All‐cause mortality and cardiovascular outcomes with sodium‐glucose Co‐transporter 2 inhibitors, glucagon‐like peptide‐1 receptor agonists and with combination therapy in people with type 2 diabetes

Aim To assess the relationship of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor analogues (GLP‐1RA) and their combination (SGLT2i + GLP‐1RA) with 5‐year risk of all‐cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes. Materials and Methods Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP‐1RA and SGLT2i + GLP‐1RA) were compared against a control cohort (no SGLT2i/GLP‐1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP‐1RA, n = 186 841; SGLT‐2i + GLP‐1RA, n = 108 504). A sub‐analysis comparing combination and monotherapy cohorts was also performed. Results The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all‐cause mortality (SGLT2i 0.49, 0.48‐0.50; GLP‐1RA 0.47, 0.46‐0.48; combination 0.25, 0.24‐0.26), hospitalization (0.73, 0.72‐0.74; 0.69, 0.68‐0.69; 0.60, 0.59‐0.61) and acute myocardial infarct (0.75, 0.72‐0.78; 0.70, 0.68‐0.73; 0.63, 0.60‐0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub‐analysis showed a significant risk reduction in all‐cause mortality for combination therapy versus SGLT2i (0.53, 0.50‐0.55) and GLP‐1RA (0.56, 0.54‐0.59). Conclusions SGLT2i, GLP‐1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all‐cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5‐year all‐cause mortality when compared directly against either monotherapy.