The DOI matches its Crossref record; 196 of the 196 references it cites were found in a registry or an index; 12 of the 233 sources its claims cite were checked for support.
Metformin: an old but still the best treatment for type 2 diabetes
Open accessAbstract
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.
Overview
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.
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Claims the paper makes
165 Not checked yet · 7 Own interpretation · 3 Supported · 2 Partly supported · 1 Supported so far · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Diabetes incidence rates were similar between treatment groups: 5.9 per 100 person-years (5.1–6.8) for lifestyle, 4.9 (4.2–5.7) for metformin, and 5.6 (4.8–6.5) for placebo.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Supportedcites [11] Diabetes Prevention Program Research Group: 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009, 374 (9702): 1677-1686. 10.1016/S0140-6736(09)61457-4. source
The Abstract Findings report that diabetes incidence rates during DPPOS were similar between treatment groups and give exactly 5.9, 4.9, and 5.6 cases per 100 person-years for lifestyle, metformin, and placebo, respectively. The Results also state that rates did not significantly differ between groups during DPPOS. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In this study, treatment of bovine capillary endothelial cells incubated in hyperglycemic medium with metformin was able to decrease the activity of NF-kB and others intracellular proteins related to cellular metabolic memory.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on oxidative stress
What the sources say
- Supportedcites [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
The Results section on bovine retinal capillary endothelial cells reports that metformin attenuated the high-glucose-induced increase in NF-κB, Bax, and PAR protein expression. This supports the claimed effect on proteins associated with metabolic memory, although the cellular result is described as reduced expression rather than a direct measurement of NF-κB activity. No page number is available in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It has also direct effects on fibrin structure and function by decreasing factor XIII activity and changing fibrin structure [92].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on hemostasis
What the sources say
- Supportedcites [92] Standeven KF, Ariens RA, Whitaker P: The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes. 2002, 51: 189-197. source
The ‘Effect of DMB on FXIII activity in vitro’ section reports that metformin decreased FXIII cross-linking activity. The clot-structure results report significantly thinner fibrin fibers and smaller pores in clots formed with metformin. These experiments support the attributed direct effects on fibrin formation, without implying that metformin binds directly to FXIII. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The reduced risk of cancer and cancer mortality observed in these studies has been consistently in the range of 25% to 30% [135-139,145-147].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Partly supportedcites [135] Li D, Yeung SJ, Hassan MM, Konopleva M, Abbruzzese JL: Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009, 137 (2): 482-488. 10.1053/j.gastro.2009.04.013. sourceExperimental — accuracy not yet measured
The Results report lower pancreatic-cancer risk among metformin users with diabetes, but the reported odds ratio of 0.38 corresponds to a 62% reduction in odds, not 25%–30%. The paper does not report cancer mortality or establish a consistent reduction across studies. (LLM, conf=0.87)
- Not checked yetcites [136] Donadon V, Balbi M, Valent F, Avogaro A: Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma. World J Gastroenterol. 2010, 16 (24): 3025-3032. 10.3748/wjg.v16.i24.3025. source
- Partly supportedcites [137] Libby G, Donnelly LA, Donnan PT: New users of metformin area at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009, 32: 1620-1625. 10.2337/dc08-2175. sourceExperimental — accuracy not yet measured
The Results (Main outcome measures and Secondary outcomes; page unavailable) report lower cancer incidence and cancer mortality among metformin users than comparators, both with an adjusted hazard ratio of 0.63—a 37% reduction. The paper therefore supports the direction of the claim, but not its stated 25%–30% range or the assertion that findings across studies were consistently in that range. (LLM, conf=0.88)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
The Results (Cancer mortality) support an association between metformin use and lower cancer mortality. But the adjusted hazard ratio is 0.43, corresponding to an estimated 57% reduction—not the claimed 25%–30%. This study measured cancer mortality rather than cancer incidence. (LLM, conf=0.88)
- Could not verifycites [139] Lee JH, Kim TI, Jeon SM: The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer. 2011, 12: 1-24. sourceExperimental — accuracy not yet measured
The Methods and Results describe a comparison of laparoscopic and open surgery for ovarian metastases from gastric cancer, not studies of metformin users. A search of our copy for metformin, cancer risk, and cancer mortality found no passage reporting a 25%–30% reduction; the Discussion’s 30% figure is a two-year survival rate after metastasectomy. (LLM, conf=0.77)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
