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Cohosts Stephen Greene, MD, and Muthiah Vaduganathan, MD, MPH, sit down with Darren McGuire, MD, to discuss the results of this groundbreaking trial.
In this episode of Don’t Miss a Beat, hosts Stephen Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, and Muthiah Vaduganathan, MD, MPH, a cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, sit down with Darren McGuire, MD, chair of cardiovascular science at the UT Southwestern Medical Center, to explore the groundbreaking results of the SURPASS-CVOT trial.
00:00:00 Intro
00:01:35 Behind the trial
00:04:35 What is imputed placebo?
00:08:32 The size and scope of SURPASS-CVOT
00:11:01 Results of SURPASS-CVOT
00:14:20 How to select comparators among obesity medicines
00:17:37 Future trials
00:18:56 Interpreting these new kinds of comparisons
00:20:50 Active comparators are the future
00:24:01 Closing
This cardiovascular outcome study is the first to directly compare two 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). Unlike the placebo-controlled GLP-1 programs of the past decade, SURPASS-CVOT represents a pivotal move toward active comparator trials in cardiometabolic medicine.
McGuire outlines the unique trial design, which combined traditional noninferiority testing against dulaglutide with an “imputed placebo” approach, drawing on prior GLP-1 placebo-controlled trial data to infer superiority versus placebo. Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) endorsed this framework, marking the first time such methodology has been formally accepted in the cardiometabolic arena. With more than 13,000 patients followed for over four years, the trial was powered to achieve exceptional statistical precision.
Results from SURPASS-CVOT confirmed tirzepatide’s noninferiority to dulaglutide for major adverse cardiovascular events (MACE), with a hazard ratio of 0.92 and an upper confidence limit just above the threshold for superiority. Beyond the primary endpoint, publicly available data highlighted several notable findings: a 16% reduction in all-cause mortality, improvements in hemoglobin A1c despite equivalent glycemic targets, robust weight loss consistent with tirzepatide’s known efficacy, and a favorable effect on eGFR slope, suggesting kidney protective benefits. While hierarchical testing will determine which outcomes are statistically confirmable, these results underscore tirzepatide’s broad potential impact.
The discussion also focuses on the trial’s broader implications. Active comparator trials, once considered too large and costly, may now be necessary as multiple effective therapies exist across GLP-1, SGLT2, and emerging tri-agonist classes. The panel emphasizes that placebo-controlled designs are becoming less tenable in established indications, particularly as therapies for diabetes, obesity, and CKM conditions advance. They also note practical strategies—such as open-label extensions and enhanced lifestyle support—to maintain trial participation and ensure high-quality data collection.
McGuire and the hosts position SURPASS-CVOT as a watershed moment in cardiometabolic outcomes research. By proving that active comparator trials are both feasible and informative, the study sets a new benchmark for evaluating next-generation therapies. As obesity and diabetes treatments continue to expand into dual and multi-pathway agents, SURPASS-CVOT charts a course for how regulatory bodies, clinicians, and payers may integrate innovative trial designs into practice, ensuring patients receive therapies that are not only effective but also rigorously compared against the current standards of care.
Editor's Note: Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others. Relevant disclosures for McGuire include Novo Nordisk, Sanofi-Aventis, Lilly USA, Merck & Co, AstraZeneca, AstraZeneca, and others.
