The effect of renin–angiotensin–aldosterone system inhibitors on continuous and binary kidney outcomes in subgroups of patients with diabetes: a meta-analysis of randomized clinical trials

Diabetic nephropathy is the leading cause of kidney failure. Clinical practice guidelines recommend prescribing renin–angiotensin aldosterone system inhibitors (RAASi) to prevent diabetic nephropathy at any stage. We conducted this systematic review and meta-analysis to compare the effects of RAASi with placebo and other antihypertensive agents in adults with diabetes on continuous and binary kidney outcomes to provide a comprehensive review of the class effect of RAASi on several subgroups.

A systematic electronic search to identify randomized clinical trials of a duration of ≥ 12 months that recruited ≥ 50 adult participants with type 1 or 2 diabetes with any stage of chronic kidney disease and proteinuria was conducted in MEDLINE, CINAHL, EMBASE, and Cochrane library with no language restriction. Studies were screened against the inclusion and exclusion criteria by two reviewers independently.

In this meta-analysis, evidence was drawn from 26,551 patients with diabetes from 46 studies. Our analysis shows that RAASi were better than placebo in reducing SrCr (the raw mean difference [RMD] = -13.4 μmol/L; 95%CI: -16.78; -10.01) and albuminuria levels (standardized mean difference [SMD] = -1; 95%CI: -1.57, -0.44, I² = 96%). When compared to other active treatments, RAASi did not reduce SrCr (RMD = 0.03 μmol/L; 95%CI: -6.4, 6.10, I² = 76%), caused a non-significant reduction of GFR levels (RMD = -1.21 mL/min; 95%CI: -4.52, 2.09, I² = 86%), and resulted in modest reduction of albuminuria levels (SMD = -0.55; 95%CI: -0.95, -0.16, I² = 90%). RAASi were superior to placebo in reducing the risks of kidney failure (OR = 0.74; 95%CI: 0.56, 0.97) and doubling of serum creatinine levels (SrCr; OR = 0.71; 95%CI: 0.55, 0.91), but not in promoting the regression of albuminuria (OR = 3.00; 95%CI: 0.96, 9.37). RAASi, however, were not superior to other antihypertensives in reducing the risks of these outcomes. Patients with type 2 diabetes, macroalbuminuria and longer duration of diabetes had less risk of developing kidney failure in placebo-controlled trials, while longer duration of diabetes, normal kidney function, and hypertension increased the probability of achieving regression of albuminuria in active-controlled trials.

While our findings revealed the non-superiority of RAASi over other antihypertensives and portrayed a class effect on several subgroups of study participants, it raised a challenging question on whether RAASi deserve their place as first-line therapy in managing diabetic nephropathy.