CoChat
Sign Up
Cited by 494Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsPharmacology and Obesity Treatment

Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study

Open access
The Diabetes Prevention Program Research Group·2012·Diabetes Care
DOI 10.2337/dc11-1299PMC PMC3308305
Open this paper in CoChat — free accountOpen PDF

Abstract

OBJECTIVE: Metformin produced weight loss and delayed or prevented diabetes in the Diabetes Prevention Program (DPP). We examined its long-term safety and tolerability along with weight loss, and change in waist circumference during the DPP and its long-term follow-up. RESEARCH DESIGN AND METHODS: The randomized double-blind clinical trial of metformin or placebo followed by a 7–8-year open-label extension and analysis of adverse events, tolerability, and the effect of adherence on change in weight and waist circumference. RESULTS: No significant safety issues were identified. Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. During the DPP, average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following randomization, with no further changes observed over time. During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001, and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001 in metformin vs. placebo, respectively). The magnitude of weight loss during the 2-year double-blind period was directly related to adherence (P < 0.001). Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence (P < 0.001). CONCLUSIONS: Metformin used for diabetes prevention is safe and well tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment.

AI snapshot

Written from the paper’s full text.

TL;DR

In the Diabetes Prevention Program and its Outcomes Study, metformin for diabetes prevention showed no significant safety issues, was well tolerated, and produced modest durable weight loss. Weight loss was directly related to metformin adherence and persisted over long-term follow-up.

Key findings

  • During the DPP, metformin vs placebo reduced body weight (2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001) and waist circumference (2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001); at 2 years, weight loss was 2.1 ± 5.7% vs. 0.02 ± 5.5%.
  • Gastrointestinal symptoms were more common with metformin than placebo (average 28% vs. 16%, P = 0.01; medication-related 9.5% vs. 1.1%, P < 0.001) and declined over time, with similar rates by years 6–9 (P > 0.10).
  • Hemoglobin and hematocrit were slightly lower in the metformin group during the DPP (13.6 vs. 13.8 mg/dL; 40.6 vs. 41.1%; P < 0.001 for both), with changes occurring in the first year and no further changes; low hematocrit was higher with metformin (12.6% vs. 8.4%, P = 0.035), while low hemoglobin was not significantly different (11.2% vs. 7.6%, P = 0.17).
  • Over total follow-up, weight loss remained greater with metformin than placebo (2.0% vs. 0.2%, P < 0.001) and was related to continuing metformin adherence (P < 0.001); highly adherent metformin participants lost 3.5% (3.1 kg). No lactic acidosis or hypoglycemia serious adverse events occurred during nearly 18,000 patient-years.

Methods

  • Randomized double-blind trial: 3,234 participants enrolled in the DPP; 2,155 assigned to metformin (1,073) or placebo (1,082), followed by a 7–8-year open-label DPPOS extension. Participants were ≥25 years, had BMI ≥24 kg/m² (≥22 kg/m² in Asian Americans), elevated fasting glucose, and impaired glucose tolerance.
  • Adverse events were collected by quarterly queries during the DPP and annual gastrointestinal symptom questions; weight was measured twice yearly, waist circumference annually, and hemoglobin/hematocrit annually. Adherence was assessed by pill counts as ≥80% or <80%.
  • Analyses covered the first 2 years of double-blind treatment and the full follow-up period; fixed-effects repeated-measures models adjusted for baseline weight and waist circumference, and generalized estimating equations assessed symptoms and adverse events over time.

Limitations

  • Stated: 12% of DPP participants chose not to continue into the DPPOS; some may have discontinued or declined open-label metformin because of side effects, potentially influencing the safety and tolerability profile during the open-label DPPOS period.
  • Stated/implied: the adherence–weight analyses were post hoc, adherence was not randomized, and placebo was discontinued during the open-label phase so adherence could not be assigned for placebo.
  • Evident: the open-label DPPOS phase was unblinded, and adherence categories may be confounded by tolerability, health behaviors, or reasons for low adherence; the paper notes that low-adherence metformin and placebo groups would not be expected to have the same characteristics.

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

Integrity signals

Registry

Crossref · 10.2337/dc11-1299

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 15 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The associations of adherence to medication with changes in waist circumference were not statistically significant for either the metformin or placebo groups.

    “The associations of adherence to medication with changes in waist circumference were not statistically significant for either the metformin or placebo groups. (Fig. 1C and D).”
    Quote in the paperNot a substantial claim
  • Findingown data

    At 2 years, 10% of metformin participants versus 5% of placebo participants lost ≥10% of body weight (P < 0.001).

    “The percentage losing ≥10% of their body weight at 1 year was 8% for the metformin versus 4% for the placebo group and at 2 years was 10% for the metformin and 5% for the placebo group (P < 0.001 for both time periods).”
    Quote in the paperSubstantial claim
  • Findingown data

    Rates of gastrointestinal symptoms were similar between metformin and placebo groups by years 6 through 9.

    “Rates of gastrointestinal symptoms were similar between groups by years 6 through 9 (P > 0.10).”
    Quote in the paperSubstantial claim
  • Findingown data

    Over the total follow-up, average weight loss from baseline in the metformin treatment group, independent of adherence, was 2.0% (1.9 kg).

