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Cited by 513Nitric Oxide and Endothelin EffectsDiabetes, Cardiovascular Risks, and LipoproteinsCardiovascular Health and Disease Prevention

Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus

Open access
Mather, Kieren J, Verma, Subodh, Anderson, Todd J·2001·Journal of the American College of Cardiology
DOI 10.1016/s0735-1097(01)01129-9
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Abstract

Objectives This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus.Background Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported.Methods Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR).Results Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012).Conclusions Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.

AI snapshot

Written from the paper’s full text.

TL;DR

In diet-treated type 2 diabetes patients without the clustered metabolic syndrome risk factors, 12 weeks of metformin improved endothelium-dependent forearm blood flow and insulin resistance compared with placebo. Post-treatment insulin resistance was the sole predictor of endothelium-dependent vasodilation, supporting a central role for insulin resistance in endothelial dysfunction.

Key findings

  • Metformin significantly improved acetylcholine-stimulated forearm blood flow versus placebo (p = 0.0027 by two-way ANOVA), while no significant treatment effect was seen for sodium nitroprusside (p = 0.27) or verapamil (p = 0.40).
  • Metformin produced a 32.5% reduction in HOMA-IR (p = 0.01), with no change in the placebo group; FFA also changed significantly (p = 0.019).
  • After treatment, stepwise multivariate analysis found insulin resistance (logHOMA-IR) was the sole predictor of endothelium-dependent blood flow (r = −0.659, adjusted r² = 0.434, p = 0.0012).
  • Glucose, HbA1c, weight, blood pressure, and cholesterol did not show significant treatment-attributable changes.

Methods

  • Randomized, placebo-controlled study of patients with diet-controlled type 2 diabetes without other major cardiovascular risk factors; participants received metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks, with 44 subjects initially enrolled and 4 withdrawals.
  • Forearm strain-gauge plethysmography measured blood flow responses to intraarterial acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), and verapamil (nitrate-independent); whole-body insulin resistance was assessed by HOMA-IR.
  • Main analyses used two-way repeated-measures ANOVA, ANCOVA, linear regression, and forward stepwise regression.

Limitations

  • The paper states that oxidative balance/oxidative stress and LDL particle size were not measured, though these variables affect endothelial function and may be affected by metformin.
  • Evident from the text: the study was small, baseline LDL cholesterol was significantly lower in the placebo group, and FFA levels showed a borderline baseline difference favoring placebo.
  • Evident from the text: pretreatment sodium nitroprusside responses unexpectedly differed between groups, and the direct correlation between change in insulin resistance and improvement in endothelial response did not reach statistical significance.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0735-1097(01)01129-9

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Metformin treatment produced a significant 32.5% reduction in HOMA-IR compared with placebo.

    “There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p ϭ 0.01)”
    • Also stated in: § Demographics. · plain
      “Metformin produced a significant 32.5% drop in HOMA-IR, whereas no change was seen in the patients receiving placebo.”
    Quote in the paperSubstantial claim
  • Findingown data

    A multivariate model including changes in insulin resistance, FFA, BMI and lipid variables accounted for more than 95% of the variation in the change in endothelial response (p = 0.005).

    “The inclusion of these variables with the change in BMI and in lipid variables in a multivariate model accounted for Ͼ95% of the variation in the change in endothelial response (p ϭ 0.005).”
    Quote in the paperSubstantial claim
  • Findingown data

    Following treatment, insulin resistance (logHOMA-IR) was the sole predictor of endothelium-dependent blood flow by stepwise multivariate analysis (r = -0.659, p = 0.0012).

    “by stepwise multivariate analysis insulin resistance was the sole predictor of endotheliumdependent blood flow following treatment (r ϭ Ϫ0.659, p ϭ 0.0012).”
    Quote in the paperSubstantial claim
  • Findingown data

    After metformin therapy, univariate ANOVA revealed an effect of logHOMA-IR (p = 0.06) and BMI (p = 0.007) on endothelial responses.

