Efficacy of Ertugliflozin on Heart Failure–Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease

Abstract

Background: In patients with type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. Methods: VERTIS CV, a double-blind, placebo-controlled trial, randomized patients with T2DM 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 hazard 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: 8246 patients were randomized 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 pre-trial ejection fraction (EF) available, including n=959 with EF≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (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). Prior 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% vs 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 three populations with baseline eGFR<60mL/min/1.73m 2 , albuminuria, and diuretic use (each P interaction<0.05). Ertugliflozin reduced total events of HHF (RR, 0.70; 95% CI, 0.56, 0.87) and total HHF/CV death (RR, 0.83; 95% CI, 0.72, 0.96). Conclusions: In patients with T2DM with or without baseline HF, ertugliflozin reduced risk for first and total HHF and total HHF/CV death, adding further support for the use of SGLT2 inhibitors in primary and secondary prevention of HHF. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01986881

Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta‐analysis

“…This included three HF‐specific trials (DAPA‐HF, EMPEROR‐Reduced, and SOLOIST‐WHF) 6–8 and four cardiovascular outcome trials: CANVAS (CANagliflozin cardioVascular Assessment Study), 3 EMPA‐REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), 4 DECLARE‐TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events), 5 and VERTIS‐CV (eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial) 21 . HF patient data from the cardiovascular outcome trials were available from published post hoc studies 22–25 . Although the recently published SCORED (Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trial did not report outcome data of patients with baseline HF separately, 26 the authors of this trial presented a pooled analysis of the SOLOIST‐WHF and SCORED trials at the American Heart Association 2020 conference.…”

“…This included three HF-specific trials (DAPA-HF, EMPEROR-Reduced, and SOLOIST-WHF) [6][7][8] and four cardiovascular outcome trials: CANVAS (CANagliflozin cardioVascular Assessment Study), 3 21 HF patient data from the cardiovascular outcome trials were available from published post hoc studies. [22][23][24][25] Although the recently published SCORED (Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trial did not report outcome data of patients with baseline HF separately, 26 the authors of this trial presented a pooled analysis of the SOLOIST-WHF and SCORED trials at the American Heart Association 2020 conference. Whenever possible, the pooled findings from these trials were used in our analysis.…”

Effect of Sodium-Glucose Cotransporter Type 2 Inhibitors on Clinical Outcomes in Patients With Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials

“…1. HF patient data from cardiovascular outcome trials were available from published post-hoc studies [22,23].…”

Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

“…Due to the significant reduction of CV risk with empagliflozin, dapagliflozin, and canagliflozin in patients with T2DM, these benefits were once considered as class effects of SGLT2 inhibitors ( 135 ). However, recent studies showed inconsistent results, suggesting that SGLT2 inhibitors may have heterogeneity ( 136 ).…”