A reference work, not a recommendation to use: this profile describes mechanism and evidence and does not replace medical advice. The claims come from marketing and forums and are tested here, not endorsed.

Claims checked

  • Slows aging even without diabetes

    Not studied

    Longevity · healthy · Animal study

    No RCT on lifespan or aging endpoints in healthy people; TAME is a study concept [8]. Mouse data inconsistent: no significant effect in the ITP [4], longer life of male mice in an earlier study [5]. The registry studies compare people with diabetes on metformin with people without diabetes and contradict each other; the Danish twin analysis found higher mortality [6][7]. Abstract only checked.[6][7]

  • Supports muscle building in old age

    Worse performance

    Muscle & performance · healthy (older adults) · Human, randomised small studiesEvery study behind this level and result had fewer than 100 participants. Small studies report larger effects on average than large ones, so the result is less certain.

    In an RCT with 94 healthy people aged 65 and older doing resistance training, the placebo group gained significantly more lean mass and thigh muscle than the metformin group; the gain in strength was only trending, not significantly, lower under metformin [10]. Abstract only checked.

  • Supports fitness in old age

    Single unconfirmed finding

    Muscle & performance · healthy (older adults) · Human, randomised small studiesEvery study behind this level and result had fewer than 100 participants. Small studies report larger effects on average than large ones, so the result is less certain.

    Two small RCTs tested metformin during training directly; neither showed a fitness gain. After endurance training (participants without chronic disease but with at least one risk factor for type 2 diabetes; 26 versus 27), VO2max rose about half as much under metformin as under placebo, and the group difference was not significant (p = 0.08); only markers were significantly blunted, the rise in insulin sensitivity and mitochondrial respiration in muscle [9]. After resistance training (94 participants), the strength gain was only trending lower under metformin [10]. By the rule for small studies that test the claim directly and miss their endpoint, the result is “Single unconfirmed finding” until a larger study is available; the blunted training adaptation is stated in the text and under the risks. Study [10] abstract only checked.

  • Prevents type 2 diabetes

    Proven benefit

    Energy & metabolism · Patients: elevated fasting and post-load glucose (prediabetes) · Human, randomised

    In the Diabetes Prevention Program RCT with 3234 participants, 31% fewer new cases of diabetes than with placebo over an average of 2.8 years; the lifestyle intervention was clearly more effective at 58% [11]. Whether this use is approved in Germany was not checked. Abstract only checked.

small studies: Every study behind this level and result had fewer than 100 participants. Small studies report larger effects on average than large ones, so the result is less certain.

Mechanism of action

Evidence map: Metformin

Each line stands for a published finding; line style and color show where it comes from. The filter hides weaker evidence levels. Sources: see references.

Metformin is a biguanide that lowers glucose production in the liver (gluconeogenesis and glycogenolysis), moderately increases insulin sensitivity, and delays glucose uptake in the gut; it does not stimulate insulin secretion and therefore does not cause hypoglycemia on its own (prescribing information of the combination product Xigduo, metformin sections) [1]. The respiratory chain is regarded as the main site of action: in hepatoma cells and isolated mitochondria, metformin inhibited complex I in a time-dependent manner, apparently after slow accumulation of the positively charged molecule in the matrix; in submitochondrial particles, very high concentrations were required (in vitro and rat) [2]. In rat hepatocytes, metformin activated AMP-activated protein kinase (AMPK), and an AMPK inhibitor abolished the reduction in glucose production; the study comes from the research laboratory of a pharmaceutical company (Merck) [3]. This pathway is the basis of the cross-reference to AICAR: there, the cell produces the AMP analog ZMP, which switches on AMPK directly, whereas metformin activates it only indirectly [3] (see AICAR profile). According to cell data, berberine also inhibits complex I and is therefore often compared with metformin (see berberine profile).

In the Interventions Testing Program, metformin alone did not significantly extend the lifespan of genetically heterogeneous mice; only the combination with rapamycin worked, which cannot be reliably attributed to metformin in the historical comparison with rapamycin alone [4]. In an earlier study, male mice lived longer with metformin started in middle age [5]. Both findings are animal data (level 2). Metformin shares with acarbose only the drug class of oral glucose-lowering agents, not the mechanism: acarbose inhibits the alpha-glucosidases in the gut and, in the same ITP round in which metformin alone had no effect, extended the median lifespan of male mice, even when started only at 16 months of age (animal finding) [4] (see acarbose profile).

