin compared with 3.3% for those randomly assigned to placebo (169). Alogliptin had no effect on the composite end point of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1.0 [95% CI 0.82–1.21]) (170). TECOS showed no difference in the rate of heart failure hospitalization for the sitagliptin group (3.1%; 1.07 per 100 person-years) compared with the placebo group (3.1%; 1.09 per 100 person-years) (171).
In four cardiovascular outcome trials of GLP-1 receptor agonists, no evidence for an increased risk of heart failure was found and the agents had a neutral effect on hospitalization for heart failure (159–162).
A benefit on the incidence of heart failure has been observed with the use of some SGLT2 inhibitors. In EMPA-REG OUTCOME, the addition of empagliflozin to standard care led to a significant 35% reduction in hospitalization for heart failure compared with placebo (8). Although the majority of patients in the study did not have heart failure at baseline, this benefit was consistent in patients with and without a prior history of heart failure (172). Similarly, in CANVAS, there was a 33% reduction in hospitalization for heart failure with canagliflozin versus placebo (9). Although heart failure hospitalizations were prospectively adjudicated in both trials, the type(s) of heart failure events prevented were not characterized. These preliminary findings, which strongly suggest heart failure–related benefits of SGLT2 inhibitors (particularly the prevention of heart failure), are being followed up with new outcomes trials in patients with established heart failure, both with and without diabetes, to determine their efficacy in treatment of heart failure.