Ertugliflozin and hospitalization for heart failure across the spectrum of pre-trial ejection fraction: post-hoc analyses of the VERTIS CV trial

Sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalization for heart failure (HHF) among those with heart failure (HF) with reduced and preserved ejection fraction (EF).1,2 However, less is known regarding the treatment efficacy at or above the normal EF range (>60%).3,4 VERTIS CV (NCT01986881) was the cardiovascular (CV) outcome trial for ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic CV disease.5 In VERTIS CV, ertugliflozin met the non-inferiority criterion for the primary endpoint of major adverse CV events.5 Superiority for the secondary endpoints, including CV death or HHF, CV death (alone), and a kidney composite (doubling of serum creatine, dialysis/transplantation, renal death), were not met; however, pre-specified secondary analyses demonstrated a significant 30% risk reduction in first and total HHF.5 In the VERTIS CV trial, ∼24% of participants had a history of HF.5 In this post hoc analysis, we evaluated the effects of ertugliflozin on the risk of first and total HHF across the spectrum of pre-trial EF. The VERTIS CV trial included participants (n = 8246) aged ≥40 years randomized (1:1:1) to receive once-daily ertugliflozin (5 mg, 15 mg), or placebo with a mean follow-up of 3.5 years.5 The two ertugliflozin dose groups were combined for all analyses vs. placebo. Data on pre-trial EF were obtained from medical records with the EF closest to the randomization date recorded. Treatment effects of ertugliflozin vs. placebo on the risk of first and total HHF were analysed using adjusted Cox models for first HHF and Andersen–Gill models for total (i.e. first + recurrent) HHF events. Multiplicative interaction terms (Pinteraction-trend EF category × treatment) were used to determine if pre-trial EF modified the efficacy of ertugliflozin. Owing to the exploratory nature of these post hoc analyses, the P-values reported should be considered nominal. Of 8246 participants in VERTIS CV, 959 (11.6%) had EF ≤ 45, 2860 (34.7%) had EF > 45%–60%, 1187 (14.4%) had EF > 60%, and 3240 (39.3%) had unknown EF. Among participants with known EF, those with EF > 60% vs. EF ≤ 45% were more likely to be women, had a lower burden of coronary artery disease (80.0% vs. 95.6%), had a higher burden of cerebrovascular disease (22.5% vs. 11.4%), and had lower use of diuretics (43.1% vs. 58.5%) and beta-blocking agents (70.3% vs. 87.3%) at baseline. In the overall cohort, ertugliflozin (vs. placebo) significantly reduced the risk of the first HHF [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.54–0.90].4 In the subgroup analysis by pre-trial EF, the interaction between treatment and EF did not reach significance for the first HHF (Pinteraction = .09; Figure 1A). However, the strength of association between ertugliflozin and risk of first HHF is numerically greater among participants with EF ≤ 45% (HR 0.48, 95% CI 0.30–0.75) than in other groups (Figure 1A). The treatment effect of ertugliflozin for the first HHF among participants with EF > 60% (HR 0.72, 95% CI 0.34–1.54) was comparable with that observed in the overall cohort. Ertugliflozin reduced the risk of total HHF events [rate ratio (RR) 0.70, 95% CI 0.56–0.87] in the overall cohort.4 The treatment effect of ertugliflozin on total HHF appeared to be modified by pre-trial EF (Pinteraction = .029; Figure 1B), with the greatest benefit noted among those with ≤45% (RR 0.39, 95% CI 0.26–0.57). The treatment effect of ertugliflozin on total HHF was attenuated among participants with EF > 60% (RR 0.68, 95% CI 0.37–1.26). Similar findings were observed in restricted quadratic splines across a continuous EF such that ertugliflozin reduced the risk of first HHF consistently across the EF distribution (Pinteraction = .2) but had a greater treatment effect for reducing total HHF among individuals with lower (vs. higher) pre-trial EF (Pinteraction = .035; Figure 1C and D). Treatment effect of ertugliflozin vs. placebo across the spectrum of pre-trial ejection fraction in VERTIS CV. (A) Treatment effects of ertugliflozin vs. placebo across pre-trial ejection fraction for the outcome of first hospitalization for heart failure. (B) Treatment effects of ertugliflozin vs. placebo across pre-trial ejection fraction for the outcome of total hospitalization for heart failure. (C, D) Treatment effects of ertugliflozin vs. placebo using a restricted quadratic spline fit to pre-trial ejection fraction subgroup data. *P-value for hazard ratio. Considering the exploratory nature of these analyses, the P-values reported are nominal. †Interaction P-value between pre-trial ejection fraction groups, defined as a continuous variable corresponding to the average ejection fraction value within each subgroup. EF, ejection fraction; ERTU, ertugliflozin; HHF, hospitalization for heart failure; HR, hazard ratio; PBO, placebo. Prior observations from the DECLARE-TIMI 58 and SOLOIST-WHF trials have demonstrated that dapagliflozin and sotagliflozin reduced the risk of first HHF comparably among individuals with T2DM and pre-existing