PMID- 32501595 OWN - NLM STAT- MEDLINE DCOM- 20200724 LR - 20220915 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 6 IP - 6 DP - 2020 Jun 5 TI - Metformin monotherapy for adults with type 2 diabetes mellitus. PG - CD012906 LID - 10.1002/14651858.CD012906.pub2 [doi] LID - CD012906 AB - BACKGROUND: Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES: To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS: We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS: We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS: There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes. CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Gnesin, Filip AU - Gnesin F AD - Department of Endocrinology, Diabetes and Metabolism, Department 7652, Rigshospitalet, Copenhagen, Denmark. FAU - Thuesen, Anne Cathrine Baun AU - Thuesen ACB AD - Steno Diabetes Center Copenhagen, Gentofte, Denmark. AD - Faculty of Health and Medical Sciences, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark. FAU - Kahler, Lise Katrine Aronsen AU - Kahler LKA AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. FAU - Madsbad, Sten AU - Madsbad S AD - Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. FAU - Hemmingsen, Bianca AU - Hemmingsen B AD - Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany. LA - eng SI - ClinicalTrials.gov/NCT00679939 SI - ClinicalTrials.gov/NCT00279045 SI - ClinicalTrials.gov/NCT00327015 SI - ClinicalTrials.gov/NCT00099866 SI - ClinicalTrials.gov/NCT00138567 SI - ClinicalTrials.gov/NCT01126580 SI - ClinicalTrials.gov/NCT00103857 SI - ClinicalTrials.gov/NCT00035568 SI - ClinicalTrials.gov/NCT03010683 SI - ClinicalTrials.gov/NCT00373178 SI - ClinicalTrials.gov/NCT00396851 SI - ClinicalTrials.gov/NCT01001962 SI - ClinicalTrials.gov/NCT01779362 SI - ClinicalTrials.gov/NCT02853630 SI - ClinicalTrials.gov/NCT03982381 PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20200605 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Carbamates) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Piperidines) RN - 0 (Sulfonylurea Compounds) RN - 668Z8C33LU (repaglinide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9100L32L2N (Metformin) SB - IM UOF - doi: 10.1002/14651858.CD012906 MH - Adult MH - Carbamates/adverse effects/therapeutic use MH - Cardiovascular Diseases/mortality MH - Cause of Death MH - Diabetes Mellitus, Type 2/*drug therapy/mortality MH - Dipeptidyl-Peptidase IV Inhibitors/adverse effects/therapeutic use MH - Glucagon-Like Peptide 1/analogs & derivatives MH - Humans MH - Hypoglycemic Agents/adverse effects/*therapeutic use MH - Insulin/therapeutic use MH - Metformin/adverse effects/*therapeutic use MH - Myocardial Infarction/epidemiology MH - Piperidines/adverse effects/therapeutic use MH - Quality of Life MH - Randomized Controlled Trials as Topic MH - Stroke/epidemiology MH - Sulfonylurea Compounds/adverse effects/therapeutic use PMC - PMC7386876 COIS- Filip Gnesin (FG): none known. Lise Katrine Aronsen Kahler (LK): none known. Anne Cathrine Thuesen (AT): has previously been employed by a subsidiary company of Novo Nordisk. Sten Madsbad (SM): Advisory Boards: Novartis Pharma, Novo Nordisk, Merck Sharp & Dome, Sanofi-Aventis, AstraZeneca, Johnson & Johnson, Astra-Zeneca, Boehringer-Ingelheim, E. Lilly, Intarcia Therapeutics, Bristol-Meyer Squibb. Fee for lectures: Novo Nordisk, Merck, Sharp & Dome, Astra-Zeneca, Sanofi-Aventis, Novartis Pharma, E. Lilly, Bristol-Meyer Squibb, Boeringer-Ingelheim, E.Lilly. Grants for research: Novo Nordisk. Bianca Hemmingsen (BH): none known. EDAT- 2020/06/06 06:00 MHDA- 2020/07/25 06:00 PMCR- 2021/06/05 CRDT- 2020/06/06 06:00 PHST- 2020/06/06 06:00 [entrez] PHST- 2020/06/06 06:00 [pubmed] PHST- 2020/07/25 06:00 [medline] PHST- 2021/06/05 00:00 [pmc-release] AID - CD012906.pub2 [pii] AID - 10.1002/14651858.CD012906.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2.