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Can the Diabetes Drug
Metformin Prevent Cancer?
E-Newsletter No. 80
Metformin (Glucophage), is a well known drug used
for Type 2 Diabetes. Metformin (MetF) is a biguanide drug. It was
officially approved by the FDA in 1992. It's classic action was thought to
mainly modulate glucose synthesis and release via the liver and provide some
increased insulin sensitivity.
MetF has been around since the 1960's. It is an oral medicine, which is the first choice medicine in treating type 2 adult onset diabetes [T2DM] as long as your kidney function is normal as determined by serum creatinine levels and other tests of renal function. [See below, other conditions for which MetF may be contraindicated.]
It is ironic that those patients with T2DM who have not been treated with MetF have an increased risk for liver, pancreatic, colon, breast and other cancers. The below text explains MetF newly discovered actions.
What is the data to support that Metformin has cancer prevention properties?
The Endocrine Society Newsletter of February, 2011 cover page stated: "Less cancer in Metformin Patients".
Epidemiologic Data and Cancer Prevention
A large body of epidemiologic data has shown that MetF users have about 40% less incidence of normally expected cancer incidence.
This growing epidemiologic data adds to accumulating evidence of a significant Metformin - cancer link stated by M. Pollak, MD., Professor of Medicine and Oncology, (McGill University in Montreal, Canada). He published a review article in Sept,
2011 in Cancer Prevention Research. He called it a "Scientific
emergency to understand this evidence better."
An Italian study of 1,340 T2DM patients on Metf were compared to 370 controls over 76 months. Results showed a lower overall lower incidence of all forms of cancer, (Eduardo Mannucci, MD., Carregi Teaching Hospital in Florence).
A similar study was presented at the Annual Endocrine Society meeting in 2012 in Houston.
However, Dr Pollak cautions that epidemiologic data are retrospective with a variety of confounding variables. He says the next step is to understand the mechanisms of MetF action and how we can use them to prevent cancer.
Fundamental Actions of Metformin
In T2DM there is insulin resistance, insulin elevations, increased risk of cancer and cancer mortality. This may occur via activation of insulin and the IGF growth factor signaling pathways through the insulin receptor. Reversal of these pathways (occur via reduction of insulin resistance by MetF) is an attractive anti-cancer strategy. These properties of MetF can also be helpful for weight loss.
Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein neogensis and gluconeogenesis during cellular distress . The main down stream effect is AMPK activation with the inhibition of mTOR, which is activated in malignant cells and thereby is associated with resistance to anti-cancer drugs. MetF can induce cell cycle arrest and apoptosis and reduce growth factor signaling.
Novel Actions of Metformin Involving Lipids
A study by X.Yang, Ph.D., (Hong Kong Institute of Diabetes and
Obesity; Chinese Univ. of Hong Kong) noted that T2DM patients with low HDL-C have a higher risk of cancer, whereas when treated with MetF had a reduced risk of cancer.
Both MetF and apolipoprotein A-1, the main lipoprotein carrier of HDL- C (the most protective form of cholesterol) activate the AMPK kinase-signaling pathway. Dr. Yang then studied MetF to see whether those with T2DM had less cancer with different values of HDL-C. They followed 2,600 T2DM patients for
about 5.5 years. He concluded that "the anticancer affect" for MetF in T2DM patients was more evident in those with low HDL-C. This is a profound finding since it establishes an interaction between low apolipoprotein A-1 [Apo A-1] with low HDL-C and MetF. Perhaps low levels of Apo A-1 and HDl-C take-on anti-cancer properties. This needs more research.
Metformin and Breast Cancer
In a paper presented by Pam Goodwin, MD., (Univ. of Toronto) at the Endocrinology Annual 2010 meeting stated: "Basicaly all of the published data have shown that [T2DM ] patients who are on MetF have significantly lower rates of cancer than those not on MetF". This seems to now be a general consensus.
Dr. Pam Goodwin noted in lab studies some mechanisms as to how MetF may work. In cell culture MetF exerts antiproliferative, anti-migratory, and proaptotic effects. In mouse models of aggressive breast cancer MetF delayed the formation of mammary tumors.
