CoChat
Sign Up
Cited by 567Diabetes Treatment and ManagementMetabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and Lipoproteins

Metformin: An Old But Still the Best Treatment for Type 2 Diabetes

Open access
Rojas, Lilian Beatriz Aguayo, Gomes, Marilia Brito·2013·Diabetology & Metabolic Syndrome
DOI 10.1186/1758-5996-5-6PMC PMC3607889
Open this paper in CoChat — free accountOpen PDF

Abstract

The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals. In this setting, metformin, an old and widely accepted first line agent, stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution. These properties may have contributed to the decrease of adverse cardiovascular outcomes otherwise not attributable to metformin's mere antihyperglycemic effects. Several other classes of oral antidiabetic agents have been recently launched, introducing the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a neuroprotective effect. Metformin's negligible risk of hypoglycemia in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an appropiate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an extended release form. We reviewed the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits beyond its glycemic effect. We also discuss its potential role for a variety of insulin resistant and pre-diabetic states, obesity, metabolic abnormalities associated with HIV disease, gestational diabetes, cancer, and neuroprotection.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that metformin remains the first-line oral agent for type 2 diabetes because of its glycemic efficacy, safety profile, and benefits extending beyond glucose lowering (vascular, inflammatory, oxidative, and possible anticancer and neuroprotective effects). It surveys evidence across pre-diabetes, combination therapy, pregnancy, pediatrics, obesity/NAFLD, heart failure, HIV lipodystrophy, cancer, and contraindications.

Key findings

  • In the Diabetes Prevention Program (DPP), lifestyle intervention and metformin reduced diabetes incidence by 58% and 31% respectively versus placebo; after a 1–2 week washout, metformin still significantly reduced incidence (risk ratio 0.75, p = 0.005), with benefit concentrated in patients <60 years (RR 0.66) and BMI >35 kg/m² (RR 0.47).
  • In the UKPDS, the metformin-treated group had risk reductions of 32% (p = 0.002) for any diabetes-related endpoint, 42% for diabetes-related death (p = 0.017), and 36% for all-cause mortality (p = 0.011) versus control; post-trial follow-up showed persistent reductions for any diabetes-related endpoint (21%, p = 0.01), myocardial infarction (33%, p = 0.005), and death from any cause (27%, p = 0.002).
  • Observational studies report reduced cancer incidence and cancer-related mortality in metformin users, consistently in the range of 25% to 30%; one cohort found cancer incidence of 7.3% in metformin users versus 11.6% in controls (unadjusted hazard ratio 0.46, 95% CI 0.40–0.53).
  • Reported lactic acidosis incidence is 6.3 per 100,000 patient-years with metformin versus 40–64 per 100,000 patient-years with biguanides (mostly phenformin); gastrointestinal intolerance occurs frequently, and about 10–30% of patients show reduced vitamin B12 absorption.

Methods

  • Narrative (non-systematic) review of the literature on metformin in type 2 diabetes, covering its mechanism (LKB-1/AMPK activation, reduced hepatic glucose output, mitochondrial respiration inhibition), clinical trials, and observational studies.
  • Evidence summarized includes major randomized trials (DPP, DPPOS, IDPP, UKPDS, ADOPT, MiG, HOME, PRESTO), meta-analyses, and retrospective/observational cohorts, presented in narrative form plus two summary tables (diabetes prevention and vasculoprotection).
  • No stated search strategy, inclusion criteria, or formal quality appraisal is described.

Limitations

  • Stated in the paper: a meta-analysis suggesting smaller cardiovascular effects of metformin "must be interpreted with caution given the low number of randomized controlled trials included"; epidemiological comparisons of sulfonylureas versus metformin "are potentially affected by unmeasured confounding variables"; pediatric studies are few, of short duration, and heterogeneous in design; the effect of metformin on endothelial function is contradictory across studies and requires further study; whether increased cancer mortality with sulfonylureas/insulin reflects harm from those agents or protection from metformin "is not known."
  • Evident from the text: as a narrative review without a described systematic search or quality assessment, selection and interpretation of cited evidence may be subject to bias; several key claims (cancer, neuroprotection, heart failure safety) rest largely on observational or in vitro/in vivo data rather than randomized trials.

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

Integrity signals

Registry

Crossref · 10.1186/1758-5996-5-6

Cites

196 of 196 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 233 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Even including the washout period, metformin significantly decreased diabetes incidence (risk ratio 0.75, p=0.005) compared with placebo.

    “Even after including the wash out period in the overall analysis, metformin still significantly decreased diabetes incidence (risk ratio 0.75, p = 0.005) compared with placebo [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Diabetes Prevention Program Research Group: Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003, 26 (4): 977-980. source

      Not checked in the free run.

  • Premisecitation

    The association of impaired fasting glucose with cardiovascular events has not been well established.

    “The association of IFG with cardiovascular events, however, has not been well established [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Petersen J, Mc Guire D: Impaired glucose tolerance and impaired fasting glucose – a review of diagnosis, clinical implications and management. Diabetes Vasc Dis Res. 2005, 2 (1): 9-15. 10.3132/dvdr.2005.007. source

      Not checked in the free run.

  • Premisecitation

    Impaired glucose tolerance and impaired fasting glucose are associated with increased and varying risk of developing type 2 diabetes mellitus.

    “Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) statuses are associated with increased and varying risk of developing type 2 diabetes mellitus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Petersen J, Mc Guire D: Impaired glucose tolerance and impaired fasting glucose – a review of diagnosis, clinical implications and management. Diabetes Vasc Dis Res. 2005, 2 (1): 9-15. 10.3132/dvdr.2005.007. source

      Not checked in the free run.

  • Interpretationreasoning

    These data suggest that, at least in the short-term, metformin may help delay the onset of diabetes.

    “These data suggest that, at least in the short-term, metformin may help delay the onset of diabetes.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In an Indian population with impaired glucose tolerance, metformin significantly reduced the risk of developing diabetes (relative risk reduction 26.4%, p=0.029) compared with control.

    “The relative risk reduction was 28.5% with lifestyle modification (p = 0.018), 26.4% with metformin (p = 0.029), and 28.2% with lifestyle modification plus metformin (p = 0.022), as compared with the control group [9] (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Ramachandran A, Snehalatha C, Mukesh M: Indian diabetes prevention programme (IDPP). the Indian diabetes prevention programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006, 49: 289-297. source

      Not checked in the free run.

  • May combine two claims. 66
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Premisecitation

    After a washout period in the Diabetes Prevention Program, diabetes incidence increased from 25.2% to 30.6% in the metformin group and from 33.4% to 36.7% in the placebo group.

