Metformin

Overall Health Benefits of Metformin

• Treats diabetes symptoms and improves blood sugar levels [1-30]
• Promotes weight loss [31-50]
• Protects against cancer [51-79]
• Improves cardiovascular health [80-94]
• Improves cognitive function [95-110]
• Treats polycystic ovary syndrome [111-126]
• Improves blood pressure [127-133]
• Fights aging and increases longevity [134-175]

What is Metformin?

Metformin is derived from the French Lilac plant called Galega officinalis. In the 1920s, the active ingredient in this plant, known as guanidine compounds, was discovered and isolated. During that time, metformin was created and has been safely prescribed for the treatment of type 2 diabetes. In the past two decades, It has become the first-line drug for treating diabetes in the U.S. and other countries. However, emerging evidence indicates that metformin may hold promise in treating or preventing a multitude of medical conditions.

How Metformin Works

The mechanism behind metformin is that it increases insulin sensitivity by increasing the number of muscle and fat cell insulin receptors and the attraction for the receptor. Metformin also decreases blood sugar production in the liver and its absorption by the intestines or stomach. This in turn improves the body’s response to the effects of insulin. Scientists also believe that the guanidine compounds in metformin have potential health benefits.

Chemical Structure of Metformin

Research on Metformin

A. Treats Diabetes Symptoms and Improves Blood Sugar Levels

Combating diabetes by reducing blood sugar is the main indication of metformin. An overwhelming body of clinical trials supports metformin’s beneficial effects on blood sugar levels:

1. In a study published by the American Diabetes Association, metformin decreased blood sugar levels by 60 to 70mg/dl in patients with non-insulin dependent type II diabetes. [1]
2. Metformin has been shown to reduce the incidence of deaths related to diabetic complications by 30% compared to other medications for diabetes such as insulin, glibenclamide, and chlorpropamide. [2]
3. In patients with pre-diabetes, metformin administration reduced the chance of developing type 2 diabetes mellitus by 31%. [3]
4. A clinical trial found that metformin and insulin have similar safety and efficacy in the treatment of gestational diabetes. [4]
5. In pregnant women, treatment of metformin instead of insulin was associated with less weight gain and improved neonatal outcomes. [5]
6. In patients with type 2 diabetes and impaired glucose tolerance, the combination of metformin and lifestyle interventions delayed the progression of the disease. [6]
7. In the Diabetes Prevention Program (DPP) trial, lifestyle intervention and metformin reduced the incidence of diabetes by 58% and 31%. [7-8]
8. In a Chinese study, subjects with impaired glucose tolerance who received low-dose metformin (750 mg/day) produced large, significant reductions for new onset of type 2 diabetes. [9-10]
9. A study found that metformin treatment was associated with a 40% reduction in the incidence of new-onset diabetes with an absolute risk reduction of 6% during a mean trial duration of 1.8 years. [11]
10. In patients with impaired glucose tolerance and impaired fasting glucose, both higher and lower metformin dosage decreased the rate of conversion from pre-diabetes to diabetes. [12]
11. In patients with type 2 diabetes, early initiation of metformin is recommended as a first-line drug for monotherapy and combination therapy. [13-14]
12. In obese patients with type 2 diabetes mellitus, metformin administration is as effective as sulfonylurea, an antidiabetic drug, in controlling blood sugar levels. [15-16]
13. In patients sub-optimally controlled by diet and exercise, the combination of metformin and insulin secretagogue reduced HbA1c (an indicator of blood sugar control) between 1.5% to 2.2%. [17-19]
14. The combination of metformin with other antidiabetic drugs such as sulfonylureas and alpha-glucosidase inhibitors significantly reduced HbA1c. [20]
15. Combination of metformin and the oral antidiabetic drug glimepiride in diabetic patients resulted in a lower HbA1c concentration and fewer hypoglycemic events (abnormally low blood sugar). [21]
16. The combination of metformin and sulfonylurea was also associated with reduced all-cause mortality. [22]
17. Metformin, as added to insulin-based regimens, has been shown to improve blood sugar control, and reduce body weight, hypoglycemic events, insulin requirements, and total insulin dosage. [23-26]
18. In patients with type 2 diabetes, the combination of metformin and dapagliflozin reduced the incidence of hyperglycemia (high blood sugar). [27-28]
19. The combination of saxagliptin and metformin led to clinically and statistically significant reductions in HbA1c. [29]
20. In patients with non-insulin-dependent diabetes mellitus (NIDDM) that is inadequately controlled by non-pharmacological measures, the addition of metformin to existing antidiabetic therapy resulted in enhanced blood sugar-lowering effects. [30]

