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Research · Medication

Metformin

Meta-analyses of trials found metformin lowered progression to type 2 diabetes by 23 to 35%, less than lifestyle change did. Longevity findings come from observational studies that disagree, and 21-year trial follow-up found no drop in cancer or multimorbidity. Metformin blunted muscle and fitness gains from training. Long-term use was linked to low vitamin B12.

Add to Bio HackChecked 2026-11-13
Status
Prescription drug in the US, FDA-approved for type 2 diabetes. It is not FDA-approved for prediabetes, aging or longevity.
Also called
Glucophage, Glumetza, Fortamet, Riomet, metformin hydrochloride, metformin XR, biguanide
Taken for
blood sugar, preventing diabetes, longevity, anti-aging, insulin sensitivity, muscle gain with training, PCOS

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help6

Reported risks5

What people take it for, and what was found

Shown to help6

Strong

Preventing type 2 diabetes

Shown to lower type 2 diabetes incidence about 31% in adults with raised blood sugar, less than the 58% from lifestyle change.

The numbers and sources
Effect
Over an average 2.8 years, diabetes incidence was 11.0, 7.8 and 4.8 cases per 100 person-years on placebo, metformin and lifestyle change. Metformin lowered incidence by 31% (95% CI 17 to 43) and lifestyle change by 58% (95% CI 48 to 66) against placebo. Preventing one case over 3 years took 13.9 people on metformin or 6.9 in the lifestyle program [1]. Over about 21 years of follow-up, incidence stayed lower in the original metformin group than placebo (HR 0.83, 95% CI 0.74 to 0.93), with median diabetes-free survival 2.5 years longer [2]. In people with metabolic syndrome, metformin 1,700 mg a day lowered type 2 diabetes incidence by 80% against placebo over about 3 years [3]. Pooling RCTs in high-risk adults, metformin lowered diabetes incidence (OR 0.77, 95% CI 0.67 to 0.88), including in prediabetes (OR 0.75, 95% CI 0.66 to 0.86). Added to a lifestyle program, it did not lower incidence more than the same program alone [4]. A second meta-analysis of 18 RCTs found a risk ratio of 0.65 (95% CI 0.55 to 0.77), lowest in impaired fasting glucose (RR 0.38) [5].
Population
3,234 adults without diabetes but with raised fasting and post-load glucose, mean age 51, mean BMI 34.0, 68% women [1]; 3,195 of the same participants over follow-up [2]; 1,442 adults with metabolic syndrome [3]; RCTs in metformin-naive high-risk adults [4]; 18 RCTs in prediabetes [5].
Sources
[1], [2], [3], [4], [5]
Caveats
Lifestyle change lowered incidence more than metformin [1][2]. After the first 3 years, placebo was stopped and metformin continued open-label [2]. The effect weakened after metformin was stopped [4]. [5] reported moderate heterogeneity.
Moderate

Blood sugar in type 2 diabetes

Shown to lower HbA1c about 1.1 points more than placebo in people with diabetes, and more at higher doses.

The numbers and sources
Effect
Across 35 trials of at least 12 weeks, metformin alone lowered HbA1c by 1.12 points more than placebo (95% CI 0.92 to 1.32). Added to other oral diabetes drugs it lowered HbA1c 0.95 points more than placebo (95% CI 0.77 to 1.13), and added to insulin 0.60 points more than insulin alone (95% CI 0.30 to 0.91). Higher doses lowered HbA1c more than lower doses, with no significant rise in side effects [6]. A Cochrane review of 29 trials found a strong benefit for HbA1c against placebo and against diet [7].
Population
People with diabetes in trials of at least 12 weeks [6]; 5,259 people with type 2 diabetes [7].
Sources
[6], [7]
Caveats
Heterogeneity was high (I² 77 to 80%) [6]. The Cochrane abstract gives no pooled effect size, so the grade rests on one review with numbers. These are people with diabetes. For people without it, see diabetes prevention above.
StrongStudied in women

Ovulation and pregnancy in PCOS

Shown to raise ovulation and clinical pregnancy rates against placebo in women with PCOS. The rise in live births rests on low-quality evidence.

