February 5, 2019
Update from Ben: please go listen to my podcast with Jay Campbell, in which we discuss updates on the information provided below, particularly:
The fear of lactic acidosis happening was based on a study from the 1940s in a massively compromised patient cohort. These patients were in end-stage renal failure and also obese and diabetic. We must be mindful that correlation does not equate to causation. While metformin has been contraindicated in moderate and severe renal impairment, the reported incidence of lactic acidosis in clinical practice has proved to be very low (fewer than 10 cases per 100,000 patients).
The studies on metformin and cardiovascular risk were also performed on a thoroughly compromised patient population group of morbidly obese diabetics who were using anywhere from 6-9 grams of metformin per day – three to five times the recommended and commonly used dose. Other studies show it’s actually the opposite: that metformin may actually reverse mitochondrial dysfunction!
Regarding B12: both B12 and folate are incredibly simple compounds to supplement with, and can easily be stacked with a metformin protocol to avoid these deficiency issues.
There have also been studies out of Taiwan showing that metformin taken by diabetics for long periods of time (12 years or longer) can nearly double the risk of Alzheimer’s and Parkinson’s, but – similar to the studies on lactic acidosis – this study involved heavy use for extended periods of time.
Regarding liver toxicity, it turns out that these issues with metformin occur in people who already have a compromised liver.
Next comes the potential impact that metformin may have on exercise performance. In the study “Impact of metformin on peak aerobic capacity”, it was shown that metformin can significantly decrease VO2 max (–2.7%), peak heart rate (–2.0%), peak ventilation (–6.2%), peak resting energy expenditure (–3.0%), and actual exercise duration (–4.1%). While these reductions were certainly slight, and potentially non-significant for the average exercise enthusiasts, they do suggest that for a professional athlete (especially a professional endurance athlete), the use of metformin may spell the difference between a 1st place finish and not even making the podium! An even newer study, recently reported in the New York Times here, highlights that metformin has also, compared to a placebo, been shown to hamper endurance and limit mitochondrial proliferation in response to an exercise protocol! And as for muscle – the bad news is that large doses of metformin negatively impact the response to strength training in healthy older individuals.
Finally, there’s the concern that metformin causes GI upset. But this seems to happen only in people with bacterial imbalances and, based on recent studies, may occur because metformin is working directly to favorably alter the microbiota. Research has shown that metformin can indeed alter the gut composition in a favorable manner by increasing levels of several different short-chain fatty acid (SFCA) bacteria and by decreasing inflammation in the gut in a manner that actually increases insulin sensitivity and lowers blood glucose! However, one newer study from September 2018 does suggest that metformin causes an “increase in abundance of opportunistic pathogens and further triggers the occurrence of side effects associated with the observed dysbiosis”.
I’ll sum it up here: don’t use metformin if you have liver and kidney issues, and definitely don’t overdose with metformin. If you get gut discomfort while using metformin, consider waiting it out to see if your gut flora becomes balanced and your symptoms subside, which typically takes 8 to 12 weeks, and proceed with caution if you have any prexisting gut issues due to potential for bacterial imbalances in the gut flora. If you use metformin, supplement with vitamin B12 and, if you’re a woman, monitor your folate levels and consider supplementation with a good multivitamin that contains a natural form of folate like methyltetrahydrofolate (MTHF). Finally, if you’re a professional athlete or aerobic performance is very high on the totem pole for you, I’d avoid metformin.
In the recent Wired magazine article “Forget The Blood Of Teens. This Pill Promises To Extend Life For A Nickel A Pop,” it is reported how Tim Ferriss, in his recent book Tools of Titans, estimates that at least a dozen of the billionaires, icons, and world-class performers in the book take metformin.
Robert Hariri, a member of the anti-aging panel at the Vatican and co-founder and president of genetic sequencing pioneer Craig Venter’s Human Longevity Cellular Therapeutics and Ray Kurzweil, of Singularity fame, along with Ned David, co-founder of Silicon Valley startup Unity Biotechnology (which is developing its own anti-aging drugs) all also take metformin.
In fact, metformin (along with rapamycin, which I will write an article on in the near future) is now considered to be one of the new darlings of the anti-aging industry and is widely used among CEOs, Silicon Valley, many of my friends in the anti-aging industry and beyond.
