Precision medicine in Type 2 Diabetes: Targeting SGLT2-inhibitor Treatment For Kidney Protection

Aims/hypothesisCurrent 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 [&ge;]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 use of SGLT2 inhibitors. MethodsThis 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 [&ge;]60 ml/min per 1.73 m2 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 ([&ge;]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 [&ge;]3 mg/mmol albuminuria threshold. ResultsIn 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/interpretationA 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 [&ge;]3 mg/mmol albuminuria threshold recommended by current international guidelines. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of kidney failure in people with type 2 diabetes C_LIO_LICurrent guidelines recommend use of SGLT2 inhibitors for kidney protection in individuals with type 2 diabetes and urinary albumin/creatinine ratio [&ge;]3 mg/mmol, but this is an extrapolation beyond current evidence from kidney outcome trials C_LIO_LIIt is unclear which people with type 2 diabetes and preserved eGFR and a normal urinary albumin/creatinine ratio or low-level albuminuria have clinically relevant kidney protection benefit from SGLT2 inhibitors C_LI What is the key question?O_LICan a model integrating an established risk score with the relative treatment effect from a SGLT2 inhibitor trial meta-analysis accurately predict individual-level kidney protection benefit? C_LI What are the new findings?O_LIThe model accurately predicted individual-level kidney protection benefit with SGLT2 inhibitor treatment in an external validation using UK primary care data C_LIO_LICompared with the [&ge;]3 mg/mmol albuminuria threshold, the model more effectively identified individuals who are likely to benefit, and could prevent more adverse kidney events C_LI How might this impact on clinical practice in the foreseeable future?O_LIThe model enables individualised prescribing of SGLT2 inhibitors for kidney protection, which could optimise treatment allocation and improve kidney outcomes C_LI