UNDERSTANDING THE IMPACT OF SGLT2 INHIBITORS IN TYPE 2 DIABETES MELLITUS WITH BIOPSY-PROVEN RENAL INVOLVEMENT

Type 2 diabetes mellitus (T2DM) leads to chronic kidney disease (CKD) in 30–40% of patients and is the major cause of end-stage renal disease (ESRD). The clinical course of diabetic kidney disease is highly heterogeneous, and discrepancies exist between clinical parameters and renal histology. Moreover, lesions of non-diabetic renal disease (NDRD) can coexist with diabetic nephropathy (DN). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiorenal outcomes in CKD patients with and without diabetes, but their effect in biopsy-confirmed DN remains unclear. This study aimed to evaluate the impact of SGLT2i in T2DM patients with biopsy-proven DN and to compare outcomes with patients presenting NDRD or mixed lesions.

This retrospective study included T2DM patients who underwent kidney biopsy. Demographic and clinical data were collected. Histological findings were classified according to the pathological classification of DN. Renal function was assessed using estimated glomerular filtration rate (eGFR, CKD-EPI, mL/min/1.73 m²), urine albumin-to-creatinine ratio (UACR, mg/g), and 24-hour proteinuria (g/24 h). Patients were categorized based on biopsy results as DN or NDRD. Follow-up extended from SGLT2i initiation up to 60 months. Kidney disease progression was defined as ≥40% decline in eGFR, doubling of serum creatinine, or ≥30% reduction in UACR or 24-hour proteinuria. ESRD and mortality were also evaluated.

Of 248 T2DM patients screened, 181 were excluded due to absence of biopsy or normal/marginal biopsy. Sixty-seven patients were included; 31(46%) had DN and 36(54%) had NDRD. Among DN patients, 14(45%) were classified as nodular sclerosis class III. Compared with NDRD, DN patients exhibited significantly more mesangial expansion, interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis.

T2DM patients with DN receiving SGLT2i showed a higher prevalence of diabetic retinopathy, better baseline eGFR, and lower UACR than untreated patients (66 mL/min and 1490 mg/g, p<0.05). SGLT2i therapy was associated with a significantly slower eGFR decline (≈2.4 mL/min/1.73 m² per year), with significant improvements at 24 months (β=+13.1, p=0.033, compared to the decline in DN: No SGLT2i) and 48 months (β=+17.6, p=0.006, compared to the decline DN: No SGLT2i). This association was particularly notable in DN patients but observed regardless of histological diagnosis.

Untreated patients showed higher rates of kidney disease progression, defined as >40% eGFR decline, doubling of serum creatinine, and fewer achieving ≥30% reduction in UACR, though differences were not statistically significant. Diabetic retinopathy and insulin therapy were associated with failure to achieve a ≥30% reduction in UACR. Histological findings associated with renal outcomes included glomerular basement membrane morphology and interstitial inflammation. Normal or thickened membranes were linked to lower risk of creatinine doubling (OR[95%CI] = 0.03 [0.00;0.39] and OR[95%CI] = 0.05 [0.00;0.56], respectively), while interstitial inflammation >5% was associated with greater eGFR decline (OR[95%CI] = 7.0 [1.04;141]). Fewer SGLT2i-treated patients progressed to ESRD or death, although these differences were not statistically significant.

In this cohort of T2DM patients with biopsy-proven kidney disease, SGLT2i therapy was significantly associated with long-term preservation of renal function, as evidenced by a slower eGFR decline. These findings are consistent with the well-established nephroprotective effect of SGLT2 inhibitors in diabetic kidney disease and further demonstrate that this beneficial effect persists even in cases with mixed diabetic nephropathy lesions. Although favorable trends were observed in hard renal outcomes and mortality, larger studies are required to confirm these benefits.