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Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials
Authors:Matteo Monami  Riccardo Candido  Basilio Pintaudi  Giovanni Targher  Edoardo Mannucci
Affiliation:1. Diabetology, Careggi Hospital and University of Florence, Italy;2. Diabetes Centre District 3, Azienda Sanitaria Universitaria Integrata di Trieste, Via Puccini 48/50, 34100, Trieste, Italy;3. SSD Diabetes Unit, Niguarda Ca’ Granda Hospital, Milan, Italy;4. Endocrinology, Diabetes and Metabolism, University of Verona, Italy
Abstract:AimsThe Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes.Data synthesisA MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH–OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH–OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH–OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH–OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH–OR: 0.57 [0.42, 0.76]).ConclusionsThis updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.
Keywords:Metformin  Mortality  Major cardiovascular events  Meta-analysis  Type 2 diabetes
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