B. Promotes Weight Loss

The benefits of metformin go beyond improving blood sugar levels. Studies show that this antidiabetic drug can also benefit obese and overweight individuals by promoting weight loss:

1. A 10-year follow-up study on obese patients with type 2 diabetes revealed reductions in body weight in the group treated with metformin compared to placebo. [31]
2. In obese individuals with type 2 diabetes, metformin administration for 6 months caused a mean weight loss of 7 kg. [32]
3. In the Diabetes Prevention Program (DPP) study, participants who took metformin had reduced body weight and waist circumference compared with placebo. [33]
4. In overweight patients with type 2 diabetes, metformin treatment was associated with lesser weight gain. [34]
5. In obese children and adolescents, metformin was associated with short-term weight loss, improvement of insulin sensitivity, and decreased visceral fat. [35]
6. In overweight and obese patients, metformin induced weight loss by improving leptin and insulin sensitivity. [36]
7. In clinically stable, overweight patients with chronic mental health disorders, metformin was modestly effective in reducing weight. [37]
8. In obese insulin-resistant patients participating in a low-intensity weight-reduction program, metformin had favorable effects on body weight and body composition. [38]
9. In overweight and obese patients, metformin treatment reduced the waist-to-hip ratio. [39]
10. In obese patients with type 2 diabetes, a 700-mg dose of metformin induced weight loss by decreasing food consumption. [40]
11. In Bahraini patients aged 20 or more, metformin treatment was associated with weight loss of 1-10 kg. [41]
12. In elderly participants (60 years and above), metformin reduced body weight without any adverse side effects. [42]
13. In obese, insulin-resistant adolescents, long-term treatment with metformin resulted in stabilization of body mass index (BMI) and improved body composition. [43]
14. In patients with antipsychotic-induced weight gain, metformin treatment resulted in significant weight reduction. [44-48]
15. In women with polycystic ovary syndrome, treatment with 850 mg of metformin twice daily for 6 months reduced weight by an average of 9.24 pounds. [49]
16. In overweight and obese participants, metformin was found to significantly decrease body mass index percentile (BMI), BMI (kg/m2), and weight (kg). [50]

C. Protects Against Cancer

Metformin also has potent anti-cancer properties. Numerous studies show that metformin can help ward off various types of cancer:

1. A study found that metformin users had a 55% decrease in the risk of stomach cancer compared with nonusers. [51-52]
2. A study composed of 27 clinical trials representing more than 24,000 patients found that metformin use was associated with an improved overall survival rate. [53]
3. In diabetic patients with tumors, metformin administration was associated with a 30% reduction in overall tumor onsets. [54-55]
4. In diabetic patients with lung cancer, pancreatic cancer, and breast cancer, metformin administration was associated with a better prognosis. [56-59]
5. A cell study found that metformin inhibited tumor growth by stimulating adenosine 5′ monophosphate-activated protein kinase (AMPK). [60-61]
6. In a breast cancer model, metformin delayed the onset of carcinoma and extended lifespan. [62]
7. Several studies found that metformin was associated with reduced cancer incidence and mortality. [63-68]
8. A study found that long-term metformin use was associated with a reduced risk of ovarian cancer. [69-70]
9. In diabetic patients with breast cancer, metformin treatment was associated with the absence of residual invasive disease. [71-72]
10. In Taiwanese men with type 2 diabetes mellitus, metformin use was associated with a decreased risk of incident prostate cancer. [73]
11. In American diabetic patients, metformin use was associated with a reduced risk of colorectal cancer. [74]
12. In diabetic patients, metformin use was associated with a reduced risk of pancreatic cancer. [75]
13. In patients with preexisting type 2 diabetes mellitus, metformin treatment significantly reduced the risk of liver cancer by more than 80%. [76]
14. In patients with type 2 diabetes, metformin was associated with lower cancer mortality. [77]
15. In diabetic patients with colorectal cancer, metformin improved the survival rate. [78]
16. In female patients with type 2 diabetes, long-term metformin use was associated with a reduced risk of breast cancer. [79]

D. Improves Cardiovascular Health

There’s also a great deal of evidence supporting the beneficial role of metformin on cardiovascular health:

1. Metformin has been shown to prevent the fragmentation of mitochondria in endothelial cells which are associated with atherosclerosis (plaque formation). [80]
2. In patients with heart failure, metformin administration reduced the risk of death by 75%. [81]
3. A study demonstrated that metformin administration in patients with heart disease reduced the risk of heart attack, abnormal heart rhythm, and related deaths. [82]
4. In overweight patients with type 2 diabetes, monotherapy of metformin was correlated with decreased risk of cardiovascular disease. [83]
5. A study found that metformin may help lower the risk of cardiovascular disease by reducing the levels of free fatty acid, triglyceride, and soluble vascular cell adhesion molecule-1 (sVCAM-1). [84]
6. In patients with type 2 diabetes, metformin treatment reduced the risk of coronary heart disease by improving cholesterol levels. [85-86]
7. Metformin may also help combat heart disease by suppressing inflammation and coagulation. [87]
8. In male participants, metformin treatment was associated with a reduced risk of atherosclerosis (coronary artery calcium). [88]
9. In patients with type 2 diabetes, the combination of insulin and metformin reduced the risk of cardiovascular disease by 40%. [89]
10. Metformin can help improve endothelial cell function, which involves the inner lining of the heart, by combating stress and inflammatory response. [90-91]
11. In patients with ischaemic cardiomyopathy (weakening of heart muscle), metformin treatment was associated with reduced rates of heart attack, chest pain, and related deaths. [92]
12. Another mechanism by which metformin improves cardiovascular health is by increasing fat redistribution. [93-94]

E. Improves Cognitive Function

Emerging evidence suggests that metformin may play an important role in preserving cognitive function:

1. In the Singapore Longitudinal Aging Study, the use of metformin was associated with a 51% reduced risk of cognitive impairment. [95]
2. A large observational study of patients with type 2 diabetes reported lower rates of dementia in metformin-treated groups compared to those treated with other antidiabetic drugs. [96]
3. In patients with type 2 diabetes, metformin administration improved cognitive performance. [97]
4. Metformin may help prevent Parkinson’s disease and Alzheimer’s disease by reducing the levels of abnormal protein aggregates in the brain. [98-101]
5. Metformin exerts its neuroprotective effects via AMPK activation. [102-105]
6. Metformin can also improve neurological deficits through various important mechanisms such as decreasing oxidative stress, preventing brain mitochondrial dysfunction, and increasing brain-derived neurotrophic factor levels. [106-109]
7. A cell study found that metformin may help enhance spatial memory by promoting the formation of new nerve cells in the brain. [110]

F. Treats Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a hormonal disorder caused by the collection of several fluids (follicles) in the ovaries, affecting its ability to release eggs. Studies show that metformin may help treat this debilitating condition:

1. In patients with PCOS, metformin helps reverse metabolic abnormalities including insulin resistance, hypertension, and abnormal lipid profiles. [111-112]
2. The mechanisms by which metformin exerts its beneficial effects on PCOS are through increased insulin sensitivity, increased secretion of estrogen by the ovaries, decreased production of androgen, and enhanced production of sex hormone binding globulin. [113-114]
3. In non-obese women with PCOS, metformin administration induced ovulation. [115-116]
4. In women with PCOS, metformin therapy was associated with significant improvement in menstrual regularity and reduction in circulating androgen levels. [117]
5. Metformin therapy in patients with PCOS improved ovarian steroidogenesis (production of estrogen and progesterone). [118-119]
6. Metformin administration in women with PCOS was associated with improved ovulation, pregnancy, and live birth rates. [120]
7. In patients with PCOS undergoing in vitro fertilization, metformin treatment improved the quality of the egg and embryos. [121-122]
8. In anovulatory women with PCOS, metformin normalized ovarian follicular development and uterine blood flow. [123]
9. In PCOS patients, metformin administration reduced the risk of miscarriage. [124-126]

G. Improves Blood Pressure

The ability of metformin to improve insulin resistance and other metabolic parameters may play a part in reducing blood pressure. Studies show that metformin has potent anti-hypertensive effects:

1. Metformin therapy in hypertensive patients reduced systolic blood pressure. [127]
2. In obese non-diabetic subjects with no cardiovascular diseases, metformin administration significantly decreased blood pressure. [128]
3. In non-diabetic patients, metformin effectively lowered systolic blood pressure. [129]
4. In non-diabetic hypertensive patients, metformin treatment induced a decline in diastolic blood pressure. [130]
5. In individuals with impaired fasting glucose, metformin treatment reduced systolic blood pressure. [131]
6. In patients with metabolic syndrome, metformin reduced blood pressure by correcting arterial stiffness. [132]
7. In rats, metformin attenuated salt-induced hypertension. [133]

H. Fights Aging and Increases Longevity

Metformin also has anti-aging benefits. According to studies, it can block or diminish various fundamental factors that accelerate the aging process:

