Abstract
Despite advances in cardiovascular risk reduction in type 2 diabetes (T2D), a persistent gap remains compared to individuals without diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have provided consistent cardiovascular benefits. With more cardiovascular protective agents available for diabetes management, their incremental effect may be nearing a ceiling. The SURPASS-CVOT trial innovatively compared the dual GIP/GLP-1RA tirzepatide with the selective GLP-1RA dulaglutide, demonstrating noninferiority for major adverse cardiovascular events (MACE; HR 0.92; 95.3% CI 0.83-1.01; p = 0.086) and suggesting a potential 28% MACE risk reduction versus an imputed placebo. However, superiority over dulaglutide was narrowly missed. Despite greater improvements in glycemia (0.8% greater HbA1c reduction) and weight (7% greater weight loss), tirzepatide appeared to confer limited incremental cardiovascular benefit, raising questions about mechanism saturation or trial design constraints. Exploratory analyses showed promising benefits on mortality and renal function but require cautious interpretation. The trial's active comparator/imputed placebo design reflects an evolving ethical and therapeutic landscape in diabetes care. Whether dual incretin receptor agonism can meaningfully exceed current cardioprotective thresholds remains uncertain. By now, we may need new paradigms to overcome what may turn out to be a therapeutic ceiling for cardiovascular protection in the T2D population.