    “Diabetes incidence increased from 25.2 to 30.6% in the metformin group and from 33.4 to 36.7% in the placebo group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Diabetes Prevention Program Research Group: Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003, 26 (4): 977-980. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired glucose tolerance is associated with increased risk of cardiovascular events and may determine increased mortality risk.

    “IGT has been associated with an increased risk of cardiovascular events and may determine an increased mortality risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Petersen J, Mc Guire D: Impaired glucose tolerance and impaired fasting glucose – a review of diagnosis, clinical implications and management. Diabetes Vasc Dis Res. 2005, 2 (1): 9-15. 10.3132/dvdr.2005.007. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Metformin's efficacy, safety profile, beneficial cardiovascular and metabolic effects, and combinability make it the first glucose-lowering agent of choice for type 2 diabetes mellitus.

    “Metformin’s efficacy, security profile, benefic cardiovascular and metabolic effects, and its capacity to be associated with other antidiabetic agents makes this drug the first glucose lowering agent of choice when treating patients with type 2 diabetes mellitus (TDM2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Aggressive treatment is required in type 2 diabetes mellitus to achieve glycemic and cardiovascular risk factor goals.

  • May combine two claims.

    Premisecitation

    In a Chinese study, metformin produced a large significant risk reduction for new onset type 2 diabetes of 77%, larger than lifestyle intervention alone.

    “Treatment with metformin or acarbose produced large, significant, and similar risk reductions for new onset of T2DM of 77% and 88%, respectively; these reductions were larger than that of lifestyle intervention alone [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Yang W, Lin L, Qi J: The preventive effect of acarbose and metformin on the IGT population from becoming diabetes mellitus: a 3-year multicentral prospective study. Chin J Endocrinol Metab. 2001, 17: 131-134.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lifestyle and pharmacological interventions reduced the rate of progression to type 2 diabetes in people with impaired glucose tolerance, and these interventions seem as effective as pharmacological treatment.

    “In their systematic review, Gillies et al. found that lifestyle and pharmacological interventions reduced the rate of progression to type 2 diabetes in people with IGT and that these interventions seem to be as effective as pharmacological treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Guillies C, Abram KR, Lambert PC, Cooper NJ, Sutton AJ: Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007, 334: 299-10.1136/bmj.39063.689375.55. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Diabetes Prevention Program trial, lifestyle intervention and metformin reduced diabetes incidence by 58% and 31%, respectively, compared with placebo.

    “Lifestyle intervention and metformin reduced diabetes incidence by 58% and 31%, respectively, when compared with placebo [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002, 346: 393-403. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin's effects are mediated by activation of LKB1, which regulates AMPK; AMPK phosphorylates TORC2, inactivating it and downregulating gluconeogenic enzyme synthesis.

    “These effects are mediated by the activation of an upstream kinase, liver kinase B1 (LKB-1), which in turn regulates the downstream kinase adenosine monophosphatase protein kinase (AMPK). AMPK phosphorylates a transcriptional co-activator, transducer of regulated CREB protein 2 (TORC2), resulting in its inactivation which consequently downregulates transcriptional events that promote synthesis of”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Shaw RJ, Lamia KA, Vasquez D: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005, 310: 1642-1646. 10.1126/science.1120781. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin acts primarily at the liver by reducing glucose output and secondarily by augmenting glucose uptake in peripheral tissues, chiefly muscle.

    “Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Shaw RJ, Lamia KA, Vasquez D: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005, 310: 1642-1646. 10.1126/science.1120781. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin's benefits in the Diabetes Prevention Program were primarily observed in patients younger than 60 years (RR 0.66) and in patients with BMI greater than 35 kg/m2 (RR 0.47).

    “The benefits of metformin were primarily observed in patients <60 years old (RR 0.66) and in patients with a BMI greater than 35 kg/m2 (RR 0.47) [7] (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002, 346: 393-403. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 27 randomized trials showed that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain, while glucagon-like peptide-1 analogs, glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change.

    “A meta-analysis of 27 randomized trials showed that thiazolidinediones, sulfonylureas, and glinides were associated with weight gain; glucagon-like peptide-1 analogs, glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Phung OJ, Scholle JM, Talwar M, Coleman CI: Effect of noninsulin Antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010, 303 (14): 1410-1418. 10.1001/jama.2010.405. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Chinese individuals have a lower prevalence of diabetes and are less insulin resistant than Indians, so results of the Chinese study may not be applicable to Asian Indian individuals.

    “Chinese individuals have a lower prevalence of diabetes and are less insulin resistant than Indians, so the results of the Chinese study may not be applicable to Asian Indian individuals [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Pan XR, Li GW, Hu YH: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care. 1997, 20: 537-544. 10.2337/diacare.20.4.537. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the ADOPT study, rosiglitazone was associated with more weight gain, edema, and greater durability of glycemic control; metformin with a higher incidence of gastrointestinal events; and glibenclamide with a higher risk of hypoglycaemia.

    “Rosiglitazone was associated with more weight gain, edema, and greater durability of glycemic control; metformin was associated with a higher incidence of gastrointestinal events and glibenclamide with a higher risk of hypoglycaemia. [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Scheen AJ: ADOPT study: which first-line glucose-lowering oral medication in type 2 diabetes?. Rev Med Liege. 2007, 62 (1): 48-52.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glimepiride/metformin combination results in lower HbA1c and fewer hypoglycemic events compared to the glibenclamide/metformin combination.

    “The glimepiride/metformin combination results in a lower HbA1c concentration and fewer hypoglycemic events when compared to the glibenclamide/metformin combination [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] González-Ortiza M, Guerrero-Romero J, Violante-Ortiz R: Efficacy of glimepiride/metformin combination versus glibenclamide/metformin in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Complications. 2009, 23: 376-379. 10.1016/j.jdiacomp.2008.09.002. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of rosiglitazone to metformin in a 24-week randomized, double-blind, parallel-group study significantly decreased HbA1c and improved insulin sensitivity and HOMA beta cell function.

    “The addition of rosiglitazone to metformin in a 24-week randomized, double-blind, parallel-group study significantly decreased HbA1c concentration and improved insulin sensitivity and HOMA ß cell function [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Bailey CJ, Bagdonas A, Rubes J: Rosiglitazone-metformin fixed-dose combination compared with uptritrated metformin alone in type diabetes mellitus:a 24 week, multicenter, randomized, double-blind, parallel-group study. Clin Ther. 2005, 27: 1548-1561. 10.1016/j.clinthera.2005.10.012. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impaired glucose tolerance is highly prevalent in native Asian Indians, who have unique features such as young age of diabetes onset, lower BMI, high insulin resistance, and lower thresholds for diabetic risk factors.

