Abstract
BACKGROUND: Guidelines recommend combination therapy with glucagonlike peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) for cardiorenal risk reduction in people with type 2 diabetes (T2D); however, there is limited real-world evidence on the long-term effects of combination therapy on cardiometabolic and renal outcomes. The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone. METHODS: This retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo's Healthcare Map from January 1, 2017, to June 30, 2023. The study included 100,455 people in the combination GLP-1RA and SGLT2i group and 339,540 people in the comparison SGLT2i group across 3 cohorts: T2D with atherosclerotic cardiovascular disease (ASCVD), T2D, and T2D with chronic kidney disease (CKD). Entropy balancing was used to balance patient characteristics. Time to first event of ischemic stroke, myocardial infarction (MI), 3-point major adverse cardiovascular event (MACE), and 5-point MACE in T2D with ASCVD cohort were measured. In the T2D cohort, follow-up and change in glycated hemoglobin (HbA(1c)) and weight, odds of achieving HbA(1c) < 7% and HbA(1c) < 8%, and odds of achieving 5%, 10%, and 15% decrease in weight were also measured. RESULTS: The combination and comparison groups included 34,690 and 130,220 people, respectively, in the T2D with ASCVD cohort; 8,220 and 22,891 people, respectively, in the T2D cohort; and 8,783 and 35,532 people, respectively, in the T2D with CKD cohort. Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD. Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA(1c), and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D. CONCLUSIONS: Combination of SGLT2i and GLP-1RA achieved significantly better cardiometabolic outcomes compared with SGLT2i alone; this supports the hypothesis that the cardioprotective benefits of GLP-1RA and SGLT2i may be additive.