Compared with placebo or no treatment [30][31]; clomiphene citrate [30]

The numbers and sources
Effect
Against placebo or no treatment, metformin raised ovulation (OR 2.64, 95% CI 1.85 to 3.75, 13 studies, 684 women, low quality) and clinical pregnancy (OR 1.98, 95% CI 1.47 to 2.65, 11 studies, 1,213 women, moderate quality). Live birth rose from 19% on placebo to between 19% and 37% on metformin (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, low quality). The effect on miscarriage was uncertain (OR 1.08, 95% CI 0.50 to 2.35). Against clomiphene citrate, women with obesity had fewer live births on metformin (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women) [30]. A second review found higher odds of clinical pregnancy on metformin than placebo (OR 3.00, 95% CI 1.95 to 4.59) [31].
Population
41 RCTs with 4,552 women with PCOS and subfertility [30]; 24 RCTs with 564 women with PCOS given metformin [31].
Sources
[30], [31]
Caveats
Evidence quality ranged from very low to moderate, limited by risk of bias, imprecision and inconsistency. Results differed by body mass index [30]. The second review's abstract does not say how many trials reported pregnancy [31].
ModerateStudied in women

Menstrual cycles in PCOS

Shown to make periods more frequent in women with PCOS, against placebo and when added to lifestyle change, on low-quality evidence.

Compared with placebo or no treatment [32]; lifestyle change with or without placebo [33]

The numbers and sources
Effect
Against placebo or no treatment, metformin raised menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, low-quality evidence) [32]. Lifestyle change plus metformin gave about one more menstrual cycle over 6 months than lifestyle change with or without placebo (MD 1.06, 95% CI 0.30 to 1.82) [33].
Population
48 RCTs with 4,451 women with PCOS and infrequent or absent ovulation, 42 of them on metformin [32]; 12 RCTs with 608 women with PCOS [33].
Sources
[32], [33]
Caveats
Each comparison rests on one review. Heterogeneity was moderate (I² 54%) [32]. Trials were small and short, with risk of bias [33].
StrongStudied in women

Weight in PCOS

Shown to lower BMI slightly more than placebo in women with PCOS, by about 0.5 to 0.8 kg/m2, or about 3 kg of body weight.

Compared with placebo [34][31]; lifestyle change with or without placebo [33]

The numbers and sources
Effect
Against placebo, metformin with or without lifestyle change lowered BMI by 0.53 kg/m2 more (95% CI 0.12 to 0.95, moderate certainty) and waist-hip ratio by 0.02 more (low certainty) [34]. A second review found 3.13 kg more weight lost (95% CI 0.93 to 5.33) and BMI 0.82 kg/m2 lower (95% CI 0.41 to 1.22) than placebo [31]. Lifestyle change plus metformin lowered BMI 0.73 kg/m2 more than lifestyle change with or without placebo over 6 months (95% CI 0.32 to 1.14). Metformin alone gave similar weight and BMI to lifestyle change [33].
Population
RCTs in women with PCOS published through July 2022 [34]; 24 RCTs with 564 women given metformin [31]; 12 RCTs with 608 women [33].
Sources
[34], [31], [33]
Caveats
The differences are small. Trials were small and short [33]. The 2023 review was written to inform the international PCOS guideline [34].
StrongStudied in women

Insulin resistance and blood sugar in PCOS

Shown to lower insulin resistance and fasting glucose slightly against placebo in women with PCOS. Added to lifestyle change, one review found no extra effect.