    “IGT is highly prevalent in native Asian Indians. This population has several unique features such as a young age of diabetes onset and lower BMI along with high rates of insulin resistance and lower thresholds for diabetic risk factors [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Ramachandran A, Snehalatha C, Vijay V: Low risk threshold for acquired diabetogenic factors in Asian Indians. Diab Res Clin Pract. 2004, 65: 189-195. 10.1016/j.diabres.2004.03.012. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All noninsulin antidiabetic drugs added to maximal metformin therapy are associated with similar HbA1c reduction but varying degrees of weight gain and hypoglycemia risk.

    “All noninsulin antidiabetic drugs when added to maximal metformin therapy are associated with similar HbA1c reduction but with varying degrees of weight gain and hypoglycemia risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Phung OJ, Scholle JM, Talwar M, Coleman CI: Effect of noninsulin Antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010, 303 (14): 1410-1418. 10.1001/jama.2010.405. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Current ADA/EASD and AACE/ACE guidelines recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with type 2 diabetes mellitus.

    “Current guidelines from the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] American Diabetes Association: Summary of revisions to the 2011 clinical practice recommendations. Diabetes Care. 2011, 34 (Suppl 1): S3-

      Not checked in the free run.

    • cites [17] Rodbard HW, Jellinger PS, Davidson JA: Statement by an American association of clinical endocrinologists/American college of endocrinology consensus panel on type 2 diabetes mellitus. An algorithm for glycemic control. Endocr Pract. 2009, 15 (6): 540-559. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin use was associated with reduced all-cause mortality and reduced cardiovascular mortality.

    “The use of metformin was associated with reduced all-cause mortality and reduced cardiovascular mortality.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Johnson JA, Majumdar SR, Simpson SH: Decreased mortality associated with the use of metformin compared with sulfonylurea Monotherapy in type 2 diabetes. Diabetes Care. 2002, 25: 2244-2248. 10.2337/diacare.25.12.2244. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin added to insulin-based regimens improves glycemic control, limits changes in body weight, reduces hypoglycemia incidence, and reduces insulin requirements, allowing a 15-25% reduction in total insulin dosage.

    “Metformin as added to insulin-based regimens has been shown to improve glycemic control, limit changes in body weight, reduce hypoglycemia incidence, and to reduce insulin requirements (sparing effect), allowing a 15–25% reduction in total insulin dosage [28,29].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Giugliano D, Quatraro A, Consoli G: Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993, 44: 107-112. 10.1007/BF00315466. source

      Not checked in the free run.

    • cites [29] Lund SS, Tarnow L, Frandsen M: Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial. BJ. 2009, 339: b4324-10.1136/bmj.b4324. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the United Kingdom Prospective Diabetes Study, the metformin-treated group had risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death, and 36% for all-cause mortality compared with control.

    “Metformin’s first-line position was strengthened by the United Kingdom Prospective Diabetes Study (UKPDS) observation that the metformin-treated group had risk reductions of 32% (p = 0.002) for any diabetes-related endpoint, 42% for diabetes-related death (p = 0.017), and 36% for all-cause mortality (p = 0.011) compared with the control group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998, 352 (9131): 854-865. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin has been shown to reduce insulin dose requirement (5.7-10.1 U/day), HbA1c (0.6-0.9%), weight (1.7-6.0 kg), and total cholesterol (0.3-0.41 mmol/l) in adolescents with type 1 diabetes.

    “Metformin has been shown to reduce insulin dose requirement (5.7–10.1 U/day), HbA1c (0.6–0.9%), weight (1.7–6.0 kg), and total cholesterol (0.3–0.41 mmol/l) [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Vella S, Buetow L, Royle P: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia. 2010, 53 (5): 809-820. 10.1007/s00125-009-1636-9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin is associated with short-term weight loss, improvement of insulin sensitivity, and decreased visceral fat.

    “Metformin is associated with short-term weight loss, improvement of insulin sensitivity, and decreased visceral fat [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Reinehr T, Kiess W, Kappellen T, Andler W: Insulin sensitivity among obese children and adolescents, according to degree of weight loss. Pediatrics. 2004, 114: 1569-1573. 10.1542/peds.2003-0649-F. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PRESTO trial showed significant reductions of any clinical event (28%), myocardial infarction (69%), and all-cause mortality (61%).

    “The PRESTO trial showed significant reductions of any clinical event (28%), myocardial infarction (69%), and all-cause mortality (61%) [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Kao J, Tobis J, Mc Clelland RL: Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004, 93: 1347-1350. 10.1016/j.amjcard.2004.02.028. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Metformin in Gestational Diabetes trial found no significant difference in composite fetal outcome between metformin and insulin; women assigned metformin had more preterm births and less weight gain.

    “The Metformin in Gestational Diabetes (MiG) trial, found no significant difference in the composite fetal outcome (composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score <7, or prematurity) between metformin and insulin. Women assigned to metformin had more preterm births and less weight gain compared to those in the insulin group [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Rowan JA, Hague WM, Gao W, Battin MR, Moore MP: MiG trial investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008, 358: 2003-2015. 10.1056/NEJMoa0707193. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the United Kingdom Prospective Diabetes Study, metformin had statistically significant reductions in risk of all-cause mortality, diabetes-related mortality (p=0.017), and any end-point related to diabetes (p=0.002), but not in myocardial infarction (p=0.052).

    “It had statistically significant reductions in the risk of all-cause mortality, diabetes-related mortality (p = 0.017), and any end-point related to diabetes (p = 0.002), but not in myocardial infarction (p = 0.052) [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998, 352 (9131): 854-865. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin increases plasma GLP-1 levels, probably by either direct inhibition of DPPIV or by increased secretion, leading to reduced food intake and weight loss.

    “Metformin has also been found to increase plasma GLP-1 levels, probably by either direct inhibition of DPPIV or by increased secretion, leading to reduced food intake and weight loss [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Mannucci E, Ognibene A, Cremasco F: Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001, 24: 489-494. 10.2337/diacare.24.3.489. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to glimepiride, metformin lowered HbA1c to <7% similar to glimepiride but was associated with significantly less weight gain.