    “After therapy with metformin, univariate ANOVA revealed an effect of logHOMA-IR (p ϭ 0.06) and of body mass index (BMI) (p ϭ 0.007) on endothelial responses.”
    Quote in the paperNot a substantial claim
  • Findingown data

    No relationship was evident between endothelium-dependent responses and LDL cholesterol, ambient glucose, HbA1c, or FFA level following therapy.

    “Of note, no relationship with LDL cholesterol, ambient glucose, Hb A1c or FFA level was evident.”
    Quote in the paperNot a substantial claim
  • The quote only partly states this claim. 2
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 13

  • The quote only partly states this claim.

    Findingown data

    In patients with diet-treated type 2 diabetes without the metabolic syndrome, metformin 500 mg twice daily for 12 weeks improved acetylcholine-stimulated forearm blood flow responses compared with placebo.

    “Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p ϭ 0.0027 by 2-way analysis of variance)”
    • Also stated in: § DISCUSSION · plain
      “In patients with IR and type 2 DM, three months of treatment with metformin improved endotheliumdependent vascular responses, whereas vascular responses of patients treated with placebo remained unchanged.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metformin treatment did not significantly change body mass index, blood pressure, or cholesterol levels compared with placebo.

    “without significant changes in body mass index, blood pressure or cholesterol levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metformin treatment did not significantly change glucose or weight compared with placebo.

    “Treatment effects on glucose (0.5 mmol/l reduction) and weight (1.5 kg) were small and did not achieve statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Although the change in response at peak dose was statistically significant for metformin-treated subjects compared with their baseline (p = 0.01), across all doses there was no statistically significant treatment effect relative to placebo (p = 0.27).

    “Although the change in response at peak dose was statistically significant for metformin-treated subjects compared with their baseline (p ϭ 0.01), across all doses there was no statistically significant treatment effect relative to placebo (p ϭ 0.27).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At baseline, no metabolic or anthropomorphic parameter had an effect on endothelial responses by univariate ANOVA, and no significant interactions were found by ANCOVA.

    “At baseline, univariate ANOVA revealed no effect of any metabolic or anthropomorphic parameters on endothelial responses, and similarly by ANCOVA there were no significant interactions of these effects on baseline responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Following therapy, linear regression revealed dependencies of endothelium-dependent responses on BMI (r = -0.43, p = 0.007), logHOMA-IR (r = -0.486, p = 0.017), and HDL cholesterol (r = 0.34, p = 0.036).

    “Following therapy, linear regression analyses revealed dependencies of endothelium-dependent responses following therapy on BMI (r ϭ Ϫ0.43, p ϭ 0.007), logHOMA-IR (r ϭ Ϫ0.486, p ϭ 0.017) (Fig. 4) and high density lipoprotein cholesterol (r ϭ 0.34, p ϭ 0.036).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Baseline endothelium-independent nitrate responses were unexpectedly higher in the placebo group, but this difference was abolished at the end of treatment.

    “Baseline endothelium-independent nitrate responses were unexpectedly higher in the group who received placebo, but at the end of treatment this difference was abolished (Fig. 2).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Abnormalities in endothelium-dependent vascular responses have been found among patients with type 2 diabetes mellitus.

    “Abnormalities in endothelium-dependent vascular responses, perhaps the earliest demonstrable alteration in vascular health, have been found among patients with type 2 DM (2,3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] McVeigh, 1992, Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus, Diabetologia source

      Not checked in the free run.

    • cites [3] Williams, 1996, Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus, J Am Coll Cardiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Medication compliance was greater than 95% by pill count.

    “Medication compliance was Ͼ95% by pill count.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The trial was designed and performed in accordance with the principles of the Declaration of Helsinki and was approved by the University's Ethical Review Board.

    “This trial was designed and performed in accordance with the principles of the Declaration of Helsinki and was approved by our University's Ethical Review Board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study did not measure oxidative balance or oxidative stress, nor LDL particle size.

    “We did not undertake any measure of oxidative balance or oxidative stress, nor was LDL particle size measured.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Written informed consent was obtained after explaining the purpose, nature and potential risks of the interventions to the subjects.