1. Metformin has been shown to slow the process of aging and prevent age-related diseases by protecting against DNA damage, poor mitochondrial function, and chronic inflammation. [134-138]
2. Metformin has also been shown to increase the cellular production of mTOR and AMPK, which are longevity-promoting signaling molecules. [139-144]
3. Animal studies have shown that metformin can increase lifespan by 20%. [145-146]
4. A study found that diabetics taking metformin lived 15% longer than healthy non-diabetic individuals. [147]
5. In different mouse breeds, long-term treatment with metformin extended lifespan. [148]
6. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin therapy increased life expectancy by reducing the risk of cardiovascular disease, cancer incidence, and overall mortality of diabetic patients. [149-150]
7. Studies found that metformin can reduce the levels of reactive oxygen species (ROS), which are the major cause of aging. [151-155]
8. A study found that metformin combats the effects of aging by suppressing inflammatory response via inhibition of nuclear factor κB (NFκB). [156-157]
9. A cell study found that metformin exerts its anti-aging effect by preventing cellular senescence (irreversible cell cycle arrest). [158-159]
10. In several rodent strains, adding metformin to the diet resulted in a significant increase in lifespan (14-40%). [160-163]
11. In a model of Huntington’s disease, metformin extended lifespan by 20%. [164]
12. In diabetic and cardiovascular disease patients, metformin increased rates of survival. [165-166]
13. In older adults with type 2 diabetes, metformin administration may help promote longevity by preventing frailty. [167]
14. Cell studies have shown that metformin may help combat internal aging by reducing neuronal injury and improving oxygen/glucose delivery to neurons. [168-171]
15. Studies show that the insulin-sensitizing and blood sugar-lowering effects of metformin can contribute to a reduced risk of a number of diseases such as cardiovascular disease, cancer, kidney disease, and other aging-associated metabolic diseases, thereby increasing life span. [172-175]

Associated Side Effects of Metformin

Metformin side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on metformin. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of metformin. Despite this, it was listed as a side effect associated with metformin even though these associated side effects are very uncommon.

Side effects associated with metformin may include the following:

• Diarrhea
• Loss of appetite
• Metallic taste in the mouth
• Nausea
• Stomachache
• Vomiting