In humans there is no RCT on lifespan or aging in healthy people. A British registry study found that people with type 2 diabetes on metformin survived longer than matched people without diabetes [6]. A Danish registry and twin analysis did not confirm this: starting metformin monotherapy was associated with higher mortality than no diabetes (incidence rate ratio after adjustment 1.32 in individuals, 1.64 in discordant twin pairs) [7]. The TAME trial of metformin against aging is so far a study concept [8]. Two RCTs in older adults without chronic disease show blunted training adaptation: in people with at least one risk factor for type 2 diabetes, metformin prevented the rise in insulin sensitivity and mitochondrial respiration in muscle (markers) after endurance training; VO2max rose about half as much under metformin, but this group difference was not significant (p = 0.08) [9]. After resistance training, the placebo group gained significantly more lean mass and thigh muscle than the metformin group, and the gain in strength was only trending lower [10].

In people at increased risk of diabetes, metformin reduced new-onset diabetes by 31% in a large RCT, less than a lifestyle intervention (58%) [11]. Vitamin B12 levels fall under long-term treatment; in an RCT in insulin-treated people with type 2 diabetes, the absolute risk of B12 deficiency rose by 7.2 percentage points after a good four years [12]. Lactic acidosis did not occur in any case in 347 comparative studies and cohorts [13]; the EMA and prescribing information list it as a very rare, severe complication, mainly with acute deterioration of kidney function, heart or lung disease, and sepsis [1][14]. Metformin is prescription-only in Germany [15]; only combination products are centrally authorized [16].

Synaptik serves solely to explain biochemistry and pharmacology and is not medical advice or a recommendation to take anything.

Mechanism of action only. Schematic cutaway, not to scale: on the left a body cell with the nutrient switches AMPK and mTORC1, on the right two senescent cells. Particles, speeds and switch positions are illustrative and only show the direction of a finding; the switch bar says where it comes from (cell culture, animal or human). Lifespan findings come from worms and mice; human lifespan has not been studied with any of these drugs.

Complex I damped · AMPK on · via AMP? disputed · hepatic glucose output falls

AMPK
onrat hepatocytes · RCT
mTORC1
smaller rise (trend)RCT, muscle after training
Autophagy
not measured
Senescent cells
not measured
Drug
View

ATP  AMP  amino acids  SASP  mTORC1 inhibitors  AMPK activators  Autophagy  Senolytics  particles illustrative

Metformin slowly accumulates in the mitochondrial matrix and inhibits complex I of the respiratory chain there (hepatoma cells, isolated mitochondria); in submitochondrial particles this needed very high concentrations (K0.5 79 mM) [14]. In rat hepatocytes metformin activated AMPK, and an AMPK inhibitor abolished the fall in glucose production; the study comes from Merck [15]. Whether AMPK is switched on by an energy deficit with more AMP is disputed: in two cell types metformin activated it without lowering the cell's energy charge, and the study did not identify the exact route [16]. The figure therefore shows no rise in AMP. In an RCT of healthy older adults doing resistance training, metformin increased AMPK signalling in muscle, and mTORC1 signalling tended to rise less than with placebo (markers only) [17]. In humans, according to the product information, metformin mainly lowers hepatic glucose production [18]. Whether it increases autophagy is not stated in the profile's sources. In the Interventions Testing Program, metformin alone did not significantly extend the lifespan of mice [19].

Tap or focus a labelled part for a one-line explanation.

Also acting here, not drawn

What the figure shows, and how sure we are

Mechanism-of-action explainer only. Not medical advice, and no statement about benefit, risk, amount or use. Sirolimus, everolimus, metformin, canagliflozin and dasatinib are prescription medicines; none of them is approved for use against ageing.

