Life Extension Magazine February 2012
Can a Diabetes Drug Prevent Cancer Death?
By James Saftig
With its near-perfect safety record, low cost, and favorable side-effect profile, the anti-diabetic drug metformin is one of the few FDA-approved drugs Life Extension® recommends its members should take every day.
Between 1990 and 2011 alone,1 over 1,000 published studies have yielded confirmatory data on its numerous anti-aging properties, from weight loss and glucose control to cardiovascular disease and cancer defense.
As the medical establishment continues to ignore this mounting body of evidence, ongoing research powerfully validates our position.
In one of the largest studies of its kind, a team of scientists analyzed cancer risk among 8,000 diabetics treated with metformin.2 Over a 10-year period, they observed a 54% lower incidence of all cancers compared to the general population.
Metformin not only exerted a major protective effect against cancer development, but those who developed cancer exhibited a significantly higher survival rate, including those with malignant cancers of the lung, colon, and breast. Of equal significance was the finding that the earlier the metformin regimen was initiated, the greater the preventive benefit.
Given that diabetics are predisposed to a horrifically wide array of cancers—of the breast, colon, liver, pancreas, kidney, endometrium (uterine lining), among others3-5—these results have profound implications for all maturing individuals.
In this article, the most recent data supporting metformin’s anti-cancer mechanisms are detailed. You will learn of its specific mechanisms of action, which shed further light on the link between obesity, diabetes, and cancer initiation. You will also discover how metformin induces cancer cell death at their earliest stages of development via metabolic pathways that also promote weight loss and optimal glucose control.
Metformin Slashes Cancer Risk in Multiple Clinical Trials
The study cited in the introduction of this article (54% lower risk of cancer) was of such medical importance as to merit an accompanying editorial by noted cancer epidemiologist Bruce B. Duncan, MD, PhD.6 Duncan observed that this was the most compelling amongst a rapidly growing set of studies, all suggesting that metformin might induce profound effects in preventing a wide range of cancers while improving prognosis in people who do develop malignancies.6
Additional supportive studies validate these findings.6 In a cohort study of more than 12,000 patients, metformin users died of cancer 30% less often than those taking another category of drug called sulfonylureas (including DiaBeta® and Glucotrol®).6,7 Of equal and even greater significance, people taking insulin had a 90% greater death rate than the metformin users in that study.6
In a second study of different design, people taking metformin for diabetes control for more than 36 months had a 72% lower risk of developing cancer than those on other regimens.6,8 Similarly, in a third study, metformin users had a 62% lower risk of developing cancer, compared with those who had never used metformin.6,9 Of significance, that study also showed an increased risk of cancer in people who were taking insulin or oral antidiabetes drugs other than metformin.
There’s additional evidence that metformin not only prevents cancer from developing, but also helps to improve the prognosis in patients who do develop tumors. In one study of breast cancer patients on chemotherapy, 24% of those who were also taking metformin had a complete response rate, compared with just 8% for those not taking it.6,10 As a result of these "incidental" findings, scientists have initiated several clinical trials to examine the impact of metformin as formal additional treatment for breast and other cancers.6,11
Numerous recent studies further support a close association between metformin use and substantially reduced cancer incidence, along with improved survival.12-16
These observations raise the question, "Why should a diabetes drug protect against cancer?"6
The answer is both simple and surprising.
Diabesity and Cancer Initiation: How Metformin Works
Years of clinical analysis have confirmed the link between obesity and diabetes, conditions whose co-occurrence has given rise to the term diabesity.
Diabesity is a direct causative factor in the development of a wide range of cancers. Diabetics have as much as a 41% increased risk for virtually all cancer types compared to healthy people. Elevated blood sugar alone increases the risk of certain cancers, including those of the kidney, pancreas, and skin (melanoma).6,17,18
Obesity increases cancer risk for more than a dozen different cancers.6 A 59% increase in cancer risk has been documented for every 5-unit increase in body mass index (BMI) alone.6,19 Studies show that obesity is responsible for up to 20% of cancer deaths in women.20
The link between diabesity and cancer points to the underlying mechanisms of action by which metformin works as a cancer-preventing agent.
