Metformin

What it is

Metformin is a prescription tablet used to lower blood glucose in type 2 diabetes. The label calls it an antihyperglycemic agent.

What the research says

In UKPDS 34, overweight people with newly diagnosed type 2 diabetes who were allocated metformin had fewer diabetes-related endpoints and lower all-cause mortality than those on diet alone. The trial was small (342 on metformin). Adding metformin early to a sulphonylurea was linked to more diabetes-related deaths. A later meta-analysis found no statistically significant cardiovascular benefit. In the Diabetes Prevention Program, metformin cut new diabetes by 31%, less than lifestyle change (58%). About 14 people needed treatment for 3 years to prevent one case. Gastrointestinal side effects such as diarrhoea are common, and long-term use is associated with lower vitamin B12. Lactic acidosis carries a boxed warning but is very rare in people without contraindications. Claims that metformin slows ageing are unproven. The TAME trial is planned, not reported, and in older adults metformin blunted muscle gains from resistance training.

Evidence grade: Well established.

How it works

Drug class: Biguanide (oral glucose-lowering drug)

Metformin lowers blood glucose by reducing how much glucose the liver produces and how much the gut absorbs. The label says it improves insulin sensitivity by increasing glucose uptake and use by tissues. (Source 1)

Boxed warning

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.

(Source 2)

What it is used for

• UKPDS 34 showed fewer diabetes-related endpoints and deaths with metformin in overweight patients. Cardiovascular benefit remains uncertain in meta-analysis, mainly because there are few trials. Evidence: established. (Source 3)
• In the DPP, metformin lowered diabetes incidence by 31% (NNT 13.9 over 3 years), while lifestyle change lowered it by 58%. The US label does not list this use. Evidence: established. (Source 4)
• No completed human trial shows longer life. TAME is planned, reviewers call the lifespan evidence controversial, and MASTERS found metformin blunted muscle gains from exercise in older adults. Evidence: not-supported. (Source 5)

Interactions

• Alcohol (label): The label says alcohol increases metformin's effect on lactate metabolism and that people taking metformin should be warned against excessive alcohol intake. (Source 6)
• Vitamin B12 (clinical trial): The label says metformin can lower B12 levels, possibly by interfering with B12 absorption, and that the fall appears to reverse rapidly with B12 supplementation or stopping metformin. (Source 7)
• Carbonic anhydrase inhibitors (e.g. topiramate) (label): These are listed as a risk factor for metformin-associated lactic acidosis. (Source 8)
• Iodinated contrast (X-ray and CT dye) (label): The label says intravascular iodinated contrast in people on metformin has led to a sudden fall in kidney function and lactic acidosis. Its position is to stop metformin at or before the procedure in people with an eGFR of 30 to 60, liver disease, alcoholism or heart failure, or who will receive contrast into an artery, then recheck kidney function 48 hours later. (Source 9)

Stopping it

• The label position is to stop metformin at or before an iodinated contrast procedure in higher-risk patients (eGFR 30 to 60, liver disease, alcoholism, heart failure, or contrast into an artery), recheck kidney function 48 hours later, and restart only if it is stable. (Source 9)
• The label says the B12 fall seen with metformin appears to reverse quickly after stopping it or taking B12. (Source 7)

What goes wrong

In the UKPDS supplementary randomised comparison, adding metformin early to a sulphonylurea was associated with more diabetes-related deaths than staying on the sulphonylurea alone. A wider epidemiological analysis did not confirm this. (Source 3)

• Randomized trial, Low certainty.
• Size: 537 randomised in supplementary trial.
• Who: patients on maximum sulphonylurea.
• How long: UKPDS follow-up.
• Result: 96% increased risk of diabetes-related death (95% CI 2-275), p=0.039; epidemiological analysis in 4416 patients risk reduction 5% (-33 to 32)
• Funding: not stated.

Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2–275], p=0·039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2–33], p=0·033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [−33 to 32], p=0·78).

