Effects of Ertugliflozin on Kidney Outcomes in Patients With Heart Failure at Baseline in the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS CV) Trial

Abstract

Introduction: In the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881), patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) were randomized (1:1:1) to placebo, ertugliflozin 5 mg or 15 mg (doses pooled for analyses as prospectively planned). In this post hoc analysis, the effects of ertugliflozin on kidney outcomes were assessed in analyses stratified by baseline heart failure (HF).

Methods: Baseline HF was defined as a history of HF or prerandomization left ventricular ejection fraction ≤45%. Outcomes included estimated glomerular filtration rate (eGFR) over time, total 5-year eGFR slopes and time to first event of a prespecified exploratory kidney composite outcome of sustained ≥40% decrease from baseline eGFR, chronic kidney replacement therapy, or kidney death. All analyses were stratified by baseline HF status.

Results: Compared with no-HF at baseline (n = 5807; 70.4%), patients with HF (n = 2439; 29.6%) had a notably faster rate of eGFR decline, which is unlikely to be explained by the slightly lower baseline eGFR in that group. Ertugliflozin treatment resulted in a slower rate of eGFR decline in both subgroups; total placebo-adjusted 5-year eGFR slopes (ml/min per 1.73 m² per year [95% confidence intervals; CI]) were 0.96 (0.67-1.24) and 0.95 (0.76-1.14) for HF and no-HF subgroups, respectively. The placebo HF (vs. placebo no-HF) subgroup had a higher incidence of the composite kidney outcome (35/834 [4.20%] vs. 50/1913 [2.61%]). Hazard ratios (95% CI) for the effect of ertugliflozin on the composite kidney outcome did not differ significantly between HF and no-HF subgroups: 0.53 (0.33-0.84) and 0.76 (0.53-1.08), respectively (P _interaction = 0.22).

Conclusion: Although patients with HF at baseline had a faster rate of eGFR decline in VERTIS CV, the beneficial effects of ertugliflozin on kidney outcomes did not differ when stratified by baseline HF.

Keywords: albuminuria; diabetic kidney disease; ertugliflozin; heart failure; sodium–glucose cotransporter 2 inhibitor; type 2 diabetes mellitus.

Graphical abstract

Figure 1

Prespecified exploratory kidney composite outcome by baseline HF status. Analyses of the prespecified exploratory kidney composite outcome (sustained ≥40% decrease from baseline in eGFR, chronic kidney replacement therapy, or kidney death) were performed with data from all randomized patients (ITT population). CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; ITT, intention-to-treat.

Figure 2

eGFR over time by baseline HF status. A RMANCOVA method was used for analysis of mean change from baseline in eGFR (calculated by the MDRD equation). BL, baseline; CI, confidence interval; eGFR, estimated glomerular filtration rate; HF, heart failure; MDRD, Modification of Diet in Renal Disease; RMANCOVA, repeated measures analysis of covariance; W, week.

Figure 3

Total 5-year eGFR slopes by baseline HF status. Yearly eGFR slope was assessed for the FAS population and analyzed by generalized random coefficient models. CI, confidence interval; eGFR, estimated glomerular filtration rate; FAS, full analysis set; HF, heart failure; LSM, least-squares mean; W, week.