Compared with placebo [34][31]; lifestyle change with or without placebo [33]; combined oral contraceptive pills [35]

The numbers and sources
Effect
Against placebo, metformin lowered HOMA-IR by 0.50 (95% CI 0.09 to 0.91) and fasting glucose by 0.13 mmol/L (95% CI 0.07 to 0.19), both moderate certainty [34]. A second review also found lower fasting glucose than placebo (SMD -0.23, 95% CI -0.40 to -0.06) [31]. Lifestyle change plus metformin did not differ from lifestyle change with or without placebo on surrogate markers of insulin resistance or fasting glucose after 6 months [33]. Against combined oral contraceptive pills, metformin lowered insulin by 27.12 pmol/L (95% CI 13.59 to 40.65) [35].
Population
RCTs in women with PCOS published through July 2022 [34]; 24 RCTs with 564 women given metformin [31]; 12 RCTs with 608 women [33]; 36 RCTs in women with PCOS [35].
Sources
[34], [31], [33], [35]
Caveats
The changes are small. The add-on comparison rests on small, short trials [33].

Mixed results2

Limited

Longevity and diseases of aging

Limited evidence: observational studies disagree on mortality, and in a long trial follow-up, cancer and multiple chronic conditions did not differ from placebo in prediabetes.

The numbers and sources
Effect
A meta-analysis of 53 studies found people with diabetes on metformin had lower all-cause mortality than people without diabetes (HR 0.93, 95% CI 0.88 to 0.99) and than people with diabetes on other drugs (HR 0.72, 95% CI 0.65 to 0.80) [8]. A Danish registry study found the reverse. People starting metformin alone for type 2 diabetes had higher mortality than matched people without diabetes (adjusted IRR 1.32, 95% CI 1.16 to 1.50), and 1.64 (95% CI 1.10 to 2.46) against their own twin without diabetes [9]. In adults with prediabetes randomized in the Diabetes Prevention Program, cancer incidence did not differ between metformin and placebo over a median 21 years (HR 0.90, 95% CI 0.73 to 1.10) [10], nor did the risk of having two or more chronic conditions (HR 0.91, 95% CI 0.78 to 1.07) [11]. In a trial in metabolic syndrome, fewer major noncommunicable diseases on metformin were fully explained by less diabetes [3].
Population
Observational studies of people with type 2 diabetes [8][9], including discordant twin pairs [9]; 3,234 adults with prediabetes followed a median 21 years [10]; 1,173 of them with Medicare records [11]; 1,442 adults with metabolic syndrome [3].
Sources
[8], [9], [10], [11], [3]
Caveats
[8] and [9] are not randomized trials. The meta-analysis authors note baseline differences between groups that could bias results [8]. In the Diabetes Prevention Program follow-ups, metformin became open-label and use outside the study rose over time [10], and [11] is an observational follow-up of the trial cohort. No trial in people without diabetes measuring lifespan was sourced.
ModerateStudied in women

Excess hair and androgens in PCOS

Mixed results: against the pill, hair growth improved about the same in one review and less in overweight women in another. Metformin lowered testosterone against placebo.

Compared with combined oral contraceptive pills [35][36]; metformin combined with the pill [36]; placebo [31]; lifestyle change with or without placebo [33]

The numbers and sources
Effect
Hirsutism did not differ between metformin and combined oral contraceptive pills, while free androgen index was 7.08 higher, SHBG 118.61 nmol/L lower and testosterone 0.48 nmol/L higher on metformin than on the pill [35]. In a Cochrane review, metformin may improve hirsutism less than the pill in women with BMI 25 to 30 (MD 1.92, 95% CI 1.21 to 2.64, 5 RCTs, 254 women), with an uncertain difference at other BMIs. Metformin alone and the pill alone each improved hirsutism less than the two combined [36]. Against placebo, metformin lowered total testosterone (SMD -0.33, 95% CI -0.49 to -0.17) [31]. Lifestyle change plus metformin did not differ from lifestyle change on clinical or biochemical hyperandrogenism, while metformin alone gave lower testosterone than lifestyle change [33].
Population
36 RCTs in women with PCOS [35]; 44 RCTs with 2,253 women and adolescents with PCOS [36]; 24 RCTs with 564 women given metformin [31]; 12 RCTs with 608 women [33].
Sources
[35], [36], [31], [33]
Caveats
Cochrane evidence quality was very low to low [36]. Hirsutism scales and trial lengths varied.