The table in the Comment section reports adjusted odds ratios of 0.75 and 0.73 for two metformin-prescription categories, consistent with roughly 25%–27% lower odds of cancer. But this pilot case-control study reports other estimates outside the claimed range, does not assess cancer mortality, and cannot establish consistency across the other cited studies. Page numbers are not available in our copy. (LLM, conf=0.87)
- Partly supportedcites [146] Bodmer M, Meier C, Krähenbühl S: Long-term metformin Use is associated with decreased risk of breast cancer. Diabetes Care. 2010, 33: 1304-1308. 10.2337/dc09-1791. sourceExperimental — accuracy not yet measured
The Conclusions report a 27% lower overall cancer risk in one earlier study (adjusted OR 0.73), which falls within the claimed range. But the paper’s own Results report a 37% lower breast cancer risk for users with ≥30 prescriptions (OR 0.63) and a 56% lower risk with ≥40 prescriptions (OR 0.44). Its discussion of cancer mortality gives no 25–30% estimate, so this source does not support the claim that the reductions were consistently in that range. (LLM, conf=0.86)
- Partly supportedcites [147] Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with type 2 diabetes who usesulfonylureas or insulin. Diabetes Care. 2006, 29: 254-258. 10.2337/diacare.29.02.06.dc05-1558. sourceExperimental — accuracy not yet measured
The Results report cancer-related mortality of 3.5% in metformin users versus 4.9% in sulfonylurea users, an approximately 29% lower unadjusted proportion. The paper did not measure cancer incidence; its introduction reports a 23% reduction in another study, so this source does not establish that reductions in both cancer risk and mortality were consistently 25%–30% across studies. The authors also say it is uncertain whether the mortality difference reflects a protective effect of metformin. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Structural and pharmacokinetic differences in metformin such as poor adherence to the mitochondrial membrane, lack of interference with lactate turnover, unchanged excretion, and inhibition of electron transport and glucose oxidation may account for such differences [161].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin contraindications
What the sources say
- Partly supportedcites [161] Tahrani AA, Varghese GI, Scarpello JH, Hanna FWF: Metformin, heart failure and lactic acidosis: is Metformin absolutely contraindicated?. BMJ. 2007, 355: 508-512. sourceExperimental — accuracy not yet measured
Table 1 (Conclusions) says pharmacological differences between metformin and phenformin might explain metformin’s lower incidence of lactic acidosis. It supports poor mitochondrial-membrane adherence, no interference with lactate turnover, and unchanged excretion for metformin. However, the citing sentence appears to attribute inhibition of electron transport and glucose oxidation to metformin; the table marks both as absent for metformin and present for phenformin. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“The association of IFG with cardiovascular events, however, has not been well established [6].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) statuses are associated with increased and varying risk of developing type 2 diabetes mellitus.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that, at least in the short-term, metformin may help delay the onset of diabetes.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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).”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 66
- Probably not a substantial claim. 21
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“It can upregulate uncoupled proteins 2 (UCP2) in adipose tissue [102] and can also cause an increase in reduced glutathione [100].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on oxidative stress
What the sources say
- Supportedcites [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
The Results section, “Metformin induces the expression of UCP2 in mouse white adipose tissue” (page not provided), reports that UCP2 protein increased markedly in mouse white adipose tissue after metformin treatment. Citation [102] is attached only to the UCP2 claim; the reduced-glutathione claim is attributed to [100] and is not part of this verdict. (LLM, conf=0.94)
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
In the paper
“Diabetes incidence increased from 25.2 to 30.6% in the metformin group and from 33.4 to 36.7% in the placebo group.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“IGT has been associated with an increased risk of cardiovascular events and may determine an increased mortality risk.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
- Rests on an assumption: Aggressive treatment is required in type 2 diabetes mellitus to achieve glycemic and cardiovascular risk factor goals.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Lifestyle intervention and metformin reduced diabetes incidence by 58% and 31%, respectively, when compared with placebo [7].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin in combination therapy
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and thiazolinediones
What the sources say
- Not checked yetcites [34] Scheen AJ: ADOPT study: which first-line glucose-lowering oral medication in type 2 diabetes?. Rev Med Liege. 2007, 62 (1): 48-52.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The glimepiride/metformin combination results in a lower HbA1c concentration and fewer hypoglycemic events when compared to the glibenclamide/metformin combination [25].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and sulfonylureas