What was simplified. One cell stands for many cell types; the findings come from liver, muscle, fat and heart cells of different species, and the figure only shows where each drug acts. Sizes, numbers of organelles, particles and speeds are illustrative; glucose output applies to liver cells only. The signal lines stand for several intermediate steps (for example AMPK via TSC2 and Raptor). Switches marked “not measured” do not follow the textbook pathway: whether metformin, for instance, increases autophagy in these cells is not stated in the profile's sources. Drugs are drawn as markers, not as skeletal formulas. Calcium alpha-ketoglutarate, pentadecanoic acid, sulforaphane, TUDCA and further substances are listed at this site in the figure catalogue but are not drawn; the reasons are given in the list below the figure. The γ subunit is drawn with four CBS domains, with nucleotides only at the three binding sites from [3]. The numbers in [5], [6], [8] to [15] and [17] to [35] come from the Synaptik profiles of the drugs, where they were checked against the sources. [1] and [2] were checked against the full text, [3], [4], [7] and [16] against the PubMed abstract (25 Oct 2026).

Targets

TargetTypeActionKey dataEvidence
Complex I of the respiratory chainEnzymeInhibitortime-dependent after accumulation in the matrix; in submitochondrial particles K0.5 79 mM (in vitro) Animal study[2]
AMP-activated protein kinase (AMPK)EnzymeActivatorrat hepatocytes; in muscle of older people AMPK signal ↑ (RCT) Human, randomised[3][10]
Hepatic gluconeogenesisSignaling pathwayInhibitormain mechanism of blood glucose lowering according to the prescribing information Human, randomised[1][2][3]

Effect profile

Which signaling systems the compound affects according to current data. ↑ enhanced, ↓ dampened, ≈ modulated, ○ no effect; dots = evidence level.

  • Dopamineno data
  • Noradrenalineno data
  • Serotoninno data
  • Acetylcholineno data
  • Glutamate · AMPAno data
  • Glutamate · NMDAno data
  • GABAno data
  • Histamineno data
  • Orexinno data
  • Adenosineno data
  • Opioidsno data
  • Melatoninno data
  • Neurotrophinsno data
  • Blood flowno data
  • Nitric oxideno data
  • Energy metabolism↓ · Inhibits complex I (cells, rat); in humans prevented the training-induced rise in mitochondrial respiration in muscle[2][9]
  • Insulin · glucose↓ · Lowers blood glucose without insulin secretion; fewer new cases of diabetes in prediabetes (RCT)[1][11]
  • Inflammation · oxidativeno data
  • Stress axisno data
  • Testosterone axisno data
  • Endocannabinoidsno data
  • Autophagy · senescencemodulated · AMPK activation (rat hepatocytes; in muscle of older people increased AMPK signal, trend toward a smaller mTORC1 rise after resistance training)[3][10]
  • Immune systemno data
  • Lipid metabolism↓ · Total and LDL cholesterol and triglycerides fall according to the prescribing information[1]
  • Coagulation · fibrinolysisno data
  • Methylationmodulated · Vitamin B12 falls, homocysteine rose only as a trend in the RCT (not significant)[12]

Routes of administration and bioavailability

How much of a compound reaches the blood or target tissue depends on the route into the body and on the dosage form. All routes of administration explained

  • Oral (swallowed) · Tablet

    ≈ 50–60% (human, healthy)

    Peak level after about 2.5 hours; 20–30% appear unabsorbed in the stool (prescribing information) [1].

    Human, non-randomised

Human studies

  • Danish registry and twin analysis (Keys 2022)

    retrospective cohort, case-control and matched cohort designs, discordant twins · People with type 2 diabetes on metformin monotherapy versus people without diabetes · 1996–2012

    Measured: all-cause mortality

    Result: Higher mortality under metformin than without diabetes, adjusted IRR 1.32 (individuals) and 1.64 (twins); no survival advantage.[7]

    Human, non-randomised

  • British registry study (Bannister 2014)

    retrospective matched cohort (CPRD) · Type 2 diabetes on metformin or sulfonylurea versus people without diabetes · n = 180926 · from 2000

    Measured: all-cause mortality

    Result: Adjusted median survival of controls without diabetes 15% shorter than under metformin; 38% shorter than under sulfonylurea.[6]