Doses studied

The Diabetes Prevention Program used 850 mg twice daily [1], continued as open-label metformin for another 9 years in its follow-up study [12]. The MASTERS training trial used 1,700 mg a day [13], as did the metabolic syndrome prevention trial [3]. The frailty trial used 500 mg three times a day for 4 months [14]. The aerobic training trials in metabolic syndrome used 1,000 or 2,000 mg a day [15][16]. Exercise metabolism studies pooled in one meta-analysis used 500 to 3,000 mg a day, from a single dose to 12 weeks [17].

Risks

Reported risks5

LimitedVery common

Low vitamin B12

One trial found low or borderline B12 more often on metformin than placebo, 19.1% against 9.5% at 5 years, with odds rising each year of use.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Low B12 (203 pg/mL or less) was more common on metformin than placebo at 5 years (4.3% vs 2.3%) but not significantly at 13 years (7.4% vs 5.4%). Low or borderline B12 (298 pg/mL or less) was more common at 5 years (19.1% vs 9.5%) and 13 years (20.3% vs 15.6%). Each year of use raised the odds of deficiency (OR 1.13, 95% CI 1.06 to 1.20). Anemia was more common on metformin, and neuropathy was more common among metformin users with low B12 [12].
Population
Participants with stored samples from the Diabetes Prevention Program and its outcomes study, 1,715 at 5 years and 1,520 at 13 years [12].
Sources
[12]
Caveats
A secondary analysis. The randomized phase lasted 3.2 years, and metformin was open-label after that [12]. In children and adolescents, pooled B12 deficiency after 12 months or more was 1.4% in RCTs and 18.7% in observational studies, and the fall in B12 levels at 6 and 12 months was not significant [22].
LimitedVery common

Adverse events in frail older adults

One trial found more hospital admissions on metformin, 34% against 8% on placebo, in frail adults with mean age 80 over 4 months.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Over 4 months, 108 adverse events occurred in all 35 people on metformin and 77 in 33 of 36 on placebo. Hospital admissions occurred in 34% on metformin and 8% on placebo. One death, on metformin, was judged unrelated [14].
Population
72 adults with mean age 80.4 with probable sarcopenia and prefrailty or frailty [14].
Sources
[14]
Caveats
One small trial, not designed to measure harms.
StrongStudied in womenVery common

Gut side effects in women with PCOS

Shown to raise gut side effects in women with PCOS, from 10% on placebo to between 22% and 40% on metformin.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Against placebo, gastrointestinal side effects rose from 10% to between 22% and 40% (OR 4.00, 95% CI 2.63 to 6.09, 7 studies, 713 women, moderate quality) [30]. A second review found more mild gastrointestinal adverse effects on metformin than placebo (OR 7.67, 95% CI 2.74 to 21.46) [34]. Against combined oral contraceptive pills, metformin may raise severe gastrointestinal adverse events (Peto OR 6.42, 95% CI 2.98 to 13.84, 11 RCTs, 602 women) and lower other severe adverse events (Peto OR 0.20, 95% CI 0.09 to 0.44) [36].
Population
Women with PCOS and subfertility [30]; RCTs in women with PCOS published through July 2022 [34]; 44 RCTs with 2,253 women and adolescents with PCOS [36].
Sources
[30], [34], [36]
Caveats
The comparison with the pill rests on low-quality evidence [36].
ModerateHow often is not known

