Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis

Abstract

Background: To evaluate whether metformin use assuredly alters overall all-cause death in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods: Pubmed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to Feb. 29, 2020 with no language restriction. All related articles comparing all-cause death of T2DM and CKD patients after metformin use (monotherapy or combination) versus non-metformin treatment were identified. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using random-effects models regardless of the heterogeneity quantified by Cochrane c 2 and I 2 statistics. Results: Totally 13 studies (9 cohort studies [CSs], 3 subanalyses or post-hoc analyses of randomized controlled trials [RCTs], and 1 nested case-control article) involving 303,540 patients were included. Metformin-based treatments relative to any other measure displayed significantly lower risks of all-cause mortality (Pooled RRs 0.71, 95%CI 0.61 to 0.84; I 2 = 79.0%) and cardiovascular events (Pooled RRs 0.76, 95%CI 0.60 to 0.97; I 2 = 87.0%) in CKD patients at stage G1-3, with substantial heterogeneity. Metformin use was not significantly related with these end points in advanced CKD patients. Conclusions: Metformin use is connected with significantly less risks of all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate CKD. However, RCTs with large sample sizes are warranted in the future to assess whether these key benefits extend to later stages of CKD by dose adjustment.

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

“…However, the lower survival rate of those in the sulfonylurea-treated group might reflect a negative effect of sulfonylurea drugs on mortality as has been reported in subsequent studies ( 162 ). On the other hand, a recent systematic review concluded that metformin significantly lowered all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate chronic kidney disease ( 163 ). Similarly, a meta-analysis with the objective of determining the cardiovascular benefits of metformin in combination with newer anti-diabetic drugs including incretins (GLP-1 agonists), dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors revealed both positive and neutral effects of adding metformin ( 164 , 165 ).…”

Global, Regional, and National Burden of Diabetes-Related Chronic Kidney Disease From 1990 to 2019

“…Type 2 diabetes is gradually replacing infectious diseases as the main cause of CKD in less economically advanced countries, thereby causing competition for scarce medical resources ( 9 ). In patients with type 2 diabetes and mild/moderate CKD, use of metformin is associated with a significant reduction in all-cause mortality ( 13 ). In addition, the incidence of CKD caused by diabetes (CKD-DM) is determined by socioeconomic, cultural, and political factors, which have led to gaps in the current status of CKD prevention and management capabilities in countries around the world ( 14 ).…”

The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease

“…It was found in a retrospective analysis that type-2 diabetic patients with CKD stage 5 who took metformin were less likely to develop ESRD than those who do not use it [57]. More recently, a systematic and meta-analysis concluded that taking metformin is associated with significantly less risks of all-cause mortality and cardiovascular events in type-2 diabetic patients with mild to moderate CKD [12].…”

“…Adenine-induced CKD causes inflammation, oxidative, and nitrosative stress, and alters the composition of the microbiota [8][9][10]. Several drugs and dietary supplements have been tested in this model for their efficacy against experimental CKD [11,12].…”