Metformin: Anti-diabetes, Anti-cancer and Anti-aging drug
Metformin is a safe and cost-effective drug which has been used for over 5 decades for the treatment of type 2 diabetes. It is presently the only available biguanide used for the treatment of type 2 diabetes (biguanides are drugs that lower glucose levels). Its mechanism of action is not well established; however it is understood that it probably involves its ability to increase the activity of hepatic insulin, aid the release of incretins, decrease deposition of amyloid and alter the metabolism of bile acids. Metformin is also sometimes prescribed for women with ovulation problems. There have also been evidence that suggests the drug to have some anticancer effects as studies from epidemiology, in vitro and animal trials have indicated. Metformin is also gaining increasing attention from researchers as it has been indicated as a geroprotector, i.e. a drug able to prolong lifespan. Continue reading...
Previously in the 1950s, another biguanide, phenformin, was released alongside metformin. However phenformin was found to be associated with lactic acidosis and for this reason was withdrawn. Prior to the buguanides, sulfonylureas were the common oral prescriptions for type 2 diabetes. They achieved similar glycemic control as metformin however metformin had the advantage of not leading to weight gain (Bailey et al, 1996) and therefore was chosen as the preferred option. To date metformin is regarded as the most effective first point treatment of type 2 diabetes. It has been recommended by the American Diabetes Association and the European Association for the Study of Diabetes. Studies have also shown less occurrence of hypoglycaemia in patients taking metformin than insulin or sulfonylureas (e.g. Andujar-Plata, et al, 2011) although, when used without any other drug, metformin still shows the same problems with maintaining optimum glycemic control as seen in other drugs, where there is often a slight overshoot or fall in glucose level above or below the desired level (Turner, 2005). When compared with insulin or sulfonylurea in the treatment of type 2 diabetes, metformin therapy resulted in less risk of diabetes-related endpoint or death (UKPDS, 1998). In a study focusing on overweight type 2 diabetes patients, it was observed that the cost of hospital stay is reduced when using metformin compared to other treatments (Clarke et al, 2001).
Metformin has also been recently suspected to be a possible anti-cancer drug. The mechanism behind this is yet to be fully established however it is thought to be associated with the boosted insulin levels and increased resistance of insulin since insulin is associated with growth and mitogenesis. This has been showed in controlled studies by scientific groups (e.g Evans et al, 2005; Bowker et al, 2006) where it was found that patients administered with metformin were less likely to develop cancer or die from cancer compared to those on sulfonylurea. Such findings have led to a deluge of research efforts on the effect of metformin on various kinds of cancer.
Metformin is sometimes prescribed to patients with ovulation problems such as polycystic ovary syndrome (Palomba et al, 2011) as studies have shown that the drug does have an effect on ovary stimulation. There are also indications that prescribing metformin to pregnant women with polycystic ovary syndrome could reduce the otherwise high chance of spontaneous abortion during the first trimester (Glueck et al, 2001).
The drugs mechanism of action
The mechanism of action of this drug is not well established; however it is understood that it probably involves its ability to increase the activity of hepatic insulin thereby decreasing hepatic glucose output, aid the release of incretins, decrease deposition of amyloid and alter the metabolism of bile acids. Sensitivity of the muscles to insulin also increases by metformin. Lactate oxidation can be increased by metformin; however, the plasma concentration of lactate is not affected since the rate at which lactate is released from the muscle is not affected either. Metformin is therefore rarely associated with lactic acidosis. Metformin is thought to cause reduction of glucose levels through its ability to reduce resistance of hepatic insulin which subsequently leads to a drop in hepatic glucose output rate. It has been hypothesised that it does this by activating AMPK (5 adenosine monophosphate-activated protein kinase), which is an enzyme significant in the maintenance of homeostasis. Metformin is capable of increasing the activation of insulin receptor in the absence of insulin via the insulin receptor substrate 2. Less is known about the mechanism by which metformin may act as an anti-cancer agent and much of the data supporting this is based mostly on population studies. More research is yet to be done to verify whether or not metformin does actually have an effect on combating any form of cancer.
Studies and clinical trials
The applicability of metformin as an anti-diabetic drug is well established as it has been in clinical use for over 50 years. Population studies on patients over a period of 10 years observed a lower incidence of cancer in patients taking metformin when compared with those on other therapies (Libby et al, 2009). There also seems to be less deaths occurring from cancer inpatients on metformin compared to others as observed in another study known as the ZODIAC (Zwolle Output Diabetes Project Integrating Available Care). For cases of specific cancers, breast cancer has received more attention in terms of impact of metformin. Future studies would elucidate the impact of metformin on cancer.
There is evidence to suggest that both the aging process and development of cancer cells are linked to hyperglycemia and hyperinsulemia such that metformin could act as a lifespan extension drug. Studies carried out on various organisms such as mice indicate prolonged lifespan of organisms following administration of metformin by up to 21%. In one particular study, the accumulation of aged cell in skin samples taken from mice was significantly reduced while the youth of the cell was prolonged (Arkadeva et al, 2011; Bulterijs, 2011). Results showed that administering metformin at an earlier age resulted in more prolonged lifespan and delayed onset of cancer indicating that the life extending characteristic of metformin may be benefited especially at a younger age (Anisimov et al, 2005; Anisimovet al, 2011).
Dosage and administration
Metformin is available for oral consumption in tablet form or as powder for suspension. The tablets can be swallowed with water while the suspension is poured in water and taken before or after meals. The recommended dose depends on the specific patient requirement and this is determined by the doctor.
Interactions with other drugs
This drug should be used with care in the elderly, or those with liver or heart disorders. Metformin should also not be taken by pregnant or breastfeeding mothers and those likely to be on general anaesthetics. The drug should not be taken alongside excessive alcohol consumption.
Ideally the doctor should be informed of any other medication you are taking or intend to take while on metformin therapy. The doctor will then inform you of whether or not to stop or start taking the drug alongside metformin depending on the specific case. This drug should not be taken without medical prescription.
Taking metformin with the following drugs may result in fatal incidences:
iodine agents used during radiotherapy
cimetidine for treating ulcers.
Andujar-Plata, P., Pi-Sunyer, X., Laferrere, B. (2011) Metformin effects revisited. Diabetes Research and Clinical Practice (in press) doi:10.1016/j.diabres. 2011 Oct 13. [Epub ahead of print].
Anisimov, V.N., Berstein, L.M., Popovich, I.G., Zabezhinski, M.A., Egormin, P.A., Piskunova, T.S., Semenchenko, A.V., Tyndyk, M.L., Yurova, M.N., Kovalenko, I.G., Poroshina, T.E. (2011) If started in early life, metformin treatment increases life span and postpones tumors in female SHR mice. Agining. 3(2): 148-157.
Anisimov, V.N., Berstein, L.M., Egormin, P.A., Piskunova, T.S., Popovich, I.G., Zabezhinski.M.A., Kovalenko, I.G., Poroshina, E.T.,Semenchenko, A.V., Provinciali, M., Re, F., Franceschi,C. (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Experimental Gerontology. 40(8-9): 685-693.
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