Precision medicine in type 2 diabetes: targeting SGLT2 inhibitor treatment for kidney protection.

AIMS/HYPOTHESIS: Current guidelines recommend use of sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) for kidney protection in people with type 2 diabetes and early-stage chronic kidney disease (CKD) based on a urinary albumin/creatinine ratio (uACR) of ≥3 mg/mmol. However, individuals with a normal uACR or low-level albuminuria were not represented in kidney outcome trials, leaving uncertainty about absolute treatment benefit in this group. To address this gap and support treatment decisions in clinical practice, we developed and validated a model to predict individual-level kidney protection benefit through the use of SGLT2 inhibitors.

METHODS

This observational cohort study used electronic health record data from UK primary care (Clinical Practice Research Datalink, 2013-2020) of adults with type 2 diabetes, eGFR ≥60 ml/min per 1.73 m and uACR <30 mg/mmol, without heart failure or atherosclerotic vascular disease, who were starting treatment with either SGLT2 inhibitors or the comparator drugs dipeptidyl peptidase-4 (DPP4) inhibitors/sulfonylureas. First, we confirmed the real-world applicability of the relative treatment effect from a previous SGLT2 inhibitor trial meta-analysis, using overlap-weighted Cox proportional hazards models. Second, we assessed calibration of the CKD-PC risk score for kidney disease progression (≥50% eGFR decline, end-stage kidney disease or kidney-related death). Third, we integrated the relative treatment effect with the risk score to predict 3 year individual-level absolute risk reductions for SGLT2 inhibitors, and validated the accuracy of predictions vs overlap-weighted estimates based on observed data. Finally, we compared the clinical utility of a model-based treatment strategy with that of the ≥3 mg/mmol albuminuria threshold.

RESULTS

In 53,096 initiations of SGLT2 inhibitor treatment compared with 88,404 initiations of DPP4 inhibitor/sulfonylurea treatment, there was a 42% lower relative risk of kidney disease progression with SGLT2 inhibitors (HR 0.58; 95% CI 0.48, 0.69), consistent with a previous trial meta-analysis. The CKD-PC risk score did not require recalibration (calibration slope 1.05; 95% CI 0.94, 1.17). The median overall model-predicted absolute risk reduction with SGLT2 inhibitors was 0.37% at 3 years (IQR 0.26-0.55), and showed good calibration (calibration slope 1.10; 95% CI 1.09, 1.12). As an illustration of clinical utility, using the model predictions to target the same proportion of the population (n=25,303, 17.9%) 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 uACR <3 mg/mmol who showed significantly greater absolute risk reduction in response to SGLT2 inhibitor treatment than the remainder with uACR <3 mg/mmol (3.2% vs 1.2% in extended 5 year observational analyses, p=0.05).

CONCLUSIONS/INTERPRETATION: A model adapting the international CKD-PC risk score can accurately predict the individual-level kidney protection benefit from treatment with SGLT2 inhibitors in people with type 2 diabetes and no or early-stage CKD. This could guide treatment decisions in clinical practice worldwide and could target treatment more effectively than the ≥3 mg/mmol albuminuria threshold recommended by current international guidelines.