Long-term metformin use in the DPP Outcomes Study was associated with biochemical B12 deficiency and anaemia. Risk rose with each year of use. (Source 10)

• Cohort study, Moderate certainty.
• Size: 2155 participants analysed from the DPP placebo (1082) and metformin (1073) arms (the DPP randomised 3234); B12 measured in 1715 at 5 years and 1520 at 13 years.
• Who: DPP/DPPOS participants.
• How long: 5 and 13 years.
• Result: low B12 at 5 years 4.3% vs 2.3%; low or borderline 20.3% vs 15.6% at 13 years; OR 1.13 per year of use.
• Funding: not stated in abstract read.

Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06-1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. Conclusions: Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia.

The label reports that in 29-week trials about 7% of patients developed subnormal B12, which appeared reversible by stopping metformin or taking B12. (Source 7)

• Official position, Certainty not rated.
• How long: 29 weeks.
• Result: about 7%.
• Funding: label.

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12 supplementation.

In the label's US placebo-controlled trial (141 patients on metformin), the label lists in its Table 1 the adverse reactions reported by more than 5% of metformin-treated patients and more often than on placebo; diarrhoea and nausea or vomiting were far more frequent on metformin. (Source 11)

• Randomized trial, Moderate certainty.
• Size: 141 metformin vs 145 placebo.
• Who: adults with type 2 diabetes.
• How long: not stated.
• Result: from Table 1 of the label (the numbers are in the table, not in the quoted sentence): diarrhoea 53% vs 12%; nausea/vomiting 26% vs 8%; flatulence 12% vs 6%.
• Funding: not stated (trial reported in the label)

In a U.S. clinical trial of metformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

The label's boxed warning says postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, low blood pressure and resistant slow heart rhythms. (Source 2)

• Official position, Certainty not rated.
• Funding: label.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.

The label's boxed warning lists risk factors for metformin-associated lactic acidosis: kidney impairment, certain drugs such as topiramate, age 65 or older, contrast imaging, surgery and other procedures, hypoxic states, excess alcohol and liver impairment. (Source 8)

• Official position, Certainty not rated.
• Funding: label.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

In the MASTERS trial, healthy adults aged 65 and older who took metformin during 14 weeks of resistance training gained less lean mass and thigh muscle than those on placebo. (Source 12)

• Randomized trial, Moderate certainty.
• Size: 94 (46 metformin, 48 placebo)
• Who: healthy adults aged 65 or older.
• How long: 14 weeks.
• Result: placebo gained more lean body mass (p=.003) and thigh muscle mass (p<.001); strength trend not significant.
• Funding: not stated in abstract read.

Although responses to PRT varied, placebo gained more lean body mass (p =.003) and thigh muscle mass (p <.001) than metformin.

What the evidence supports

In UKPDS 34, overweight patients with newly diagnosed type 2 diabetes allocated metformin had fewer diabetes-related endpoints and lower all-cause mortality than those on conventional (mainly diet) policy. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 753 randomised (342 metformin, 411 conventional)
• Who: overweight adults with newly diagnosed type 2 diabetes.
• How long: median 10.7 years.
• Result: relative risk reductions: any diabetes endpoint 32% (95% CI 13-47); diabetes-related death 42% (9-63); all-cause mortality 36% (9-55). Absolute numbers not in the abstract read.
• Funding: not stated in abstract read.

Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13–47, p=0·002) for any diabetes-related endpoint, 42% for diabetes-related death (9–63, p=0·017), and 36% for all-cause mortality (9–55, p=0·011).

In the Diabetes Prevention Program, metformin 850 mg twice daily reduced new diabetes by 31% compared with placebo, while the lifestyle programme reduced it by 58%. (Source 4)

• Randomized trial, High certainty.
• Size: 3234 randomised.
• Who: non-diabetic adults with raised fasting and post-load glucose, mean BMI 34.
• How long: average 2.8 years.
• Result: incidence 11.0 (placebo), 7.8 (metformin), 4.8 (lifestyle) per 100 person-years; NNT 13.9 for metformin and 6.9 for lifestyle over 3 years.
• Funding: not stated in abstract read.

The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin.

What the evidence does not support

A meta-analysis of randomised trials found no statistically significant effect of metformin on death, cardiovascular death, heart attack or stroke. The data were few and dominated by UKPDS. (Source 13)

• Meta-analysis, Low certainty.
• Size: 13 trials, 2079 on metformin.
• Who: people with type 2 diabetes.
• How long: varied.
• Result: all-cause mortality RR 0.96 (0.84-1.09); CV death 0.97 (0.80-1.16); MI 0.89 (0.75-1.06); stroke 1.04 (0.73-1.48)
• Funding: not stated in abstract read.

