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Anti-Aging Benefits of Metformin

What is metformin?

Metformin, is a drug currently on the market, used to treat type 2 diabetes (mellitus). Metformin works by inhibiting glucose production by the liver and it also opposes the action of a hormone, glucagon, which raises the level of glucose in the blood [1]. Overall these actions result in reduced circulating insulin levels and an increased ability of cells to respond to insulin (increased insulin sensitivity). Recently, metformin was also shown to influence signalling pathways important in cancer development and it is also being investigated for its anti-aging properties which were observed in laboratory animals.

How does metformin influence longevity in laboratory animals?

Metformin was found to increase longevity when given to laboratory animals. In nematodes (C. elegans) metformin was shown to increase mean lifespan by 18%, 36% and 3% at doses of 25, 50, and 100 mM [2].

In mice susceptible to mammary tumors (HER-2/neu transgenic mice) metformin (100mg/kg given in the drinking water) increased life span by 8% and the mice experienced a decreased incidence and size of tumors (adenocarcinomas) [3]. Another study by the same researchers showed that metformin was effective at increasing the life-span of mice by 14% if the mice were given metformin at a relatively young age (3 months). If metformin was given to older mice (15 months) however, it had no effect on life-span [4]. In a study from a different laboratory researchers looked at the effect of metformin on two different strains of mice. They found that both strains of mice had increased life-spans when treated with metformin, longevity was increased by 5.83% in the first strain and by 4.15% in the second strain [5]. The first dose they used (0.1% w/w) provided benefits whereas, a higher dose (1% w/w) was detrimental. The authors of this study show that aside from an increased life-span the mice were also observed to show anti-aging properties such as increased insulin sensitivity, reduced LDL and cholesterol levels as well as decreased oxidative damage and inflammation.  
    

How does metformin influence cancer in humans?

According to the CDC (Centers for Disease Control and Prevention) heart disease and cancer are the two leading causes of death in the western world, accounting for about 2/3 of all deaths. Preventing or curing these diseases would greatly increase the average person’s lifespan. A very interesting observational study monitoring cancer incidence in type 2 diabetics taking metformin found a decreased death rate as compared to type 2 diabetics with cancer not taking metformin [6]. This raised the possibility that metformin may have anti-cancer properties. After this seminal study other independent studies looking at type 2 diabetics with specific types of cancer found patients taking metformin had either a lowered death rate or a decreased risk of developing; pancreatic cancer, breast cancer, lung cancer, prostate cancer and colon cancer [7-12]. Although this is very encouraging news it should be noted that some studies found no benefit from metformin in preventing or treating breast or prostate cancer in type 2 diabetics [12,13]. Larger and longer trials will be needed in order to clarify the anti-cancer benefits of metformin and whether they also apply to a non-diabetic population.

 

 How does metformin influence cardiovascular disease in humans?

 

Cardiovascular disease is prevalent in the general population however, patients with diabetes are at an increased risk for cardiovascular disease about 2- to 4-fold increased risk above conventional risk factors [14]. The first study to examine a decreased risk of cardiovascular disease for type 2 diabetics taking metformin was published in 1998. The researchers found that compared to type 2 diabetics controlling their insulin levels through diet alone, patients taking metformin had a 42% decreased risk of diabetes-related death and a 36% risk reduction for general all-cause mortality [15]. Compared to other drugs used to treat diabetes, especially the sulphonylurea drugs (i.e. glimepiride, glibenclamide, and glipizide) metformin has a much higher safety profile as well as the possibility it may protect against heart disease whereas the latter may actually increase a patient’s risk of heart disease [16]. Only one small study has been conducted in non-diabetic patients to see if metformin can reduce cardiovascular risk in high-risk patients. This study found no benefit of taking metformin to reduce cardiovascular risk in non-diabetic patients however, the authors state that further studies need to be completed to confirm their results [17].