Blunted gains from exercise training

Shown to blunt gains from exercise training, including smaller rises in lean mass, VO2 max and insulin sensitivity, in older and at-risk adults. One trial found no blunting.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Over 14 weeks of resistance training, the placebo group gained more lean body mass and thigh muscle mass than the metformin group, with greater gains in thigh muscle area and density. Strength gains trended lower on metformin without reaching significance [13]. Over 12 weeks of aerobic training, metformin attenuated the rise in whole-body insulin sensitivity and VO2 max and abolished the rise in muscle mitochondrial respiration [18]. Pooled across controlled trials, metformin with exercise produced smaller gains in VO2 peak than exercise alone (MD -1.19, 95% CI -2.33 to -0.04) and smaller drops in systolic (3.76 mm Hg, 95% CI 0.63 to 6.89) and diastolic (1.98 mm Hg, 95% CI 0.42 to 3.55) blood pressure [19]. During exercise, metformin raised blood lactate (SMD 0.98, 95% CI 0.36 to 1.60) [17]. Over 16 weeks of low- or high-intensity aerobic training, VO2 max rose on placebo but not on metformin 2,000 mg a day, and metformin blunted the rise in vascular insulin sensitivity [15]. In the same trial, metabolic insulin sensitivity rose after high-intensity training on placebo but not on metformin [20]. Over 5 weeks of aerobic training, VO2 peak rose 0.11 L/min on metformin and 0.26 L/min on placebo, while fat oxidation rose more on metformin [16]. In a 12-week trial in prediabetes, metformin did not reduce the muscle changes seen on MRI with aerobic exercise [21].
Population
94 healthy adults aged 65 and older [13]; 53 older adults, mean age 62 [18]; 827 adults across the spectrum of glucose dysregulation in 9 studies [19]; 325 participants in 21 studies [17]; 91 adults at risk for metabolic syndrome [15][20]; 22 adults with metabolic syndrome completing [16]; 42 adults with prediabetes [21].
Sources
[13], [18], [19], [17], [15], [20], [16], [21]
Caveats
Body weight, glucose, HbA1c, insulin and lipids did not differ between groups in the pooled trials [19]. GRADE certainty was moderate for VO2 peak and blood pressure [19]. Responses in [18] were highly variable between people. [21] did not find the blunting seen in the other trials. The added trials were small.
ModerateHow often is not known

Gastrointestinal side effects

Linked to gut side effects more often in women than men on metformin, at about 1.85 times the odds.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Across 7 studies, women had higher odds of gastrointestinal adverse events attributed to metformin than men (OR 1.85, 95% CI 1.58 to 2.17) [25].
Population
7,968 participants, 3,106 women and 4,862 men, in 5 cohort studies, 1 case-control study and 1 RCT [25].
Sources
[25]
Caveats
Mostly observational. The abstract does not give the overall rate of gastrointestinal effects [25].

Checked, no increase found2

Moderate

Lactic acidosis

Lactic acidosis was about as common as on other treatments in people with type 2 diabetes, with no cases in over 70,000 patient-years.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Across 347 comparative trials and cohort studies, no cases of fatal or nonfatal lactic acidosis occurred in 70,490 patient-years of metformin use or 55,451 patient-years on other treatments. The estimated upper limit was 4.3 cases per 100,000 patient-years on metformin and 5.4 on other treatments. Lactate levels did not differ [23].
Population
People with type 2 diabetes in prospective trials and cohort studies of at least 1 month [23].
Sources
[23]
Caveats
The review is from 2010 and covers people with type 2 diabetes only. In observational studies of people with chronic kidney disease and type 2 diabetes, lactic acidosis tended to be more common on metformin in stage 4 disease (HR 1.93, 95% CI 0.95 to 3.87), with very low certainty [24].
Moderate

Use in pregnancy and by fathers

Linked to fewer birth malformations than insulin when used in pregnancy, and not linked to malformations when fathers used it. Child BMI was similar by age 4.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Against insulin, metformin in pregnancy was associated with fewer congenital malformations overall (RR 0.83, 95% CI 0.71 to 0.99) [26]. Paternal use during sperm development was not associated with major congenital malformations in 4 studies (RR 1.03, 95% CI 0.88 to 1.21) [27]. Children exposed in the womb had BMI similar to unexposed children at a weighted mean age of 4.4 years (SMD -0.02, 95% CI -0.11 to 0.07). BMI was slightly higher at 1 to 3 years (SMD 0.15) and in the polycystic ovary syndrome subgroup (SMD 0.31) [28].
Population
RCTs and cohort studies of maternal use [26]; more than 11,000 children whose fathers used metformin [27]; 7,975 exposed children and more than 1 million unexposed [28].
Sources
[26], [27], [28]
Caveats
Mostly observational. [28] rated its certainty low.

