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Kidney Compass: The Future of Cardiovascular-Kidney-Metabolic Trial Design
Neuen is joined by Richard Pratley, MD, and Muthiah Vaduganathan, MD, MPH, to discuss the evolving landscape of CKM trial design.
Welcome Back to Kidney Compass: Navigating Clinical Trials!
In this episode of Kidney Compass, host Brendon Neuen, MBBS, PhD, is joined by Richard Pratley, MD, medical director at the Advent Health Diabetes Institute, and Muthiah Vaduganathan, MD, MPH, codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, to discuss the evolving landscape of clinical trials in cardiovascular-kidney-metabolic (CKM) syndrome, exploring how various study designs, patient engagement, and infrastructure development are reshaping research and evidence generation in this growing field.
A central focus of the discussion is the value and nuances of different trial designs, focusing specifically on SURPASS CVOT. The cardiovascular outcome study is the first to directly compare 2 incretin-based therapies, tirzepatide, a dual GIP/GLP-1 receptor agonist, and dulaglutide, a GLP-1 receptor agonist, among patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD).
Topline results showed tirzepatide achieved the primary objective by demonstrating a non-inferior rate of major adverse cardiovascular events (MACE-3), including cardiovascular death, heart attack or stroke, versus dulaglutide. Additionally, while not controlled for multiplicity-adjusted type-1 error, tirzepatide showed improvements on key measures of A1C, weight, renal function and all-cause mortality.
The speakers noted the active control design of the trial with a prespecified hierarchy of testing, highlighting the proven noninferiority of tirzepatide and its lack of association with excess cardiovascular risk, but no proven superiority. Additionally, the group discussed the use of imputed placebo analysis based on data from the REWIND trial of dulaglutide, allowing comparison of tirzepatide against a virtual placebo group and suggesting tirzepatide reduced major adverse cardiovascular events while remaining safe.
With the ability to conduct placebo controlled trials getting “narrower and narrower,” especially in areas like the incretin space, the speakers emphasize the importance of trial designs like SURPASS CVOT, additionally drawing parallels to the FLOW trial of semaglutide for diabetic kidney disease and assessing the possibility of applying a similar imputed placebo design to evaluate new incretin based therapies in CKD.
With standards of care shifting so rapidly in nephrology, the group explores how trials may need to be adjusted moving forward, discussing the need to account for more patients being on background therapy, mandate local standards of care, and incorporate aspects like active comparison against a traditional, accepted standard of care.
The trio goes on to describe potential trial designs for incretin-based therapies, citing the continued need for large outcomes-based trials and potential strategies to minimize placebo exposure as well as the pros and cons of different trial designs. Despite these challenges, the group notes that the difficulties in trial design are far outweighed by the benefits of bringing highly effective drugs to patients to decrease the risk of CKD progression and the cardiovascular consequences of CKD.
Editors’ note: Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Pratley include Novo Nordisk, Merck, Bayer, Eli Lilly and Company, Rivus Pharmaceuticals, and others. Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others.
References
Brooks A. SURPASS-CVOT: Tirzepatide Bests Dulaglutide for Cardiovascular Protection. HCPLive. July 31, 2025. Accessed September 29, 2025. https://www.hcplive.com/view/surpass-cvot-tirzepatide-bests-dulaglutide-cardiovascular-protection
Isaacs D, Bellini N. Diabetes Dialogue: FLOW Trial and Semaglutide's Benefit in Chronic Kidney Disease. HCPLive. May 25, 2024. Accessed September 29, 2025. https://www.hcplive.com/view/diabetes-dialogue-flow-trial-and-semaglutide-s-benefit-in-chronic-kidney-disease
Neuen B, Wadhwani S. Kidney Compass: FLOW Insights from Kidney Week 2024, with Katherine Tuttle, MD. HCPLive. October 28, 2024. Accessed September 29, 2025. https://www.hcplive.com/view/kidney-compass-flow-insights-from-kidney-week-2024-with-katherine-tuttle-md