    “When compared to glimepiride (1–8 mg once daily), metformin (500–1000 mg twice daily) lowered HbA1c to <7%, similar to glimepiride, but was associated with significantly less weight gain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Gottschalk M, Danne T, Vlajnic A, Cara J: Glimepiride Versus Metformin as Monotherapy in Pediatric Patients With Type 2 Diabetes.A randomized, single-blind comparative study. DiabetesCare. 2007, 30: 790-794.

      Not checked in the free run.

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

    Premisecitation

    Diabetic patients are at high risk of cardiovascular events, particularly coronary heart disease by about 3-fold.

    “Diabetic patients are at high risk of cardiovascular events, particularly of coronary heart disease by about 3-fold [67,68].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Kannel WB, McGee DL: Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care. 1979, 2: 120-126. 10.2337/diacare.2.2.120. source

      Not checked in the free run.

    • cites [68] Wingard DL, Barrett-Connor E: NationalDiabetes Data Group. Diabetes in America. Heart disease and diabetes. 1995, Washington, D.C: GPO, 429-48. NIH publication no.95-1468, 2

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The United Kingdom Prospective Diabetes Study post-trial reported significant and persistent risk reductions for any diabetes-related end point (21%, p=0.01), myocardial infarction (33%, p=0.005), and death from any cause (27%, p=0.002).

    “The UKPDS pos-trial reported significant and persistent risk reductions for any diabetes-related end point (21%, p = 0.01), myocardial infarction (33%, p = 0.005), and death from any cause (27%, p = 0.002) [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008, 359: 1577-1589. 10.1056/NEJMoa0806470. source

      Not checked in the free run.

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

    Premisecitation

    A recent meta-analysis suggested that cardiovascular effects of metformin could be smaller than had been hypothesized on the basis of the United Kingdom Prospective Diabetes Study; however, its results must be interpreted with caution given the low number of randomized controlled trials included.

    “A recent meta-analysis suggested that the cardiovascular effects of metformin could be smaller than had been hypothesized on the basis of the UKPDS; however, its results must be interpreted with caution given the low number of randomized controlled trials included [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Boussageon R, Supper I, Bejan-Angoulvant T: Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012, 9 (4): e1001204-10.1371/journal.pmed.1001204. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin may not be as effective as behavioral interventions in reducing BMI, and compared with drugs licensed for obesity, its effects are moderate.

    “Metformin may not be as effective as behavioral interventions in reducing BMI and when compared with drugs that are licensed for obesity, its effects are moderate [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Oude Luttikhuis H, Baur L, Jansen H, Shrewsbury VA, O’Malley C, Stolk RP, Summerbell CD: Interventions for treating obesity in children. Cochrane Database Syst Rev. 2009, CD001872-1 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A retrospective analysis of Saskatchewan databases reported significant reductions for all-cause mortality and cardiovascular mortality of 40% and 36%, respectively.

    “A retrospective analysis of patients databases in Saskatchewan, Canada reported significant reductions for all-cause mortality and cardiovascular mortality of 40% and 36%, respectively [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Johnson JA, Majumdar SR, Simpson SH: Decreased mortality associated with the use of metformin compared with sulfonylurea Monotherapy in type 2 diabetes. Diabetes Care. 2002, 25: 2244-2248. 10.2337/diacare.25.12.2244. source

      Not checked in the free run.

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

    Premisecitation

    Type 2 diabetic patients without a previous history of myocardial infarction have the same risk of coronary artery disease as non-diabetic subjects with a history of myocardial infarction.

    “It has been stated that type 2 diabetic patients without a previous history of myocardial infarction have the same risk of coronary artery disease (CAD) as non-diabetic subjects with a history of myocardial infarction [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998, 339: 229-234. 10.1056/NEJM199807233390404. source

      Not checked in the free run.

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

    Premisecitation

    The risk of developing cardiac heart failure in diabetic individuals nearly doubles as the population ages.

    “The risk of developing cardiac heart failure (CHF) in diabetic individuals nearly doubles as the population ages [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Boussageon R, Supper I, Bejan-Angoulvant T: Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012, 9 (4): e1001204-10.1371/journal.pmed.1001204. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The US Food and Drug Administration removed the heart failure contraindication from the packaging of metformin although a strong warning for cautious use still exists.

    “The US Food and Drug Administration removed the heart failure contraindication from the packaging of metformin although a strong warning for the cautious use of metformin in this population still exists [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Food and Drug Administration. Product label approval: metformin. 2006, http://packageinserts.bms.com/pi/piglucophage.pdf ,

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent review concluded that congestive heart failure could not be considered an absolute contraindication for metformin use and suggests its protective effect in reducing the incidence of congestive heart failure and mortality in type 2 diabetes mellitus.

    “A recent review concluded that CHF could not be considered an absolute contraindication for metformin use and also suggest its protective effect in reducing the incidence of CHF and mortality in T2DM [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Papanas N, Maltezos E, Mikhailidis DP: Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012, 1: 1-8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The United Kingdom Prospective Diabetes Study demonstrated that tight glycemic control has beneficial effects on microvascular end points but failed to show improvements in macrovascular outcomes.

    “The UKPDS recruited patients with newly diagnosed type 2 diabetes and demonstrated that tight glycemic control has beneficial effects on microvascular end points. However, it failed to show improvements in macrovascular outcomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998, 352 (9131): 854-865. source

      Not checked in the free run.

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

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Mather KJ, Verma S, Anderson TJ: Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001, 37 (5): 1344-1350. 10.1016/S0735-1097(01)01129-9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin can upregulate uncoupled proteins 2 in adipose tissue and can cause an increase in reduced glutathione.

    “It can upregulate uncoupled proteins 2 (UCP2) in adipose tissue [102] and can also cause an increase in reduced glutathione [100].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Anedda A, Rial E, Gonzalez Barroso : Metformin induces oxidative stress in white adipocytes and raises uncoupling proten levels. J Endocrinol. 2008, 199: 33-40. 10.1677/JOE-08-0278. source

      Not checked in the free run.

    • cites [100] Faure P, Rossini E, Wiernsperger N: An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes. 1999, 48: 353-357. 10.2337/diabetes.48.2.353. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several retrospective studies in patients with congestive heart failure and diabetes reported lower risk of death from any cause, lower hospital readmissions for congestive heart failure, and hospitalizations for any cause.

    “Several retrospective studies in patients with CHF and diabetes reported lower risk of death from any cause [81-83], lower hospital readmissions for CHF [81], and hospitalizations for any cause [81,82].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM: Thiazolinediones, metformin, and outcomes in older patients with diabetes and heart failure. Circulation. 2005, 111: 583-590. 10.1161/01.CIR.0000154542.13412.B1. source

      Not checked in the free run.

