Effects of SGLT2 Inhibitors with and without Metformin in High-Risk, Treatment-Naïve Patients with Diabetes.

Background: Contemporary evidence supports the cardiovascular and renal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2is) in patients with diabetes. While metformin has traditionally been recommended as a first-line treatment, its exact role in improving cardiovascular outcomes remains uncertain. This study aims to evaluate the impact of combination therapy with metformin on the cardiovascular and renal outcomes in high-risk, treatment-naïve diabetic patients who have undergone SGLT2i therapy. Methods: Using the National Health Insurance Research Database in Taiwan, a retrospective cohort study was conducted. Treatment-naïve patients with diabetes and established atherosclerotic cardiovascular disease (ASCVD) undertaking SGLT2i therapy from 1 January 2016 to 31 December 2021 were included. Patients were categorized based on the concomitant use of metformin. Propensity score matching was employed to minimize confounding factors. The primary outcome was major adverse cardiovascular events (MACEs), with secondary outcomes including cardiovascular death, hospitalization for heart failure, and renal outcomes. Results: In total, 10,151 treatment-naïve diabetic patients with ASCVD were identified, with 2570 in the only SGLT2i therapy group and 7581 in the SGLT2i plus metformin group. In total, 2262 pairs were analyzed after propensity score adjustment. The risk of MACEs (36.6 vs. 42.1 events per 1000 person-years; hazard ratio 0.87, 95% confidence interval 0.70-1.09) and other outcomes did not significantly differ between the two treatment groups. Conclusions: In high-risk, treatment-naïve diabetic patients, initiating SGLT2i therapy alone or in combination with metformin resulted in comparable cardiovascular and renal outcomes. These findings suggest that metformin might not be mandatory as a first-line treatment for achieving cardiovascular benefits in such patients.