Comparative effectiveness of GLP-1 receptor agonists versus SGLT2 inhibitors in obese patients with valvular heart disease: a target-trial emulation

Background LP-1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in high-risk cardiometabolic populations, yet comparative effectiveness data in valvular heart disease (VHD) are sparse. Purpose To compare 1-year all-cause mortality after initiation of GLP-1RA versus SGLT2i among adults with common non-rheumatic VHD and obesity. Methods Using a large federated electronic health record network, we emulated four parallel target trials in adults (≥18 years) with BMI ≥30 kg/m² and a diagnosis of non-rheumatic aortic stenosis, aortic insufficiency, mitral insufficiency, or tricuspid insufficiency recorded within the year before treatment start. Time zero was the first prescription of GLP-1RA (dulaglutide, liraglutide, semaglutide, or tirzepatide) or SGLT2i (canagliflozin, dapagliflozin, or empagliflozin). A 365-day washout for both drug classes and exclusion of pre-index crossover were applied to approximate new users. Each VHD cohort underwent 1:1 propensity-score matching for demographics, cardiometabolic comorbidities (including diabetes, heart failure, chronic kidney disease), and key cardiovascular medications. Follow-up was 365 days. Results After matching, 2,767 pairs with aortic stenosis, 1,549 pairs with aortic regurgitation, 3,493 pairs with mitral regurgitation, and 1,626 pairs with tricuspid regurgitation were analysed. One-year all-cause mortality was similar for GLP-1RA versus SGLT2i in aortic stenosis (5.9% vs 5.6%; HR 1.06; p=0.585) and mitral regurgitation (5.3% vs 5.9%; HR 0.92; p=0.388). In regurgitant lesions, GLP-1RA showed numerically lower mortality in aortic regurgitation (4.2% vs 5.6%; HR 0.77; p=0.118) and tricuspid regurgitation (6.9% vs 8.1%; HR 0.88; p=0.306), without statistical significance. Conclusions In obese adults with common non-rheumatic VHD, initiation of GLP-1RA compared with SGLT2i was not associated with higher 1-year mortality, with consistent numerical trends favouring GLP-1RA in regurgitant phenotypes. Prospective studies are needed to clarify whether incretin-based therapy confers incremental benefit in valvular populations beyond established cardiometabolic effects.