    • cites [82] Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA: Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005, 28: 2345-2351. 10.2337/diacare.28.10.2345. source

      Not checked in the free run.

    • cites [83] Papanas N, Maltezos E, Mikhailidis DP: Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012, 1: 1-8. source

      Not checked in the free run.

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

    Premisecitation

    Metformin significantly improves endothelium-dependent flow without a significant effect on endothelium-independent response.

    “Conversely, Vitale et al. found significant improvement of endothelium dependent flow without a significant effect on endothelium independent response [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Vitale C, Mercuro G, Cornoldi A, Fini M: Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005, 258: 250-256. 10.1111/j.1365-2796.2005.01531.x. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways, increasing lipolysis and beta-oxidation in white adipose tissue and reducing neoglucogenesis.

    “Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways [100], increasing lipolysis and ß-oxidation in white adipose tissue [102] and reducing neoglucogenesis [2].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [100] Faure P, Rossini E, Wiernsperger N: An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes. 1999, 48: 353-357. 10.2337/diabetes.48.2.353. source

      Not checked in the free run.

    • cites [102] Anedda A, Rial E, Gonzalez Barroso : Metformin induces oxidative stress in white adipocytes and raises uncoupling proten levels. J Endocrinol. 2008, 199: 33-40. 10.1677/JOE-08-0278. source

      Not checked in the free run.

    • cites [2] Shaw RJ, Lamia KA, Vasquez D: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005, 310: 1642-1646. 10.1126/science.1120781. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin reduces reactive oxygen species by inhibiting mitochondrial respiration and decreases advanced glycosylation end product indirectly through reduction of hyperglycemia and directly through an insulin-dependent mechanism.

    “It reduces reactive oxygen species (ROS) by inhibiting mitochondrial respiration [100] and decreases advanced glycosylation end product (AGE) indirectly through reduction of hyperglycemia and directly through an insulin-dependent mechanism [101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Faure P, Rossini E, Wiernsperger N: An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes. 1999, 48: 353-357. 10.2337/diabetes.48.2.353. source

      Not checked in the free run.

    • cites [101] Beisswenger P, Rugiero-Lopez D: Metformin inhibition of glycation processes. Diabetes Metab. 2003, 29 (6S): 95-103.

      Not checked in the free run.

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

    Premisecitation

    The authors suggested that metformin's action on NF-kB and metabolic memory proteins could be mediated by histone deacetylase sirtuin 1 (SIRT-1).

    “The authors suggested that this action could be mediated by histone deacetylase sirtuin 1 (SIRT-1), a multifunctional protein involved in many intracellular pathways related to metabolism, stress response, cell cycle, and aging [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xun X: Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012, 61 (1): 217-228. 10.2337/db11-0416. source

      Not checked in the free run.

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

    Premisecitation

    AMPK forms a molecular hub for cellular metabolic control.

    “The activated protein kinase (AMPK) forms a molecular hub for cellular metabolic control [122].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Santomauro Júnior AC, Ugolini MR, Santomauro AT, Souto RP: Metformina e AMPK: Um Antigo Fármaco e Uma Nova Enzima no Contexto da Síndrome Metabólica. Arq Bras Endocrinol Metabol. 2008, 52 (1): 120-125. 10.1590/S0004-27302008000100017. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin significantly decreases TSH without reciprocal changes in any thyroid function parameter in hypothyroid diabetic patients, but not in euthyroid ones.

    “A significant decrease in TSH (P < 0.001) without reciprocal changes in any thyroid function parameter in diabetic patients had also been reported but only in hypothyroid subjects, not in euthyroid ones [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Capelli C, Rotondi M, Pirola I, Agosti B, Gandossi E: TSH-lowering effect of metformin in type 2 diabetic patients differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care. 2009, 32: 1589-1590. 10.2337/dc09-0273. source

      Not checked in the free run.

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

    Premisecitation

    Oxidative stress has been implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

    “Oxidative stress has been implicated in a variety of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis disease [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Detaille D, Guigas B, Chauvin C: Metformin prevents high glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes. 2005, 54: 2179-2187. 10.2337/diabetes.54.7.2179. source

      Not checked in the free run.

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

    Premisecitation

    Nucleoside reverse transcriptase inhibitors, particularly thymidine analogues, are associated with morphological changes, particularly extremity fat loss.

    “Nucleoside reverse transcriptase inhibitors (NRTIs), particularly thymidine analogues (zidovudine and stavudine), have been associated with morphological changes, particularly extremity fat loss [116]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Moyle GJ, Sabin CA, Cartledge J: A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. Acquir Immune Defic Syndr. 2006, 20: 2043-2050.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin is associated with improvements in lipoprotein metabolism, including decreases in LDL-C, fasting and postprandial triglycerides, and free fatty acids.

    “Metformin is associated with improvements in lipoprotein metabolism, including decreases in LDL-C [95], fasting and postprandial TGs, and free fatty acids [106].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Glueck CJ, Fontaine RN, Wang P: Metformin reduces weight, centripetalobesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001, 50: 856-861. 10.1053/meta.2001.24192. source

      Not checked in the free run.

    • cites [106] Eleftheriadou I, Grigoropoulou P, Katsilambros N, Tentolouris N: The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism. Curr Diabetes Rev. 2008, 4: 340-356. 10.2174/157339908786241133. source

      Not checked in the free run.

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

    Premisecitation

    Lipodystrophy is highly prevalent in patients on highly active antiretroviral therapy, occurring in 40% to 80% of patients.

    “Lipodystrophy, characterized by morphological (peripheral lipoatrophy, localized fat accumulation) and metabolic changes (hyperlipidemia, insulin resistance and hyperglycemia), is highly prevalent in patients on highly active antiretroviral therapy (HAART), occurring in 40% to 80% of patients [115].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Kinlaw WB, Marsh B: Adiponectin and HIV-lipodystrophy:taking HAART. Endocrinology. 2004, 145: 484-486. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin has favorable effects on insulin levels, insulin sensitivity, weight, flow-mediated vasodilation, and lipid profiles in HIV lipodystrophy.

    “Favorable effects on insulin levels [98], insulin sensitivity [119], weight [97], flow-mediated vasodilation [119], and lipid profiles [98,119] have also been described.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [98] Sheth S, Larson L: The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis. 2010, 10: 183-10.1186/1471-2334-10-183. source

      Not checked in the free run.

    • cites [119] van Wijk , de Koning E, Castro M: Comparison of Rosiglitazone and Metformin for treating HIV Lipodistrophy. Ann Inter Med. 2005, 143: 337-346. source

      Not checked in the free run.