    “Written informed consent was obtained after the purpose, nature and potential risks of the interventions were explained to the subjects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metformin has recently been reported to have antioxidant effects in addition to known favorable effects on circulating lipids and FFAs.

    “In fact, metformin has recently been reported to have antioxidant effects (34) in addition to the known favorable effects on circulating lipids (10) and FFAs (35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Faure, 1999, An insulin sensitizer improves the free radical defence system potential and insulin sensitivity in high fructose-fed rats, Diabetes source

      Not checked in the free run.

    • cites [10] Bailey, 1996, Metformin, N Engl J Med source

      Not checked in the free run.

    • cites [35] Abbasi, 1998, Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin, Diabetes Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    End point measures including blood flow data analyses were blinded to patient name, treatment assignment and treatment timing.

    “End point measures including blood flow data analyses were blinded to patient name, treatment assignment and treatment timing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In ex-vivo preparations of vascular smooth muscle, a direct vasodilating action of metformin has been reported, possibly due to altered calcium handling.

    “Also, in ex-vivo preparations of vascular smooth muscle, a direct vasodilating action of metformin has been reported, possibly due to altered calcium handling (35,37,38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Abbasi, 1998, Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin, Diabetes Care source

      Not checked in the free run.

    • cites [37] Bhalla, 1996, Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat, Am J Hypertens source

      Not checked in the free run.

    • cites [38] Dominguez, 1996, Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle, Endocrinology source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Insulin resistance is felt to be central to the pathogenesis of the metabolic syndrome, a clustering of traditional cardiovascular risk factors in patients with type 2 diabetes mellitus.

    “Insulin resistance is felt to be central to the pathogenesis of the metabolic syndrome (Syndrome X), a clustering of traditional cardiovascular risk factors in patients with type 2 DM (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Reaven, 1988, Role of insulin resistance in human disease, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Subjects assigned to metformin and placebo were well matched for degree of obesity and level of glycemic control, and had equivalent degrees of insulin resistance at baseline.

    “Subjects assigned to metformin and placebo were well matched for degree of obesity and level of glycemic control, and both the fasting insulin level and the calculated index of IR indicated equivalent degrees of IR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Four subjects withdrew from the study before the second set of measurements, two of whom had been assigned to metformin.

    “Four subjects withdrew from the study before the second set of measurements, two of whom had been assigned to receive metformin therapy.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Flow data analysis was performed by investigators blind to patient name, study day and treatment assignment.

    “Flow data analysis was performed at a later date by investigators blind to patient name, study day and treatment assignment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    LDL cholesterol was significantly lower in the placebo group at baseline.

    “The level of low density lipoprotein (LDL) cholesterol was significantly lower in the group who received placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    ANCOVA revealed no interactions, suggesting that chance imbalances between groups, particularly LDL cholesterol, did not influence the results.

    “Again, ANCOVA revealed no interactions, suggesting that the chance imbalances between groups, particularly with regard to LDL cholesterol, did not influence the results.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    In patients with type 2 diabetes and insulin resistance but without other metabolic abnormalities, metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables.

    “Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables.”
    • Also stated in: § Conclusions. · plain
      “In our group of patients with type 2 DM and IR but without other metabolic abnormalities, we found that treatment with metformin resulted in improved IR and improved endothelial function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In one prior publication, troglitazone given to obese insulin-resistant subjects improved insulin sensitivity but did not improve insulin-mediated or agonist-stimulated vasodilation.

    “Despite a clear improvement in insulin sensitivity with treatment, no improvement in insulin-mediated or agonist-stimulated vasodilation was seen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Tack, 1998, Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone, Diabetologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A direct metformin effect in vascular endothelial cells is supported by recent findings in insulin-resistant rats.

    “A direct metformin effect in vascular endothelial cells is also possible, and supported by recent findings in insulin-resistant rats (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Katakam, 2000, Metformin improves vascular function in insulin-resistant rats, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    An important effect of insulin resistance per se on endothelial function is suggested by the fact that a relationship was not evident at baseline but was brought out by metformin therapy, which concurrently improved insulin sensitivity and endothelial function.

