Several hypotheses have been proposed that SGLT2 inhibitors and GLP-1 receptor agonists may have additional mechanisms to further reduce risks of cardiovascular complications unexplained by traditional risk factors control. This study aimed to examine and quantify the magnitude of additional protective effects of these two drugs on cardiovascular outcomes in individuals with type 2 diabetes (T2D) . Patient characteristics were extracted from four cardiovascular outcomes trials (CVOTs) of SGLT2 inhibitors and four CVOTs of GLP-1 receptor agonists completed before Nov 2021. We used the BRAVO simulation model to translate risk factors reductions from the newer drugs into risk reductions in cardiovascular complications, assuming the simulated risk reductions are only driven by traditional risk factors (i.e., A1c, SBP, LDL, and BMI) . We then derived the relative risk (RR) between observed risk reductions and simulated risk-factor-driven risk reductions in study outcomes to determine whether additional cardiovascular benefit of the newer drugs exist that can be explained by improvement of traditional risk factor control. Controlling for effect from traditional risk factors, SGLT2 inhibitor was associated with an additional risk reduction of hospitalization for heart failure (HHF) (RR: 0.74, 95% confidence interval (CI) : 0.59-0.94) , and a meaningful but not significant reduction in all-cause mortality (RR: 0.90, 95% CI: 0.77-1.03) , but an increased risk of stroke (RR: 1.29, 95% CI: 1.03-1.62) . No additional benefit was observed in preventing MI or CVD mortality from SGLT2 inhibitors. No additional benefit in preventing any study outcomes was associated with GLP-1 receptor agonists. Except for the benefit on HHF by SGLT2i, improvement in traditional CVD risk factors largely account for all the benefit associated with GLP-1 and SGLT2i to reduce CVD.
S.Niu: None. D.Guan: None. N.Singh ospina: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. L.Shi: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.