    • cites [97] Hadigan C, Corcoran C, Basgoz N: Metformin in the Treatment of HIV Lipodystrophy Syndrome A Randomized Controlled Trial. JAMA. 2000, 284: 472-477. 10.1001/jama.284.4.472. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A prospective study found that metformin use at baseline was associated with lower cancer-related mortality, and the association appeared dose dependent.

    “A prospective study (median follow-up time of 9.6 years) found that metformin use at baseline was associated with lower cancer-related mortality and that this association appeared to be dose dependent [138].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Landman GW, Kleefstra N, van Hateren KJ: Metformin associated with lower cancer mortality in type 2 diabetes ZODIAC-16. Diabetes Care. 2010, 33: 322-326. 10.2337/dc09-1380. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The underlying mechanisms of tumorigenesis in type 2 diabetes seem related to insulin resistance, hyperinsulinemia, elevated IGF-1, and hyperglycemia driving ATP production in cancer cells through the glycolytic pathway (Warburg effect).

    “The underlying mechanisms of tumorigenesis in T2DM seem to be related to insulin resistance, hyperinsulinemia, elevated levels of IGF-1 [140-142], and hyperglycemia with the latter driving ATP production in cancer cells through the glycolytic pathway, a mechanism known as the Warburg effect [142].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [140] Inoue M, Iwasaki M, Otami T: Diabetes mellitus and the risk of cancer. Results from a large-scale population-based cohort study. Arch Intern Med. 2006, 166: 1871-1877. 10.1001/archinte.166.17.1871. source

      Not checked in the free run.

    • cites [141] Grimberg A, Cohen P: Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol. 2000, 183: 1-9. 10.1002/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J. source

      Not checked in the free run.

    • cites [142] Smith U, Gale EAU: Cancer and diabetes: are we ready for prime time?. Diabetologia. 2010, 53: 1541-1544. 10.1007/s00125-010-1815-8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin significantly reduces tumorigenesis and cancer cell growth.

    “Metformin significantly reduces tumorigenesis and cancer cell growth although how it does it is not well understood.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Papanas N, Maltezos E, Mikhailidis DP: Metformin and cancer: licence to heal?. Expert Opin Investig Drugs. 2010, 19: 913-917. 10.1517/13543784.2010.499122. source

      Not checked in the free run.

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

    Premisecitation

    Insulin regulates food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory, as well as neuronal proliferation, apoptosis, and synaptic transmission in the central nervous system.

    “Insulin has been shown to regulate a wide range of processes in the central nervous system such as food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory [129], as well as neuronal proliferation, apoptosis, and synaptic transmission [130].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129] Gupta A, Bisht B, Dey CS: Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like change. Neuropharmacology. 2011, 60: 910-920. 10.1016/j.neuropharm.2011.01.033. source

      Not checked in the free run.

    • cites [130] Selkoe DJ: The cell biology of ßamyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol. 1998, 8: 447-453. 10.1016/S0962-8924(98)01363-4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When insulin is added to metformin, it potentiates insulin's effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and Alzheimer's disease-associated neuropathological characteristics by activating the insulin signaling pathway.

    “However, when insulin is added to metformin, it potentiates insulin’s effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and AD-associated neuropathological characteristics by activating the insulin signaling pathway [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Gupta A, Bisht B, Dey CS: Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like change. Neuropharmacology. 2011, 60: 910-920. 10.1016/j.neuropharm.2011.01.033. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTOR is a key integrator of growth factor and nutrient signals and a critical mediator of the PI3K/PKB/Akt pathway, one of the most frequently dysregulated signaling pathways in human cancer.

    “The mTOR is a key integrator of growth factor and nutrient signals as well as a critical mediator of the PI3K/PKB/Akt pathway, one of the most frequently disregulated signaling pathways in human cancer [144].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Kalender A, Selvaraj A, Kim SY: Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPasedependent manner. Cell Metab. 2010, 11: 390-401. 10.1016/j.cmet.2010.03.014. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Many studies showed reduced incidence of different types of cancer as well as reduced cancer-related mortality in patients using metformin.

    “Many studies showed reduced incidence of different types of cancer in patients as well a reduced cancer-related mortality in patients using metformin (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Metformin's anticancer effect may be due to effects on insulin reduction and hyperinsulinemia, and consequently on IGF-1 levels, but may also involve specific AMPK-mediated pathways.

    “It may be due to its effects on insulin reduction and hyperinsulinemia, and consequently on IGF-1 levels, which have mitogenic actions enhancing cellular proliferation,but may also involve specific AMPK-mediated pathways [133].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Papanas N, Maltezos E, Mikhailidis DP: Metformin and cancer: licence to heal?. Expert Opin Investig Drugs. 2010, 19: 913-917. 10.1517/13543784.2010.499122. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin promotes rodent and human neurogenesis in culture by activating the PKC-CBP pathway, recruiting neural stem cells, and enhancing neural function, particularly spatial memory.

    “Metformin has been shown to promote rodent and human neurogenesis in culture by activating a protein kinase C-CREB binding protein (PKC-CBP) pathway, recruiting neural stem cells and enhancing neural function, particularly spatial memory function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Wang J, Gallagher D, De Vito L: Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012, 11: 23-35. 10.1016/j.stem.2012.03.016. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When compared to those on other treatments, metformin users had a lower risk of cancer, and a dose-relationship has been reported.

    “When compared to those on other treatments, metformin users had a lower risk of cancer. A dose-relationship has been reported [138,144,145].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138] Landman GW, Kleefstra N, van Hateren KJ: Metformin associated with lower cancer mortality in type 2 diabetes ZODIAC-16. Diabetes Care. 2010, 33: 322-326. 10.2337/dc09-1380. source

      Not checked in the free run.

    • cites [144] Kalender A, Selvaraj A, Kim SY: Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPasedependent manner. Cell Metab. 2010, 11: 390-401. 10.1016/j.cmet.2010.03.014. source

      Not checked in the free run.

    • cites [145] Evans J, Donelly L, Emslie A: Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005, 330 (7503): 1304-1305. 10.1136/bmj.38415.708634.F7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About 10-30% of patients prescribed metformin have evidence of reduced vitamin B12 absorption due to calcium-dependent ileal membrane antagonism, an effect that can be reversed with supplemental calcium.

