Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses

Background: Medications aimed at inhibiting the renin–angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. Methods and Findings: Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke—singly and as a composite endpoint, major cardiovascular outcome—and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality—singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90–1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79–1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96–1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73–1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90–1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72–1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65–1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78–1.84). 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. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. Conclusions: In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. Review registration: PROSPERO CRD42014014404 In a systematic review with network meta-analyses, Ferrán Catalá-López and colleagues synthesize published and unpublished data from randomized controlled trials of renin-angiotensin system inhibitors.Background: Chronic high blood pressure can damage blood vessels, heart, and kidneys, and cause cardiovascular and kidney (or renal) disease. Diabetes increases the risk for high blood pressure. An estimated two-thirds of adults with diabetes have high blood pressure or take blood-pressure-reducing drugs (also called antihypertensives). Because diabetes itself increases the risk for heart and kidney diseases, controlling blood pressure is important. Several of the drugs commonly prescribed to patients with diabetes target the renin–angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. When renal blood flow is low, kidney cells produce renin and secrete it into the blood stream. Renin in the blood generates a protein called angiotensin I. The angiotensin-converting enzyme (ACE) in the lungs subsequently converts angiotensin I to angiotensin II, and angiotensin II docks with its partner, the angiotensin receptor. This then leads to a signaling cascade that causes blood vessels to constrict and the kidneys to secrete water and salt into the blood, resulting in increased blood pressure. Why Was This Study Done?: As many adults with diabetes are prescribed RAS blockers and likely need to take them or related drugs for the rest of their lives, the question of which drug (or drug combination) has the best results and the least side effects is important. Data from many randomized controlled trials (RCTs, which are the most rigorous clinical tests) have generated results that address this question. Their combined analysis, however, is complicated because the trials often don’t compare all treatments directly, don’t use the exact same treatments in patients with the exact same conditions, or don’t measure the exact same outcomes. Nonetheless, scientists have developed methods to analyze such complex data, including a method called network meta-analysis, which helps to integrate and synthesize diverse results to determine the relative merits of multiple treatments. Here the researchers apply network meta-analysis to all available data from RCTs in which adults with diabetes were given RAS blockers, alone or in combination with other high blood pressure treatments, and that measured cardiovascular or renal outcomes. What Did the Researchers Do and Find?: The researchers started with a systematic search of the medical literature for RCTs that tested RAS blockers alone or in combination in adults with diabetes. They also contacted the sponsors of many studies to find out whether they had additional data that were not included in the published reports. They included all trials that had at least 100 participants, followed the participants for at least 12 months, and reported cardiovascular or renal outcomes. In all, 71 trials that tested a total of 14 different treatment regimens in 103,120 participants met these criteria. With network meta-analysis, the researchers were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of RAS blockers within the same trial (where those were available) with indirect comparisons across all trials. The primary endpoints in their analysis were major cardiovascular outcome (a composite of cardiovascular mortality, nonfatal heart attack, and nonfatal stroke) and progression of renal disease (a composite of end-stage renal disease, doubling of serum creatinine [a marker of reduced kidney function], and all-cause mortality). They also analyzed the individual cardiovascular or renal outcomes separately, but these results carried more uncertainty because fewer patients had the individual, compared with the combined, outcomes. What Do These Findings Mean?: The findings reinforce North American and European guidelines that recommend ACE inhibitors and ARBs for antihypertensive therapy in patients with diabetes. The fact that combinations of two drugs had outcomes no better than those of a single ACE inhibitor or ARB—together with results from other studies that reported increased adverse effects in patients who took drug combinations—cautions against the use of combination therapy. The findings also contradict earlier reports suggesting that ARBs may increase the risk of cardiovascular outcomes. There were not enough data comparing direct renin inhibitors (a drug class that was developed more recently and therefore has been studied less) with ACE inhibitors or ARBs to allow strong conclusions; additional research might therefore be warranted. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001971.