Metformin is an oral glucose-lowering drug from the biguanide class. It is approved in the US as an add-on to diet and exercise for type 2 diabetes, and it is the most prescribed glucose-lowering medicine worldwide (Bailey, Diabetologia 2017). Outside medicine it turns up in bodybuilding, longevity and “insulin sensitivity” circles.
The most important facts for that second audience: metformin carries a boxed warning for lactic acidosis, and in two randomized trials in older adults it blunted the gains from exercise training, including muscle growth from resistance training. No controlled trials have studied it in people using anabolic steroids.
This page summarizes what the FDA label, the major clinical trials and the WADA list report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Biguanide; oral antihyperglycemic |
| Brands / approval | Glucophage (US approval 1995, NDA 020357), Glucophage XR, Glumetza; many generics |
| Route and forms | Oral immediate-release (IR) tablets 500, 850 and 1,000 mg; extended-release (ER) tablets 500 and 750 mg |
| Labeled adult dose | IR: start 500 mg twice daily or 850 mg once daily, maximum 2,550 mg/day. ER: start 500 mg with the evening meal, maximum 2,000 mg/day |
| Half-life (label) | About 6.2 h in plasma; about 17.6 h in whole blood |
| Elimination | Excreted unchanged in urine; no liver metabolism |
| Boxed warning | Lactic acidosis |
| US status | Prescription drug; not a controlled substance |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Metformin is dimethylbiguanide, formula C₄H₁₁N₅, molecular weight 129.16 g/mol (PubChem). Tablets contain the hydrochloride salt. A 500 mg metformin hydrochloride tablet holds about 390 mg of metformin base (current generic label).
Its history goes back to goat’s rue (Galega officinalis), a European herbal remedy rich in guanidine, which was shown to lower blood glucose in 1918 (Bailey, Diabetologia 2017). Key steps from that review:
- 1957: the French physician Jean Sterne first reported metformin for diabetes.
- Late 1970s: the related biguanides phenformin and buformin were largely withdrawn because of a high risk of lactic acidosis. Metformin’s reputation suffered by association.
- 1995: metformin was introduced in the US. Drugs@FDA lists Glucophage (NDA 020357) as a new molecular entity approved on March 3, 1995 (Drugs@FDA). The Glucophage brand tablets are now listed as discontinued there, but generics are widely available.
How it works
The FDA label states that metformin lowers blood glucose in three ways (Glucophage label):
- it decreases glucose production by the liver;
- it decreases intestinal absorption of glucose;
- it improves insulin sensitivity by increasing glucose uptake in peripheral tissues.
Unlike insulin or sulfonylureas, it does not raise insulin secretion. Fasting insulin levels may actually fall. That is why metformin on its own rarely causes hypoglycemia (low blood sugar).
At the molecular level the mechanism is still debated. A 2023 review describes effects on liver mitochondria, a newer target on the lysosome surface at low concentrations, and actions in the gut and gut microbiome (Foretz et al., Nat Rev Endocrinol 2023). The same review covers proposed repurposing for cancer, age-related and inflammatory diseases; none of these is an approved use. In muscle biopsies from a resistance-training trial, metformin increased signaling through AMPK (AMP-activated protein kinase, a cellular energy sensor) (Walton et al., Aging Cell 2019).
Pharmacokinetics
From the Glucophage label and the current generic label:
| Parameter | Value |
|---|---|
| Oral bioavailability (500 mg, fasting) | About 50–60% |
| Effect of food (IR, 850 mg) | About 40% lower peak and 25% lower AUC; peak delayed by about 35 minutes |
| Time to peak, ER tablet | Median 7 h (range 4–8 h) |
| Protein binding | Negligible |
| Metabolism | None identified in humans |
| Elimination | About 90% of absorbed drug cleared by the kidneys within 24 h, mainly by tubular secretion |
| Plasma half-life | About 6.2 h |
| Whole-blood half-life | About 17.6 h (red cells act as a storage compartment) |
Absorption is less than dose-proportional at higher doses. Because the kidneys clear almost all of the drug, the half-life gets longer and exposure rises when kidney function falls. In a label table, peak levels after a single 850 mg dose were about 1.6 µg/mL in healthy adults and about 4 µg/mL in adults with moderate or severe kidney impairment. This dependence on the kidneys drives most of the label’s safety rules.
