Life Extension Magazine November 2012
Metformin Makes Headline News
by William Faloon
Metformin is the first-line drug of choice in the treatment of type II diabetes. It was first approved in Europe in 1958.1Americans had to wait until 1994 to legally obtain metformin.1
The holdup in approving metformin goes beyond the FDA. It is an indictment of a political/legal system that will forever cause needless suffering and death unless substantively changed.
When Life Extension® informed Americans about drugs like metformin in the 1980s, the FDA did everything in its power to incarcerate me and shut down our Foundation.2 FDA propaganda at the time was that consumers needed to be "protected" against "unproven" therapies.
As history has since proven, the result of the FDA's embargo has been unparalleled human carnage. So called "consumer protection" translated into ailing Americans being denied access to therapies that the FDA now claims are essential to saving lives.
Today's major problem is not drugs available in other countries that Americans can't access. Instead, it is a political/legal system that suffocates medical innovation.
Headline news stories earlier this year touted the anti-cancer effects of metformin, data that Foundation members were alerted to long ago.3
The problem is that it is illegal for metformin manufacturers to promote this drug to cancer patients or oncologists. It's also illegal to promote metformin to healthy people who want to reduce their risk of cancer, diabetes, vascular occlusion, and obesity.
This fatal departure from reality continues unabated, as our dysfunctional political/legal system denies information about metformin that could spare countless numbers of lives.
Type II diabetics suffer sharply higher rates of cancer4-7and vascular disease.8-11 The anti-diabetic drug metformin has been shown in numerous scientific studies to slash the risk of cancer12-24 and lower markers of vascular disease.25-28
Metformin was shown to reduce blood sugar levels in the 1920s.28 One reason it fell off the radar screen is that insulin quickly became popular because it produced an immediate glucose-lowering effect.
What doctors back then did not realize is that while insulin saved the lives of type I diabetics (who produce little or no insulin), those with type II diabetes often produce too much insulin as their pancreas tries to offset multiple metabolic imbalances.
One of the metabolic imbalances of type II diabetes is the excess formation of glucose in the liver. To ensure that blood glucose never drops too low, the liver manufactures glucose in a process called gluconeogenesis. In type II diabetes, despite an elevated blood glucose level, the liver inappropriately continues to pump out glucose. This inappropriate outburst of glucose from the liver in type II diabetes patients is a classic hallmark of the disease. In fact, scientific data that measures glucose output by the liver shows that the typical type II diabetic produces three times more glucose in their liver than non-diabetics.29 And, as previously reported in this publication, even most non-diabetics produce too much glucose in their liver as they age.
Scientific data shows that metformin reduces glucose production and the rate of gluconeogenesis by anywhere from 24% to 36%, respectively, thus reducing blood glucose levels while lowering the amount of insulin that is chronically secreted.29 Metformin also enhances insulin sensitivity, thus enabling cells to remove more glucose from the bloodstream, which further lowers glucose and insulin levels.30-33 In a recent study conducted by a team of researchers in Italy, 500 mg three times a day of metformin reduced insulin levels by 25%.33
Excess Insulin Is a "Death Hormone"
In response to continuous over-production of glucose by the liver, the pancreas secretes huge amounts of insulin to suppress it. This excess amount of insulin damages blood vessel walls34-36 and promotes tumor growth.37-41 For a type II diabetic who is over-producing insulin, the use of insulin injections provides a relatively brief respite from high blood glucose levels—with horrific long-term consequences.Drug companies today are heavily promoting convenient insulin injection devices to physicians and suggesting that many of them have forgotten about insulin's proven glucose-lowering effects. The harsh reality is that for most type II diabetics, excess insulin represents a "death hormone" that causes weight gain,42-44 cancer,45-47 and vascular disease.48-51
It was not only the discovery of insulin that delayed recognition of metformin. Drugs known as sulfonylureas promote the insulin release from the pancreas. Sulfonylureas were liberally prescribed for decades and are another ill-conceived way of temporarily suppressing blood glucose at the expense of systemic metabolic havoc.
Like insulin, sulfonylurea drugs induce weight gain, which is the opposite effect one is seeking when treating most type II diabetics. All sulfonylureas carry an FDA-mandated warning about increased risk of cardiovascular death.
