Elsevier

The Lancet

Volume 385, Issue 9982, 23–29 May 2015, Pages 2047-2056
The Lancet

Articles
Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis

https://doi.org/10.1016/S0140-6736(14)62459-4Get rights and content

Summary

Background

The comparative efficacy and safety of pharmacological agents to lower blood pressure in adults with diabetes and kidney disease remains controversial. We aimed to investigate the benefits and harms of blood pressure-lowering drugs in this population of patients.

Methods

We did a network meta-analysis of randomised trials from around the world comparing blood pressure-lowering agents in adults with diabetic kidney disease. Electronic databases (the Cochrane Collaboration, Medline, and Embase) were searched systematically up to January, 2014, for trials in adults with diabetes and kidney disease comparing orally administered blood pressure-lowering drugs. Primary outcomes were all-cause mortality and end-stage kidney disease. We also assessed secondary safety and cardiovascular outcomes. We did random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and we presented these estimates as odds ratios or standardised mean differences with 95% CIs. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities.

Findings

157 studies comprising 43 256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0·62, 95% CI 0·43–0·90) and after ARB monotherapy (0·77, 0·65–0·92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2·69, 95% CI 0·97–7·47 for hyperkalaemia; 2·69, 0·98–7·38 for acute kidney injury).

Interpretation

No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. ACE inhibitors and ARBs, alone or in combination, were the most effective strategies against end-stage kidney disease. Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury.

Funding

Canterbury Medical Research Foundation, Italian Medicines Agency.

Introduction

Diabetes mellitus affects 3–4% of adults worldwide, with prevalence projected to double over the first three decades of the 21st century.1 Chronic kidney disease occurs in 25–40% of patients with diabetes within 20–25 years of onset, and diabetes is now the leading cause of end-stage kidney disease,2 accounting for nearly half of all patients treated with dialysis.3 The combination of diabetes and kidney disease is associated with a four-fold increase in the prevalence of atherosclerotic vascular disease and death.4 Blood pressure lowering with pharmacological agents has been central to the treatment of diabetic kidney disease for decades, and improved care—including antihypertensive treatment—has been credited with decreased prevalence of end-stage kidney disease over the past 10 years.5

The pharmacology of blood pressure-lowering agents is becoming increasingly complex as new drugs are introduced, but the comparative efficacy and safety of available drugs is largely unknown, mainly because of an absence of head-to-head trials.6 In clinical practice guidelines, the equivalence of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) is assumed. Furthermore, concurrent use of these two classes of agent is not recommended, partly because concomitant salt restriction or combined treatment with other drugs has been judged equally effective and possibly safer.7, 8 Concern over the risks of acute kidney injury and hyperkalaemia with dual ACE inhibitor and ARB treatment led to premature termination of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial9 in adults with diabetes and proteinuria, resulting in inconclusive effects on clinical endpoints. Moreover, in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET),10 the absence of a benefit of dual treatment was argued to be possibly attributable to the low proportion of patients recruited with chronic kidney disease, for whom dual treatment might be selectively effective.11 In a network meta-analysis of blood pressure drugs in adults with diabetes, dual ACE inhibitor and ARB treatment was not investigated.12 The aim of our study was to assess the comparative effects of all blood pressure-lowering agents in adults with diabetes and kidney disease using the technique of network meta-analysis.

Section snippets

Study design

We did a network meta-analysis using a frequentist model. Network meta-analysis integrates data from direct comparisons of treatments within trials and from indirect comparisons of interventions assessed against a common comparator in different trials, to compare all investigated treatments. We followed a prespecified study protocol (appendix pp 2–15) and reported the meta-analysis according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement.13

Participants

We

Results

188 studies including 45 338 adults were eligible for the systematic review, and 157 studies with data for 43 256 participants were available for network meta-analysis (appendix pp 16–36). The PRISMA13 flowchart showing electronic searching processes is shown in the appendix (p 37). Seven drug classes alone or in combination were compared with placebo or standard treatment—ACE inhibitors, ARBs, aldosterone antagonists, β blockers, calcium-channel blockers, endothelin inhibitors, and renin

Discussion

Our network meta-analysis provides unified hierarchies of evidence for all blood pressure-lowering agents in adults who have diabetes and kidney disease, overcoming the absence of comparative data in head-to-head trials. No blood pressure-lowering strategy was superior to placebo with respect to survival. However, ACE inhibitor and ARB treatment (alone or in combination) and endothelin inhibitors were ranked as the most effective agents for prevention of end-stage kidney disease, although only

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