Introduction: The Shift Toward Personalized Renal Protection
The management of type 2 diabetes (T2D) has undergone a paradigm shift from a purely glucocentric approach to one focused on organ protection. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone of this strategy, demonstrating robust efficacy in slowing the progression of chronic kidney disease (CKD). However, current clinical guidelines primarily recommend these agents for kidney protection based on a specific biochemical threshold: a urinary albumin/creatinine ratio (uACR) of 3 mg/mmol or higher. This threshold-based approach, while practical, leaves a significant clinical gap. Many patients with normal uACR or low-level albuminuria remain at risk for renal decline, yet they are often excluded from treatment because their absolute benefit has remained unquantified in major clinical trials. A recent study by Jansz et al., published in Diabetologia, introduces a precision medicine model designed to bridge this gap by predicting individual-level absolute risk reduction (ARR) for kidney disease progression.
Study Highlights
– The study confirmed a 42% lower relative risk of kidney disease progression with SGLT2 inhibitors compared to other second-line glucose-lowering agents in a real-world setting.
– By integrating the international CKD-PC risk score, the researchers developed a model that accurately predicts individual-level absolute kidney protection benefits.
– Utilizing this precision model to guide treatment decisions could prevent 10% more renal events than current albuminuria-based guidelines.
– The model identified a high-risk subgroup of patients with ‘normal’ albuminuria (uACR <3 mg/mmol) who derived significant absolute benefit from SGLT2 inhibitors.
Methodological Rigor: Bridging Trials and Real-World Data
This observational cohort study leveraged electronic health record data from the UK Clinical Practice Research Datalink (CPRD), covering the period from 2013 to 2020. The researchers analyzed 53,096 initiations of SGLT2 inhibitors and 88,404 initiations of comparator drugs, specifically dipeptidyl peptidase-4 (DPP4) inhibitors and sulfonylureas. The study population focused on adults with T2D, preserved renal function (eGFR ≥60 ml/min/1.73 m2), and relatively low albuminuria (uACR <30 mg/mmol), specifically excluding those with heart failure or established atherosclerotic vascular disease.
To ensure scientific validity, the team first confirmed that the relative treatment effect observed in large-scale randomized controlled trials (RCTs) held true in a real-world clinical population using overlap-weighted Cox proportional hazards models. They then assessed the calibration of the Chronic Kidney Disease Prognosis Consortium (CKD-PC) risk score for predicting major kidney outcomes, including a 50% or greater decline in eGFR, end-stage kidney disease, or kidney-related death.
Key Findings: The Power of Absolute Risk Reduction
The results reinforce the renal benefits of SGLT2 inhibitors while highlighting the limitations of current guidelines. The study reported a Hazard Ratio (HR) of 0.58 (95% CI 0.48, 0.69), signifying a 42% relative risk reduction in kidney disease progression. More importantly, the CKD-PC risk score proved highly accurate in this population without requiring recalibration (slope 1.05).
The median predicted 3-year absolute risk reduction (ARR) with SGLT2 inhibitors was 0.37%. While this may seem modest across a broad population, the precision model revealed significant heterogeneity. When the model was used to target treatment to the same number of people currently eligible under the uACR ≥3 mg/mmol threshold, it identified a different subset of patients. This model-based strategy would prevent 253 events compared to the 228 events prevented by the uACR-only strategy—a greater than 10% improvement in clinical utility.
Critically, the model identified a subgroup (6.7% of the population) with uACR <3 mg/mmol who nonetheless had a high risk of progression. In extended 5-year analyses, this group showed an ARR of 3.2%, compared to only 1.2% in the remaining low-uACR population. This suggests that relying solely on albuminuria thresholds may deprive high-risk 'normoalbuminuric' patients of life-changing therapy.
Expert Commentary: Clinical Implications and Future Directions
The findings from the MASTERMIND Consortium suggest that we are moving toward a more nuanced application of SGLT2 inhibitors. In clinical practice, the decision to initiate SGLT2 inhibitors often involves balancing benefits against costs and potential side effects, such as genitourinary infections or, more rarely, euglycemic ketoacidosis. For patients with uACR <3 mg/mmol, clinicians have historically lacked the data to justify treatment for renal protection. This model provides the necessary evidence to advocate for treatment in high-risk individuals who do not meet traditional biochemical criteria.
However, some limitations must be considered. As an observational study using electronic health records, there is potential for residual confounding, although the use of overlap weighting and alignment with trial meta-analyses mitigates this risk. Furthermore, the model's performance in populations with different ethnic backgrounds or healthcare systems requires further external validation.
Conclusion: Beyond the Threshold
Precision medicine is no longer just about genetics; it is about using the data we already collect—age, eGFR, hemoglobin A1c, and blood pressure—to make smarter clinical decisions. The model developed by Jansz and colleagues demonstrates that an integrated risk-score approach is superior to a single-biomarker threshold for targeting SGLT2 inhibitor therapy. By identifying the ‘hidden’ high-risk patients with normal albumin levels, clinicians can more effectively prevent the progression to end-stage kidney disease and reduce the global burden of diabetic complications.
References
1. Jansz TT, Young KG, Hopkins R, et al. Precision medicine in type 2 diabetes: targeting SGLT2 inhibitor treatment for kidney protection. Diabetologia. 2026 Feb;69(2):374-385. doi: 10.1007/s00125-025-06577-2.
2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.
3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306.