In one study lasting more than 10 years, patients who primarily received metformin had a 39% reduction in the risk of heart attack and a 36% reduction of death from any cause.52 The same study showed that metformin did not cause weight gain in overweight patients, while patients prescribed sulfonylureas gained more than 7 pounds, and those using insulin injections gained over 10 pounds.53
For the multi-decade period Americans were denied access to metformin, doctors felt they had little choice but to prescribe sulfonylurea drugs and insulin injections. The needless suffering and death endured by diabetics during this "dark age" of American medicine is incalculable.
Why American Doctors Were Afraid of Metformin
For decades, the American medical establishment labored under an egregious misconception about the safety of metformin.
The reason was that drugs in the same class of metformin (biguanides) can cause a potentially fatal condition called lactic acidosis, where the body becomes overly acidic in the presence of excess lactic acid. While other biguanide drugs were withdrawn because of lactic acidosis risk, it turned out that metformin did not induce this same side effect in healthier people.54 As long as one has sufficient kidney, liver, cardiac, and pulmonary function, any excess lactic acid caused by metformin is safely removed by the kidneys.55-57
It turned out that only patients with severe kidney, liver, pulmonary, or cardiac impairment had to avoid metformin because of lactic acidosis concerns, and even these worries were overblown.
I'll never forget what a brilliant medical doctor personally told me after a large study came out that dispelled the myth connecting metformin with lactic acidosis. This doctor knew how effective metformin was, but was terrified of creating lactic acidosis in any of his patients. He told me something to the effect of, "If this study showing lactic acidosis is not a risk for metformin users is true, then the multi-decade oversight that caused doctors to fear metformin represents one of the great blunders in medical history."
The regrettable fact is that doctors in the United States were taught to avoid drugs in the class of metformin, even though metformin itself was being safely used throughout the world. If only the medical establishment in the United States had looked across the border as close as Canada, they would have seen metformin being liberally prescribed with nowhere near the incidences of lactic acidosis they feared.
In the early years, when I was taking metformin for anti-aging purposes, most doctors warned me about lactic acidosis risk. I always asked where in the scientific literature does it show a healthy person is at risk for lactic acidosis when taking metformin? They could never cite a reference, so I continued taking my metformin.
Analysis Shows Metformin Does Not Cause Lactic Acidosis
How Metformin Functions
Metformin reduces blood glucose levels primarily by suppressing glucose formation in the liver (hepatic gluconeogenesis).59
More importantly, it activates an enzyme called AMPK (AMP-activated protein kinase) that plays an important role in insulin signaling, systemic energy balance, and the metabolism of glucose and fats.60
Activation of AMPK is one mechanism that may explain why diabetics prescribed metformin have sharply lower cancer rates. For instance, in a controlled study at MD Anderson Cancer Center, the risk of pancreatic cancer was 62% lower in diabetics who had taken metformin compared to those who had never taken it.61 Diabetics suffer sharply higher incidences of pancreatic cancer than non-diabetics.61
Your Nutrients "May" Work As Well As Metformin
Virtually every Life Extension® member takes curcumin on a daily basis.
Curcumin activates the same AMPK enzyme at a rate that may be higher than metformin.
Curcumin also increases insulin sensitivity while reducing expression of glucose-producing genes.80
Coffee rich in chlorogenic acid or green coffee extract supplements have demonstrated a profound reduction in gluconeogenesis—with a corresponding decrease in post-meal glucose elevations.81-83
We know that suppression of gluconeogenesis, enhanced insulin sensitivity, and activation of AMPK are some of the mechanisms behind metformin's broad-spectrum benefits.
It is not possible at this time, however, to know for sure if aging humans can derive identical benefits from nutrients like curcumin and chlorogenic acid as are provided by metformin.
With my understanding of the beneficial mechanisms of curcumin and chlorogenic acid, I personally take these nutrients plus a high dose (850 mg) of metformin two to three times a day.
How Metformin May Increase Heart Attack Risk
One study found that when metformin was added to a group of non-overweight patients taking sulfonylurea drugs, there was a significant increase in overall mortality.71 This suggests that metformin should not be combined with sulfonylureas.
Furthermore, not all studies show that metformin reduces cardiovascular risk or improves overall survival in type II diabetic patients. There are several reasons to explain these discrepancies.
