Angiotensin-converting-enzymeinhibitors and angiotensin receptorblockers for preventing theprogression of diabetic kidneydisease

Background Guidelines suggest that adults with diabetes and kidney disease receive treatment withangiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB).This is an update of a Cochrane review published in 2006. Objectives We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or incombination) on cardiovascular and kidney outcomes in adults with diabetes and kidneydisease. Search methods We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024through contact with the Information Specialist using search terms relevant to this review.Studies in the Register are identified through searches of CENTRAL, MEDLINE, andEMBASE, conference proceedings, the International Clinical Trials Registry Platform(ICTRP) Search Portal, and ClinicalTrials.gov. Selection criteria We included studies evaluating ACEi or ARB alone or in combination, compared to eachother, placebo or no treatment in people with diabetes and kidney disease. Data collection and analysis Two authors independently assessed the risk of bias and extracted data. Summaryestimates of effect were obtained using a random-effects model, and results wereexpressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomousoutcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CIfor continuous outcomes. Confidence in the evidence was assessed using the Grading ofRecommendations Assessment, Development and Evaluation (GRADE) approach. Main results One hundred and nine studies (28,341 randomised participants) were eligible for inclusion.Overall, the risk of bias was high. Compared to placebo or no treatment, ACEi may make little or no difference to all-causedeath (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I2 = 23%; low certainty)and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI0.90 to 1.19; I2 = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643participants: RR 0.61, 95% CI 0.39 to 0.94; I2 = 0%; low certainty). Compared to placebo or no treatment, ARB may make little or no difference to all-causedeath (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I2 = 0%; low certainty).ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR0.85, 95% CI 0.58 to 1.26; I2 = 2%; low certainty) and cardiovascular death (6 studies, 878participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure(3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I2 = 0%; low certainty), doublingof serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I =32%; low certainty), and the progression from microalbuminuria to microalbuminuria (5studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I2 = 74%; low certainty). Compared to ACEi, ARB had uncertain effects on all-cause death (15 studies, 1739participants: RR 1.13, 95% CI 0.68 to 1.88; I2 = 0%; low certainty), withdrawal fromtreatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I2 = 0%; low certainty),cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I2 = 0%;low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I2 =0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52to 1.48; I2 = 0%; low certainty). Compared to ACEi plus ARB, ACEi alone has uncertain effects on all-cause death (6studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I2 = 20%; low certainty),withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I2 =0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to2.32; I2 = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95%CI 0.70 to 1.85; I2 = 0%; low certainty). Compared to ACEi plus ARB, ARB alone has uncertain effects on all-cause death (7 studies,2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I2 = 0%; low certainty), withdrawn fromtreatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I2 = 0%; lowcertainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93;low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I2 = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI0.85 to 1.64; I2 = 0%; low certainty) Comparative effects of different ACEi or ARB and low-dose versus high-dose ARB wererarely evaluated. No study compared different doses of ACEi. Adverse events of ACEi and ARB were rarely reported. Authors' conclusions ACEi or ARB may make little or no difference to all-cause and cardiovascular deathcompared to placebo or no treatment in people with diabetes and kidney disease but mayprevent kidney failure. ARB may prevent the doubling of SCr and the progression frommicroalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despitethe international guidelines suggesting not combining ACEi and ARB treatment, the effectsof ACEi or ARB monotherapy compared to dual therapy have not been adequatelyassessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes andkidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.