    “About 10–30% of patients who are prescribed metformin have evidence of reduced vitamin B12 absorption due to calcium-dependent ileal membrane antagonism, an effect that can be reversed with supplemental calcium [166].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Bauman WA, Shaw S, Jayatilleke E: Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000, 23: 1227-1231. 10.2337/diacare.23.9.1227. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several reports related an increased risk of lactic acidosis with biguanides, mostly phenformin, with an event rate of 40-64 per 100,000 patient years, whereas the reported incidence with metformin is 6.3 per 100,000 patient years.

    “Several reports in literature related an increased risk of lactic acidosis with biguanides, mostly phenformin, with an event rate of 40–64 per 100,000 patients years [159] whereas the reported incidence with metformin is 6.3 per 100,000 patients years [160].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] Rosand J, Friedberg J, Yang J: Fatal phenformin-associated lactic acidosis. Ann Intern Med. 1997, 127: 170- source

      Not checked in the free run.

    • cites [160] 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, 1: CD002967-

      Not checked in the free run.

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

    Premisecitation

    As much as 5% of patients do not tolerate even the lowest dose of metformin.

    “However, as much as 5% of patients do not tolerate even the lowest dose [165].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Cusi K, DeFronzo RA: Metformin: a review of its metabolic effects. Diabetes Rev. 1998, 6: 89-131.

      Not checked in the free run.

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

    Premisecitation

    Other adverse reactions of metformin are sporadic, such as leucocytoclastic vasculitis, allergic pneumonitis, cholestatic jaundice, and hemolytic anaemia.

    “Other adverse reactions are sporadic, such as leucocytoclastic vasculitis, allergic pneumonitis [170], cholestatic jaundice [171], and hemolytic anaemia [172].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [170] Klapholz L, Leitersdorf E, Weinrauch L: Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ. 1986, 293: 483- source

      Not checked in the free run.

    • cites [171] Desilets DJ, Shorr AF, Moran KA, Holtzmuller KC: Cholestatic jaundice associated with the use of metformin. Am J Gastroenterol. 2001, 96: 2257-2258. 10.1111/j.1572-0241.2001.03972.x. source

      Not checked in the free run.

    • cites [172] Kashyap AS, Kashyap S: Haemolytic anaemia due to metformin. Postgrad Med J. 2000, 76: 125-126. 10.1136/pmj.76.892.125. source

      Not checked in the free run.

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

    Premisecitation

    Vitamin B12 deficiency in metformin users is rarely associated with megaloblastic anemia.

    “This vitamin B12 deficiency is rarely associated with megaloblastic anemia [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Callaghan TS, Hadden DR, Tomkin GH: Megaloblastic anemia due to vitamin B12 malaborsption associated with long-term metformin treatment. Br Med J. 1980, 280: 1214-1215. 10.1136/bmj.280.6225.1214. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vitamin B12 deficiency is related to dose and duration of metformin use and occurs more frequently among patients who use it for more than 3 years and in higher doses.

    “Vitamin B12 deficiency has been related with dose and duration of metformin use and occurs more frequently among patients that use it for more than 3 years and in higher doses [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Wei Ting RZ, Szeto CC, Chan M, Ma K: Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin. Arch Intern Med. 2006, 166: 1975-1979. 10.1001/archinte.166.18.1975. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Some proposed anti-cancer mechanisms of metformin may be through inhibition of cell growth, IGF-1 signaling, mTOR pathway, reduction of HER-2 expression, inhibition of angiogenesis and inflammation, induction of apoptosis and p53 activation, cell cycle arrest, and enhancement of CD8 T cell memory.

    “Some of these mechanisms may be through inhibition of cell growth [148], IGF-1 signaling [149], inhibition of the mTOR pathway [150], reduction of human epidermal growth factor receptor type 2 (HER-2) expression (a major driver of proliferation in breast cancer) [151], inhibition of angiogenesis and inflammation [152], induction of apoptosis and protein 53 (p53) activation [153], cell cycle arrest”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [148] Ben Sahra I, Laurent K, Loubat A: The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008, 27: 3576-3586. 10.1038/sj.onc.1211024. source

      Not checked in the free run.

    • cites [149] Pollak M: Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer. 2008, 8: 915-928. 10.1038/nrc2536. source

      Not checked in the free run.

    • cites [150] Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006, 66: 10269-10273. 10.1158/0008-5472.CAN-06-1500. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Above 30 ml/min/1.73 m2, metformin levels rarely go above 20 mmol/l, which seems to be a safe level.

    “Frid et al. supports these recommendations through findings that above 30 ml/min/1.73 m2 metformin levels rarely goes above 20 mmol/l, which seems to be a safe level [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Frid A, Sterner GN, Londahl M: Novel assay of metformin levels in patients with type 2 diabetes mellitus and varying levels of renal function. Diabetes Care. 2010, 33: 1291-1293. 10.2337/dc09-1284. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gastrointestinal side-effects of metformin are generally transient, arise early in the course of treatment, and tend to subside over time.

    “These effects are generally transient, arise early in the course of treatment, and tend to subside over time [176].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H: Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab. 1991, 17: 224-231.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin XR has been associated with improved tolerability and increased compliance.

    “Metformin XR has been associated with improved tolerability [182] and increased compliance [183].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Raz I, Delaet I, Goyvaerts H: Safety and efficacy of novel extended-release formulation of metformin in patients with type 2 diabetes. Diabetes. 2000, 49 (Suppl 1): A363-

      Not checked in the free run.

    • cites [183] Donnelly LA, Morris AD, Pearson ER: Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab. 2009, 11: 338-342. 10.1111/j.1463-1326.2008.00973.x. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In recent years, metformin has become the first-line therapy for patients with type 2 diabetes.

    “In recent years, metformin has become the first-line therapy for patients with type 2 diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gastrointestinal side-effects are common with the use of metformin of standard release and are usually associated with rapid titration and high-dose initiation.

    “Gastrointestinal side-effects are common with the use of metformin of standard release and are usually associated with rapid titration and high-dose initiation of metformin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H: Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab. 1991, 17: 224-231.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoglycemia is very uncommon with metformin monotherapy but has been reported in combination regimens, likely due to metformin potentiating other therapeutic agents.

    “Hypoglycemia is very uncommon with metformin monotherapy [173] but has been reported in combination regimens [174], likely due to metformin potentiating other therapeutic agents.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [173] Giugliano D, De Rosa N, Di Maro G: Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care. 1993, 16: 1387-1390. 10.2337/diacare.16.10.1387. source

      Not checked in the free run.

    • cites [174] United Kingdom Prospective Diabetes Study (UKPDS) Group: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years (UKPDS 13). BMJ. 1995, 310: 83-88. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a prospective open label study, no significant differences were observed in any anthropometric, clinical, or laboratory measures except plasma triglycerides, which were lower in the group switched to metformin XR.