    Human, non-randomised

  • Metformin and endurance training (Konopka 2019)

    RCT, double-blind, placebo-controlled · without chronic disease, with at least one risk factor for type 2 diabetes (older adults, mean age 62) · n = 53 · 12 weeks of training

    Measured: insulin sensitivity, VO2max, mitochondrial respiration in muscle

    Result: Metformin prevented the training-induced rise in insulin sensitivity and mitochondrial respiration (significant); VO2max rose about half as much as under placebo, the group difference was not significant (p = 0.08).[9]

    Human, randomised

  • MASTERS: metformin and resistance training (Walton 2019)

    RCT, double-blind, placebo-controlled, multicenter · healthy (aged 65 and older) · n = 94 · 14 weeks of training

    Measured: lean mass, thigh muscle (CT), strength, muscle biopsy

    Result: Placebo gained more lean mass and thigh muscle; strength gain only trending lower under metformin; AMPK signal increased.[10]

    Human, randomised

  • Diabetes Prevention Program (Knowler 2002)

    RCT, three arms (placebo, metformin, lifestyle) · Patients: elevated fasting and post-load glucose · n = 3234 · on average 2.8 years

    Measured: new cases of diabetes

    Result: Metformin −31%, lifestyle −58% versus placebo.[11]

    Human, randomised

  • Vitamin B12 under long-term metformin (de Jager 2010)

    RCT, placebo-controlled, multicenter · Patients: insulin-treated type 2 diabetes · n = 390 · 4.3 years

    Measured: vitamin B12, folate, homocysteine

    Result: B12 −19% versus placebo; absolute risk of B12 deficiency +7.2 percentage points; homocysteine not significantly elevated. Funded by Merck Sharp & Dohme.[12]

    Human, randomised

Risks and warnings

  • Gastrointestinal complaints

    Nausea, vomiting, diarrhea, abdominal pain, and loss of appetite are very common according to the prescribing information, occur mainly at the start, and usually resolve on their own [1].

    Human, randomised

  • Vitamin B12 deficiency

    In an RCT over 4.3 years, B12 fell by 19% versus placebo, and the absolute risk of deficiency rose by 7.2 percentage points [12]. The prescribing information names a risk that rises with duration and amount and recommends checks when deficiency is suspected (anemia, neuropathy) [1].

    Human, randomised

  • Lactic acidosis

    Very rare, but severe; mainly with acute deterioration of kidney function, heart or lung disease, sepsis, alcohol excess, or prolonged fasting. Contraindicated in severely impaired renal function; stop temporarily after iodinated contrast media and around surgery [1][14]. In 347 studies with over 70,000 patient-years, not a single case, and no difference in lactate levels either [13].

    Human, randomised

  • Blunted training adaptation

    In two RCTs in older adults without chronic disease, metformin blunted training adaptation: significantly in the gain in lean mass and thigh muscle after resistance training [10] and in insulin sensitivity and mitochondrial respiration after endurance training; VO2max and strength only as a trend [9][10].

    Human, randomised

  • Mitochondrial diseases

    In known mitochondrial diseases (e.g., MELAS, MIDD), metformin is not recommended according to the prescribing information because of the risk of lactic acidosis and neurological complications [1].

    Human, non-randomised

Interactions

  • Alcohol: Alcohol intoxication raises the risk of lactic acidosis, especially with fasting, malnutrition, or liver damage (prescribing information) [1].
  • Iodinated contrast media: Can trigger kidney failure with metformin accumulation; stop temporarily (prescribing information) [1].
  • Cationic substances with tubular secretion (e.g., cimetidine): Compete for renal transporters and increase metformin exposure (prescribing information) [1].

Fact check: common claims

  • not supported

    “People with diabetes live longer on metformin than healthy people, so metformin slows aging”

    The British registry study found a survival advantage [6]; the Danish registry and twin analysis, which accounts for familial factors, found higher mortality instead and considers differences in design or method unlikely as an explanation [7]. Both are retrospective observational studies with opposite results; they can neither prove nor refute the causal claim and say nothing about healthy people.

