Metformin Update

I have been an advocate of metformin for everyone, and enthusiastic about Nir Barzilai’s trial of metformin as an anti-aging drug.  Last week, I learned fromBrian Hanley that metformin has a dark side, to wit, a statistical association with higher frequency of Alzheimer’s disease [ref, ref].  There is a biochemical mechanism that makes the epidemiology more compelling.  B12 supplementationmay mitigate the risk.

Other studies [ref, ref]  have found that diabetes patients have elevated risk of dementia, and that that risk is reduced when they take metformin.  So it’s fair to say that there is contradictory evidence, and the direction of the effect may depend on individual variation.  Here is a balanced view of both sides.

A reader of this blog, George Goldsmith has written to me that berberine is a good herbal substitute for metformin.  Everything we know about berberine looks really good–it is an anti-inflammatory as well as helping preserve insulin sensitivity, acting through the AMPK pathway.  But we have much more experience with metformin, both clinically and in the lab.

Metformin increases life span in mice, and to my knowledge, this test has yet to be performed with berberine.  Magnesium supplements also can help prevent insulin resistance, and there are other good reasons to take magnesium.

Gynostemma pentaphyllum, sold by LEF under the brand name AMPK Activator, is another herbal alternative to metformin.

CAN BOTANICALS REPLACE METFORMIN?

Posted on October 13, 2015

Gymnema, Jiaogulan and Berberine: Can herbs replace metformin?

We all lose insulin sensitivity with age, and this is is a primary mechanism by which we become more vulnerable to all the diseases of old age. But there is much that we can do to retain insulin sensitivity: diet, exercise, drugs and herbs. Because these act differently on the metabolism, there is reason to hope that combining treatments will yield combined benefits (this is theoretical–there is no data available on combinations.)
While emerging anti-aging technologies are still emerging, the best-tested treatments we have for the present all rely on the insulin metabolism. Our bodies are evolved to sense stress–especially food scarcity–and adjust our rate of aging to compensate for those around us who may be starving to death. (This is the demographic theory of aging, and though the theory may still be controversial, the fact that we can address the rate of aging through the insulin metabolism is undisputed.)
Insulin manipulation works much better in mice than in larger animals like us, but it’s the best-studied, surest way to improve your odds for a long and healthy life, and there are vitality, alertness, productivity, freedom from infectious disease–almost every aspect of your quality of life is improved with more exercise and less food.

The best measure of diabetes risk is glucose tolerance. The body is challenged by swallowing a dose of sugar, and glucose levels in the blood rise immediately. Over several hours, follow-up blood tests measure how quickly the blood levels come back to normal.

Metformin

For anyone who doesn’t choose to maintain the most rigorous program of exercise and caloric restriction, metformin can make up the difference. Metformin is a fifty-year-old drug, long out of patent and cheap. Mice fed metformin live longer. We have a great deal of epidemiological data on metformin, because tens of millions of people have been taking it for decades. Diabetics who take metformin have much lower rates of cancer, heart disease, and AD. Arguably, their survival statistics may even be better than non-diabetics who don’t take metformin. There are researchers who are proposing that Alzheimer’s Disease should be regarded as type 3 diabetes. (FightAging! led me to this article.)

The numbers look so good that Nir Barzilai (Einstein Hospital, New York) has banked the future of FDA policy on a clinical trial to demonstrate that aging is a risk factor that can be mitigated, and that aging should be recognized as a treatable condition. Last month, there was a major article in Science Magazine about his program. It is hardly a radical claim, from a scientific perspective. But government policy lags science, and what Barzilai is doing will be a boon for us all, if it works.

Metformin is a safe drug, without serious side-effects except rarely among people taking high doses. I have recommended it to anyone over 40 who is overweight, or over 60 even if you’re not overweight.

Many people prefer a natural alternative, and I’m witing today about three good ones. The reasons for preferring “natural” may transcend science. There is a general feeling that natural products are safer, though in this case we know a heck of a lot about the safety of metformin. There are decades of epidemiological data for metformin, vs centuries of traditional wisdom for the herbal products. Readers of this column are accustomed to my periodic rants about the fact that capitalism has distorted funding priorities for medical research, hence we know a lot less about natural products than about patentable ones.

Gymnema

Thanks to Bill Sardi for introducing me to Gymnema. Here is a review of limited evidence for Gymnema and diabetes that was available as of 2007. Gymnema has a long pedigree through the Indian ayurvedic tradition of life extension, in which it is called mesasrngi [sic]. Gymnema reduces uptake of sugar from the small intestine, and also increases generation of insulin in the pancreas. The former is definitely beneficial; the latter is helpful for diabetes type 1, but not for type 2 which is associated with aging. In this study, Gymnema improved cholesterol profiles, fasting glucose, and also results from the (most predictive) glucose tolerance test. This study found similar benefits in obese mice.

Berberine

Berberine is a chemical, not a plant, though it is extracted from several different plant sources. The best source is goldenseal. Berberine has a 5,000-year legacy in Chinese medicine–even longer than Gymnema has in Indian medicine.