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and thiazolinediones
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin in combination therapy
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin in the management of adult diabetic patients
What the sources say
- Not checked yetcites [16] American Diabetes Association: Summary of revisions to the 2011 clinical practice recommendations. Diabetes Care. 2011, 34 (Suppl 1): S3-
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The use of metformin was associated with reduced all-cause mortality and reduced cardiovascular mortality.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and sulfonylureas
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and insulin
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin in the management of adult diabetic patients
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin use in childhood and adolescence
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Metformin is associated with short-term weight loss, improvement of insulin sensitivity, and decreased visceral fat [59].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin indications for management of obesity, insulin resistance, and non-alcoholic fatty liver in children and adolescents
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The PRESTO trial showed significant reductions of any clinical event (28%), myocardial infarction (69%), and all-cause mortality (61%) [74].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pregnancy
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and incretin-based therapies
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin use in childhood and adolescence
What the sources say
- Not checked yetcites [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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Diabetic patients are at high risk of cardiovascular events, particularly of coronary heart disease by about 3-fold [67,68].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin indications for management of obesity, insulin resistance, and non-alcoholic fatty liver in children and adolescents
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The risk of developing cardiac heart failure (CHF) in diabetic individuals nearly doubles as the population ages [77].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and heart failure
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and heart failure
What the sources say
- Not checked yetcites [80] Food and Drug Administration. Product label approval: metformin. 2006, http://packageinserts.bms.com/pi/piglucophage.pdf ,
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and heart failure
What the sources say
- Not checked yetcites [83] Papanas N, Maltezos E, Mikhailidis DP: Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012, 1: 1-8. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Beyond glycemic control
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on endothelial function
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and heart failure
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [83] Papanas N, Maltezos E, Mikhailidis DP: Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012, 1: 1-8. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Conversely, Vitale et al. found significant improvement of endothelium dependent flow without a significant effect on endothelium independent response [90].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on endothelial function
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on oxidative stress
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on oxidative stress
What the sources say
- Not checked yetcites [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 yetcites [101] Beisswenger P, Rugiero-Lopez D: Metformin inhibition of glycation processes. Diabetes Metab. 2003, 29 (6S): 95-103.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on oxidative stress
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The activated protein kinase (AMPK) forms a molecular hub for cellular metabolic control [122].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and neuroprotection
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on thyroid function
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oxidative stress has been implicated in a variety of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis disease [126].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and neuroprotection
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Nucleoside reverse transcriptase inhibitors (NRTIs), particularly thymidine analogues (zidovudine and stavudine), have been associated with morphological changes, particularly extremity fat loss [116]”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and HIV lypodystrofy
What the sources say
- Not checked yetcites [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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Metformin is associated with improvements in lipoprotein metabolism, including decreases in LDL-C [95], fasting and postprandial TGs, and free fatty acids [106].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects on lipid profile
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and HIV lypodystrofy
What the sources say