    “Over the total follow-up, average weight loss from baseline in the metformin treatment group, independent of adherence, was 2.0% (1.9 kg).”
    Quote in the paperSubstantial claim
  • Findingown data

    During the 2-year double-blind DPP phase, metformin participants had greater weight loss than placebo participants (2.1% vs 0.02%, P < 0.001).

    “During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001, and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001 in metformin vs. placebo, respectively).”
    • Also stated in: § DPP—results from the double-blind phase · plain
      “After 2 years, weight loss was 2.1 ± 5.7% in the metformin group compared with 0.02 ± 5.5% (P < 0.001) in the placebo group.”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingown data

    Placebo participants in all adherence subgroups remained within 1% of their baseline weight, on average, over the 2 years, except for the 7% who were highly adherent with placebo, who had a small weight gain of 1.2%.

    “Placebo participants in all adherence subgroups remained within 1% of their baseline weight, on average, over the 2 years (Table 1), except for the 7% who were highly adherent with placebo, who had a small weight gain of 1.2% (P < 0.05 for the highly adherent compared with the >50% adherent group; all other P values >0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among placebo participants, body weight was relatively stable but waist circumference increased after the fourth year, continuing throughout the entire open-label follow-up.

    “Among placebo participants, body weight was relatively stable but waist circumference increased after the fourth year, continuing throughout the entire open-label follow-up (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Average weight of highly adherent metformin participants was 3.5 ± 0.35% below baseline at 2 years, very close to their 1-year weight loss.

    “Average weight of highly adherent participants was 3.5 ± 0.35% below baseline at 2 years, very close to their 1-year weight loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Metformin participants in the low adherence group lost weight but placebo participants with low adherence did not.

    “Metformin participants in the low adherence group lost weight but placebo participants with low adherence did not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No unexpected adverse events or treatment group differences in adverse events were identified.

    “No unexpected adverse events or treatment group differences in adverse events were identified, either by the study’s Data and Safety Monitoring Board or in this analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Waist circumference remained significantly lower than at baseline in the highly adherent group through the 7-year visit, whereas in the partially adherent groups it was lower up to the 4-year visit, and in the low-adherence group only through 2 years.

    “Waist circumference remained significantly lower than at baseline in the highly adherent group (P < 0.05) through the 7-year visit, whereas in the partially adherent groups it was lower up to the 4-year visit, and in the low-adherence group only through 2 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Waist circumference increased in all groups after year 2, except for the highly adherent participants where the increase began after 5 years and waist circumference remained lower than baseline.

    “Waist circumference increased in all groups after year 2, except for the highly adherent participants where the increase began after 5 years and waist circumference remained lower than baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nonserious adverse events for hypoglycemia and anemia during the DPP were uncommon and similar in metformin and placebo participants.

    “Nonserious adverse events for hypoglycemia and anemia during the DPP were also uncommon and similar in metformin and placebo participants, with seven metformin participants and eight placebo participants ever reporting hypoglycemia, and fifty metformin participants and thirty-eight placebo participants ever reporting anemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Waist circumference initially declines, then steadily increases after a nadir at 12-36 months in all groups except in the highly adherent group, in which this increase was delayed for 5 years.

    “Waist circumference initially declines, then steadily increases after a nadir at 12–36 months in all groups except in the highly adherent group, in which this increase was delayed for 5 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were three SAE reports for anemia (two metformin and one placebo participant), and none for lactic acidosis or hypoglycemia during nearly 18,000 patient-years of follow-up.

    “There were three SAE reports for anemia (two metformin and one placebo participant), and there were none for lactic acidosis or hypoglycemia during nearly 18,000 patient-years of follow-up.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Weight loss in the metformin group was maintained throughout the combined DPP and DPPOS period, with metformin participants having an average 2.5-kg weight loss over time.

    “Weight loss in the metformin group was maintained throughout the combined DPP and DPPOS period with metformin participants having an average 2.5-kg weight loss over time (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Knowler, 2009, 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Metformin used for diabetes prevention in overweight or obese individuals with elevated fasting glucose and impaired glucose tolerance is safe and well tolerated over many years.

    “Metformin used for diabetes prevention is safe and well tolerated.”
    • Also stated in: § CONCLUSIONS · plain
      “Metformin used in overweight or obese individuals with elevated fasting glucose and impaired glucose tolerance was associated with modest but durable weight loss and was safe and well tolerated over many years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Weight loss was a strong predictor of diabetes prevention in both the metformin and placebo groups, accounting for 64% of the metformin versus placebo effect on diabetes prevention.

    “Weight loss was a strong predictor of diabetes prevention in both the metformin and placebo groups with weight loss accounting for 64% of the metformin versus placebo effect on diabetes prevention (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Lachin, 2007, Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In summary, metformin produces a highly significant reduction in body weight and waist circumference with minimal safety issues and limited issues of tolerability.

    “In summary, metformin produces a highly significant reduction in body weight and waist circumference with minimal safety issues and limited issues of tolerability (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Fujioka, 2005, Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Adherence to placebo did not affect weight loss, suggesting that metformin, rather than nonspecific adherence to positive health behaviors, was the relevant factor.

