Meta-Analysis
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Nov 15, 2020; 11(11): 553-566
Published online Nov 15, 2020. doi: 10.4239/wjd.v11.i11.553
Endothelin receptor antagonists for the treatment of diabetic nephropathy: A meta-analysis and systematic review
Li Zhang, Shuai Xue, Jie Hou, Guang Chen, Zhong-Gao Xu
Li Zhang, Jie Hou, Zhong-Gao Xu, Department of Nephrology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Shuai Xue, Guang Chen, Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Author contributions: Zhang L and Chen G searched for articles and assessed search results; Zhang L evaluated the risk of bias in each included study; Zhang L and Xue S wrote the manuscript; Hou J checked the risk of bias in the assessment; Hou J was responsible for valuable intellectual content during the revision of the manuscript; any disagreement was resolved through discussions or consultations with Xu ZG; all authors issued a final approval for the submitted version.
Conflict-of-interest statement: The authors declare no conflict of interests.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Zhong-Gao Xu, MD, PhD, Director, Professor, Department of Nephrology, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, Jilin Province, China. nephrology_jdyy@hotmail.com
Received: July 18, 2020
Peer-review started: July 18, 2020
First decision: August 9, 2020
Revised: August 22, 2020
Accepted: October 15, 2020
Article in press: October 15, 2020
Published online: November 15, 2020
Processing time: 117 Days and 20.8 Hours
ARTICLE HIGHLIGHTS
Research background

Diabetic nephropathy (DN) is the main cause of chronic kidney disease and end-stage renal disease worldwide. Current treatment approaches for DN rely on angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor blockers (ARBs) to control blood pressure (BP), reduce proteinuria, and delay chronic kidney disease progression. However, renin–angiotensin–aldosterone system (RAAS) blockade may increase the long-term risk for end-stage renal disease in patients with diabetes. Thus, identifying novel, effective treatments for DN beyond RAAS blockade is imperative.

Research motivation

Although available clinical trials have shown that endothelin receptor (ER) antagonists may be a novel and beneficial drug for DN, no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.

Research objectives

This meta-analysis aimed to assess the effectiveness and safety of ER antagonists among patients with DN.

Research methods

We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in estimated glomerular filtration rate (eGFR) showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were observed in the invention group.

Research results

We enrolled seven studies with six data sets and 5271 participants. The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40% reduction in urinary albumin-to-creatinine ratio than the control group (P < 0.0001 and P = 0.02, respectively). Subgroup analysis for reductions in eGFR showed that for the middle-dosage subgroup, the ER antagonists group exhibited lower eGFR reduction than the control group (P < 0.00001; mean difference, 0.70 95%CI: 0.66, 0.74). Moreover, significant reductions in SBP and DBP were observed in the invention group.

Research conclusions

ER blockades combined with ACEI/ARBs may be an effective treatment to lower BP and reduce proteinuria in DN with declined eGFR. However, attention should be given to adverse events, including cardiac failure, anemia, and hypoglycemia, as well as serious adverse events.

Research perspectives

ER blockade (optimal dosage) combined with ACEI/ARB may be an effective treatment for lowering BP, reducing proteinuria and delaying renal function progression in DN with declined eGFR. However, more long-term randomized controlled trials are still needed to validate the long-term effectiveness and safety of ER antagonists.