Metformin operates at the molecular level by activating adenosine monophosphate-activated protein kinase or AMPK, a molecule essential to life. AMPK or its molecular analogs are present in virtually all living organisms.6,21 It also happens to be intimately involved in cellular processes whose dysregulation play a central role in both diabesity and cancer initiation.
Diabetes and obesity result from various metabolic derangements. Cancer results from disordered regulation of cell growth. AMPK is critical to normal regulation of both metabolism and cell growth, as a result of millions of years of evolutionary development.6
As a fuel-sensor and metabolic master switch, AMPK recognizes and responds to changes in cellular energy levels, determining how fats and carbohydrates will be used in storing or utilizing energy.6 In metabolic terms, AMPK tells cells to conserve and generate new energy stores. In so doing, it lowers sugar output from the liver, increases glucose uptake from the blood, maintains insulin sensitivity, and ultimately lowers blood sugar.6,21
AMPK exerts similar effects in terms of regulating cell growth and replication, instructing cells to conserve energy, slowing and often shutting down aberrant cell growth entirely. In essence, when AMPK is activated, incipient cancer cells starve themselves to death for lack of adequate energy supplies.22
We can naturally activate AMPK in our bodies through several time-honored mechanisms. Calorie restriction lowers cellular energy stores and activates AMPK.23 Known to increase life span in virtually all species, calorie restriction has been shown to reduce cancer incidence and death in primate studies.24,25 And a recent study showed that gastric bypass surgery not only produced sustained weight loss, but also reduced cancer incidence by 42% in women patients (no effect was seen in men).6,26
Exercise is another strong natural activator of AMPK, and studies show that people with the highest levels of physical activity are protected against cancers of the lung and colon by as much as 30%.6,27,28
Exercise and weight loss are lifestyle changes that most of us need to make, while bariatric surgery and massive calorie restriction have more limited appeal and application as means of activating AMPK and lowering cancer risk.
Metformin, a natural product of the French lilac,29 is a safe, readily available, and inexpensive way to activate AMPK and starve cancer cells of their energy supplies.6,30,31 In doing so, metformin powerfully restores healthy regulation—both of metabolic factors and of those that regulate cell growth.
Let’s now examine how metformin halts incipient cancers by quelling abnormal cellular proliferation, one of the earliest steps in cancer development.
Metformin’s Anti-Cancer Power Confirmed in Lab Studies
Healthy, normal people develop incipient cancer cells in their bodies daily; these cells are normally destroyed by a number of natural processes. When those processes break down, the cancer cells are free to proliferate and form a tumor. An ideal anti-cancer drug, then, would eliminate these altered, "precancerous" cells before they could replicate and become invasive and malignant.32
Even in their earliest stages, aggressive cancer cells are notoriously energy-hungry, burning calories at a frenetic rate as they grow out of control.33 For that reason, targeting cancer cell metabolism now stands at the forefront of cancer prevention research.34 With its potent ability to shut off the cellular energy pipeline by activating AMPK, metformin is showing its value in preventing or slowing a host of cancer types in laboratory studies.
The consequences of AMPK activation by metformin are numerous. Metformin, added to cultures of many different cancer cell types, blocks proliferation by "stalling" cells at one of several phases of the cell replication cycle, preventing them from reproducing.34-37 Metformin’s ability to starve cancer cells of energy also enhances the rate of cell death by the process known as apoptosis, one of the body’s natural means of cancer control.34,38
Perhaps the most detailed picture of metformin’s antiproliferative actions comes from a 2011 study in France.38 Researchers there added metformin to melanoma skin cancer cells in culture, and monitored the effects. At 24 hours, metformin had starved the cancer cells to the point that their replicative cell cycle was arrested. By 72 hours, the cells underwent autophagy, a mechanism whereby starving cells literally "eat themselves" in a desperate attempt to survive. And by 96 hours, the cancer cells began dying off en masse by apoptosis.
Several additional antiproliferative mechanisms have recently been demonstrated for metformin in addition to its effects on the AMPK energy-sensing pathway.35,39-42 That ability to act by multiple mechanisms is called pleiotropy. It is powerfully beneficial because it prevents development of resistance to any one pathway. Pleiotropy is seen much more commonly with natural products such as metformin than with mono-targeted pharmaceutical drugs.
