Mediators of ertugliflozin effects on heart failure and kidney outcomes among patients with type 2 diabetes mellitus

Abstract

Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown.

Materials and methods: Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes.

Results: For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome.

Conclusions: In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods.

Gov identifier: NCT01986881.

Keywords: Ertugliflozin; SGLT2 inhibitor; VERTIS CV; hospitalization for heart failure; kidney outcomes; mediation analyses; type 2 diabetes mellitus.

Conflict of interest statement

MWS and AAK declare that they have no competing interests. CPC has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk and Pfizer, as well as 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 serves on Data and Safety Monitoring Boards for the Veteran's Administration, Applied Therapeutics, and Novo Nordisk. FC 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 Inc. SD‐J has led clinical trials for AstraZeneca, Boehringer Ingelheim and Novo Nordisk Inc.; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Merck & Co., Inc. and Sanofi; and has equity interests in Jana Care Inc. and Aerami Therapeutics. DKM has received consulting fees from Afimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Esperion, Lexicon, Lilly USA, Merck Sharp & Dohme, Metavant, Novo Nordisk, Pfizer Inc. and Sanofi US; has received honoraria from Boehringer Ingelheim; has received payment for expert testimony from Kirkland & Ellis on behalf of Boehringer Ingelheim; and has participated on data safety monitoring boards/advisory boards for CSL Behring, AbbVie, Eidos, Otsuka, Arena and Akebia. REP has received grants (directed to his institution) from Hanmi Pharmaceutical Co., Ltd, Janssen, Metavention, Novo Nordisk, Poxel SA and Sanofi; has received consulting fees (directed to his institution) from AstraZeneca, Corcept Therapeutics Incorporated, Glytec LLC, Hanmi Pharmaceutical Co., Ltd, Janssen, Merck & Co., Inc., Mundipharma, Novo Nordisk, Pfizer Inc., Sanofi, Scohia Pharma Inc. and Sun Pharmaceutical Industries; and has received support for attending meetings/travel (directed to his institution or to the travel provider) from AstraZeneca, Glytec LLC, Merck & Co., Inc., Mundipharma, Novo Nordisk and Pfizer Inc. Am.P. has served on the advisory board of Roche Diagnostics and has received research support from the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960‐01) and Applied Therapeutics. DZIC has received honoraria from Boehringer Ingelheim‐Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi‐Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL‐Behring, Otsuka, Novartis, Yeungene, Lexicon and Novo‐Nordisk, and has received operational funding for clinical trials from Boehringer Ingelheim‐Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL‐Behring, and Novo‐Nordisk. RF and NBC are employees and shareholders of Pfizer Inc. JL, CL and AnP are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA), and may own stock and/or stock options in Merck & Co., Inc. MM is an employee of MSD Limited, London, UK, who owns stock in Merck & Co., Inc.

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

Figures

FIGURE 1

Percentage of mediation by biomarkers on hospitalization for heart failure. HR (95% CI) for the unweighted prespecified HHF. †First change from baseline measurement. ‡Weighted average of change from baseline from all post‐baseline measurements. Mediators in blue were associated with decreases in placebo‐adjusted changes from baseline with ertugliflozin; mediators in red were associated with increases in placebo‐adjusted changes from baseline. ALT, alanine aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; HDL‐C, high‐density lipoprotein cholesterol; HHF, hospitalization for heart failure; HR, hazard ratio; SBP, systolic blood pressure; UACR, urine albumin‐to‐creatinine ratio

FIGURE 2

Percentage of mediation by biomarkers on a prespecified exploratory kidney composite outcome. HR (95% CI) for the unweighted prespecified exploratory kidney composite outcome comprising sustained 40% decrease from baseline in estimated glomerular filtration rate, chronic kidney replacement therapy, or kidney death was 0.66 (0.50‐0.88). †First change from baseline measurement. ‡Weighted average of change from baseline from all post‐baseline measurements. Mediators in blue were associated with decreases in placebo‐adjusted changes from baseline with ertugliflozin; mediators in red were associated with increases in placebo‐adjusted changes from baseline. HbA1c, glycated haemoglobin; HDL‐C, high‐density lipoprotein cholesterol; HR, hazard ratio; RBC, red blood cell; SBP, systolic blood pressure

FIGURE 3

Criteria for mediation and possible mediators for effect of ertugliflozin on HHF and composite renal outcomes. Adapted from Li et al. Copyright © 2020 with permission from Elsevier on behalf of the American College of Cardiology Foundation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; HDL‐C, high‐density lipoprotein cholesterol; HHF, hospitalization for heart failure; LDL‐C, low‐density lipoprotein cholesterol; RBC, red blood cell; SBP, systolic blood pressure; UACR, urine albumin‐to‐creatinine ratio