Combining Sodium-Glucose Co-Transporter-2 Inhibitor Plus Glucagon-Like Peptide-1 Receptor Agonist for Glucose-Lowering in Type 2 Diabetes: Effects of Drug Initiation Sequence on Kidney Function in Real-World Clinical Practice (CombiKid Study).

AIMS: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have separately shown renoprotective effects in clinical trials in people with type 2 diabetes. It is unclear whether combining these agents produces incremental kidney outcome benefits. MATERIALS AND METHODS: Retrospective cohort study with a prevalent new-user design using pseudonymised data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care sentinel network. We extracted data for two cohorts prescribed SGLT2is and/or GLP-1 RAs between January 2013 and December 2021. We 1:1 propensity score matched SGLT2i plus GLP-1 RA combination users with monotherapy (SGLT2i or GLP-1RA) users. Multivariable linear regression analyses estimated adjusted mean differences in absolute change in estimated glomerular filtration rate (eGFR) (baseline to 1- and 2-years follow-up) between combination and monotherapy. RESULTS: Across the matched combination and SGLT2i monotherapy groups (N = 14 774), mean decline in eGFR, baseline to 1-year, was -4.5 mL/min/1.73 m2 and 2-years, -5.0 mL/min/1.73 m2, with no difference when comparing combination and SGLT2i monotherapy. Across the matched combination and GLP-1 RA monotherapy groups (N = 14 154), mean decline in eGFR, baseline to 1-year, was -5.4 mL/min/1.73 m2 and 2-years, -6.1 mL/min/1.73 m2, but combination therapy was associated with a smaller eGFR reduction compared with GLP-1 RA monotherapy (difference in eGFR at 1-year: [mean, 95% confidence interval, CI] 2.2, 1.7 to 2.8, p < 0.001; and at 2-years: 2.1, 1.4-2.7, p < 0.001). CONCLUSIONS: In real-world clinical practice, the combination of SGLT2i and GLP-1 RA may be more effective for preserving kidney function than GLP-1 RA monotherapy. This effect was not seen with combination versus SGLT2i monotherapy.