The combined effect of all of metformin’s pleiotropic mechanisms is a marked reduction of tumor growth in lab animals implanted with human cancer cells.36,43 To date, metformin-induced antiproliferative effects have been demonstrated in cancers of the brain, lung, breast, ovary, prostate, and colon.35-38,44-47 And human studies are now showing important reductions in various tumor markers when metformin is provided to breast cancer patients prior to tumor surgery.48 Importantly, in breast cancer cells, metformin is most active against cancer strains that are resistant to standard chemotherapy drugs.46
Metformin Prevents Cancers in Non-Diabetic Individuals
Perhaps the most exciting news to come out of the recent surge in interest in metformin is that the drug can prevent cancers from forming in animals and humans who are not diabetic. As a "mimicker" of a calorie-restricted state, that might be expected of metformin, given that calorie restriction is such a potent cancer-preventive strategy.33,49-51
Since 2008, a small explosion of studies has appeared demonstrating how effective metformin can be in this context, ultimately suggesting that it should be taken regularly by anyone who wants to reduce their risk of dying from cancer.
Research now demonstrates that metformin, provided orally to lab animals, prevents deadly colorectal cancers52 (the second leading cause of cancer deaths in the US, and an astonishingly preventable disease).53 Metformin suppresses intestinal polyp growth, a precursor of colorectal cancer, in mice predisposed to that disease.54 And, in a study of chemically induced colon cancer, metformin significantly reduced formation of so-called "aberrant crypt foci," which in humans represent an early stage in cancer development.55
Those studies led to the first human study of metformin as a cancer preventive agent in non-diabetic people. Researchers studied 26 non-diabetic people with aberrant crypt foci that had been found on routine colonoscopy.56 They randomly assigned them to receive metformin 250 mg per day, or no treatment, and then performed repeat colonoscopy one month later. The metformin group had a significant decrease in the number of aberrant crypt foci, from nearly 9 per patient down to about 5 per patient, while control patients had no change. This represent a 55% reduction in this cancer precursor in patients taking low-dose metformin.
Chemoprevention studies now also demonstrate similar effects in other cancers. Mice supplemented with oral metformin, exposed to a potent tobacco carcinogen, developed 53% fewer lung cancers than did control animals.57 And when metformin was administered by injection, that protection rate rose to 72%.
Breast cancer prevention would represent a huge forward stride in extending human life span and reducing suffering. There’s encouraging data here as well. Mice given metformin in their drinking water for 13 days prior to injection with a powerful breast carcinogen had significantly delayed onset of tumor development.58 Several other studies have demonstrated that metformin-supplemented mice experience a reduction in proliferation of cancer-prone breast cells and inhibition of tumor growth.31
There is now a tremendous body of literature showing that metformin prevents cancer cells from proliferating, and moreover it prevents clinically relevant human cancers from developing, even in non-diabetic, non-obese individuals.59 As a result, one might expect to see large clinical trials of metformin in healthy older adults as a cancer chemopreventive agent.
Sadly, even though calls for such studies are gathering strength, to date no trial has been designed, let alone implemented.60-62 Given metformin’s impressive safety record over nearly 50 years of clinical use,43 there is simply no reason for sensible people to wait for an "official" medical establishment recommendation. People who are concerned about their growing risk of cancer should simply speak to their physicians now, and present them with a synopsis of the data, so that they can begin potentially lifesaving use of metformin today.
The anti-diabetic drug metformin was recently shown to slash risk of all cancers by 54% among 8,000 diabetics over a 10-year period while significantly improving prognosis among those who developed cancer, including cancers of the lung, colon, and breast.
Diabetes and obesity are twin risks for cancer development. Metformin offers powerful protection against cancer in those populations. Aggressive scientific research is revealing that metformin’s action, activating the cellular energy sensor AMPK, is the key to both its metabolic benefits and its cancer chemopreventive capabilities.
Both human and animal studies definitively confirm that metformin lowers cancer risk dramatically while also preventing new cancer formation, in both diabetic and non-diabetic individuals. Metformin’s 50-year safety record, coupled with its low cost and favorable side effect profile, provide an ironclad rationale for most aging humans to consider taking metformin.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
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