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Efficacy and Safety of Dual Blockade of the Renin–Angiotensin–Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis

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Abstract

Introduction

Current guidelines recommend renin–angiotensin–aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events.

Objectives

Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD.

Methods

This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors.

Results

Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria.

Conclusion

Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.

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  1. Yanhuan Feng and Rongshuang Huang contributed equally to this work.

Authors and Affiliations

  1. Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China

    Yanhuan Feng, Rongshuang Huang, Lingzhi Li, Xiaoxi Zeng & Ping Fu

  2. Kidney Epidemiology and Cost Center, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA

    Janet Kavanagh & Yi Li

  3. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Janet Kavanagh & Yi Li

  4. West China Biostatistics and Cost-Benefit Analysis Center, West China Hospital of Sichuan University, Chengdu, China

    Xiaoxi Zeng & Ping Fu

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Contributions

PF and YL coordinated the review and organized the team. PF and YF contributed to developing the protocol. YF and RH assessed the studies and extracted data. LL, XZ, RH, JK, and LL contributed to the data analysis and interpretation. YF and RH drafted the review. JK and XZ edited and formatted the review text. YL and PF reviewed the review and made important intellectual contributions.

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Correspondence to Yi Li or Ping Fu.

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Funding

This study was funded by the National Postdoctoral Program for Innovative Talents of China (BX201600112).

Conflict of interest

Yanhuan Feng, Rongshuang Huang, Janet Kavanagh, Lingzhi Li, Xiaoxi Zeng, Yi Li, and Ping Fu have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Feng, Y., Huang, R., Kavanagh, J. et al. Efficacy and Safety of Dual Blockade of the Renin–Angiotensin–Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis. Am J Cardiovasc Drugs 19, 259–286 (2019). https://doi.org/10.1007/s40256-018-00321-5

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