Table 2.
Summary of clinical studies of metformin
| Diseases | Type of studies | Status | Characteristics | Year | Outcomes | Effect size | P-values / 95% CI | References |
|---|---|---|---|---|---|---|---|---|
| Diabetes mellitus | Randomized-controlled trial | Finished | 29 patients to receive either metformin or troglitazone for three months | 1998 | Plasma glucose concentrations | Metformin, decreased by 20%; Troglitazone, decreased by 25% | P < 0.001 | [192] |
| Randomized controlled double-blind trial | Finished | 390 patients to receive either the placebo or metformin, in addition to insulin therapy | 2002 | Mean daily glucose at 16 weeks | 7.8 vs. 8.8 mmol/l | P = 0.006 | [193] | |
| Cardiovascular diseases | Randomized controlled trial | Finished | 1,673 patients to receive either conventional or metformin | 1998 | Risk of myocardial infarction | 39% reduction | P = 0.01 | [196] |
| Randomized controlled trial | Finished | 4209 patients to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control, 10-year follow-up | 2008 | Risk of myocardial infarction | 33% reduction | P = 0.005 | [197] | |
| Randomized controlled trial | Finished | 304 patients to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years | 2013 | Adjusted hazard ratio (HR) of cardiovascular events | 0.54 | P = 0.026 | [198] | |
| Randomized controlled trial | Finished | 36 HFrEF patients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy | 2020 | Reduce myocardial oxygen uptake | 17% | P = 0.01 | [199] | |
| Randomized controlled trial | Ongoing | 1,500 patients with T2DM and heart failure to receive either metformin (2000 mg / d) or placebo, and the follow-up period was expected to be 4 years | 2021 | [200] | ||||
| Neurodegenerative diseases | Prospective, observational | Finished | 1,037 community-dwelling older participants, 123 had diabetes; 67 received metformin | 2020 | OR of rate of cognitive decline | 5.29 | P = 0.05 | [201] |
| Retrospective | Finished | a representative cohort of 800,000 was obtained between 1996–01-01 and 2007–12-31 | 2012 | HR | 0.95 | 95% CI (0.53–1.71) | [202] | |
| Reproductive diseases | Randomized controlled trial | Finished | 487 patients to receive metformin (n = 244) or placebo (n = 243) | 2019 | OR of rate of miscarriage and preterm birth | 0.50 | P = 0.08 | [203] |
| Randomized controlled trial | Finished | 153 patients to receive metformin (n = 77) or placebo (n = 76) | 2016 | incidence of moderate-severe OHSS | Placebo = 12.2%, metformin = 16% | P = 0.66 | [204] | |
| Randomized controlled trial | Finished | 357 obese pregnant women to receive either metformin or placebo | 2020 | OR of the rate of preeclampsia | 0.17 | 95%CI (0.10–0.41) | [205] | |
| Randomized controlled trial | Finished | 180 women with preterm pre-eclampsia between 26 + 0 to 31 + 6 weeks' gestation undergoing expectant management: 90 were randomized to extended-release metformin and 90 to placebo | 2021 | Median prolongation of gestation | 17.5 days in the metformin group compared with 7.9 days in the placebo group | P = 0.057 | [206] | |
| Cancer | Delayed start randomized trial | Finished | 100 patients were enrolled (51 in chemotherapy alone vs. 49 in metformin with chemotherapy arm) | 2019 | dose-limiting toxicities | 6.1% in the metformin with chemotherapy arm compared to those who received only chemotherapy 7.8% | 95% CI (0.39–0.92) | [207] |
| Double blind phase II randomized trial | Finished | 40 patients were randomized to receive metformin 850 mg po bid or placebo bid | 2019 | HR of PFS | 1.2 | 95% CI (0.63–2.31) | [208] | |
| Phase II randomized trial | Finished | 128 patients to receive metformin 250 mg orally per day or placebo tablets of identical appearance in the same regimen for a convenient duration of 7 to 14 days before surgery | 2020 | Infiltration of CD8+ T cells | - | P < 0.001 | [209] | |
| RCT | Finished | 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy | 2022 | PFS | ? | P = 0.021 | [210] | |