Approved medical use
The current US label approves metformin as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes (current generic label):
- IR tablets for adults and children aged 10 and older;
- ER tablets for adults only.
| Population | Labeled dosing |
|---|---|
| Adults, IR | Start 500 mg twice daily or 850 mg once daily with meals; increase by 500 mg weekly or 850 mg every 2 weeks; maximum 2,550 mg/day in divided doses |
| Adults, ER | Start 500 mg once daily with the evening meal; increase by 500 mg weekly; maximum 2,000 mg/day |
| Children 10 and older, IR | Start 500 mg twice daily; maximum 2,000 mg/day |
| eGFR 30–45 mL/min/1.73 m² | Starting metformin not recommended |
| eGFR under 30 mL/min/1.73 m² | Contraindicated |
The older Glucophage label notes that clinically significant responses are generally not seen below 1,500 mg/day. The slow titration exists mainly to limit stomach and bowel side effects. ER tablets must be swallowed whole.
Diabetes prevention, polycystic ovary syndrome (PCOS), weight management, aging and athletic performance are not approved US indications. The label does warn that metformin may restore ovulation in some anovulatory premenopausal women, which can lead to unintended pregnancy.
What the research shows
Glucose control
In the label’s 29-week placebo-controlled trial, 286 obese adults with type 2 diabetes received Glucophage up to 2,550 mg/day or placebo (Glucophage label):
| Outcome (net vs placebo) | Result |
|---|---|
| Fasting plasma glucose | −59 mg/dL |
| Post-meal plasma glucose | −83 mg/dL |
| HbA1c | −1.8 percentage points |
| Body weight | No significant difference (−1.4 lb vs −2.4 lb) |
Long-term outcomes in type 2 diabetes (UKPDS 34)
The UK Prospective Diabetes Study randomized 753 overweight adults with newly diagnosed type 2 diabetes to metformin or to a conventional diet-based policy, with a median follow-up of 10.7 years (UKPDS Group, Lancet 1998). Median HbA1c was 7.4% on metformin and 8.0% on conventional treatment.
| Outcome, metformin vs conventional | Risk reduction (95% CI) |
|---|---|
| Any diabetes-related endpoint | 32% (13–47) |
| Diabetes-related death | 42% (9–63) |
| All-cause mortality | 36% (9–55) |
A supplementary trial in the same paper gave a less reassuring result. Adding metformin early to sulfonylurea therapy was linked to a 96% higher risk of diabetes-related death (95% CI 2–275). A wider epidemiological analysis of 4,416 patients did not confirm that signal. These results helped make metformin the usual first-line drug for type 2 diabetes.
Diabetes prevention (DPP)
The Diabetes Prevention Program randomized 3,234 adults with prediabetes and a mean BMI of 34 to placebo, metformin 850 mg twice daily, or an intensive lifestyle program, for an average of 2.8 years (Knowler et al., NEJM 2002):
| Group | New diabetes per 100 person-years | Reduction vs placebo (95% CI) | Average weight loss |
|---|---|---|---|
| Placebo | 11.0 | — | 0.1 kg |
| Metformin | 7.8 | 31% (17–43) | 2.1 kg |
| Lifestyle | 4.8 | 58% (48–66) | 5.6 kg |
The lifestyle program was significantly more effective than metformin. About 14 people needed metformin for three years to prevent one case of diabetes.
Exercise training and muscle growth
Metformin and exercise both improve insulin sensitivity, so it was assumed they would add up. Three controlled trials suggest they partly cancel out instead.