Metformin is known to cause vitamin B12 deficiency which translates into higher levels of artery-clogging homocysteine.72-74 The tiny amount of vitamin B12 and other B-vitamins found in commercial supplements is not always sufficient to offset this problem. Those who take metformin should ensure they are taking higher doses of B-vitamins (at least 300 mcg of vitamin B12) and check their homocysteine levels to make sure it stays in the safer ranges.75 One study showed that the addition of 5,000 mcg of folic acid to patients taking metformin reduced their homocysteine from 15.1 µmol/L to 12.1 µmol/L.76 Optimal homocysteine levels are probably under 8 µmol/L, but any reduction is helpful. Sadly, most diabetics prescribed metformin don't check their homocysteine levels and don't take enough B-vitamins to prevent a deficiency.
Some studies show that metformin reduces free testosterone and total testosterone levels in men.77 Testosterone is especially important in male diabetics as it significantly enhances insulin sensitivity.78 Life Extension has previously published clinical data showing the critical importance of diabetic men to maintain youthful testosterone levels in order to improve glucose utilization.79
The greatest challenge in evaluating clinical data on metformin is that it is often prescribed to debilitated patients who have undergone severe arterial attack for many decades. These diabetic patients are at significant risk of cardiovascular disease from a number of underlying causes. They need to take aggressive steps to correct all independent risk factors for vascular disease, something that is never done in clinical studies.
Politicians Overlook Most Important Issue
Billions of dollars are being spent on campaign ads by politicians. Most of the issues raised will not directly affect you in a meaningful way.
Overlooked is a problem that will affect every one of us—the suffocating impact of antiquated legislation on medical progress.
Once you or a family member is diagnosed with a disease like pancreatic cancer, campaign ads become background clutter. Your only concern is finding a therapy that offers some hope of survival.
The best our current archaic system offers for pancreatic cancer is a drug called gemcitabine.
Compared to another chemo drug, gemcitabine increased average survival by a meager 36 days, which conventional doctors described as a "significant improvement."91
A team of researchers was able to improve on gemcitabine by using instead a toxic combination of chemotherapy drugs (called FOLFIRINOX). Compared to the gemcitabine group, patients able to tolerate the debilitating side effects of FOLFIRINOX lived 4.3 months longer than the gemcitabine group, but suffered greater toxicity.92,93
The fact that pancreatic cancer still quickly kills virtually everyone who contracts it is a stark example of how today's regulatory system stifles innovation. Unregulated environments have produced technologies like hand-held computers that perform miraculously and are affordable to mostly everyone. Life Extension® for years has provided hard-core scientific documentation about the anti-cancer properties of metformin. Yet unless the current political/legal stranglehold over medical innovation is lifted, the only cancer patients likely to benefit from metformin will be Foundation members who insist their doctors prescribe it.
Recall that metformin was discovered 90 years ago, yet conventional doctors are still failing to use it in the prevention and treatment of a host of age-related disorders.
Should You Ask Your Doctor About Metformin?
The challenge some members find is persuading their doctors to prescribe metformin if they are not diabetic. You may recall the many articles we have published showing that any elevation of fasting glucose above 85 mg/dL increases one's risk for contracting classic diabetic complications like heart attack and stroke.84-90
Therefore, those whose glucose levels exceed 85 mg/dL should consider metformin for its glucose-lowering properties alone, though chlorogenic acid-standardized coffee extracts may accomplish a similar effect.
No one should take metformin without having a complete battery of blood tests to show their doctor that it is not contraindicated because of disorders like kidney failure. Those with low blood sugar (hypoglycemia) may not be able to use metformin.
A suggested starting dose of metformin is 250 mg before a large meal. The dose may be increased after a week to 250 mg before three meals a day. After a month, you may consider increasing to 500 mg before meals and eventually go up to 850 mg before meals, which is the upper limit dose.
If you notice a slight reduction in appetite, use it to cut back on your calorie intake and hopefully shed some fat pounds. By stabilizing blood sugar and insulin levels, metformin can help reduce food cravings.
The Political/Legal System Must Be Changed
Human clinical research has long been oppressed in the United States by a variety of laws that conspire to deny medical progress.
The few new therapies that are approved are mediocre, expensive, and often laden with side effects. The current system represents the worst of all worlds when it comes to the kind of scientific advances that aging people need to significantly extend their healthy life spans.
Your support of Life Extension® enables us to continue our relentless campaign to tear down the strangleholds erected by public and private institutions.
The 37-year delay in approving metformin provides a real world example of how broken our political/legal systems are when it comes to finding cures for degenerative disease and the aging process itself.