Preliminary data in a new study by Dr. Goodwin showed that women who received MetF in early stage breast cancer exhibited significantly less cell proliferation and increased apoptosis with reduced insulin levels. There is starting to develop a convergence of evidence on the mode of action of MetF. It appears to suppress mammary tumor growth in mice. Partly via an AMP-kinase mediated mechanism.
Since the data presented in 2010 there have been a number of new papers that explain some of the other mechanisms how MetF may promote cancer prevention. MetF also may be a gene protector, may delete ontogenic stem cells and may lower NF-kB as well as have other mechanisms of action. The cancer stem cell (ontogenic stem cell) deletion concept is a favorite thesis by James D. Watson of DNA fame (with Crick).
Dr. Pollak of McGill University concludes that the effect of MetF is a most important finding since it covers a wide range of cancers.
CONCLUSION: Metformin useage is associated with less cancer overall.
Metformin and Hepaitis C
There is emerging data that MetF may have some beneficial effects on hepatitis C. The data is preliminary.
Who Should Not Use Metformin?
MetF has been associated with risk for lactic acidosis. This is a medical emergency. Symptoms may include muscle pain, difficulty breathing, nausea, and vomiting.
Lactic acidosis is rare, but potentially fatal condition.
People with conditions such as the below may not be candidates for MetF therapy:
1. Congestive heart failure, liver impairment, and renal impairment should be advised against use of MetF.
2. Those who have ketoacidosis (Atkins diet etc) , those who take the lipid med Gemfibrozil, Itraconazole, sufonurea diabetic meds with MetF or are binge drinkers.
3. MetF should be stopped before doing imaging tests that use dye excreted by the kidneys. Type 1 Diabetics should not use MetF.
4.Those with recent stroke or heart attack should not take MetF.
5. Recent surgery, dehydration, pregnancy and breast feeding are contraindications.
6. MetF should not be used with the sulfonurea class of diabetes meds since there may be an increase in heart attack risk.
7. MetF can cause Vit B12 deficiency. So all those on MetF should take Methyl B 12 and/or use homocysteine supplements.
8. Some studies have shown that MetF reduces total and free Testosterone in men. But many diabetics (approximately 40%) already have low T. Testosterone at youthful levels has been shown to improve glucose utilization.
9. Those with renal impairment. Some Diabetologists and Nephrologists allow MetF use up to creatinine values of 2.0. These patients need close monitoring. Creatinine builds up in the blood when kidney function is impaired.
Should Those Not at Risk for Diabetes Take Metformin?
If there is a strong family history for cancers like lung, colon,
breast, prostate,ovarian and others then MetF maybe a good preventive strategy.
If you are otherwise in good health and do not have the
contraindications listed and are an optimum health person, you should consider using MetF.
What about the cost?
1 gm tab of MetF is about 15-25 cents each or about 50 cents a day for 2 grams .
Protective dose is thought to be about 1.5 gm per day. Insurance usually covers this medicine.
How to take MetF?
Always take with food. First start with 250-500 mg with a large meal. If no problems, take 250-500 mg twice daily with largest meal. Then go up to 500 mg three times daily. Later can use 850 mg three times daily or 1 gm twice daily. Maximum dose in otherwise healthy people is 850 gm three times daily with food.
Avoid excess alcohol use. 1 to 2 glasses of wine may be permitted if used on a regular basis. I recommend my patients to stop MetF for 24-48 hours before and after"Party Drinking".
1. There is more likely to gain than to lose by using MetF as a cancer protective medicine or even as adjunctive therapy for cancer.
2. I personally feel Metf is a good call for Anti-Aging effects. There are some ways in which MetF can slow inflammation by modulating NF-kB and via other mechanisms thereby slowing aging. [I have been taking MetF at 2.0 gm daily for over 13 years.]
3. There is some new evidence that MetF may have positive effects on Hepatitis C.
What about Herbs and Supplements that Lower Glucose?
At least a dozen or more can lower blood glucose. So far I have not seen any data that they can prevent cancer. Just lowering glucose is not the total answer. Each supplement needs to be studied in thousands of diabetic patients before it could be considered as being cancer-protective. I have no objection to using some well studied supplements along with MetF as long as the blood levels of glucose drop (via HbA1C test) and inflammation markers are kept low. But we have no data on MetF-supplement combinations and cancer prevention.
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