Summary estimates were based on a small number of events: 416 myocardial infarctions/ischaemic heart disease events in seven studies and 111 strokes in four studies. The UK Prospective Diabetes Study (UKPDS) contributed the majority of data to the summary estimates, with weights ranging from 52.3% for myocardial infarction to 70.5% for stroke. All outcomes, with the exception of stroke, favoured metformin, with limited heterogeneity between studies, but none achieved statistical significance.

A Cochrane review found no cases of lactic acidosis in 347 trials and cohorts covering more than 70,490 patient-years of metformin use. (Source 14)

• Systematic review, Moderate certainty.
• Size: 347 studies, more than 70,490 patient-years on metformin (Cochrane review summarised in American Family Physician)
• Who: people with type 2 diabetes.
• Result: upper limit (Poisson statistics) of the true incidence: 4.3 cases per 100,000 patient-years on metformin vs 5.4 on other treatments.
• Funding: not stated.

The authors of this Cochrane review found no cases of fatal or nonfatal lactic acidosis in 347 prospective trials and cohort studies with more than 70,490 patient-years of metformin use.

A critical narrative review concluded that, despite some data supporting anti-ageing benefits, the evidence that metformin extends lifespan remains controversial. (Source 5)

• Expert review, not systematic, Low certainty.
• Size: narrative critical review.
• Who: humans and animal models.
• Result: none (no lifespan trial reported)
• Funding: not stated.

We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial.

Where the research disagrees

Whether metformin is an anti-ageing drug

• TAME investigators, as described by Mohammed et al. (2021), a planned RCT, not yet reported, based on observational data and animal studies: Targeting Aging with Metformin (TAME) trial is a double-blinded, placebo-controlled, multicenter trial that is planned to involve 14 research centers in the USA, and subject to funding and approval, will enroll 3000 ethnically diverse, non-diabetic subjects aged 65–80 (60, 261). (Source 15)
• Mohammed et al., critical review (2021), critical narrative review: We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. (Source 5)

Whether metformin reduces cardiovascular disease

• UKPDS Group (1998), RCT, 342 on metformin: Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13–47, p=0·002) for any diabetes-related endpoint, 42% for diabetes-related death (9–63, p=0·017), and 36% for all-cause mortality (9–55, p=0·011). (Source 3)
• Griffin et al. meta-analysis (2017), meta-analysis of 13 RCTs: There remains uncertainty about whether metformin reduces risk of cardiovascular disease among patients with type 2 diabetes, for whom it is the recommended first-line drug. (Source 16)

How much

• Reference intake: Dosing is set by the prescriber. As a position, the US label (revised 7/2025) gives a starting dose of 500 mg twice a day or 850 mg once a day with meals. (Source 17)
• Upper limit: The label's maximum is 2550 mg per day in divided doses (US label, 7/2025). (Source 18)
• Studied: The DPP used metformin 850 mg twice daily. (Source 4)
• Studied: MASTERS used 1,700 mg/day metformin in adults aged 65 and older. (Source 12)

A common belief, and what the research shows

The belief: Metformin is a proven longevity drug that healthy people should take.

What the research shows: No completed human trial shows it extends life. A critical review concluded 'the evidence that metformin increases lifespan remains controversial'. TAME has not reported results. In older adults, MASTERS found 'metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals.'

Questions and answers

What is it?

Metformin is a prescription tablet for type 2 diabetes. The label calls it an antihyperglycemic agent, meaning it lowers high blood glucose. (Source 1)

What does it do in the body?

It reduces the glucose the liver produces and the glucose absorbed from the gut. The label says it improves insulin sensitivity by increasing glucose uptake and use by tissues. (Source 1)

Is it good or bad for you?

It depends on the use; the trial results for benefit and harm are listed separately. On the most feared harm, lactic acidosis, a Cochrane review summarised in American Family Physician concluded that in people without the standard contraindications, metformin does not increase the risk. (Source 19)

How do you get more of it?