Claims tested and not found

  1. That metformin adds to muscle gain from resistance training. The MASTERS trial tested this in older adults and found less lean mass and thigh muscle gain on metformin than placebo [13].
  2. That metformin adds to fitness gains from aerobic training. Metformin attenuated VO2 max gains in one trial [18] and VO2 peak gains across 9 studies [19].
  3. That metformin prevents cancer or multiple chronic diseases in people without diabetes. Over a median 21 years, cancer incidence [10] and multimorbidity [11] did not differ between metformin and placebo in adults with prediabetes.
  4. That metformin improves physical function in older adults. In frail older adults, 4-meter walk speed at 4 months did not differ from placebo (difference 0.001 m/s, 95% CI -0.06 to 0.06) [14]. Added to intensive diet and exercise in older adults with obesity, metformin did not change physical performance scores against placebo (difference 0.1 points, 95% CI -1.2 to 1.4) [29].

Sources

  1. Diabetes Prevention Program Research Group. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. New England Journal of Medicine. 2002. https://doi.org/10.1056/NEJMoa012512
  2. Knowler WC, Doherty L, Edelstein SL, et al. Long-term effects and effect heterogeneity of lifestyle and metformin interventions on type 2 diabetes incidence over 21 years in the US Diabetes Prevention Program randomised clinical trial. The Lancet Diabetes & Endocrinology. 2025. https://doi.org/10.1016/s2213-8587(25)00022-1
  3. Pasanisi P, Oliverio A, Baldassari I, et al. Metformin Treatment With or Without Mediterranean Diet for the Prevention of Age-Related Diseases in People With Metabolic Syndrome: The MeMeMe Randomized Trial. Diabetes Care. 2025. https://doi.org/10.2337/dc24-1597
  4. Tsironikos GI, Tsolaki V, Zakynthinos GE, et al. Metformin's Overall Effectiveness and Combined Action with Lifestyle Interventions in Preventing Type-2 Diabetes Mellitus in High-Risk Metformin-Naïve Patients: An Updated Systematic Review and Meta-Analysis of Published RCTs. Journal of Clinical Medicine. 2025. https://doi.org/10.3390/jcm14144947
  5. Qian X, Wang B, Yang X, et al. Meta-Analysis of the Effect of Metformin on the Progression of Different Types of Prediabetes Mellitus. Diabetes, Metabolic Syndrome and Obesity. 2026. https://doi.org/10.2147/dmso.s596986
  6. Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012. https://doi.org/10.2337/dc11-1465
  7. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2005. https://doi.org/10.1002/14651858.cd002966.pub3
  8. Campbell JM, Bellman SM, Stephenson MD, et al. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Research Reviews. 2017. https://doi.org/10.1016/j.arr.2017.08.003
  9. Keys MT, Thinggaard M, Larsen LA, et al. Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study. International Journal of Epidemiology. 2022. https://doi.org/10.1093/ije/dyac200
  10. Heckman-Stoddard BM, Crandall JP, Edelstein SL, et al. Randomized Study of Metformin and Intensive Lifestyle Intervention on Cancer Incidence over 21 Years of Follow-up in the Diabetes Prevention Program. Cancer Prevention Research. 2025. https://doi.org/10.1158/1940-6207.capr-23-0461
  11. Salive ME, Tjaden AH, Ames JR, et al. Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes. JAMA. 2026. https://doi.org/10.1001/jama.2026.8492
  12. Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. The Journal of Clinical Endocrinology & Metabolism. 2016. https://doi.org/10.1210/jc.2015-3754
  13. Walton RG, Dungan CM, Long DE, et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging Cell. 2019. https://doi.org/10.1111/acel.13039
  14. Witham MD, McDonald C, Wilson N, et al. Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial. The Lancet Healthy Longevity. 2025. https://doi.org/10.1016/j.lanhl.2025.100695