  • partly supported

    “Metformin extends life in mice”

    Longer life of male mice in one study with treatment started in middle age [5]; in the ITP with genetically heterogeneous mice at three sites, no significant effect of metformin alone [4].

  • refuted

    “Metformin works like exercise”

    In two RCTs the effects did not add up; metformin blunted training adaptation in older adults [9][10].

  • not supported

    “The TAME trial has shown that metformin slows aging”

    The cited publication describes TAME as a planned study, not as a result [8].

  • refuted

    “Metformin often leads to dangerous lactic acidosis”

    No case in over 70,000 patient-years from 347 studies [13]; the EMA classifies lactic acidosis as rare or very rare, with increased risk in severely impaired renal function [1][14].

Pharmacokinetics

Absorption
Absolute bioavailability about 50–60% in healthy people, peak level after about 2.5 hours [1].
Half-life
Apparent terminal elimination half-life about 6.5 hours [1].
Metabolism
Is not metabolized and is excreted unchanged via the kidneys (glomerular filtration and tubular secretion); plasma protein binding negligible [1].
Entry into the brain
Not checked against a primary source.

Legal status

Germany
Prescription-only as a medicinal product (AMVV Annex 1, entry “Metformin”, version of the ordinance of May 19, 2026) [15]. Single-ingredient products are nationally authorized; the authorizations were not checked against AMIce/PharmNet (not verified). Use against aging is not an approved indication (off label).
EU
No centrally authorized single-ingredient product in the EMA data export; combinations with metformin are centrally authorized, e.g., Synjardy (with empagliflozin, EMEA/H/C/003770) and Xigduo (with dapagliflozin, EMEA/H/C/002672), each for type 2 diabetes [16]. An EU referral (EMEA/H/A-31/1432, Commission decision December 12, 2016) allowed use in moderately impaired renal function and retained the contraindication in severely impaired renal function [14].
USA
According to Drugs@FDA, Glucophage tablets (NDA 020357) were approved on March 3, 1995; all strengths are discontinued (“Discontinued”, not for safety or efficacy reasons according to the Federal Register notice) [17]. Other products (e.g., extended-release forms), generics, and indications not checked against a primary source.

Related compounds

Berberinesame classAcarbosesame class (German only)AICARsame class (German only)

Open questions

  • Does metformin slow age-related diseases in people without diabetes (TAME results are pending)?
  • Can the blunted training adaptation be avoided in healthy people, and how relevant is it in the long term?
  • Which mechanism (complex I, AMPK, or other pathways) accounts for blood glucose lowering at therapeutic concentrations?