As a label position, the recommended starting dose is 500 mg twice a day or 850 mg once a day, with meals. The dose is set by the prescriber; this is not advice to the reader. (Source 17)

If it is harmful, what reduces it?

For its main long-term side effect, low vitamin B12, the label says the fall, possibly due to interference with B12 absorption, appears to reverse rapidly with stopping metformin or taking vitamin B12. (Source 7)

Why might someone be low in it or missing it?

Not answered by the sources we read. They describe metformin as a prescribed drug and do not discuss anyone being low in or missing it. (Source 1)

We searched: The metformin label (DailyMed, 7/2025), UKPDS 34, the Diabetes Prevention Program and DPPOS reports, and the Mohammed 2021 review

Which whole foods contain it or feed it?

Not answered by the sources we read. None of them describes a whole food that contains metformin. (Source 1)

We searched: The metformin label (DailyMed, 7/2025) and the trial and review abstracts listed for this drug

What happens if you do not have it?

In people at high risk, not taking metformin meant a higher diabetes rate than taking it in the DPP (11.0 vs 7.8 cases per 100 person-years). Lifestyle change did better than either (4.8). (Source 4)

How can you test for it?

For its side effects, the label advises checking blood counts every year and vitamin B12 every 2 to 3 years in people taking metformin. (Source 20)

References

1. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 12.1. 2025. Read the source
2. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, boxed warning. 2025. Read the source
3. The Lancet (UK Prospective Diabetes Study Group); abstract read on ScienceDirect. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). 1998. PMID 9742977, DOI 10.1016/S0140-6736(98)07037-8. Read the source
4. New England Journal of Medicine (Knowler WC et al., Diabetes Prevention Program Research Group); abstract read on Albert Einstein College of Medicine research portal. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. 2002. PMID 11832527, DOI 10.1056/NEJMoa012512. Read the source
5. Frontiers in Endocrinology (Mohammed I, Hollenberg MD, Ding H, Triggle CR). A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. 2021. PMID 34421827, DOI 10.3389/fendo.2021.718942. Read the source
6. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, alcohol. 2025. Read the source
7. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 5 (vitamin B12). 2025. Read the source
8. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, boxed warning (risk factors). 2025. Read the source
9. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 5.1 (radiologic studies with contrast). 2025. Read the source
10. Journal of Clinical Endocrinology and Metabolism (Aroda VR et al.); abstract read on Albert Einstein College of Medicine research portal. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. 2016. PMID 26900641, DOI 10.1210/jc.2015-3754. Read the source
11. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 6.1. 2025. Read the source
12. Aging Cell (Walton RG et al.); abstract read on UTMB Health Research Expert Profiles. 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. 2019. DOI 10.1111/acel.13039. Read the source
13. Diabetologia (Griffin SJ, Leaver JK, Irving GJ); abstract read on Edge Hill University research portal. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. 2017. DOI 10.1007/s00125-017-4337-9. Read the source
14. American Family Physician (Cayley WE Jr). Does Metformin Increase the Risk of Fatal or Nonfatal Lactic Acidosis? (Cochrane for Clinicians, summarising Salpeter SR et al., Cochrane Database Syst Rev 2010, CD002967). 2010. Read the source
15. Frontiers in Endocrinology (Mohammed I, Hollenberg MD, Ding H, Triggle CR). A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. 2021. PMID 34421827, DOI 10.3389/fendo.2021.718942. Read the source
16. Diabetologia (Griffin SJ, Leaver JK, Irving GJ); abstract read on Edge Hill University research portal. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. 2017. DOI 10.1007/s00125-017-4337-9. Read the source
17. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 2 (starting dose). 2025. Read the source
18. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 2 (titration and maximum). 2025. Read the source
19. American Family Physician (Cayley WE Jr). Does Metformin Increase the Risk of Fatal or Nonfatal Lactic Acidosis? (Cochrane for Clinicians, summarising Salpeter SR et al., Cochrane Database Syst Rev 2010, CD002967). 2010. Read the source
20. US FDA-approved label via DailyMed (NLM). Metformin Hydrochloride Tablets prescribing information (A-S Medication Solutions), revised 7/2025, section 5 (B12 monitoring). 2025. Read the source