  15. Malin SK, Heiston EM, Battillo DJ, et al. Metformin Blunts Vascular Insulin Sensitivity After Exercise Training in Adults at Risk for Metabolic Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2026. https://doi.org/10.1210/clinem/dgaf551
  16. Methnani J, Moussa A, Dhahbi W, et al. Does Metformin Interfere with Cardiorespiratory and Substrate Oxidation Adaptations to Exercise Training in Metabolic Syndrome Patients? A Randomized Placebo-Controlled Trial. Biomolecules. 2026. https://doi.org/10.3390/biom16070971
  17. Grammer EE, Stahl ME, Ortiz de Zevallos J, et al. Influence of metformin on exercise metabolism and capacity: a systematic review and meta-analysis. American Journal of Physiology-Endocrinology and Metabolism. 2026. https://doi.org/10.1152/ajpendo.00012.2026
  18. Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019. https://doi.org/10.1111/acel.12880
  19. Etayo-Urtasun P, Sáez de Asteasu ML, Izquierdo M. The effects of metformin and exercise training on cardiorespiratory, blood pressure, and metabolic adaptations across the spectrum of glucose dysregulation: a systematic review and meta-analysis. eClinicalMedicine. 2026. https://doi.org/10.1016/j.eclinm.2026.103915
  20. Malin SK, Heiston EM, Battillo DJ, et al. Metformin attenuates metabolic insulin sensitivity and insulin-stimulated carbohydrate oxidation after high-intensity exercise training in adults at risk for metabolic syndrome. Diabetes, Obesity and Metabolism. 2026. https://doi.org/10.1111/dom.70478
  21. Yu F, Dong Y, Ye N, et al. Multiparameter MRI assessment of metformin and exercise effects on skeletal muscle in prediabetes: a randomized controlled trial. European Radiology Experimental. 2025. https://doi.org/10.1186/s41747-025-00658-y
  22. Tahir EA, Ahmed MG, Al Swayah MB, et al. The Impact of Metformin on Vitamin B12 Levels in Children and Adolescents: A Systematic Review and Single-Arm Meta-Analysis. Endocrinology, Diabetes & Metabolism. 2026. https://doi.org/10.1002/edm2.70232
  23. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2010. https://doi.org/10.1002/14651858.CD002967.pub4
  24. Patiño-Cardona S, Pascual-Morena C, Sequí-Domínguez I, et al. Safety of metformin in chronic kidney disease and type 2 diabetes mellitus: a systematic review and meta-analysis. European Journal of Pharmacology. 2026. https://doi.org/10.1016/j.ejphar.2026.178560
  25. Kumar A, Catalano A, Biamonte E, et al. Sex differences in the risk of metformin-associated gastrointestinal adverse events: A systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2026. https://doi.org/10.1016/j.diabres.2026.113560
  26. Ji H, Wu Y, Wu S, et al. Impact of metformin use during pregnancy on fetal congenital malformations across 11 organ systems: a meta-analysis and drug-target Mendelian randomization study. Diabetes Research and Clinical Practice. 2026. https://doi.org/10.1016/j.diabres.2026.113118
  27. Damkier P, van Gelder MMHJ, Huybrechts KF, et al. Paternal use of metformin and risk of major congenital malformations: A meta-analysis of 4 studies. British Journal of Clinical Pharmacology. 2026. https://doi.org/10.1002/bcp.70547
  28. Fu J, Tabbara N, Tomlinson G, et al. Intrauterine metformin exposure and adiposity outcomes in children: a systematic review and meta-analysis. BMJ Open. 2025. https://doi.org/10.1136/bmjopen-2024-088653
  29. Nava MLD, Viola V, Aguilar M, et al. Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial. The Lancet Healthy Longevity. 2026. https://doi.org/10.1016/j.lanhl.2026.100883
  30. Sharpe A, Morley LC, Tang T, Norman RJ, Balen AH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2019. https://doi.org/10.1002/14651858.cd013505
  31. Abdalla MA, Shah N, Deshmukh H, et al. Impact of metformin on the clinical and metabolic parameters of women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials. Therapeutic Advances in Endocrinology and Metabolism. 2022. https://doi.org/10.1177/20420188221127142
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