Metformin reduces blood glucose by shutting off the source (in the liver), while berberine reduces blood glucose by augmenting the sink (glucose uptake in muscle and nerve cells). Berberine affects cells in much the same way as insulin, increasing the uptake of glucose from the blood into the cell. This means that if you take berberine before exercise, it might (theoretically) enhance your performance, while taking metformin before exercise might (theoretically) reduce your performance.

This study compared metabolic benefits from berberine with metformin head-on in a three-month trial. 500 mg berberine had benefits equal to 500 mg metformin, with fewer reported stomach upsets and better triglyceride control for berberine.

This column by Frank Shallenberger raves about the advantages of berberine.

“Berberine has low rates of absorption when taken orally due to both being subject to P-Glycoprotein (ejects Berberine back into the intestines) and increasing the activity of P-Glycoprotein (augmenting its own ejection), but absorption is greatly increased when taken with P-Glycoprotein inhibitors such as Silymarin from Milk Thistle.” [Examine.com]

Jiaogulan

This traditional Chinese herb (绞股蓝) has recently been marketed by LEF under the name “AMPK Activator”. The latin name of the plant is Gynostemma pentaphyllum. It is sometimes known as “southern ginseng” because it contains some of the same active ingredients as ginseng, deemed the king of all Oriental medicines. But the anti-diabetic benefits of jiaogulan derive from constituents that are not found in ginseng. In parts of Southeast Asia, jiaogulan has a reputation as an “immortality herb”.

Like Gymnema, jiaogulan shows promise, both theoretically and in limited human trials, but there isn’t yet enough data to know how well it works. In one study, it improved both fasting glucose levels and (more important) tolerance.

In promoting its new product, LEF has made a case that low AMPK is part of a keystone aging pathway. We have less AMPK as we get older. Both fasting and vigorous exercise increase AMPK levels. Less body fat leads to more AMPK expression, and, even better, more AMPK leads to burning more fuel, storing less as fat. This is a positive feedback loop that can work in either direction. AMPK → faster metabolism → less fat → more AMPK or low AMPK → slower metabolism → more fat → less AMPK. By adding AMPK, they claim, we can be sure to go around the circle in the right direction. Like many LEF reports, I find this one to be well-rooted in truth but a bit breathless in presentation and overstated in its significance.

Other measures

Weight control is still your first line defense against the creeping insulin resistance that affects all of us as we get older, and only is diagnosed as diabetes in its more severe form. There’s a school that says low protein diet offers best protection, and another that favors low carbs. (I have favored carb restriction, but I may be tipping toward low protein.) You can’t do both without raising fat intake, and there is good agreement that dietary fat shouldn’t be more than 40% of your calories.

Exercise prodigiously. Exercise right before eating can change your body’s insulin response to the sugar challenge. Even a minute of high-intensity exercise can make a difference [ref, ref].
Vegan diets are associated with much lower incidence of diabetes. In this study, vegans had half the incidence of diabetes, even after controlling for the fact that they had lower BMI. Non-vegan vegetarian diets were not far behind.

Almost all of us can benefit from magnesium supplements. Zinc [ref, ref] and tiny quantities of chromium might also help. Resveratrol extends life span in fat mice. There is some evidence for thiamin (vit B1). Large quantities of cinnamon may or may not be helpful. One small study showed a substantial benefit from boswellia=frankincense.

The Bottom Line

Loss of insulin sensitivity is so closely intertwined with all the diseases of old age that it is hardly distinguishable from “normal aging”. It’s an issue that we all face, and there is a whole Chinese menu of measures you can take to better your odds for health, vitality and a long life.

The mechanisms of metformin, berberine, jiaogulan and Gymnema are quite different, and there is reason to think that combining them offers more benefit than any treatment separately; but there is as yet no data on combined therapies.

Is Metformin an Anti-aging Drug?

 As we age, we all lose sensitivity to insulin and begin, gradually or rapidly, to poison our bodies with excess sugar in the blood. This happens to almost everyone, and it is only when the symptom is particularly severe that it is diagnosed as (type 2) diabetes. Metformin is a drug that has been used to treat diabetes for 50 years, but it is only recently that epidemiologists have begun to notice that patients on metformin have lower rates of cancer and heart disease. Of course, cancer and heart disease were elevated to begin with in diabetics. But the question has been asked: will metformin provide a benefit for “normal” aging, and lower cancer risk for people who are not diagnosed with diabetes?

Vladimir Anisimov from University of Glasgow has proposed that it’s time to test metformin for its anti-cancer and life extension potential for non-diabetics. He is a biostatistician, an epidemiologist and not a physiologist. But a good part of the reason to think that this might work comes from theory.

