Cardiorenal outcomes with ertugliflozin assessed according to baseline glucose-lowering agent: An analysis from VERTIS CV

Abstract

Aim: To assess selected cardiorenal outcomes with ertugliflozin according to use of baseline glucose-lowering agent.

Materials and methods: VERTIS CV was a cardiovascular (CV) outcome trial for ertugliflozin versus placebo, conducted in patients with type 2 diabetes and established atherosclerotic CV disease. The primary outcome was time to the first event of CV death, myocardial infarction or stroke (major adverse CV events [MACE]), with other CV outcomes also assessed. Outcomes were analysed using Cox proportional hazards models stratified by baseline use of metformin, insulin, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, with interaction testing to assess for treatment effect modification. Changes from baseline in glycaemic, metabolic and haemodynamic variables were also assessed.

Results: Of 8246 randomized patients, at baseline 6286 (76%) were on metformin, 3898 (47%) were on insulin, 3383 (41%) were on SUs and 911 (11%) were on DPP-4 inhibitors, alone or in combination therapy (67% used >1 glucose-lowering agent at baseline). For each glucose-lowering agent evaluated, no evidence for effect modification was observed for MACE by baseline use of metformin (with: hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.790, 1.073; without: 1.13, 95% CI 0.867, 1.480), insulin (with: HR 0.91, 95% CI 0.765, 1.092; without: 1.06, 95% CI 0.867, 1.293), SUs (with: HR 1.11, 95% CI 0.890, 1.388; without: 0.90, 95% CI 0.761, 1.060) or DPP-4 inhibitors (with: HR 0.77, 95% CI 0.502, 1.173; without: 1.00, 95% CI 0.867, 1.147) (all Pinteraction > 0.05). Similar results were observed for all secondary outcomes analysed.

Conclusion: In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes were consistent across subgroups of patients stratified by baseline glucose-lowering agent.

Clinicaltrials: gov identifier: NCT01986881.

Keywords: SGLT2 inhibitor; cardiovascular disease; type 2 diabetes.

Conflict of interest statement

S.D.‐J. has led clinical trials for AstraZeneca, Boehringer Ingelheim and Novo Nordisk, has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Merck & Co. and Sanofi, and has equity interests in Jana Care and Aerami Therapeutics. C.P.C. has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi Sankyo, Janssen, Merck and Pfizer, fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan and Sanofi, and has served on data and safety monitoring boards for the Veteran's Administration, Applied Therapeutics and Novo Nordisk. D.Z.I.C. has received consulting fees and/or speaking honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co., Mitsubishi‐Tanabe, Novo Nordisk, Prometic and Sanofi, and has received operating funds from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co., Novo Nordisk and Sanofi. F.C. has received research grants from the Swedish Research Council, Swedish Heart & Lung Foundation and King Gustav V and Queen Victoria Foundation, and has received consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Merck Sharp & Dohme, Mundipharma, Novo Nordisk and Pfizer. R.E.P. has received grants (directed to his institution) from Hanmi Pharmaceutical, Janssen, Metavention, Novo Nordisk, Poxel and Sanofi, consulting fees (directed to his institution) from AstraZeneca, Corcept Therapeutics, Glytec, Hanmi Pharmaceutical, Janssen, Merck & Co., Mundipharma, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma and Sun Pharma, and support for attending meetings/travel (directed to his institution or to the travel provider) from AstraZeneca, Glytec, Merck & Co., Mundipharma, Novo Nordisk and Pfizer. J.L., A.P. and I.G. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, who own stock in Merck & Co., Inc., Kenilworth, New Jersey. R.F. and J.P.M. are employees and shareholders of Pfizer Inc.

© 2022 Pfizer Inc. and Merch Sharp & Dohme Corp. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Cardiovascular (CV) and kidney outcomes with ertugliflozin versus placebo by baseline (A) metformin and insulin, (B) sulphonylurea (SU) and dipeptidyl peptidase‐4 (DPP‐4) inhibitor use. The analysis of major adverse CV events (MACE) was performed with data from all the patients who had undergone randomization and received at least one dose of ertugliflozin (n = 5493) or placebo (n = 2745). For patients who permanently discontinued the trial regimen prematurely, only MACE that occurred up to 365 days after the confirmed last dose were included in the primary analysis. The analyses of the other outcomes were performed on an intention‐to‐treat basis with data from all the patients who had undergone randomization to receive ertugliflozin (n = 5499) or placebo (n = 2747), and all time on‐study for each patient. The interaction P value is shown for the two‐level treatment group (all ertugliflozin vs. placebo). BL, baseline; CI, confidence interval; Cr, creatinine; eGFR, estimated glomerular filtration rate; ERTU, ertugliflozin; HHF, hospitalization for heart failure; PBO, placebo

FIGURE 2

Changes in estimated glomerular filtration rate (eGFR) over time with ertugliflozin versus placebo by baseline (A) metformin, (B) insulin, (C) sulphonylurea (SU) and (D) dipeptidyl peptidase‐4 (DPP‐4) inhibitor use. Mean (standard deviation [SD]) baseline eGFR levels by treatment are shown in the key for each baseline glucose‐lowering class. N is the number of patients without missing data at each time point. BL, baseline; ERTU, ertugliflozin; PBO, placebo; SE, standard error