| Trial | Population | Metformin dose | Main finding |
|---|---|---|---|
| Malin et al., Diabetes Care 2012 | 32 adults with prediabetes, 12 weeks, n = 8 per group | 2,000 mg/day | Insulin sensitivity rose 25–30% more with exercise plus placebo than with exercise plus metformin (difference not significant) |
| Konopka et al., Aging Cell 2019 | 53 older adults (mean age 62), 12 weeks of aerobic training | Up to 2,000 mg/day | Metformin attenuated the training gains in VO₂max and whole-body insulin sensitivity, and abolished the rise in muscle mitochondrial respiration |
| Walton et al., Aging Cell 2019 (MASTERS) | 94 healthy adults aged 65 and older, 14 weeks of resistance training | 1,700 mg/day | Metformin blunted gains in lean mass and thigh muscle mass |
The MASTERS trial is the closest thing to a muscle-building study. Its body-composition results after 14 weeks of supervised resistance training were:
| Outcome | Placebo | Metformin | Between groups |
|---|---|---|---|
| Total lean mass | +1.95% | +0.41% (not significant) | p = 0.003 |
| Thigh muscle mass | +3.90% | +0.45% (not significant) | p under 0.001 |
| Peak knee extension power | +29.4% | +14.3% | p = 0.064 (trend) |
Metformin increased AMPK signaling in muscle and showed a trend toward blunted mTORC1 (the main muscle-growth signaling pathway) activation. These trials were in older, non-diabetic adults. Whether the same blunting happens in young, trained people or in steroid users has not been tested.
Use in bodybuilding and with anabolic agents
No controlled human trials have tested metformin in people using anabolic-androgenic steroids, growth hormone or insulin for physique purposes. Claims that it “protects” insulin sensitivity during such use, or improves body composition in lean athletes, are not supported by trial data. The best available evidence, from MASTERS, points the other way for muscle gain.
Side effects and risks
Boxed warning: lactic acidosis
All US metformin labels carry a boxed warning for lactic acidosis, a dangerous build-up of lactate in the blood (current generic label). Postmarketing cases have caused death, low body temperature, low blood pressure and slow heart rhythms that resist treatment. Early symptoms are vague: malaise, muscle aches, breathing difficulty, sleepiness and abdominal pain.
Risk factors listed in the boxed warning:
- kidney impairment (most postmarketing cases);
- carbonic anhydrase inhibitors such as topiramate;
- age 65 or older;
- radiology studies with iodinated contrast;
- surgery and other procedures with restricted food and fluids;
- hypoxic states such as acute heart failure;
- excessive alcohol intake;
- liver impairment;
- mitochondrial diseases such as MELAS and MIDD (listed in the current label’s boxed warning, not in the 2017 Glucophage label).
In overdose, lactic acidosis was reported in about 32% of cases. Metformin can be removed by hemodialysis.
At labeled doses in eligible patients, the event is rare. A Cochrane review pooled 347 trials and cohort studies and found no cases of lactic acidosis in 70,490 patient-years on metformin or 55,451 patient-years on other drugs (Salpeter et al., Cochrane 2010). The estimated upper limit was 4.3 cases per 100,000 patient-years with metformin and 5.4 without. Lactate levels did not differ between groups.
Gastrointestinal effects
Stomach and bowel symptoms are the most common side effects, and they are less frequent with the ER form (Glucophage label):
| Adverse reaction | IR metformin (n = 141) | Placebo (n = 145) | ER metformin (n = 781) | Placebo (n = 195) |
|---|---|---|---|---|
| Diarrhea | 53.2% | 11.7% | 9.6% | 2.6% |
| Nausea/vomiting | 25.5% | 8.3% | 6.5% | 1.5% |
| Flatulence | 12.1% | 5.5% | — | — |
| Stopped drug for diarrhea | 6% | — | 0.6% | — |
Vitamin B12 deficiency
In 29-week label trials, about 7% of patients with normal vitamin B12 levels dropped below the normal range. The label links this to reduced B12 absorption, and recommends checking blood counts yearly and B12 every 2–3 years.
Longer data come from the DPP Outcomes Study, with up to about 13 years of follow-up (Aroda et al., JCEM 2016):
| B12 status | Metformin | Placebo |
|---|---|---|
| Low B12 (≤203 pg/mL), year 5 | 4.3% | 2.3% |
| Low or borderline B12 (≤298 pg/mL), year 5 | 19.1% | 9.5% |
| Low or borderline B12 (≤298 pg/mL), year 13 | 20.3% | 15.6% |
Each year of metformin use raised the odds of B12 deficiency by 13% (OR 1.13, 95% CI 1.06–1.20). Anemia was more common in the metformin group, and neuropathy was more common in metformin users with low B12.
Hypoglycemia
Metformin alone does not usually cause low blood sugar. The label notes it can occur with poor food intake, strenuous exercise without extra calories, alcohol, or other glucose-lowering drugs such as sulfonylureas and insulin. A lower insulin dose may be needed when the two are combined.