    “No significant differences were observed by any anthropometric, clinical, or laboratory measures except for plasma triglycerides which were lower in the group switched to metformin XR [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Levy J, Cobas RA, Gomes MB: Assessment of efficacy and tolerability of oncedaily extended release metformin in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2010, 2: 16-10.1186/1758-5996-2-16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin XR releases the active drug through hydrated polymers that expand after uptake of fluid, prolonging gastric residence time, leading to slower drug absorption in the upper gastrointestinal tract and allowing once-daily administration.

    “The metformin XR formulation releases the active drug through hydrated polymers which expand after uptake of fluid, prolonging gastric residence time which leads to slower drug absorption in the upper gastrointestinal tract and allows once-daily administration [180].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Donahue S, Marathe P, Guld T, Meeker J: The phamacokinetics and pharmacodynamics of extended-release metformin tablets vs immediate-release metformin in subjects with type 2 diabetes. Diabetes. 2002, 51 (Suppl 2): A468-

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin tolerability as well as patient acceptance was greater in the group switched to metformin XR.

    “Metformin tolerability as well as patient acceptance was greater in the group switched to metformin XR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Levy J, Cobas RA, Gomes MB: Assessment of efficacy and tolerability of oncedaily extended release metformin in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2010, 2: 16-10.1186/1758-5996-2-16. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Thus far, metformin is the only antidiabetic agent that has shown reduced macrovascular outcomes, which is likely explained by its effects beyond glycemic control.

    “Thus far, metformin is the only antidiabetic agent which has shown reduced macrovascular outcomes which is likely explained by its effects beyond glycemic control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A large amount of evidence supports metformin use even in cases where it would be contraindicated, because available data suggest that lactate levels and risk of lactic acidosis do not differ appreciably in patients taking metformin versus other glucose-lowering agents.

    “A large amount of evidence in literature supports its use even in cases where it would be contra-indicated mainly due to the fear of lactic acidosis which has been over-emphasized as the available data suggest that lactate levels and risk of lactic acidosis do not differ appreciably in patients taking this drug versus other glucose-lowering agents.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Some cationic agents eliminated by renal tubular secretion may compete with metformin for elimination.

    “Some cationic agents such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin that are eliminated by renal tubular secretion may compete with metformin for elimination.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Glucophage® and Glucophage XRproduct information. Bristol-Myers Squibb Company. 2003, Available at: http://www.drugs.com/pro/glucophage.html

      Not checked in the free run.

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

    Premisecitation

    Concomitant administration of cimetidine, furosemide, or nifedipine may increase the concentration of metformin.

    “Concomitant administration of cimetidine, furosemide, or nifedipine may also increase the concentration of metformin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Glucophage® and Glucophage XRproduct information. Bristol-Myers Squibb Company. 2003, Available at: http://www.drugs.com/pro/glucophage.html

      Not checked in the free run.

81 of 81

  • The paper relies on this without support.

    Aggressive treatment is required in type 2 diabetes mellitus to achieve glycemic and cardiovascular risk factor goals.

    “The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals.”

  • The paper relies on this without support.

    Lifestyle modifications such as diet and exercise and switching antiretroviral therapies are of limited value in reducing visceral abdominal fat.

    “Lifestyle modifications such as diet and exercise and switching antiretroviral therapies seems to be of limited value in reducing visceral abdominal fat (VAT).”

  • The paper relies on this without support.

    Mitochondrial dysfunction has a pivotal role in oxidative stress.

    “Mitochondrial dysfunction has a pivotal role in oxidative stress.”

  • The paper relies on this without support.

    Renal dysfunction is the most common risk factor associated with lactic acidosis in patients using metformin.

    “Renal dysfunction is the most common risk factor associated with lactic acidosis”
4 of 4

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?

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.

  • Table 3 attributes reference 135 to Evans instead of Li

    Minor

    Table 3 identifies reference 135 as an Evans study of an unspecified tumor type, but reference 135 is a Li study of pancreatic cancer.

  • Table 2 labels reference 18 UKPDS 33, but the reference is UKPDS 34

    Minor

    The study number in Table 2 disagrees with the study number in its cited reference.

  • Table 2 attributes reference 24 to Johnson instead of Hanefeld

    Minor

    Table 2 cites reference 24 for a Johnson study, but reference 24 is authored by Hanefeld and colleagues.

  • IDPP lifestyle risk reduction differs between text and Table 1

    Minor

    Table 1 assigns the 28.2% reduction to lifestyle modification. The text instead assigns 28.5% to lifestyle modification and 28.2% to lifestyle modification plus metformin.

4 of 4

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 2

  1. Donahue S, Marathe P, Guld T, Meeker J: The phamacokinetics and pharmacodynamics of extended-release metformin tablets vs immediate-release metformin in subjects with type 2 diabetes. Diabetes. 2002, 51 (Suppl 2): A468-
  2. Raz I, Delaet I, Goyvaerts H: Safety and efficacy of novel extended-release formulation of metformin in patients with type 2 diabetes. Diabetes. 2000, 49 (Suppl 1): A363-

Cited by

Sorted by citations

Related

Authors
Rojas, L. B. A., & Gomes, M. B.
Affiliations
Universidade do Estado do Rio de Janeiro (BR)
Corresponding author
Rojas, Lilian Beatriz Aguayo
Venue
Diabetology & Metabolic Syndrome
Publisher
Springer Science and Business Media LLC
Published
2013-02-15
Volume
5
Issue
1
Pages
6-6
ISSN
1758-5996 (ISSN-L)
DOI
10.1186/1758-5996-5-6
PMC
PMC3607889
OpenAlex
W2119008227
Semantic Scholar
8aecf912fff7c01ab9a5048ab405b159114ee63e
Cited by
567
References
194
Citations by year
2026: 18 · 2025: 39 · 2024: 33 · 2023: 57 · 2022: 41 · 2021: 49 · 2020: 67 · 2019: 45 · 2018: 46 · 2017: 62 · 2016: 46 · 2015: 26 · 2014: 28 · 2013: 10
FWCI
28.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetology & Metabolic Syndrome (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
metformin, type 2 diabetes, first-line therapy, glycemic control, cardiovascular risk reduction, insulin resistance, endothelial dysfunction, oxidative stress, hemostasis, lipid profile, fat redistribution, oral antidiabetic drugs, drug interactions, hypoglycemia, dose titration, sustained drug release, prediabetes, obesity, gestational diabetes mellitus, cancer, neuroprotection

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