Capturing the Additional Cardiovascular Benefits of SGLT2 Inhibitors and GLP-1 Receptor Agonists Beyond the Control of Traditional Risk Factors in People With Diabetes

Objectives This study aimed to quantify the additional cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond the traditional risk factors control in individuals with type 2 diabetes. This helps calibrate the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model to capture the total cardiovascular benefits of new diabetes medications accurately. Methods We extracted patient characteristics and treatment efficacy data from 4 cardiovascular outcome trials (CVOTs) of SGLT2is and 4 CVOTs of GLP-1RAs completed before May 2023. Using the BRAVO diabetes simulation model, we translated reductions in traditional risk factors (ie, glycated hemoglobin, systolic blood pressure, low-density lipids, and body mass index) from the newer drugs into risk reductions in cardiovascular outcomes (ie, myocardial infarction [MI], stroke, congestive heart failure [CHF], and mortality), assuming that the drug-associated risk reductions were only driven by traditional risk factors. Then, we compared the simulated risk-factor-driven risk reductions of cardiovascular outcomes with observed risk reductions from the trials and calculated drug-specific incremental benefits (DIB). Results After accounting for the cardiovascular effects from traditional risk factors control, SGLT2is was associated with an additional 19% risk reduction in CHF (DIB: 0.81, 95% CI 0.72-0.90). Furthermore, the uncalibrated model predicted a risk reduction in stroke with SGLT2is, which was not observed in CVOTs. This discrepancy highlights the need for an SGLT2i-specific calibrator to align the simulation results with the observed outcomes. In contrast, no additional cardiovascular benefit was associated with GLP-1RAs after controlling for traditional risk factors. Conclusions Our study revealed that SGLT2is could further reduce CHF risk beyond the control of traditional risk factors but may offer additional pathways to offset the overall benefits of traditional risk factor control in stroke risk. No additional cardiovascular benefits were observed for GLP-1RAs beyond traditional risk factor control. The BRAVO model calibration enhances cardiovascular outcome prediction with these newer antidiabetic therapies.