CARDIOVASCULAR EFFECTS OF INCRETIN RECEPTOR AGONISTS: BEYOND GLYCEMIC CONTROL.

Abstract

Incretin-based therapies have evolved from selective GLP-1RA to dual GLP-1/ GIP agonists and unimolecular triple GLP-1/GIP/glucagon receptor agonists. This review examines the cardiovascular effects of these three pharmacological tiers, with emphasis on mechanisms that operate beyond glycaemic control. Mediation analyses of major CVOTs indicate that glycaemic improvement accounts for less than 15 to 20 percent of the reduction in major adverse cardiovascular events achieved by these agents. The remainder reflects converging effects on weight reduction, lipid remodelling, blood pressure, systemic inflammation, and direct myocardial protection. At the cellular level, incretin signalling preserves mitochondrial bioenergetics, activates antioxidant defences, and inhibits multiple cardiomyocyte death pathways. At the tissue level, recent investigations in isolated human atrial preparations demonstrate direct positive inotropic effects of both GLP-1RA and the triple agonist retatrutide. Cardiac magnetic resonance evidence from the SUMMIT programme documents reverse left ventricular remodelling with tirzepatide in obesity-related heart failure with preserved ejection fraction. Phase 2 data for triple agonists have produced unprecedented surrogate cardiovascular improvements, while Phase 3 outcome data from the TRIUMPH programme remain awaited. The cardiovascular pharmacology of metabolic disease has been fundamentally reshaped, and ongoing trials will determine whether multi-receptor agonism establishes a new therapeutic standard.