    “However, an important effect of IR per se on endothelial function is suggested by the fact that a relationship was not evident at baseline but was brought out by metformin therapy, which concurrently improved insulin sensitivity and endothelial function.”
    Quote in the paperSubstantial claim
25 of 25

  • The paper relies on this without support.

    The effects of altering insulin resistance with metformin on endothelial function in humans have not been previously reported.

    “The effects of altering IR with metformin on endothelial function in humans have not been previously reported.”
    “The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported.”

  • The paper relies on this without support.

    No evidence links alterations in antioxidant, lipid, or FFA parameters with improvements in vascular function separate from improvements in insulin resistance.

    “However, no evidence links alterations in these parameters with improvements in vas-cular function separate from improvements in IR, and therefore the hypothesis of the central role of IR remains plausible.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mather et al. reported that compared to placebo, metformin improved endothelium-dependent, but not endothelium-independent vasodilation in patients with T2DM.

    “Mather et al. reported that compared to placebo, metformin improved endothelium-dependent, but not endothelium-independent vasodilation thus highlighting the primary dysfunction in blood flow was not the vascular smooth muscle response but was secondary to endothelial dysfunction (106).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [106]

  • Based on critical reviews of the literature, the answer appears to be yes that metformin exerts a direct anti-aging effect on the endothelium, although clinical data could be interpreted as secondary to metformin's actions to enhance insulin sensitivity and lower blood glucose.

    “Based on critical reviews of the literature, the answer appears to be “yes”, although the clinical data could be interpreted as secondary to metformin’s actions to enhance insulin sensitivity and lower blood glucose levels (34, 106, 173).”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [106]

  • Metformin has no effect on endothelium-dependent blood flow but has a significant effect on endothelium-independent blood flow and reduces insulin resistance.

    “Mather et al. reported that metformin has no effect on endothelium dependent blood flow but has a significant effect on endothelium independent blood flow and insulin resistance reduction [89].”

    From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [89]

  • Many different mechanisms beyond glycemic control have been implicated in vascular protection induced by metformin, including improvements in the inflammatory pathway, coagulation, oxidative stress and glycation, endothelial dysfunction, haemostasis, insulin resistance, lipid profiles, and fat redistribution.

    “Many different mechanisms, beyond glycemic control, have been implicated in vascular protection induced by metformin such as improvements in the inflammatory pathway [86], coagulation [87], oxidative stress and glycation [88-92], endothelial dysfunction [88-90], haemostasis [88,91-93], insulin resistance improvement [94], lipid profiles [95,96], and fat redistribution [97,98].”

    From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [89]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Metformin gender counts exceed the stated group size

    Minor

    Table 1 lists 15 men and 14 women in the metformin group, totaling 29 people, but its column heading states n = 28.

    Reported 28 · recomputed 29

1 of 1

Cites

Flagged first, then by citations

2 of the 47 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Paradisi, 1999, Troglitazone therapy improves endothelial function in women with polycystic ovary syndrome, Diabetes, 48, A129

Cited by

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Related

Authors
Mather, K. J., Verma, S., & Anderson, T. J.
Affiliations
  • Indiana University Indianapolis (US)
  • University of Toronto (CA)
  • University of Calgary (CA)
Corresponding author
Anderson, Todd J
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2001-04
Volume
37
Issue
5
Pages
1344-1350
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/s0735-1097(01)01129-9
OpenAlex
W2114391822
Cited by
513
References
47
Citations by year
2026: 7 · 2025: 8 · 2024: 15 · 2023: 10 · 2022: 15 · 2021: 17 · 2020: 19 · 2019: 18 · 2018: 18 · 2017: 27 · 2016: 13 · 2015: 23 · 2014: 20 · 2013: 25 · 2012: 25
FWCI
17.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Alberta Heritage Foundation for Medical Research
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords
metformin, endothelial dysfunction, type 2 diabetes, insulin resistance, acetylcholine-induced vasodilation, forearm blood flow, HOMA-IR, insulin-sensitizing drugs, vascular disease
MeSH terms
Blood Flow Velocity, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Endothelium, Vascular, Female, Forearm, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Middle Aged, Plethysmography, Vasodilation

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