Kidney outcomes using a sustained ≥40% decline in eGFR: A meta-analysis of SGLT2 inhibitor trials

Abstract

Background: A recent meta-analysis of sodium-glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials.

Hypothesis: The apparent heterogeneity of the meta-analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials.

Methods: We performed a meta-analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE-TIMI 58 (NCT01730534), and EMPA-REG OUTCOME (NCT01131676).

Results: Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51-0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I2 = 0.0%).

Conclusions: Our meta-analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors.

Keywords: SGLT2 inhibitor; kidney disease; kidney failure; meta-analysis; randomized clinical trials; type 2 diabetes mellitus.

Conflict of interest statement

David Z.I. Cherney has received consulting fees or speaking honoraria, or both, from Bristol Myers Squibb, Novo Nordisk, Mitsubishis‐Tanabe, MAZE, Janssen, Bayer, Boehringer Ingelheim‐Eli Lilly, AstraZeneca, Merck & Co., Inc., Prometic, and Sanofi; and has received operating funds from Janssen, Boehringer Ingelheim‐Eli Lilly, Sanofi, AstraZeneca, and Merck & Co., Inc. Samuel Dagogo‐Jack has led clinical trials for AstraZeneca, Novo Nordisk, Inc., and Boehringer Ingelheim; has received fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co., Inc., and Sanofi; and holds equity interests in Jana Care, Inc. and Aerami Therapeutics. Darren K. McGuire has had leadership roles in clinical trials for AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co., Inc., Novo Nordisk, CSL Behring, and Sanofi USA; and has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Lilly USA, Merck & Co., Inc., Pfizer, Novo Nordisk, Metavant, Afimmune, and Sanofi. Francesco Cosentino has received fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Novo Nordisk, and Pfizer; as well as research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and the King Gustav V and Queen Victoria Foundation. Richard Pratley has received the following (directed to his institution): speaker fees from Novo Nordisk; consulting fees from Merck & Co., Inc., Novo Nordisk, Pfizer, Sanofi, Scohia Pharma Inc., and Sun Pharmaceutical Industries; and grants from Lexicon Pharmaceuticals, Hanmi Pharmaceutical Co., Novo Nordisk, Poxel SA, and Sanofi. Weichung J. Shih has received fees for an ertugliflozin advisory board of Merck & Co., Inc., Kenilworth, New Jersey, USA. Robert Frederich and Shuai Wang are employees and shareholders of Pfizer Inc. Mario Maldonado is an employee of MSD UK. He may own stock and/or stock options in Merck & Co., Inc., Kenilworth, New Jersey, USA. Jie Liu is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA, and may own stock and/or stock options in Merck & Co., Inc., Kenilworth, New Jersey, USA. Christopher P. Cannon reports grants and personal fees from Pfizer Inc., Amgen, Boehringer Ingelheim, Bristol Myers Squibb, and Janssen; grants and personal fees from Merck & Co., Inc., during the conduct of the trial; grants from Daiichi Sankyo and Novo Nordisk; and personal fees from Aegerion, Alnylam, Amarin, Applied Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Innovent, Kowa, Sanofi, Eli Lilly, and Rhoshan, outside the submitted work.

© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.

Figures

FIGURE 1

Effects of sodium–glucose cotransporter 2 inhibitors on the kidney composite outcome of sustained* ≥40% decline in eGFR from baseline, kidney replacement therapy, or kidney death. *In the EMPA‐REG OUTCOME and DECLARE‐TIMI 58 trials, 'sustained' was defined as a reduction that was present on at least two consecutive occasions ≥4 weeks apart. In the CANVAS Program and VERTIS CV trial, 'sustained' was defined as a reduction that was present on at least two consecutive occasions >30 days apart. CI, confidence interval; eGFR, estimated glomerular filtration rate. Weights are initially calculated as 1/variance of the hazard ratio and then standardized so that they sum up to 1. Studies with higher precision (i.e. smaller confidence intervals) will be given more weights