reduced EF vs. preserved EF.2,6 The present study adds to these observations by evaluating the efficacy of ertugliflozin in reducing the risk of first HHF across the spectrum of EF. The treatment effect was numerically greater at pre-trial EF < 45% and attenuated at EF > 60%. Furthermore, we observed that the pre-trial EF modified the treatment effect of ertugliflozin on total HHF, with greater RR reduction among individuals with EF ≤ 45% than those with EF > 60%. Our study findings should be interpreted in the context of recent observations from the pooled phase 3 trials of other SGLT2 inhibitors in patients with HF across the spectrum of EF. The pooled analysis of the DAPA-HF and DELIVER trials demonstrated that dapagliflozin is associated with a consistent reduction in the risk of first and total HHF across the EF spectrum, including those with EF > 60%.3,7,8 In contrast, prior observation from the EMPEROR-Preserved trial demonstrated a greater treatment effect of empagliflozin in reducing the risk of first and total HHF among individuals with EF < 60% vs. those with EF > 60%.4 Taken together, our study findings suggest that the treatment effect of ertugliflozin on HHF demonstrated in the overall analyses are exaggerated at lower pre-trial EF thresholds (<45%) and attenuated at higher EF thresholds. Our study has several noteworthy limitations. These findings are limited by a small number of events, which led to wide CIs. There were relatively few events within the highest EF subgroup, and the reported findings should be considered hypothesis generating. The difference in treatment interaction observed for the outcomes of total HHF and time to first HHF event may have been due to a higher burden of recurrent events among those with lower EF at baseline compared with those with EF > 60% or related to event dispersion. Last, the time interval from pre-trial EF assessment to enrolment was unavailable. Editorial support was provided by Marion James, PhD, of Engage Scientific Solutions (Horsham, UK) and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer Inc., New York, NY, USA. A.P. has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529), has received grant funding from Applied Therapeutics and Gilead Sciences, has received honoraria outside of the present study as an advisor/consultant for Cytokinetics, Emmi Solutions, Lilly USA, Pieces Technologies, Rivus, Roche Diagnostics, and Tricog Health Inc., has received non-financial support from MSD and Pfizer, and is a consultant for Palomarin Inc. with stock compensation. A.A.K. has no competing interests. F.C. has received research grants from the King Gustav V and Queen Victoria Foundation and Swedish Research Council, Swedish Heart & Lung Foundation and has received consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novo Nordisk, and Pfizer Inc. C.P.C. has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, MSD, Novo Nordisk, and Pfizer and fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Lexicon, MSD, Pfizer, Rhoshan, and Sanofi and serves on Data and Safety Monitoring Boards for Applied Therapeutics, Novo Nordisk, and the US Veteran’s Administration. R.C.F., N.B.C., and J.P.M. are employees and shareholders of Pfizer Inc. D.Z.I.C. has received consulting fees and speaking honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Mitsubishi-Tanabe, Novo Nordisk, Prometic, and Sanofi and received operating funds from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, MSD, Novo Nordisk, and Sanofi. S.D.-J. has led clinical trials for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk Inc., received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, MSD, and Sanofi, and has equity interests in Aerami Therapeutics and Jana Care Inc. R.E.P. has received grants (directed to his institution) from Hanmi Pharmaceutical Co., Ltd, Janssen, Metavention, Novo Nordisk, Poxel SA, and Sanofi, received consulting fees (directed to his institution) from AstraZeneca, Corcept Therapeutics Incorporated, Glytec LLC, Hanmi Pharmaceutical Co. Ltd, Janssen, MSD, Mundipharma, Novo Nordisk, Pfizer Inc., Sanofi, Scohia Pharma Inc., and Sun Pharmaceutical Industries, and received support for attending meetings/travel (directed to his institution or to the travel provider) from AstraZeneca, Glytec LLC, MSD, Mundipharma, Novo Nordisk, and Pfizer Inc. I.G. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. D.K.M. has received consulting fees from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Esperion, Lexicon, Lilly USA, Novo Nordisk, Pfizer Inc, and Altimmune; Intercept Pharma and participated on data safety monitoring boards/advisory boards for AbbVie, Akebia, Arena, CSL Behring, Eidos, and Otsuka, Pfizer, Boehringer Ingelheim. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. This study was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA in collaboration with Pfizer Inc., New York, NY, USA. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each study centre. All patients provided written informed consent. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.

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