Interactions
From the Glucophage and current generic labels:
| Drug or factor | Effect |
|---|---|
| Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide) | Metabolic acidosis; higher lactic acidosis risk |
| OCT2/MATE transporter inhibitors (e.g. ranolazine, dolutegravir, cimetidine) | Higher metformin exposure; cimetidine raised peak levels by 60% and AUC by 40% |
| Iodinated contrast | Can cause acute kidney injury; metformin is stopped before some procedures and eGFR rechecked after 48 h |
| Alcohol | Potentiates metformin’s effect on lactate |
| Insulin and insulin secretagogues | Higher risk of hypoglycemia |
| Corticosteroids, thiazides, thyroid hormones, estrogens, sympathomimetics and others | Can raise blood glucose and weaken control |
Who should not use it
The label contraindicates metformin in people with:
- an eGFR under 30 mL/min/1.73 m²;
- hypersensitivity to metformin;
- acute or chronic metabolic acidosis, including diabetic ketoacidosis.
The label also says to avoid it in people with clinical or laboratory evidence of liver disease, and does not recommend it in mitochondrial diseases such as MELAS and MIDD. It is stopped temporarily around surgery and other procedures that restrict food and fluids.
Product quality: NDMA recalls
In 2020, several manufacturers recalled lots of extended-release metformin because they could contain N-nitrosodimethylamine (NDMA), a nitrosamine impurity, above the acceptable intake limit (FDA). FDA said its testing had not shown NDMA in immediate-release products. It advised patients not to stop a recalled product without talking to a health care professional.
Legal status and use outside medicine
In the US, metformin is a prescription drug. It is not listed as a controlled substance in 21 CFR 1308.13.
Metformin is not named on the WADA 2026 Prohibited List. The list’s metabolic-modulator class (S4.4.1) names AICAR, BAM15 and MOTS-c as examples of AMPK activators, and S4.4.2 covers insulins and insulin mimetics. Metformin, which increases AMPK signaling, does not appear among the examples. See the AICAR page for a compound that is named.
Related library pages: berberine, a supplement often compared with metformin; semaglutide, tirzepatide and SGLT2 inhibitors, other diabetes drug classes.
Key takeaways
- A first-line diabetes drug, not a performance drug. Metformin is approved only for type 2 diabetes. In the DPP it cut new diabetes by 31% in people with prediabetes, less than the 58% from lifestyle change.
- It can blunt training gains. In the MASTERS trial, older adults on 1,700 mg/day gained about a fifth as much lean mass from resistance training as those on placebo. It also blunted aerobic fitness gains in another trial.
- No evidence in steroid users. No controlled trials have tested metformin alongside anabolic steroids, growth hormone or insulin for physique purposes.
- Kidneys set the safety limits. Metformin is cleared unchanged by the kidneys. It is contraindicated below an eGFR of 30 and carries a boxed warning for lactic acidosis, which is rare at labeled doses in eligible patients.
- Common side effects are gastrointestinal. Diarrhea affected 53% on IR tablets in the label trial and about 10% on ER tablets.
- Long-term use lowers vitamin B12. About 1 in 5 long-term users in the DPP Outcomes Study had low or borderline B12 levels.
Sources
- Laurus Labs. Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets, prescribing information, revised July 2026. DailyMed.
- Bristol-Myers Squibb. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets, prescribing information, NDA 020357/021202, 2017. FDA.
- Food and Drug Administration. Drugs@FDA: NDA 020357, Glucophage (metformin hydrochloride). Drugs@FDA.
- National Center for Biotechnology Information. Metformin, PubChem CID 4091. PubChem.
- Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–1576. PubMed.
- Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460–476. PubMed.
- UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865. PubMed.
- Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. PubMed.
- Malin SK, Gerber R, Chipkin SR, Braun B. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care. 2012;35(1):131–136. PubMed.
- Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880. PubMed.
- 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;18(6):e13039. PubMed.
- Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;(4):CD002967. PubMed.
- Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754–1761. PubMed.
- Food and Drug Administration. FDA updates and press announcements on NDMA in metformin. FDA.
- World Anti-Doping Agency. 2026 Prohibited List. WADA.
- US Code of Federal Regulations. 21 CFR 1308.13, Schedule III. eCFR.