Metformin was found to have a protective effect on stroke risk [18]. Type 2 diabetics were followed for 4 years to determine stroke incidence and metformin users were found to have a decreased risk of having a stroke as compared to non-metformin users. Of the non-metformin users, 701 of 3,999 (17.5%) had a stroke during the 4 year follow-up as compared to 994 of 10,857 (9.2%) of metformin users. A major risk factor for stroke is atherothrombosis. Atherothrombosis occurs when the fat that has built up in a blood vessel (artery) ruptures causing blood to clot around the rupture. These blood clots can then travel to the brain and cause a stroke. Type 2 diabetics who also had atherothrombosis and were taking metformin had a lower risk of death as compared to non-metformin users [14]. The mortality rates were 6.3% with metformin use and 9.8% without metformin use.

Another risk factor for the development of cardiovascular disease is high blood pressure (hypertension). Metformin was found to decrease high blood pressure in a very small pilot study of non-obese, non-smoking, non-diabetic middle aged men [19]. The men took metformin at a dose of 850 mg twice a day for six weeks.

How does metformin influence weight-loss?

A risk factor for the development of cardiovascular disease and cancer is being overweight or obese. A recent study investigated the effect metformin had on weight loss in patients suffering from schizophrenia or schizoaffective disorder [20]. The study found that the placebo group lost on average   1 kg (2.2 lbs) whereas the metformin treated patients lost on average 3 kg (6.6 lbs) during the 16 week study.

Another study examined the benefits of metformin for adolescents with type 1 diabetes. The study found that patients taking metformin had decreased BMIs and waist circumferences at 3 and 6 months as compared to the placebo [21]. The metformin group decreased their waist circumference by 2 cms whereas the placebo group experienced no change. The patients also required a lower insulin dose as compared to the placebo group demonstrating metformin’s insulin sensitizing properties.

Metformin was also shown to increase weight loss in a non-diabetic obese population after 24 weeks. On average the metformin treated group (500 mg once per day) lost 0.7 kg (1.5 lbs), decreased waist circumference by 0.9 cm and decreased both visceral and subcutaneous fat amounts [22].

Conclusion:

In conclusion metformin has been found to be a front-line treatment for type 2 diabetics as it may decrease cardiovascular risk and death, cancer risk and death and may aid in weight loss. Metformin has also shown promise as an anti-aging drug in laboratory animals however, no studies have evaluated its anti-aging properties in humans. How metformin may benefit a non-diabetic population is under investigation and many studies are currently being conducted to see if metformin can lower cancer and cardiovascular risk for the general population.

References:

1. Pernicova I, Korbonits M (2014) Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10: 143-156.

2. Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cocheme HM, et al. (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153: 228-239.

3. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, et al. (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40: 685-693.

4. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, et al. (2011) If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 3: 148-157.

5. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, et al. (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4: 2192.

6. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, et al. (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32: 1620-1625.

7. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D (2012) Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 18: 2905-2912.

8. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, et al. (2014) Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract.

9. Tseng CH (2014) Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res Treat 145: 785-790.

10. Zhang ZJ, Bi Y, Li S, Zhang Q, Zhao G, et al. (2014) Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis. Am J Epidemiol 180: 11-14.

11. Preston MA, Riis AH, Ehrenstein V, Breau RH, Batista JL, et al. (2014) Metformin Use and Prostate Cancer Risk. Eur Urol.

12. Lega IC, Shah PS, Margel D, Beyene J, Rochon PA, et al. (2014) The effect of metformin on mortality following cancer among patients with diabetes. Cancer Epidemiol Biomarkers Prev.

13. Bensimon L, Yin H, Suissa S, Pollak MN, Azoulay L (2014) The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol Biomarkers Prev.

14. Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC, Jr., et al. (2010) Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 170: 1892-1899.

15. (1998) 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 352: 854-865.

16. Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, et al. (2011) Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 32: 1900-1908.

17. Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, et al. (2014) Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2: 116-124.

18. Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, et al. (2014) Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis 23: e99-105.

19. Landin K, Tengborn L, Smith U (1991) Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med 229: 181-187.

20. Jarskog LF, Hamer RM, Catellier DJ, Stewart DD, Lavange L, et al. (2013) Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry 170: 1032-1040.

21. Nadeau KJ, Chow K, Alam S, Lindquist K, Campbell S, et al. (2014) Effects of low dose metformin in adolescents with type I diabetes mellitus: a randomized, double-blinded placebo-controlled study. Pediatr Diabetes.

22. He H, Zhao Z, Chen J, Ni Y, Zhong J, et al. (2012) Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial. J Hypertens 30: 1430-1439.

 

 
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