    “Adherence to placebo did not affect weight loss, suggesting that metformin, rather than nonspecific adherence to positive health behaviors, was the relevant factor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Adherence to metformin improved the magnitude of weight loss-but not waist circumference-during the first 2 years.

    “Adherence to metformin improved the magnitude of weight loss—but not waist circumference—during the first 2 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Metformin was well tolerated with few side effects.

    “Metformin was well tolerated with few side effects.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    One potential bias is that 12% of DPP participants chose not to continue into the DPPOS, and it is likely that some of those who discontinued the study or who continued but chose not to take open-label metformin did so because of side effects, which may have influenced the safety and tolerability profile of metformin during the open-label DPPOS period.

    “One potential bias is that 12% of DPP participants chose not to continue into the DPPOS. It is likely that some of those who discontinued the study or who continued but chose not to take open-label metformin did so because of side effects, which may have influenced the safety and tolerability profile of metformin during the open-label DPPOS period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The weight reduction persists for up to 10 years and is related to adherence to metformin.

    “The weight reduction persists for up to 10 years and is related to adherence to metformin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metformin lowers glucose and reduces risk for diabetes in part through weight loss.

    “Metformin lowers glucose and reduces risk for diabetes in part through weight loss (2,7,16,17).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] UK Prospective Diabetes Study (UKPDS) Group, 1998, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), Lancet source

      Not checked in the free run.

    • cites [7] Lachin, 2007, Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program, Diabetes source

      Not checked in the free run.

    • cites [16] Yanovski, 2011, Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial, Diabetes source

      Not checked in the free run.

    • cites [17] Avenell, 2004, Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement, Health Technol Assess source

      Not checked in the free run.

20 of 20

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?

  • Data from the Diabetes Prevention Program indicates that metformin is effective in preventing the development of diabetes in patients with pre-diabetes and its use following a 10-year follow up is associated with an average 2.1-kg weight loss.

    “In addition, data from the Diabetes Prevention Program (DPP) indicates that metformin is effective in preventing the development of diabetes in patients with pre-diabetes and its use following a 10-year follow up associated with an average 2.1-kg weight loss (7).”

    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 [7]

  • Metformin lowers the atherosclerotic burden in non-diabetic persons at risk of developing T2DM.

    “In addition to its benefits as an anti-hyperglycemic agent, metformin also lowers the atherosclerotic burden in non-diabetic persons at risk of developing T2DM (1, 7).”

    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 [7]

  • In the Diabetes Prevention Program study, lifestyle intervention was more effective than metformin in reducing the risk of developing diabetes.

    “data from the Diabetes Prevention Program study of 3234 pre-diabetic subjects over an average of 2.8 years who were randomized to receive placebo, metformin (850 mg bid), or lifestyle intervention, indicated that although both metformin and lifestyle changes were effective in reducing the risk of developing diabetes, lifestyle intervention was more effective (7).”

    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 [7]

  • In the Diabetes Prevention Program study of 3234 pre-diabetic subjects over an average of 2.8 years, both metformin and lifestyle changes were effective in reducing the risk of developing diabetes.

    “data from the Diabetes Prevention Program study of 3234 pre-diabetic subjects over an average of 2.8 years who were randomized to receive placebo, metformin (850 mg bid), or lifestyle intervention, indicated that although both metformin and lifestyle changes were effective in reducing the risk of developing diabetes, lifestyle intervention was more effective (7).”

    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 [7]

  • Metformin decreases body weight in both diabetic and non-diabetic individuals.

    “In contrast to other antidiabetic drugs including insulin, metformin can lead independently to glycemic control and weight loss by decreasing food intake in both diabetic and non-diabetic individuals (18–20).”

    From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [19]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Combined adherence categories described as highly adherent

    Minor

    The conclusions say that 72% of metformin participants during the double-blind phase and 62% over the full trial were highly adherent. The results say those percentages include participants in either the ≥50% adherent or the highly adherent category.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
The Diabetes Prevention Program Research Group
Affiliations
Pennington Biomedical Research Center (US)
Corresponding author
The Diabetes Prevention Program Research Group
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2012-03-13
Volume
35
Issue
4
Pages
731-737
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc11-1299
PMC
PMC3308305
OpenAlex
W2096559770
Cited by
494
References
24
Citations by year
2026: 19 · 2025: 34 · 2024: 68 · 2023: 44 · 2022: 31 · 2021: 51 · 2020: 36 · 2019: 35 · 2018: 36 · 2017: 25 · 2016: 28 · 2015: 35 · 2014: 19 · 2013: 22 · 2012: 10
FWCI
22.06
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes Care (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Hispana (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK017047)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
metformin, diabetes prevention, long-term safety, tolerability, weight loss, waist circumference, gastrointestinal adverse effects, hemoglobin, hematocrit, medication adherence, type 2 diabetes prevention, open-label extension
MeSH terms
Adult, Aged, Aged, 80 and over, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Placebos, Prediabetic State, Time Factors, Weight Loss, Treatment Outcome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review