Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial

Abstract

Background: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes.

Methods: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events.

Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; P=0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min^-1·1.73 m^-2, albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96]).

Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.

Keywords: cardiovascular diseases; diabetes mellitus, type 2; heart failure; sodium-glucose cotransporter 2 inhibitors.

Figure 1.

Time to first event analyses. Time to first hospitalization for heart failure (A) and composite of hospitalization for heart failure/cardiovascular death (B), overall and by the dose of ertugliflozin using the Fine and Gray method. CI indicates confidence interval.

Figure 2.

Percentage of patients with first and subsequent events by treatment. Analyses were conducted using the Andersen-Gill model. The prespecified analysis of total HHF was not adjusted for the competing risk of all-cause death because there was no difference between treatment groups in the competing risk event (death) and analyses of first HHF using the Fine and Gray method to adjust for competing risk of death produced similar results to the unadjusted analyses of first HHF. CVD indicates cardiovascular death; HHF, hospitalization for heart failure; and RR, rate ratio.

Figure 3.

Cumulative incidence of first and total (first+recurrent) HHF events. Ertugliflozin includes 5 mg and 15 mg doses. CI indicates confidence interval; HHF, hospitalization for heart failure; and HR, hazard ratio.

Figure 4.

Time to first hospitalization for heart failure overall and by history of heart failure at baseline or by pretrial ejection fraction. CI indicates confidence interval.

Figure 5.

Time to first hospitalization for HF by history of HF at baseline and pretrial ejection fraction. CI indicates confidence interval; EF, ejection fraction; and HF, heart failure.

Figure 6.

Time to first hospitalization for heart failure overall and by eGFR, albuminuria, and use of diuretic and loop diuretic at baseline. *Includes loop and nonloop diuretics and mineralocorticoid antagonists. CI indicates confidence interval; eGFR, estimated glomerular filtration rate.