Precision Medicine in Type 2 Diabetes: Targeting SGLT2-Inhibitor Treatment for Kidney Protection
Authors: Jansz Thijs T , Young Katherine G , Hopkins Rhian , McGovern Andrew P , Shields Beverley M , Hattersley Andrew T , Jones Angus G , Pearson Ewan R , Bingham Coralie , Oram Richard A , Dennis John M 
Published: September 2024

ABSTRACTBackgroundCurrent guidelines recommend sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) for kidney protection in people with type 2 diabetes (T2D) based on a ≥3mg/mmol albuminuria threshold. However, individuals with preserved estimated glomerular filtration rate (eGFR) and normal or low-level albuminuria were not represented in kidney outcome trials, leaving uncertainty about who may have absolute benefit. We therefore developed and validated a model using routine clinical features to predict kidney protection benefit with SGLT2-inhibitors in these individuals.MethodsWe developed a model to predict kidney protection benefit with SGLT2-inhibitors (3-year individual-level absolute risk reductions) by integrating the relative treatment effect from previous trial meta-analysis with the internationally validated CKD Prognosis Consortium (CKD-PC) risk score for kidney disease progression (≥50% eGFR decline, end-stage kidney disease, or kidney-related death). We validated this approach using electronic health record data from UK primary care (Clinical Practice Research Datalink, 2013-2020) including adults with T2D, eGFR ≥60mL/min/1.73m2, albuminuria <30mg/mmol, without atherosclerotic vascular disease or heart failure, starting either SGLT2-inhibitors or comparator drugs dipeptidyl peptidase-4 inhibitors/sulfonylureas (DPP4i/SU). We evaluated the real-world applicability of the relative treatment effect using overlap-weighted Cox proportional hazard models and assessed calibration of the CKD-PC risk score. We validated the accuracy of model-predicted benefit by comparing predicted and observed absolute risk reductions with SGLT2-inhibitors vs DPP4i/SU. We then compared clinical utility of a model-based treatment strategy to the ≥3mg/mmol albuminuria threshold.FindingsIn 53,096 initiations of SGLT2-inhibitor treatment compared with 88,404 initiations of DPP4i/SU, SGLT2-inhibitors were associated with a 43% relative risk reduction (HR 0.57 95% CI 0.48-0.68) in kidney disease progression, consistent with previous trial meta-analysis. The CKD-PC risk score did not require recalibration (calibration slope 1.05, 95% CI 0.94-1.17). Overall model-predicted benefit with SGLT2-inhibitors was median 0.37% at 3 years (IQR 0.26-0.55) and showed good calibration (calibration slope 1.04, 95% CI 0.91-1.17). Using model predictions to target the same proportion of the population as the albuminuria threshold would prevent over 10% more events over 3 years (253 vs 228), by identifying a subgroup of 6.7% of individuals with albuminuria <3mg/mmol with significantly greater benefit from SGLT2-inhibitor treatment than the rest with albuminuria <3mg/mmol (3.2% vs 1.2% in extended 5-year observational analyses, p=0.05).InterpretationA model based on adapting the international CKD-PC risk score can accurately identify which individuals with T2D have clinically relevant kidney protection benefit from SGLT2-inhibitors. This allows more effective targeting of SGLT2-inhibitor treatment than the ≥3mg/mmol albuminuria threshold recommended by current international guidelines and could be applied worldwide.