Putting Evidence into Practice
ACE Inhibitors vs. ARBs for Patients with Diabetic Kidney Disease
Am Fam Physician. 2007 Jul 1;76(1):68-69.
A 57-year-old man presents with hypertension, diabetes, and early-stage diabetic kidney disease. His serum creatinine level is 1.6 mg per dL (140 μmol per L), and his blood pressure is in the 140s/80s mm Hg. An antihypertensive needs to be selected for this patient.
Are angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs) better for all-cause mortality reduction and renal protection in patients with diabetic kidney disease?
Studies comparing ACE inhibitors or ARBs with placebo found no mortality benefit in patients with diabetic kidney disease. A subgroup analysis of five studies (2,034 total patients) found that, when given at full or maximally tolerated doses, ACE inhibitors reduce all-cause mortality (relative risk = 0.78, 95% confidence interval, 0.61 to 0.98). Both classes of drugs are similarly effective at preventing the progression of diabetic kidney disease. However, there were too few trials comparing ACE inhibitors with ARBs to draw clear conclusions.1
Within two to three decades of diagnosis, roughly one third of patients with diabetes will have some degree of diabetic kidney disease.2 Patients with diabetic nephropathy are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes.3 Drugs used to delay the progression of diabetic kidney disease include beta blockers, calcium channel blockers, diuretics, ACE inhibitors, and ARBs. Studies have shown that after a patient develops diabetic kidney disease, ACE inhibitors and ARBs are superior to the other drugs in reducing disease progression, making them the drugs of choice.4 The Cochrane review confirms this conclusion. Although the overall analysis did not find that ACE inhibitors and ARBs reduce mortality compared with placebo, a subgroup analysis found that full doses or maximally tolerated doses of ACE inhibitors had mortality benefit.
Progression to end-stage kidney disease is also an important clinical outcome for patients with diabetic kidney disease. ACE inhibitors reduced the incidence of end-stage renal disease by 40 percent, and ARBs reduced this progression by 22 percent. However, the absolute benefit was small (1.5 versus 0.8 percent over approximately one year; number needed to treat = 160). Both drug classes reduced the risk of disease-oriented renal outcomes such as doubling of creatinine concentration and progression of micro- to macroalbuminuria. Both classes also increased rates of regression from micro- to normoalbuminuria, with ACE inhibitors somewhat more effective than ARBs in placebo-controlled trials. Although these results suggest that ACE inhibitors are more effective than ARBs at reducing the progression of diabetic kidney disease, there are insufficient data directly comparing ACE inhibitors with ARBs.
Although this review found a mortality benefit with full doses or maximally tolerated doses of ACE inhibitors in patients with diabetic kidney disease, there were weaknesses in the included studies: suboptimal allocation concealment, incomplete blinding, and significant loss to follow-up. In addition, there is a risk of “data dredging” with subgroup analysis (i.e., if enough subgroup analyses are performed, some would be significant by chance alone).
Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) are considered to be equally effective for patients with diabetic kidney disease, but renal and not mortality outcomes have usually been considered.
Objectives: To evaluate the benefits and harms of ACE inhibitors and ARBs in patients with diabetic kidney disease.
Search Strategy: We searched Medline (1966 to December 2005), Embase (1980 to December 2005), and the Cochrane Central Register of Controlled Trials (Central, the Cochrane Library, issue 4, 2005) and contacted known investigators.
Selection Criteria: Studies comparing ACE inhibitors or ARBs with placebo or each other in patients with diabetic kidney disease were included.
Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CIs). Heterogeneity among studies was explored using the Cochran Q statistic and the I2 test, subgroup analyses, and random effects metaregression.
Main Results: Forty-nine studies (12,067 patients) were identified. Thirty-eight compared ACE inhibitors with placebo, five compared ARBs with placebo, and seven compared ACE inhibitors with ARBs. There was no significant difference in the risk of all-cause mortality for ACE inhibitors versus placebo (RR = 0.91; 95% CI, 0.71 to 1.17) and ARBs versus placebo (RR = 0.99; 95% CI, 0.85 to 1.17). A subgroup analysis of studies using full-dose ACE inhibitors versus studies using one half or less than one half of the maximally tolerated dose of ACE inhibitors showed a significant reduction in the risk of all-cause mortality with the use of full doses (RR = 0.78; 95% CI, 0.61 to 0.98). Baseline mortality rates were similar in the ACE inhibitor and ARB studies. The effects of ACE inhibitors and ARBs on renal outcomes (end-stage kidney disease, doubling of creatinine levels, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial. Reliable estimates of effect of ACE inhibitors versus ARBs could not be obtained from the three studies in which they were directly compared because of small sample sizes.
Authors' Conclusions: Although the survival benefits of ACE inhibitors are known for patients with diabetic kidney disease, the relative effects on survival of ACE inhibitors with ARBs are unknown because of the lack of adequate direct comparison studies. In placebo-controlled studies, only ACE inhibitors (at the maximally tolerated dose, but not lower, so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Address correspondence to Justin Bailey, MD, at firstname.lastname@example.org. Reprints are not available from the author.
Author disclosure. Nothing to disclose.
The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Department or the U.S. Air Force Service at large.
1. Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2006(4):CD006257.
2. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med. 1999;341:1127–33.
3. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997;157:1413–8.
4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al., for the National High Blood Pressure Education Program Committee. The Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [Published correction appears in JAMA 2003;290:197]. JAMA. 2003;289:2560–72.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Bailey presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab006257.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
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