References

1. Cusi, K., DeFronzo, RA. Metformin: a review of its Metabolic effects. Diabetes Reviews. V6 N2 1998:89-131.
2. Rafieian-Kopaei M, Baradaran A. Combination of metformin with other antioxidants may increase its renoprotective efficacy. J RenInj Prev. 2013;2:35–6.
3. Nasri H. On the occasion of the world diabetes day2013; Diabetes education and prevention; a nephrology point of view. J RenInj Prev. 2013;2:31–2.
4. Tertti K, Ekblad U, Vahlberg T, Rönnemaa T. Comparison of metformin and insulin in the treatment of gestational diabetes: A retrospective, case-control study. Rev Diabet Stud. 2008;5:95–101.
5. Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: A case-control study. Diabet Med. 2009;26:798–802.
6. 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. doi: 10.1136/bmj.39063.689375.55.
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.
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.
9. 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 EndocrinolMetab. 2001;17:131–134.
10. 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. doi: 10.1016/S0140-6736(09)61457-4.
11. Salpeter SR, Buckley NS, Kahn JA. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008;121:149–157. doi: 10.1016/j.amjmed.2007.09.016.
12. Lily M, Godwin M. Treating prediabetes with metformin systematic review and meta-analysis. Can Fam Physician. 2009;55:363–369.
13. American Diabetes Association. Summary of revisions to the 2011 clinical practice recommendations. Diabetes Care. 2011;34(Suppl 1):S3.
14. 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. EndocrPract. 2009;15(6):540–559.
15. 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.
16. Ito H, Ishida H, Takeuchi Y. Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus. NutrMetab. 2010;7:83. doi: 10.1186/1743-7075-7-83.
17. Gerich J, Raskin P, Jean-Louis L. PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. Diabetes Care. 2005;28:2093–2099. doi: 10.2337/diacare.28.9.2093.
18. Charbonnel B, Shernthaner G, Brunetti P. Long-term efficacy and tolerability of add-on piogçitazone therapy to falilingmonotherapy compared with addition of glicazide or metformin in patients with type 2 diabetes. Diabetologia. 2005;48:1093–1104. doi: 10.1007/s00125-005-1751-1.
19. Hanefeld M, Brunetti P, Schhernthaner GH. One year glycemic control with sulphonylurea plus pioglitazone versus sulphonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004;27:141–147. doi: 10.2337/diacare.27.1.141.
20. 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. doi: 10.1001/jama.2010.405.
21. 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. doi: 10.1016/j.jdiacomp.2008.09.002.
22. 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. doi: 10.2337/diacare.25.12.2244.
23. 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 ClinPharmacol. 1993;44:107–112. doi: 10.1007/BF00315466.
24. 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. doi: 10.1136/bmj.b4324.
25. 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. doi: 10.1007/s00125-009-1636-9.
26. Abdelghaffar S, AttiaAM. Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database Syst Rev. 2009. p. CD006691.
27. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. ClinPharmacolTher. 2009;85:513–519. doi: 10.1038/clpt.2008.250.
28. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–657. doi: 10.2337/dc08-1863.
29. DeFronzo RA, Hissa MN, Garber AJ. forSaxagliptin Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32(9):1649–1655. doi: 10.2337/dc08-1984.
30. Dunn, C. J., & Peters, D. H. (1995). Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs, 49(5), 721–749. https://doi.org/10.2165/00003495-199549050-00007.
31. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86.
32. Seifarth C, Schehler B, Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. ExpClinEndocrinol Diabetes. 2013;121:27–31.
33. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35:731–737.
34. UK 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;352:854–865.
35. 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. doi: 10.1542/peds.2003-0649-F.
36. Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. CurrOpinEndocrinol Diabetes Obes. 2014;21(5):323-9.
37. Jarskog LF, Hamer RM, Catellier DJ, et al. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry. 2013;170(9):1032–1040. doi:10.1176/appi.ajp.2013.12010127.
38. Yanovski JA, Krakoff J, Salaita CG, et al. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes. 2011;60(2):477–485. doi:10.2337/db10-1185.
39. Levri KM, Slaymaker E, Last A, et al. Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med. 2005;3(5):457–461. doi:10.1370/afm.343.
40. Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47-53.
41. Available from https://www.scopemed.org/?mno=217826.
42. Solymár M, Ivic I, Pótó L, et al. Metformin induces significant reduction of body weight, total cholesterol and LDL levels in the elderly – A meta-analysis. PLoS ONE. 2018;13(11):e0207947.
43. Van der aa MP, Elst MA, Van de garde EM, Van mil EG, Knibbe CA, Van der vorst MM. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial. Nutr Diabetes. 2016;6(8):e228.
44. Zhuo C, Xu Y, Liu S, et al. Topiramate and Metformin Are Effective Add-On Treatments in Controlling Antipsychotic-Induced Weight Gain: A Systematic Review and Network Meta-Analysis. Front Pharmacol. 2018;9:1393. Published 2018 Nov 28. doi:10.3389/fphar.2018.01393.
45. Wang M, Tong JH, Zhu G, et al. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012;138(1):54-7.
46. Wu RR, Jin H, Gao K, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2012;169(8):813-21.
47. Chen CH, Huang MC, Kao CF, et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(5):e424-30.