| COVID-19 | Retrospective | Finished | 2,449 patients were enrolled, 1496 were to receive metformin and 953 were not | 2020 | Tracheal intubation and/or death within 7 days of admission | 28.0% of metformin users (vs 29.0% in non-users) | P = 0.613 | [211] |
| Retrospective | Finished | 422,554 patients who tested positive for SARS-CoV-2 were enrolled (23,327 metformin users; 8,639 metformin non-users) | 2022 | OR of the risk of total mortality | 0.70 | 95% CI (0.66–0.75) | [212] | |
| Retrospective | Finished | 24,722 subjects who tested negative for COVID-19 and 604 subjects who had a confirmed positive COVID-19 test were included | 2021 | OR of death for subjects | 0.33 | P = 0.0210 | [213] | |
| RCT | Finished | 663 patients receiving metformin and 660 patients not receiving metformin | 2021 | OR of death for subjects | 0.58 | 95%CI, (0.35–0.94) | [214] | |
| Adverse effects of metformin | ||||||||
| Vitamin B12 deficiency | Case–control study | Finished | 155 patients with metformin-related vitamin B12 deficiency were compared with 310 matched controls | 2006 | OR for developing vitamin B12 deficiency | 2.88 | P < 0.001 | [215] |
| RCT | Finished | 4,351 drug-naive individuals recently diagnosed with type 2 diabetes were assigned randomly to thiazolidinediones (TZDs), metformin, or sulfonylurea monotherapy and monitored for 5 years (1,343 metformin, 1,289 sulfonylurea, and 1,335 TZD users) | 2020 | OR for anemia | 1.93 | 95% CI, (1.10–3.38) | [216] | |
| RCT | Finished | 136 patients with Type 2 diabetes were divided into metformin exposed (n = 84) and non-metformin exposed groups (n = 52) | 2013 | Mean neuropathy score | 5.72 ± 2.04 versus 4.62 ± 2.12 | P = 0.0064 | [217] | |
| Lactic acidosis | Retrospective study | Finished | 1,213 individuals with T2D, including 678 subjects (male, 53.8%) treated with metformin or metformin plus other anti-diabetic drugs (referred to as the metformin group) and 535 individuals (male, 49.9%) treated with anti-diabetic drugs other than metformin (referred to as the non-metformin group) | 2020 | Numbers of cases with severe COVID-19 | 32.60% versus 33.83% | P = 0.695 | [218] |
| Retrospective nested case–control study | Finished | 29,264 patients with type 2 diabetes including 2,662 lactic acidosis cases and 26,602 matched controls | 2020 | adjusted hazard ratio of MALA | 3.09 | 95%, CI (3.51–17.61) | [219] | |
| Offspring impairment | RCT | Finished | 257 pregnant women with PCOS participated with 274 pregnancies | 2018 | difference in height z score means | difference in means: 0.38 (0.07 to 0.69) | P = 0.017 | [220] |
| RCT | Finished | 208 children assessed (28% of the original cohort). In Adelaide, 109 children (metformin n = 58, insulin n = 51) were assessed and, in Auckland, 99 (metformin n = 45, insulin n = 54) were assessed | 2018 | Infants with birth weight > 90th percentile | 20.7% vs 5.9% | P = 0.029 | [221] | |
| Population-based cohort study | Finished | 1,996 children exposed to metformin during the fetal period and 1,932 treated with insulin | 2019 | Mean difference in the average weight z score | − 0.03 | 95% CI, (− 0.13 to 0.07) | [222] | |
| Finished | 7,029 offspring were exposed to paternal diabetes medications, including insulins (n = 5,298), metformin (n = 1,451), and sulfonylureas (n = 647) | Percentage of genital birth defects | In metformin-exposed group vs. 0.24% in control group, aOR = 3.39 | 5%CI, (1.82- 6.30) | [49] | |||
| Neurodegenerative disease | Nested case–control study | Finished | Diabetes diagnosed ≥ 3 years before AD diagnosed (n = 7552) and controls received at least once metformin (n = 14,528) | 2020 | Adjusted odds ratios (aORs) | 0.99 | P = 0.775 | [223] |
| Case–control study | Finished | 14,172 patients (7,086 AD and 7,086 matched controls) | 2012 | aOR of AD | 1.71 | 95% CI, (1.12–2.60) | [224] | |
| Cohort study | Finished | 4651 metformin users and an equal number of non-metformin users | 2017 | HR of PD | 2.27 | 95% CI, (1.68–3.07) | [225] | |