What You Can Do To Stop Needless Suffering and Death
Scientists have identified novel ways of treating cancer and other illnesses, but too little of this new technology is being used in clinical practice. When new discoveries are made, drug companies spend years seeking a patent, and then more years carrying it through the cumbersome bureaucratic approval process. A major reason so many cancer patients die today is an antiquated regulatory system that causes effective therapies to be delayed (or suppressed altogether).
This system must be changed, if the 1,500 American cancer patients who perish each day are to have a realistic chance of being saved. Our long-standing proposal has been to change the law so that anyone can opt out of the FDA's umbrella of "protection." This approach will allow companies to sell drugs that have demonstrated safety and a reasonable likelihood of effectiveness, which are clearly labeled "Not Approved by the FDA." Patients who wish can still use only FDA-approved drugs, while those willing to take a risk, in consultation with their doctors, will be allowed to try drugs shown to be safe that are still not approved.
We believe that this initiative will result in a renaissance in the practice of medicine similar to the computer technology revolution of the past four decades. In this environment, many lethal diseases will succumb to cures that are less expensive than is presently the case. And greater competition will help eliminate the health care cost crisis that exists today.
Seriously ill people, in consultation with their doctors, should be able to make up their own minds about what drugs they are willing to try.
This is the time when political leaders will at least listen to their constituent's concerns. I encourage each of you to log on to our legislative action website at www.lef.org/lac to easily email your representative and two senators a letter demanding they enact legislation that will enable those with serious illness to obtain therapies far enough along in the clinical trials process to be deemed safe, but not yet approved by the FDA.
Take Action Now!
For longer life,
William Faloon
Tell Congress to Change the Law! There are millions of cancer patients alive right now who face possible or probable death in the next twelve months. If you add their family members and friends, there are tens of millions of Americans who should be outraged by an outdated regulatory system that bans access to potentially life-saving therapies. The FDA continues to suppress innovative therapies because the public has failed to demand that our elected officials rein in the FDA's arbitrary authority. The first step in changing today's outmoded system is for those who understand the magnitude of this problem to communicate the urgent need for change to Congress. Those concerned about this serious issue should log on to www.lef.org/lac to insist that their Representative and two Senators help enact legislation that will enable cancer patients to obtain therapies far enough along in the clinical trials process to be deemed safe, but not yet approved by the FDA. Take Action Now!Those without computer access can photocopy the next page and mail it to their Representative at The US House of Representatives, Washington, DC, 20515 and two Senators at The US Senate, Washington, DC, 20510. We also ask that you phone your Congressional members at 1-202-224-3121 to let them know how disgusted you are that doctors and patients are not allowed to choose drugs that may be effective against an often fatal disease.
The Honorable: I am writing to ask that you sponsor or co-sponsor legislation to enable cancer patients (and those with other serious diseases) to purchase medications while they are pending final approval by the FDA. This approach will allow companies to sell novel drugs with a label clearly stating that they are "Not Approved by the FDA."
Consumers who wish to rely on the FDA can limit their choices to fully approved drugs only, while those willing to take a risk (in consultation with their doctors) will be allowed to try what they choose. (Companies that make fraudulent claims for products can be prosecuted under the laws that exist today.) This initiative can result in a renaissance in the practice of medicine, similar to the computer technology revolution that has occurred over the past three decades. In this environment free of regulatory burden, many inexpensive cures will very likely be found for lethal diseases. And greater competition will help eliminate the health care cost crisis that exists today. I am tired of reading about medical breakthroughs, only to be told that I will have to wait years before the therapy might become available. As 1,500 Americans die of cancer each day, I consider the introduction and passage of such a law an extremely high priority. Seriously ill people have the fundamental right to make up their own minds about what drugs they are allowed to try, in consultation with their physicians. Please let me know that you will sponsor or co-sponsor such legislation, which will provide us with quicker access to drugs that the FDA has found safe and potentially effective, but have not yet received final approval. Sincerely, Name: Address: City: ST: Zip: References1. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1464-5491.2011.03469.x/pdf. Accessed August 2, 2012. 2. Available at: http://www.lef.org/magazine/mag96/sept96_freedom.html. Accessed May 11, 2012.3. Available at: http://www.cnn.com/2012/04/05/health/diabetes-drug-fights-cancer/. Accessed May 11, 2012. 4. Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood. 2012 May 24;119(21):4845-50. 5. 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