Metformin and Caloric Restriction

The only intervention that is known to consistently extend life span across many different species is caloric restriction. Animals seem to be widely adapted to stabilize their populations by suppressing death from aging under conditions of starvation (and raising the internally-programmed death rate when there is plenty of food). How does the individual metabolism detect when it is starving? The signal comes mainly from the insulin metabolism. The body responds to chronically elevated insulin by decreasing sensitivity to insulin, and raising insulin levels yet further in a positive feedback loop that cascades toward death. Metformin interrupts this cycle in a manner similar to lowered food intake. Since most people don’t tolerate chronic hunger very well, a drug that offers the benefits of a lean diet without having to cut calories would be highly prized. Such a drug is called a caloric restriction mimetic, and there is some reason to believe that is what metformin does. (Many people taking metformin experience actual weight loss as well.)

The health benefits of metformin for diabetics are striking, and are not shared by other drugs that treat only the diabetes. Metformin cuts cancer rates by 37%.  But cancer is already elevated in diabetics. If the reduction in cancer had been to values below the rates in non-diabetics, then metformin for non-diabetics would seem to be a slam dunk. But in reality this sizable benefit brings cancer rates down just about to their level in non-diabetics, but not further. So the benefits for non-diabetics remain speculative.

Life extension in rats and mice

Over the years, there have been many studies of metformin’s effects on mice and rats. Most show some life extension, and the best result increased life span by 38%. Metformin seems to work better for mice than rats, and better for females than males.  Here is a table (from Anisimov) summarizing results in rodents.

STRAIN	SEX	TREATMENT	NO. OF ANIMALS	LIFE SPAN, DAYS			REFERENCES
				MEAN	LAST 10% OF SURVIVORS	MAXIMUM
Mouse
C3H/Sn	Female	Control	30	450 ± 23.4	631 ± 11.4	643	[67]
		Phenformin	24	545 ± 39.2 (+21.1%)	810 ± 0 * (+28.4%)	810 (+26%)
FVB/N	Female	Control	34	264 ± 3.5	297 ± 7.3	311	[68]
		Metformin	32	285 ± 5.2 (+8.0%)	336 ± 2.7 (+13.1%)*	340 (+16.2%)
FVB/N	Female	Control	15	285 ± 12	396 ± 0	396	[69]
		Metformin	20	304 ± 10	352 ± 7	359
SHR	Female	Control	50	388 ± 29.2	727 ± 22.5	814	[70]
		Metformin	50	535 ± 31.9* (+37.9%)	878 ± 6.6* (+20.8%)	898 (+10.3%)
NMRI	Female	Control	50	346 ± 11.9	480 ± 9.2	511	[71]
		Diabenol	50	369 ± 12.9	504 ± 6.4* (+5.9%)	518
129/Sv	Male	Control	41	662 ± 27.7	951 ± 32.3	1029	[72]
		Metformin	46	573 ± 26.5 (-13.4%)*	931 ± 30.4	1044
129/Sv	Female	Control	47	706 ± 20.8	910 ± 8.9	930
		Metformin	48	742 ± 16.3 (+5.1%)	913 ± 19.2	966 (+3.9%)
Rat
LIO	Female	Control	41	652 ± 27.3	885 ± 11.3	919	[1,73]
		Phenformin	44	652 ± 28.7	974 ± 16.2** (+10.1%)	1009 (+9.8%)
	Female	Control	74	687 ± 19.2	925 ± 22.5	1054	[74]
		Buformin	42	737 ± 26.4 (+7.3%)	1036± 38.9* (+12%)	1112 (+5.5%)
Fischer-344	Male	Control	31	796 ± 170	1039 ± 29.6	1065	[75]
		Metformin	40	815 ± 186	1061 ± 2.5	1062

The difference with control is significant: * – p < 0.05 ; ** p < 0.01 (Student’s test)
(Phenformin and buformin are chemical sisters of metformin. Metformin is prescribed for people because it has the lowest rate of complications and side effects.)

Mechanism for protection against cancer

There is also “test tube” evidence for metformin’s effect on cancer: Cancer cells are supposed to detect that they are diseased  and eliminate themselves harmlessly and promptly via a mechanism called apoptosis. Cancer can’t become cancer until this mechanism is suppressed, mutated away so that the cancer cells don’t automatically commit suicide.   In lab studies of cell cultures, cancer cells respond to metformin by restoring the apoptosis mechanism that was suppressed when they became cancerous in the first place.  Metformin shrinks tumors by inducing cancer cells to commit suicide.  On this basis, metformin is just beginning to be tried as a treatment for cancer patients, with first application to breast cancer.

Side-effects

Complications and risks from metformin are unusual, but they do exist. The main one is called lactic acidosis – a rare but serious disease that is almost unknown outside metformin patients. A conscientious doctor who prescribes metformin will counsel the patient to be alert to the symptoms.

Research study would be most beneficial – but who will pay the bill?

For those who are overweight in middle age or pre-diabetic, there is much to recommend metformin. But are there benefits for middle-aged people who are not in this category? The only way to know for sure is through double-blind clinical trials with at least several thousands of patients. But who will fund such a study? Metformin is a cheap, generic prescription, decades out of patent. There is no company with the motivation to invest in it.

Even if such a study is begun, it will require ten years at best before we know anything.  In the meantime, a few avid life extensionists are taking the chance and asking their doctors for a prescription, or even self-medicating through on-line pharmacies.  Perhaps we will learn from their experience.