References

  1. European Medicines Agency. Xigduo (dapagliflozin/metformin): EPAR – Product Information, Annex I: Summary of Product Characteristics (Metformin-Abschnitte). EMEA/H/C/002672 [Internet]. Amsterdam: EMA; letzte Aktualisierung 05.06.2026 [abgerufen 24.10.2026]. Verfügbar unter: https://www.ema.europa.eu/en/documents/product-information/xigduo-epar-product-information_en.pdf
  2. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3:607-14. doi:10.1042/bj3480607 · PubMed
  3. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-74. doi:10.1172/JCI13505 · PubMed
  4. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016;15(5):872-84. doi:10.1111/acel.12496 · PubMed
  5. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi:10.1038/ncomms3192 · PubMed
  6. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-73. doi:10.1111/dom.12354 · PubMed
  7. Keys MT, Thinggaard M, Larsen LA, Pedersen DA, Hallas J, Christensen K. Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study. Int J Epidemiol. 2022;51(6):1886-1898. doi:10.1093/ije/dyac200 · PubMed
  8. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-1065. doi:10.1016/j.cmet.2016.05.011 · PubMed
  9. Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880. doi:10.1111/acel.12880 · PubMed
  10. Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, 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. doi:10.1111/acel.13039 · PubMed
  11. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403. doi:10.1056/NEJMoa012512 · PubMed
  12. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181. doi:10.1136/bmj.c2181 · PubMed
  13. 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;2010(4):CD002967. doi:10.1002/14651858.CD002967.pub4 · PubMed
  14. European Medicines Agency. Metformin and metformin-containing medicines – referral (Article 31), EMEA/H/A-31/1432. CHMP-Gutachten 13.10.2016, Kommissionsbeschluss 12.12.2016 [Internet]. Amsterdam: EMA [abgerufen 24.10.2026]. Verfügbar unter: https://www.ema.europa.eu/en/medicines/human/referrals/metformin-metformin-containing-medicines
  15. Verordnung über die Verschreibungspflicht von Arzneimitteln (Arzneimittelverschreibungsverordnung – AMVV), Anlage 1 (zu § 1 Nr. 1 und § 5), zuletzt geändert durch Art. 1 der Verordnung vom 19.05.2026 (BGBl. 2026 I Nr. 149). Bundesministerium der Justiz [Internet]. Abgerufen am 24.10.2026. Verfügbar unter: https://www.gesetze-im-internet.de/amvv/anlage_1.html
  16. European Medicines Agency. Synjardy (EMEA/H/C/003770, zugelassen 27.05.2015) und Xigduo (EMEA/H/C/002672, zugelassen 16.01.2014): Status „Authorised“ und Anwendungsgebiete laut Medicines output – medicines JSON report [Internet]. Amsterdam: EMA; Stand 24.10.2026 [abgerufen 24.10.2026]. Verfügbar unter: https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json
  17. U.S. Food and Drug Administration. Drugs@FDA (openFDA-Abfrage): Metforminhydrochlorid, NDA 020357 Glucophage (Tabletten), alle Produkte „Discontinued“; Originalzulassung (ORIG, AP) 03.03.1995 [Internet]. Silver Spring (MD): FDA; Datenstand 23.10.2026, abgerufen am 25.10.2026. Verfügbar unter: https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA020357
How this profile was checked

Last reviewed: 2026-10-25. All sources with a DOI or PMID were resolved automatically via Crossref or doi.org and PubMed.

Translated from the German profile (version of 2026-10-25); translation checked on 2026-10-26.

