ArticlesComparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis
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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2022, Biochemical PharmacologyCitation Excerpt :Evidence supports the use of ACEI/ARB as first line therapy given their renoprotection, improvement in insulin resistance, and other positive metabolic effects [105]. The recommendation to use ACEI/ARB is partly based on a meta-analysis of RCTs that demonstrated a significant reduction in progression of moderate-severe albuminuria with the use of ACEI/ARBs in patients with T2DM [106]. Both the 2022 ADA guidelines and 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines support the use of medications that have demonstrated cardiovascular benefit such as ACEI/ARBs, CCB, and thiazide/thiazide-like diuretics as first-line therapies [96,107], with the preferred combination being a ACEI/ARB with CCB or thiazide/thiazide-like diuretic.