SGLT2 Inhibitors May Not Benefit Lean Non-Diabetic CKD Patients

SGLT2 inhibitors have become a cornerstone of CKD management following landmark trials demonstrating reduced kidney disease progression and cardiovascular death. However, this review by Romagnani challenges the assumption that these benefits extend uniformly to all CKD patients. The central argument is that the populations studied in pivotal trials do not represent the full spectrum of CKD, and that the drugs' mechanisms of action may simply not apply to many underrepresented subgroups.

The two cornerstone trials — DAPA-CKD and EMPA-KIDNEY — enrolled patients with mean BMIs of 29.4 and 29.7, and mean eGFRs of 43.2 and 37.4 mL/min, respectively. In EMPA-KIDNEY, 46% of participants had diabetes and 79% had eGFR below 45 mL/min. These populations share a common pathophysiology: sodium retention, expanded fluid volume, and glomerular hyperfiltration — the exact mechanisms targeted by SGLT2 inhibition. In non-diabetic EMPA-KIDNEY participants, the hazard ratio for kidney disease progression or cardiovascular death was 0.82 (CI 0.68–0.99), compared with 0.64 (CI 0.54–0.77) in diabetic participants, still suggesting benefit — but this non-diabetic group was still predominantly overweight with advanced CKD.

Post-hoc subgroup analyses reveal further confounding. In the DAPA-CKD IgA nephropathy subgroup, mean BMI was 27 and 17.5% of dapagliflozin-treated patients were diabetic. In the focal segmental glomerulosclerosis subgroup, mean BMI was 30.7 with eGFR of 40 mL/min. These characteristics closely mirror the general trial population, not the leaner, earlier-stage patients typical of clinical IgA nephropathy or Alport syndrome cohorts in Asia and Europe. The DIAMOND trial, specifically evaluating dapagliflozin in non-diabetic CKD patients (mean BMI 28, eGFR 58.2 mL/min), found no significant effect on proteinuria.

A key piece of evidence comes from a nationwide epidemiological study of over 6,000 type 2 diabetic patients comparing SGLT2 inhibitors to DPP4 inhibitors. While SGLT2 inhibitors were associated with slower annual eGFR decline overall, the protective effect showed a strong interaction with BMI: benefits were markedly greater in higher-BMI individuals, and negligible in those with BMI below 25. This BMI-dependent efficacy persisted across multiple outcome measures, including 30% and 40% eGFR decline thresholds, and was most evident in those with preserved kidney function.

Molecular and animal data support this mechanistic interpretation. Single-cell RNA sequencing confirms SGLT2 mRNA expression is overwhelmingly restricted to the proximal tubule, even in diabetes. Human Protein Atlas data corroborate minimal SGLT2 protein expression elsewhere. In mouse models of Alport nephropathy, SGLT2 inhibitors showed no additive benefit over RAS blockers and were less effective than RAS blockers alone. In APOL1 nephropathy models, SGLT2 inhibitors had no significant impact on CKD progression. In chronic oxalosis models, the renoprotective mechanisms of SGLT2 inhibition in diabetic kidney disease did not apply.

The review concludes that while SGLT2 inhibitors have unquestionably transformed CKD care for hyperfiltration-driven conditions — diabetes, obesity, heart failure, advanced CKD — their role in lean, non-diabetic patients with early-stage or immune/genetic CKD remains genuinely uncertain. Dedicated clinical trials are called for in these underrepresented groups, including pediatric patients, dialysis patients, transplant recipients, and those with polycystic kidney disease, to enable truly personalized, evidence-based treatment.