Checked

  • Abstracts read via PubMed (efetch); DOIs and PMIDs resolved with tools/pruefe_profile.py. The DOI of [2] is missing from the PubMed record and was resolved via Crossref.
  • At the abstract: complex I inhibition time-dependent, K0.5 79 mM in submitochondrial particles [2]; AMPK activation in rat hepatocytes, AMPK inhibitor abolishes the effect, first author at Merck Research Laboratories [3]; metformin alone not significant in the ITP, combination with rapamycin only in the historical comparison [4]; male mice live longer [5]; STR 0.85 for controls without diabetes [6]; IRR 1.52/1.90 crude, 1.32/1.64 adjusted [7]; TAME as a planned study [8]; 26 versus 27, VO2max and insulin sensitivity blunted [9]; 46 versus 48, lean mass and thigh muscle, AMPK ↑, mTORC1 trend [10]; 3234 participants, −31% or −58%, 2.8 years [11]; 390 participants, −19%, +7.2 percentage points, funding Merck Sharp & Dohme [12]; 347 studies, no cases, 70,490 patient-years [13].
  • Prescribing information for Xigduo (EPAR, English version) read, only the metformin sections used: mechanism of action, lactic acidosis, contrast media, surgery, B12, MELAS/MIDD, gastrointestinal complaints, pharmacokinetics [1].
  • EMA referral page EMEA/H/A-31/1432 read (renal function, lactic acidosis) [14]; data from the referrals JSON export (CHMP October 13, 2016, Commission December 12, 2016).
  • AMVV Annex 1 retrieved on October 24, 2026: entry “Metformin” without exception [15].
  • EMA data export (medicines JSON, October 24, 2026): no centrally authorized metformin single-ingredient product found; Synjardy and Xigduo authorized [16].
  • Cross-check against the full text of [9] (PMC6351883): all participants without chronic disease but with at least one risk factor for type 2 diabetes; VO2max increase about 50% lower under metformin, group difference not significant (p = 0.08); significant interaction for insulin sensitivity (Matsuda index) and mitochondrial respiration. Abstract of [10]: strength gain only as a nonsignificant trend.
  • October 25, 2026, decision q072 (rule q007): full text of [9] (Europe PMC, PMC6351883) reread: 26 versus 27 randomized, 12 weeks of endurance training; VO2max increase about 50% lower under metformin, “did not reach statistical significance (p = 0.08)”; insulin sensitivity and mitochondrial respiration significantly blunted. Small study that tests the claim directly and shows no fitness gain: “Supports fitness in old age” from level 4 “No benefit” to level 4 “Single unconfirmed finding”. The blunting of training adaptation was already in wirkweise_text and listed as a risk; no change there.
  • October 25, 2026, decision q099: cross-links with “same class” remain: berberin (shared target complex I according to cell data, named in wirkweise_text) and acarbose (same drug class of oral glucose-lowering agents, ATC group A10B according to the CIMA register of the AEMPS, entries 55211 for metformin and 59420 for acarbose, retrieved October 25, 2026; mechanism different). On October 25, 2026, a sentence on this was added to wirkweise_text; abstract of [4] reread: acarbose “significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months”.
  • October 25, 2026, decision q012 (abstract only checked): all ratings from journal articles except Konopka 2019 [9] are based only on the abstracts; read in the original wording were the full text of [9], the prescribing information [1], the EMA referral page [14], the EMA export [16], and the AMVV [15].
  • October 25, 2026, decision q018 (trade names): “Glucophage” added: EU referral under Article 30 “Glucophage/Glucophage Forte/Risidon/Dianben” (CPMP/4082/00, CHMP opinion October 19, 2000, Commission decision February 6, 2001; EMA referrals JSON export, timestamp October 24, 2026, retrieved October 25, 2026) and Drugs@FDA NDA020357 (queried via openFDA on October 25, 2026). Generics and combination products (e.g., Synjardy, Xigduo) not included; they are listed in status.
  • October 25, 2026, decision q040: rx_referenz set (package P1; prescription requirement according to AMVV Annex 1 [15]).
  • October 25, 2026, package w3-p8: backlink to the new profile aicar added as “same class” (shared main mechanism of AMPK activation: AICAR directly via the monophosphate ZMP, metformin indirectly; q099 reading). In the fix round on October 25, 2026, the shared mechanism was named in one sentence in wirkweise_text, as with the cross-link to acarbose, because the guideline requires this for “same class”; the evidence is the already cited paper [3] (Zhou 2001, PMID 11602624, abstract checked). No statement, number, or rating in this profile changed.
  • October 25, 2026, legal status (FDA identifiers): Drugs@FDA queried directly via openFDA (data as of October 23, 2026, query October 25, 2026): NDA 020357 Glucophage (tablets), all products “Discontinued” (Federal Register notice: not discontinued for safety or efficacy reasons), ORIG AP March 3, 1995 [17]. status.usa changed from “nicht verifiziert” to this primary source; the contradiction with the trade name note (q018), which already named the NDA, is thereby resolved.
  • Precision flags (m004, implemented by Claude October 26, 2026, pending confirmation by Tilman): “Supports muscle building in old age” → “kleine_studien”: [10] n = 94 (46 + 48; abstract).
  • Precision flags (m004, implemented by Claude October 26, 2026, pending confirmation by Tilman): “Supports fitness in old age” → “kleine_studien”: [9] n = 53 (26 + 27), [10] n = 94 (each per abstract).
  • Cross-check October 26, 2026 (m004, implemented by Claude, pending confirmation by Tilman): evidence for the precision flags that were set (participant numbers or funding and conflict-of-interest statements) carried over from the review notes into the rationale so that readers can verify them; participant numbers rechecked against the PubMed abstracts.

Not verified

  • National authorizations and prescribing information of the metformin single-ingredient products (AMIce/PharmNet, BfArM) not checked; the risks rely on the metformin sections of the prescribing information of a combination product.
  • The sample size of the Danish analysis [7] is not in the abstract.
  • Whether diabetes prevention in prediabetes is an approved indication in Germany was not checked.
  • The status of the TAME trial beyond 2016 was not researched.
  • Whether and which metformin products (generics, extended-release forms) are currently on the market in the United States was not checked against a primary source.

No dosages, no sources of supply. This information does not replace medical advice.

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