Combinations of Renin-Angiotensin-Aldosterone System Inhibitors, Statins, SGLT2 Inhibitors, and GLP-1 Receptor Agonists and Survival

Background: Combinations of renin-angiotensin-aldosterone system inhibitors (RAASi), statins, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) that maximize survival in populations with Type 2 diabetes mellitus (T2DM) remain undefined. Methods: A total of 743,226 subjects with T2DM naïve to RAASi, statins, SGLT2i, and GLP-1 RA on January 1st, 2020 were followed until December 31st, 2023. With an incident, intention-to-treat approach, dates of initiation of all 16 possible treatment phenotypes possible were determined and mortality hazards ratios were calculated in time-dependent proportional hazards models. Results: With adjustment for all baseline characteristics and era of initiation (AHR), the 5 lowest medication phenotype-associated hazards ratios (vs. No Agent, P < 0.001 unless indicated) were SGLT2i alone: AHR 0.44 (CI 0.40,0.47) followed by: SGLT2i/GLP-1 RA: AHR 0.49 (CI 0.42,0.58); statin: AHR 0.55 (CI 0.53,0.56); statin/SGLT2i/GLP-1 RA: AHR 0.57 (CI 0.49,0.67); and GLP-1 RA: AHR 0.58 (CI 0.52,0.64). Observed AHR with RAASi were lowest in combination with SGLT2i/GLP-1 RA: AHR 0.60 (CI 0.47,0.76) and with statin/SGLT2i/GLP-1 RA: AHR 0.63 (CI 0.57,0.70). The AHRs were lowest with SGLT2i alone in half the subgroups examined and combinations of 2 or 3 classes in the others. Conclusion: In the overall population, use of SGLT2i alone was associated with the lowest mortality risk in subjects with T2DM; no subgroup exhibited minimum mortality risk with a combination of all four classes.