Placebo-Referenced Class-Level Treatment Effects on Chronic Kidney Disease Progression in Patients With Diabetes: A...

Multiple pharmacologic therapies reduce chronic kidney disease (CKD) progression in patients with diabetes; however, the absence of head-to-head trials and heterogeneity across studies limits the interpretation of indirect comparisons. We evaluated class-level treatment effects within a predominantly placebo-centred evidence network.

We conducted a systematic review and class-level frequentist random-effects network meta-analysis of randomised controlled trials evaluating major pharmacologic therapy classes for CKD progression in patients with diabetes. The primary outcome was CKD progression, defined according to the principal composite kidney endpoint reported in each trial. Exploratory analyses evaluated albuminuria reduction and trial-level surrogate associations between albuminuria and clinical kidney outcomes.

Nine trials involving 37,749 participants were included. The evidence network was star-shaped with placebo as the central comparator. All therapeutic classes were associated with reduced CKD progression compared with placebo. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated the most precise estimate (HR 0.66, 95% CI 0.60-0.74) and were supported by high-confidence evidence. Confidence in placebo-referenced estimates for other therapeutic classes ranged from moderate to low because of indirectness, limited trial numbers and differences in study design and patient populations. Findings were generally consistent across sensitivity analyses. No significant association was observed between treatment-induced albuminuria reduction and clinical kidney outcomes (R² = 0.007), although interpretation was limited by ecological bias and the small number of included studies.

Multiple pharmacologic classes were associated with reduced CKD progression compared with placebo in patients with diabetes. Among placebo-referenced comparisons, the most consistent and highest-confidence estimates were observed for SGLT2i. However, the predominantly placebo-centred network, absence of direct active-comparator trials and important transitivity concerns limit inference regarding comparative efficacy among therapies. Findings should therefore be interpreted as placebo-referenced class-level treatment effects rather than evidence of comparative superiority. Direct comparative effectiveness and combination-therapy trials are needed to define optimal treatment strategies.