Tirzepatide and SGLT2 Inhibitors for Heart Failure With Preserved Ejection Fraction and Obesity: Entering a New Cardiometabolic Therapeutic Era

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure hospitalizations, with obesity increasingly recognized as a central driver through expansion of epicardial adipose tissue, chronic low-grade inflammation and obesity-related haemodynamic overload culminating in ventricular hypertrophy. METHODS: We synthesized high-impact evidence from pivotal randomized trials and mechanistic studies published between 2015 and 2026, focusing on cardiometabolic outcomes, adipose tissue remodelling and haemodynamic effects of both drug classes. RESULTS: Tirzepatide produced substantial weight loss (> 20%), significant reductions in epicardial and paracardiac adipose tissue and a 19.5-point improvement in Kansas City Cardiomyopathy Questionnaire scores in the SUMMIT trial. SGLT2i, exemplified by empagliflozin, demonstrated foundational benefit through natriuresis, improved myocardial energetics and reduced heart failure hospitalization independent of diabetes status, with additional renal-protective effects. Because SUMMIT and EMPEROR-Preserved differed in design and populations, direct comparison between agents is not statistically valid; each should be assessed on its own evidence base. CONCLUSION: Tirzepatide and SGLT2i act through distinct, physiologically complementary pathways converging on the cardio-renal-metabolic axis. While their combined use is mechanistically promising, it has not yet been tested in a dedicated randomized controlled trial, and prospective studies are needed to establish safety and long-term efficacy in obesity-related HFpEF.