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 ( <scp>CombiKid</scp> St

ABSTRACT 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 m 2 and 2‐years, −5.0 mL/min/1.73 m 2 , 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 m 2 and 2‐years, −6.1 mL/min/1.73 m 2 , 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 &lt; 0.001; and at 2‐years: 2.1, 1.4–2.7, p &lt; 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.