- Not checked yetcites [115] Kinlaw WB, Marsh B: Adiponectin and HIV-lipodystrophy:taking HAART. Endocrinology. 2004, 145: 484-486. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Favorable effects on insulin levels [98], insulin sensitivity [119], weight [97], flow-mediated vasodilation [119], and lipid profiles [98,119] have also been described.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and HIV lypodystrofy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Metformin significantly reduces tumorigenesis and cancer cell growth although how it does it is not well understood.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and neuroprotection
What the sources say
- Not checked yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and neuroprotection
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and neuroprotection
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“When compared to those on other treatments, metformin users had a lower risk of cancer. A dose-relationship has been reported [138,144,145].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Future roles for metformin in cancer therapy
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin contraindications
What the sources say
- Not checked yetcites [159] Rosand J, Friedberg J, Yang J: Fatal phenformin-associated lactic acidosis. Ann Intern Med. 1997, 127: 170- source
- Not checked yetcites [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-
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, as much as 5% of patients do not tolerate even the lowest dose [165].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [165] Cusi K, DeFronzo RA: Metformin: a review of its metabolic effects. Diabetes Rev. 1998, 6: 89-131.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Other adverse reactions are sporadic, such as leucocytoclastic vasculitis, allergic pneumonitis [170], cholestatic jaundice [171], and hemolytic anaemia [172].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [170] Klapholz L, Leitersdorf E, Weinrauch L: Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ. 1986, 293: 483- source
- Not checked yetcites [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 yetcites [172] Kashyap AS, Kashyap S: Haemolytic anaemia due to metformin. Postgrad Med J. 2000, 76: 125-126. 10.1136/pmj.76.892.125. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This vitamin B12 deficiency is rarely associated with megaloblastic anemia [167].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin contraindications
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“These effects are generally transient, arise early in the course of treatment, and tend to subside over time [176].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Tolerability
What the sources say
- Not checked yetcites [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.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Metformin XR has been associated with improved tolerability [182] and increased compliance [183].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin XR
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In recent years, metformin has become the first-line therapy for patients with type 2 diabetes.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Conclusions
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Tolerability
What the sources say
- Not checked yetcites [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.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Hypoglycemia is very uncommon with metformin monotherapy [173] but has been reported in combination regimens [174], likely due to metformin potentiating other therapeutic agents.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Adverse effects
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin XR
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin XR
What the sources say
- Not checked yetcites [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-
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Metformin tolerability as well as patient acceptance was greater in the group switched to metformin XR.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin XR
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus far, metformin is the only antidiabetic agent which has shown reduced macrovascular outcomes which is likely explained by its effects beyond glycemic control.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Conclusions
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Drug interactions
What the sources say
- Not checked yetcites [175] Glucophage® and Glucophage XRproduct information. Bristol-Myers Squibb Company. 2003, Available at: http://www.drugs.com/pro/glucophage.html
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Concomitant administration of cimetidine, furosemide, or nifedipine may also increase the concentration of metformin.”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Drug interactions
What the sources say
- Not checked yetcites [175] Glucophage® and Glucophage XRproduct information. Bristol-Myers Squibb Company. 2003, Available at: http://www.drugs.com/pro/glucophage.html
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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”
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?
In the citing paper
“Metformin is a synthetic biguanide, orally effective and insulin sensitizing anti-diabetic drug, which for most patients is the first line anti-hyperglycemic for the treatment of type 2 diabetes mellitus (T2DM) (1).”