48. Peng PJ, Ho PS, Tsai CK, et al. A Pilot Study of Randomized, Head-to-Head of Metformin Versus Topiramate in Obese People With Schizophrenia. ClinNeuropharmacol. 2016;39(6):306-10.
49. Trolle B, Flyvbjerg A, Kesmodel U, et al. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod. 2007;22(11):2967-73.
50. Hui, F., Zhang, Y., Ren, T., Li, X., Zhao, M., & Zhao, Q. (2019). Role of metformin in overweight and obese people without diabetes: a systematic review and network meta-analysis. European journal of clinical pharmacology, 75(4), 437–450. https://doi.org/10.1007/s00228-018-2593-3.
51. Figueiredo RA, Weiderpass E, Tajara EH, et al. Diabetes mellitus, metformin and head and neck cancer. Oral Oncol. 2016;61:47-54.
52. Tseng CH. Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Aging (Albany NY). 2016;8(8):1636-49.
53. Coyle C, Cafferty FH, Vale C, et al. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27(12):2184-95.
54. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–1305.
55. He H, Ke R, Lin H, Ying Y, Liu D, Luo Z. Metformin, an old drug, brings a new era to cancer therapy. Cancer J. 2015;21(2):70-4.
56. Wan G, Yu X, Chen P, Wang X, Pan D, Wang X, Li L, Cai X, Cao F. Metformin therapy associated with survival benefit in lung cancer patients with diabetes. Oncotarget. 2016;7:35437–35445.
57. Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer. J Gastrointest Surg. 2016;20:1572–1580.
58. 1 Cabello P, Pineda B, Tormo E, Lluch A, Eroles P. The Antitumor Effect of Metformin Is Mediated by miR-26a in Breast Cancer. Int J Mol Sci. 2016:17.
59. 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. doi: 10.2337/dc08-2175.
60. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 2010;6(3):457-70.
61. Deepa SS, Zhou L, Ryu J, Wang C, Mao X, Li C, Zhang N, Musi N, DeFronzo RA, Liu F, Dong LQ. APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway. MolEndocrinol. 2011;25:1773–1785.
62. Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 2010;9:188–197.
63. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33:322–326.
64. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20.
65. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620–1625.
66. Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, Vitale V, Romano D, Barchielli A, Marchionni N, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2011;34:129–131.
67. Tseng CH. Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol. 2012;167:409–416.
68. Evans J, Donelly L, Emslie A. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–1305. doi: 10.1136/bmj.38415.708634.F7.
69. Bodmer M, Becker C, Meier C, Jick SS, Meier CR. Use of metformin and the risk of ovarian cancer: a case-control analysis. GynecolOncol. 2011;123(2):200–204.
70. Tseng CH. Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2015;31(6):619–626.
71. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J ClinOncol. 2009;27(20):3297–3302.
72. Campagnoli C, Pasanisi P, Abbà C, et al. Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin Breast Cancer. 2012;12(3):175–182.
73. Tseng CH. Metformin significantly reduces incident prostate cancer risk in Taiwanese men with type 2 diabetes mellitus. Eur J Cancer. 2014;50(16):2831–2837.
74. Sehdev A, Shih YC, Vekhter B, Bissonnette MB, Olopade OI, Polite BN. Metformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population. Cancer. 2015;121(7):1071–1078.
75. Li D, Yeung SJ, Hassan MM, Konopleva M, Abbruzzese JL. Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482–488. doi: 10.1053/j.gastro.2009.04.013.
76. 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. doi: 10.3748/wjg.v16.i24.3025.
77. 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. doi: 10.2337/dc09-1380.
78. 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.
79. Bodmer M, Meier C, Krähenbühl S. Long-term metformin Use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304–1308. doi: 10.2337/dc09-1791.
80. Wang Q, Zhang M, Torres G, et al. Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission. Diabetes. 2017;66(1):193-205.
81. Abualsuod A, Rutland JJ, Watts TE, et al. The Effect of Metformin Use on Left Ventricular Ejection Fraction and Mortality Post-Myocardial Infarction. Cardiovasc Drugs Ther. 2015;29(3):265-75.
82. Anabtawi A, Miles JM. Metformin: Nonglycemic Effects and Potential Novel Indications. EndocrPract. 2016;22(8):999-1007.
83. UK 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;352:854–865.
84. Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism. 2004;53:159–164.
85. Ansell BJ, Watson KE, Fogelman AM. An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines. National Cholesterol Education Program. JAMA. 1999;282:2051–2057.
86. Goldberg R, Temprosa M, Otvos J, Brunzell J, Marcovina S, Mather K, Arakaki R, Watson K, Horton E, Barrett-Connor E. Lifestyle and metformin treatment favorably influence lipo-protein subfraction distribution in the Diabetes Prevention Program. J ClinEndocrinolMetab. 2013;98:3989–3998.
87. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, Marcovina S, Mather K, Orchard T, Ratner R, Barrett-Connor E Diabetes Prevention Program Research Group. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566–1572.
88. Goldberg R, Temprosa M, Aroda VR, Barrett-Connor EL, Budoff M, Crandall J, Dabelea D, Horton ES, Mather KJ, Orchard TJ, et al. Effect of long-term interventions in the Diabetes Prevention Program (DPP) and its Outcome Study on coronary artery calcium (CAC) Diabetes. 2015;64(Supplement 1A):LB5.
89. Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, Stehouwer CD. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169:616–625.
90. Wan X, Huo Y, Johns M, et al. 5′-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. ArteriosclerThrombVasc Biol. 2013;33(11):2470–2480.
