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Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis.
Am J Cardiovasc Drugs. 2019 Jun; 19(3):259-286.AJ

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.

Authors+Show Affiliations

Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.Kidney Epidemiology and Cost Center, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China. West China Biostatistics and Cost-Benefit Analysis Center, West China Hospital of Sichuan University, Chengdu, China.Kidney Epidemiology and Cost Center, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA. yili@umich.edu. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA. yili@umich.edu.Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China. fupinghx@scu.edu.cn. West China Biostatistics and Cost-Benefit Analysis Center, West China Hospital of Sichuan University, Chengdu, China. fupinghx@scu.edu.cn.

Pub Type(s)

Journal Article
Meta-Analysis
Systematic Review

Language

eng

PubMed ID

30737754

Citation

Feng, Yanhuan, et al. "Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: a Meta-Analysis." American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, vol. 19, no. 3, 2019, pp. 259-286.
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. 2019;19(3):259-286.
Feng, Y., Huang, R., Kavanagh, J., Li, L., Zeng, X., Li, Y., & Fu, P. (2019). Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis. American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, 19(3), 259-286. https://doi.org/10.1007/s40256-018-00321-5
Feng Y, 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. 2019;19(3):259-286. PubMed PMID: 30737754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis. AU - Feng,Yanhuan, AU - Huang,Rongshuang, AU - Kavanagh,Janet, AU - Li,Lingzhi, AU - Zeng,Xiaoxi, AU - Li,Yi, AU - Fu,Ping, PY - 2019/2/10/pubmed PY - 2019/12/21/medline PY - 2019/2/10/entrez SP - 259 EP - 286 JF - American journal of cardiovascular drugs : drugs, devices, and other interventions JO - Am J Cardiovasc Drugs VL - 19 IS - 3 N2 - 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. SN - 1179-187X UR - https://www.unboundmedicine.com/medline/citation/30737754/Efficacy_and_Safety_of_Dual_Blockade_of_the_Renin_Angiotensin_Aldosterone_System_in_Diabetic_Kidney_Disease:_A_Meta_Analysis_ L2 - https://dx.doi.org/10.1007/s40256-018-00321-5 DB - PRIME DP - Unbound Medicine ER -