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 [1]
In the citing paper
“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 [1]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and cancer
“| Evans [135] | Pilot Observational Study | Not specified | Tayside, Scotland. UK | 11,876 | 8 | IMC, smoking, blood pressure, material deprivation |”
§ Metformin: an old but still the best treatment for type 2 diabetes > References
“135. Li D Yeung SJ Hassan MM Konopleva M Abbruzzese JL Anti-diabetic therapies affect risk of pancreatic cancer”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
“| UKPDS 33 [18] | Prospective | 10 yr | Significant reduction in all-cause mortality, diabetes related mortality, and any end-point related to diabetes. |”
§ Metformin: an old but still the best treatment for type 2 diabetes > References
“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)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Effects of metformin on vascular protection
“| Johnson et al.[24] | Retrospective | 9 yr | Reduction of all-cause mortality and of cardiovascular mortality |”
§ Metformin: an old but still the best treatment for type 2 diabetes > References
“24. Hanefeld M Brunetti P Schhernthaner GH One year glycemic control with sulphonylurea plus pioglitazone versus sulphonylurea plus metformin”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
“| IDPP [9] | yes | India | 522 | 3 | −26.4% | −28.2% |”
§ Metformin: an old but still the best treatment for type 2 diabetes > Introduction > Metformin and pre-diabetes
“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)”
Citations
Cites
1 retracted
Interventions for treating obesity in children
Oude Luttikhuis, H., Baur, L., Jansen, H., Shrewsbury, V. A., O'Malley, C., Stolk, R. P., & Summerbell, C. D. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001872.pub2 · Cited by 1,531
RetractedGrundy, S. M., Bilheimer, D. W., Chait, A., Clark, L. T., Denke, M. A., Havel, R. J., Hazzard, W. R., Hulley, S. B., Hunninghake, D. B., Kreisberg, R. A., et al. (1993) · JAMA · doi:10.1001/jama.269.23.3015 · Cited by 27,944
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297
Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)
Grundy, S. M., Becker, D. M., Clark, L. T., Cooper, R., Denke, M. A., Howard, J. L., Hunninghake, D. B., Illingworth, D. R., Luepker, R. V., McBride, P. E., et al. (2002) · Civil War Book Review · Cited by 12,198
10-year follow-up of intensive glucose control in type 2 diabetes
Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R., & Neil, H. A. W. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0806470 · Cited by 7,751
Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199807233390404 · Cited by 7,000
Pan, X.-R., Li, G.-W., Hu, Y.-H., Wang, J.-X., Yang, W.-Y., An, Z.-X., Hu, Z.-X., Juan-Lin, Xiao, J.-Z., Cao, H.-B., et al. (1997) · Diabetes Care · doi:10.2337/diacare.20.4.537 · Cited by 4,320
Research works printed but not linked: 2
- 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-
- 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
Items 101–109 of 109
The Influence of Metformin on IGF-1 Levels in Humans: A Systematic Review and Meta-Analysis
Yang, X., Kord-Varkaneh, H., Talaei, S., Clark, C. C. T., Zanghelini, F., Tan, S. C., Zarezadeh, M., Mousavi, S. M., Rahmani, J., & Zhang, Y. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2019.104588 · Cited by 43
The emerging role of metformin in gestational diabetes mellitus
Gray, S. G., McGuire, T. M., Cohen, N., & Little, P. J. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12893 · Cited by 40
Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor Behind the Scene
Anwar, M. A., Kheir, W. A., Eid, S., Fares, J., Liu, X., Eid, A. H., & Eid, A. A. (2014) · Journal of Cancer · doi:10.7150/jca.9726 · Cited by 35
Chu, P. Y., Hackstadt, A. J., Chipman, J., Griffin, M. R., Hung, A. M., Greevy, R. A., Grijalva, C. G., Elasy, T., & Roumie, C. L. (2020) · Diabetes Care · doi:10.2337/dc19-2391 · Cited by 31
Mathews Samuel, S., Satheesh, N. J., Ghosh, S., Büsselberg, D., Majeed, Y., Ding, H., & Triggle, C. R. (2019) · Cancers · doi:10.3390/cancers11111737 · Cited by 28
Durden, E., Lenhart, G., Lopez-Gonzalez, L., Hammer, M., & Langer, J. (2016) · Journal of Medical Economics · doi:10.3111/13696998.2015.1131703 · Cited by 23
Sapkota, B., Subramanian, A., Priamvada, G., Finely, H., Blackett, P. R., Aston, C. E., & Sanghera, D. K. (2015) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2015.07.025 · Cited by 25
Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder
Trujillo-Del Río, C., Tortajada-Pérez, J., Gómez-Escribano, A. P., Casterá, F., Peiró, C., Millán, J. M., Herrero, M. J., & Vázquez-Manrique, R. P. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111670 · Cited by 19
Zafarvahedian, E., Roohi, A., Sepand, M. R., Ostad, S. N., & Ghahremani, M. H. (2017) · Cell Biochemistry and Function · doi:10.1002/cbf.3289 · Cited by 8
Metadata
- 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
- Published
- 2013-02-15
- Volume
- 5
- Issue
- 1
- Pages
- 6-6
- ISSN
- 1758-5996 (ISSN-L)
- 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
- gold
- doi.org
- 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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