91. Isoda K, Young JL, Zirlik A, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. ArteriosclerThrombVasc Biol. 2006;26(3):611–617.
92. Sgambato S, Varricchio M, Tesauro P, Passariello N, Carbone L. Use of metformin in ischemic cardiopathy. ClinTher. 1980;94:77–85.
93. Hadigan C, Corcoran C, Basgoz N. Metformin in the Treatment of HIV Lipodystrophy Syndrome A Randomized Controlled Trial. JAMA. 2000;284:472–477. doi: 10.1001/jama.284.4.472.
94. 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. doi: 10.1186/1471-2334-10-183.
95. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis. 2014;41:61–68.
96. Cheng C, Lin CH, Tsai YW, Tsai CJ, Chou PH, Lan TH. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A BiolSci Med Sci. 2014;69:1299–1305.
97. Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, Wang B. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. ClinExpPharmacol Physiol. 2014;41:650–656.
98. Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. ProcNatlAcadSci U S A. 2010;107(50):21830–21835.
99. Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. PharmacolBiochemBehav. 2012;101(4):564–574.
100. Picone P, Nuzzo D, Caruana L, et al. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-kappaB activation: use of insulin to attenuate metformin’s effect. BiochimBiophysActa. 2015;1853(5):1046–1059.
101. Hettich MM, Matthes F, Ryan DP, et al. The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. PLoS One. 2014;9(7):e102420.
102. Poels J, Spasić MR, Callaerts P, Norga KK. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays. 2009;31(9):944–952.
103. Jin Q, Cheng J, Liu Y, et al. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun. 2014;40:131–142.
104. Jiang T, Yu JT, Zhu XC, et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol. 2014;171(13):3146–3157.
105. Venna VR, Li J, Hammond MD, Mancini NS, McCullough LD. Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci. 2014;39(12):2129–2138.
106. Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci. 2012;91(11–12):409–414.
107. Zhao RR, Xu XC, Xu F, et al. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. BiochemBiophys Res Commun. 2014;448(4):414–417.
108. Alzoubi KH, Khabour OF, Al-Azzam SI, Tashtoush MH, Mhaidat NM. Metformin eased cognitive impairment induced by chronic l-methionine administration: potential role of oxidative stress. CurrNeuropharmacol. 2014;12(2):186–192.
109. Chen F, Dong RR, Zhong KL, et al. Antidiabetic drugs restore abnormal transport of amyloid-beta across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology. 2016;101:123–136.
110. 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. doi: 10.1016/j.stem.2012.03.016.
111. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43(5):647–654.
112. Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J ClinEndocrinolMetab. 2000;85(1):139–146.
113. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS) J Adolesc Health. 2001;29(3):160–169.
114. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligoamenorrhoea and subfertility. Cochrane Database Syst Rev. 2012;5:CD003053.
115. Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2(6):56. doi:10.3978/j.issn.2305-5839.2014.04.15.
116. Lord J.M., Flight I.H., Norman R.J. (2003) Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev 3: CD003053.
117. Velazquez E.M., Mendoza S., Hamer T., Sosa F., Glueck C.J. (1994) Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43: 647–654.
118. Mansfield R., Galea R., Brincat M., Hole D., Mason H. (2003) Metformin has direct effects on human ovarian steroidogenesis. FertilSteril 79: 956–962.
119. Arlt W., Auchus R.J., Miller W.L. (2001) Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3beta -hydroxysteroid dehydrogenase. J BiolChem 276: 16767–16771.
120. Palomba S., Pasquali R., Orio F., Jr, Nestler J.E. (2009) Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. ClinEndocrinol (Oxf) 70: 311–321.
121. Doldi N., Persico P., Di Sebastiano F., Marsiglio E., Ferrari A. (2006) Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. GynecolEndocrinol 22: 235–238.
122. Qublan H.S., Al-Khaderei S., Abu-Salem A.N., Al-Zpoon A., Al-Khateeb M., Al-Ibrahim N., et al. (2009) Metformin in the treatment of clomiphene citrate-resistant women with polycystic ovary syndrome undergoing in vitro fertilisation treatment: a randomised controlled trial. J ObstetGynaecol 29: 651–655.
123. Palomba S., Russo T., Orio F., Jr, Falbo A., Manguso F., Cascella T., et al. (2006) Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome. Hum Reprod 21: 457–465.
124. Thatcher S.S., Jackson E.M. (2006) Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. FertilSteril 85: 1002–1009.
125. Glueck C.J., Wang P., Goldenberg N., Sieve-Smith L. (2002) Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 17: 2858–2864.
126. Jakubowicz D.J., Iuorno M.J., Jakubowicz S., Roberts K.A., Nestler J.E. (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J ClinEndocrinolMetab 87: 524–529.
127. Granberry MC, Fonseca VA. Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents. Am J Cardiovasc Drugs. 2005;5:201–209. doi: 10.2165/00129784-200505030-00006.
128. Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles A. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385–391. doi: 10.1016/j.diabet.2009.03.005.
129. Zhou L, Liu H, Wen X, Peng Y, Tian Y, Zhao L. Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trials. J Hypertens. 2017;35(1):18-26.
130. Snorgaard O, Køber L, Carlsen J. The effect of metformin on blood pressure and metabolism in nondiabetic hypertensive patients. J Intern Med. 1997;242(5):407-12.
131. Available from https://www.ashjournal.com/article/S1933-1711(17)30002-5/abstract.
132. Available from https://clinicaltrials.gov/ct2/show/NCT00105066.
