A systematic meta-analysis 3 included 26 RCTs - including 20 for angiotensin-converting enzyme inhibitors (ACE inhibitors) and 6 for angiotensin II receptor blockers (ARBs) - with a total of 10,378 diabetic patients with microalbuminuria. Compared with placebo, ARBs significantly reduced the risk of end stage renal disease (ESRD) by 23% (odds ratio 0.77, 95% CI 0.65 to 0.92), while ACE inhibitors showed a trend towards decreased risk of ESRD (OR 0.69, 0.43 to 1.10). Both ACE inhibitors and ARBs reduced the risk of doubling of the serum creatinine level (OR 0.60, 0.39 to 0.91 for ACE inhibitors; OR 0.75, 0.64 to 0.88 for ARBs), and subgroup analyses for patients with macroalbuminuria or microalbuminuria showed similar results.
Another systematic review with network meta-analyses 4 assessing renal outcomes of renin-angiotensin system blockade in adults with diabetes (with or without proteinuria) included 71 trials with 103,120 participants. For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARBs (OR 1.10; 95% CI 0.90 to 1.40), ACE inhibitor plus ARB (0.97; 95% CI 0.72 to 1.29), direct renin (DR) inhibitor plus ACE inhibitor (0.99; 95% CI 0.65 to 1.57), and DR inhibitor plus ARB (1.18; 95% CI 0.78 to 1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies.
A systematic review 1 including 9 RCTs, with a total of 642 diabetic patients with microalbuminuria (30 to 300 mg of albumin excreted over 24 hours in urine) was abstracted in DARE. Average age was 35 to 36 years, 56% to 59% were male, average serum creatinine was within the normal range at baseline, and mean arterial pressure (MAP) was either elevated or normal. Post therapy, the average MAP was less in ACE inhibitor treated patients across all studies but one. ACE inhibitors significantly reduced the risk of macroalbuminuria; RR = 0.35 (95% CI: 0.24, 0.53). There was no evidence of heterogeneity (Q = 2.26; P = 0.95).
Another systematic review 2 including 12 RCTs, with a total of 698 non-hypertensive patients with type 1 diabetes mellitus was abstracted in DARE. The following treatment regimes were compared with placebo or a non-intervention: captopril, 12.5 to 50 mg, twice daily; lisinopril, 10 to 20 mg/day; enalapril, 10 to 20 mg/day; perindopril, 2 mg/day; and ramipril, 1.25 or 5 mg/day. Microalbuminuria was defined as an albumin excretion rate of 20 to 200 microg/minute at baseline. The age of the patients ranged from 15 to 68 years.
All the studies with at least 2 years of follow-up (10 studies, n=646) demonstrated a marked beneficial effect of ACE inhibitors on the rate of change in albumin excretion rate at 2 years. The albumin excretion rate was 51.2% (95% confidence interval, CI: 33.6, 64.2) lower in those receiving ACE inhibitors when using the fixed-effect model and 50.2% (95% CI: 30.0, 64.6) lower when using the random-effects model. When adjustment was made for changes in blood-pressure and albumin excretion rate, the treatment effect was attenuated from 50.7% (95% CI: 29.8, 65.4) to 45.1% (95% CI: 18.6, 63.1). The estimated 2-year difference in albumin excretion rate was 74.1% in patients whose baseline albumin excretion rates were at the upper boundary of microalbuminuria (200 microg/minute), compared with just 17.8% in those who were at the lower boundary of microalbuminuria (20 microg/minute) at baseline (p=0.04).
Considering progression to macroalbuminuria and regression to normoalbuminuria, with the exception of one study, each trial demonstrated a beneficial effect and the fixed-effect model showed an overall OR of 0.38 (95% CI: 0.25, 0.57, p<0.001) in favour of ACE inhibitors. Regression to normoalbuminuria was greater in treated patients (fixed-effect OR 3.07, 95% CI: 2.15, 4.44, p<0.001)).
The following decision support rules contain links to this evidence summary:
1. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000 Apr;35(4):695-707. [PMID:10739792]
2. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001 Mar 6;134(5):370-9. [PMID:11242497]
3. Wang K, Hu J, Luo T et al. Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality and Renal Outcomes in Patients with Diabetes and Albuminuria: a Systematic Review and Meta-Analysis. Kidney Blood Press Res 2018;43(3):768-779. [PMID:29794446]
4. Catalá-López F, Macías Saint-Gerons D, González-Bermejo D et al. Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses. PLoS Med 2016;13(3):e1001971. [PMID:26954482]
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