133. Available from https://www.ahajournals.org/doi/10.1161/01.HYP.33.5.1135.
134. Formoso G, De Filippis EA, Michetti N, et al. Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects. Diabetes Metab Res Rev. 2008;24(3):231-7.
135. Garg G, Singh S, Singh AK, et al. Metformin Alleviates Altered Erythrocyte Redox Status During Aging in Rats. Rejuvenation Res. 2016.
136. Cameron AR, Morrison VL, Levin D, et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016;119(5):652-65.
137. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
138. Lee YS, Doonan BB, Wu JM, et al. Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair. Oncol Rep. 2016;35(6):3735-41.
139. deKreutzenberg SV, Ceolotto G, Cattelan A, et al. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. NutrMetabCardiovasc Dis. 2015;25(7):686-93.
140. Lien F, Berthier A, Bouchaert E, et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest. 2014;124(3):1037–1051.
141. Lu J, Shi J, Li M, et al. Activation of AMPK by metformin inhibits TGF-beta-induced collagen production in mouse renal fibroblasts. Life Sci. 2015;127:59–65.
142. Duca FA, Côté CD, Rasmussen BA, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015;21(5):506–511.
143. Nair V, Sreevalsan S, Basha R, et al. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem. 2014;289(40):27692–27701.
144. Pérez-Revuelta BI, Hettich MM, Ciociaro A, et al. Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 2014;5:e1209.
145. De Haes W, Frooninckx L, Van Assche R, et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. ProcNatlAcadSci U S A. 2014;111(24):E2501-9.
146. Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–239.
147. Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylureamonotherapy and matched, non-diabetic controls. Diabetes ObesMetab. 2014;16(11):1165-73.
148. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
149. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–865.
150. Wu JW, Boudreau DM, Park Y, Simonds NI, Freedman AN. Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature. Expert Opin Drug Saf. 2014;13(8):1071–1099.
151. Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462(3):475–487.
152. Batandier C, Guigas B, Detaille D, El-Mir MY, Fontaine E, Rigoulet M, Leverve XM. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Bio-membr. 2006;38:33–42.
153. Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462:475–487.
154. Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xu X. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012;61:217–228.
155. Zheng Z, Chen H, Li J, et al. 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.
156. Saisho Y. Metformin and inflammation: its potential beyond glucose-lowering effect. EndocrMetab Immune Disord Drug Targets. 2015;15(3):196–205.
157. Saisho Y. Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. EndocrMetab Immune Disord Drug Targets. 2015;15:196–205.
158. Jadhav KS, Dungan CM, Williamson DL. Metformin limits ceramide-induced senescence in C2C12 myoblasts. Mech Ageing Dev. 2013;134:548–559.
159. Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, Bourdeau V, Pollak MN, Ferbeyre G. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013;12:489–498.
160. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–2773.
161. Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–239.
162. De Haes W, Frooninckx L, Van Assche R, SmoldersA, Depuydt G, Billen J, Braeckman BP, Schoofs L, Temmerman L. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. ProcNatlAcadSci USA. 2014;111:E2501–E2509.
163. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany, NY) 2011;3:148–157.
164. Ma TC, Buescher JL, Oatis B, Funk JA, Nash AJ, Carrier RL, Hoyt KR. Metformin therapy in a transgenic mouse model of Huntington’s disease. NeurosciLett. 2007;411:98–103.
165. Scarpello JH. 2003. Improving survival with metformin: The evidence base today. Diabetes Metab 29: 6S36–6S43.
166. Yin M, Zhou J, Gorak EJ, Quddus F. 2013. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: A systematic review and meta-analysis. Oncologist 18: 1248–1255.
167. Wang CP, Lorenzo C, Espinoza SE. 2014. Frailty attenuates the impact of metformin on reducing mortality in older adults with type 2 diabetes. J Endocrinol Diabetes Obes 2: 1030.
168. Meng X, Chu G, Yang Z, et al. Metformin protects neurons against oxygen-glucose deprivation/reoxygenation -induced injury by down-regulating MAD2B. Cell PhysiolBiochem. 2016;40:477–485.
169. El-Mir MY, Detaille D, R-Villanueva G, et al. Neuroprotective role of antidiabetic drug Metformin against apoptotic cell death in primary cortical neurons. J MolNeurosci. 2008;34:77–87.
170. Kumar A, Al-Sammarraie N, DiPette DJ, Singh US. Metformin impairs Rho GTPasesignaling to induce apoptosis in neuroblastoma cells and inhibits growth of tumors in the xenograft mouse model of neuroblastoma. Oncotarget. 2014;5:11709–11722.
171. Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. 2011;60:910–920.
172. Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R., Hollenberg, M. D., & Hill, M. A. (2022). Metformin: Is it a drug for all reasons and diseases?. Metabolism: clinical and experimental, 133, 155223. https://doi.org/10.1016/j.metabol.2022.155223.
173. Holman R. (2007). Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journees annuelles de diabetologie de l’Hotel-Dieu, 13–20.
174. Drzewoski, J., & Hanefeld, M. (2021). The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharmaceuticals (Basel, Switzerland), 14(2), 122. https://doi.org/10.3390/ph14020122.
175. Yerevanian, A., & Soukas, A. A. (2019). Metformin: Mechanisms in Human Obesity and Weight Loss. Current obesity reports, 8(2), 156–164. https://doi.org/10.1007/s13679-019-00335-3.