So what’s my beef with this supposed wonder-drug?
It turns out that there are all kinds of potential problems with metformin. In recent years, evidence has accumulated that metformin may not be all its cracked up to be. Or at least, even if it does what it claims to do, it has a number of adverse side effects. But up until now, pharmaceutical companies have somewhat sugar-coated the drug’s effects.
In this article, I'll briefly highlight why I don't personally take metformin. I'll also introduce you to natural compounds that I personally use to regulate my blood sugar.
Is Metformin Healthy?
Metformin falls into a category of a biguanide molecule. Biguanides are derivatives of guanidine, a naturally occurring substance found in vegetables such as turnips and cereals. They exert a blood glucose-lowering effect in type 2 (non-insulin dependent) diabetes mellitus, and since they do not increase plasma insulin concentrations and do not cause hypoglycemia (unless, as noted below, combined with exercise), they are generally regarded as antihyperglycemic (rather than hypoglycemic) agents.
But one of the problems with these type of molecules is that they can increase the generation of lactate, which then enters the circulation and produces lactic acidosis.
The study “Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation” describes quite clearly this metformin effect on lactate production. But before getting into that, a quick note on phenformin. Phenformin is another member of the biguanide family and was a popular medication for diabetes starting in the 1950s. It was withdrawn from clinical use in the 1970s once it was discovered that it caused severe lactic acidosis. Although phenformin is associated with a 10- to 20-fold greater incidence of lactic acidosis than its relative metformin, metformin’s effects on acidosis are still significant enough in my opinion not to be ignored (especially if you're an athlete who is already flirting regularly with acidosis – although admittedly I've seen little performance data on metformin's effect on lactic acid formation during exercise).
Furthermore, despite being the most commonly prescribed drug for the treatment of type II diabetes for more than five decades, the bioenergetic mechanisms underlying metformin activity remain largely unknown. This ignorance of the inner workings of the drug has triggered many endeavors to uncover how exactly it works – but the results are often contradictory. The study “Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes: a double-blind, randomized, placebo-controlled trial” found that while metformin may play a very wide role in managing cardiovascular risks, it doesn’t necessarily improve glycemia, and it had no average effect on insulin requirement. In fact, while there were two deaths in the placebo group, there were five among the patients allocated to metformin.
But cardiovascular risk management also falls under scrutiny under certain conditions. True, metformin may be beneficial when used on its own. But, according to the study “Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes,” when combined with sulphonylurea (another common antidiabetic medication), metformin can actually result in an increased risk of cardiovascular complications and all-cause mortality. Studies are inconclusive at the time being, but the drug has been shown to have no proven efficacy against microvascular complications. Indeed, the possibility that metformin is not effective at all shouldn’t be dismissed out of hand. After all, the first molecule of this type, phenformin, did induce cardiovascular risk, and, pharmacologically speaking, there’s little difference between phenformin and metformin.
All that to say, the specific efficacy of metformin to prevent death or cardiovascular disease has not been proven beyond reasonable doubt by current studies. So metformin may not be the best comparator for evaluating hypoglycemic drugs – and that’s not even the end of the story.
Metformin can also cause a deficiency of vitamin B12 levels. The study “Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency” observed this effect. While the drug did cause reported improvements in cardiovascular morbidity and mortality (but, as you’ve seen, that’s already been called into question), it stimulated vitamin B12 malabsorption.
Decreased B-12 concentrations can cause increased homocysteine concentrations, which is, surprise, an independent risk factor for cardiovascular disease, particularly among individuals with type 2 diabetes. During the 52 months of the study, the placebo group experienced an increase in vitamin B-12 concentrations, while the metformin group experienced an average 19% decrease in B12 concentrations, a decrease which continues to grow over time. While the lower B12 concentrations were not a novel idea, the progressive nature was – they can result in macrocytic anemia, neuropathy, and mental changes, potentially making metformin a dangerous treatment to use.
Another study, “Metformin and Exercise in Type 2 Diabetes,” determined the effects of metformin on the metabolic response to submaximal exercise, the effect of exercise (relevant to activity patterns of type 2 diabetics) on plasma metformin concentrations, and the interaction between metformin and exercise on the response to a standardized meal. There is evidence that suggests that the benefits of exercise and metformin aren’t cumulative. In a study whose results were noted in this one, the reductions in diabetic risk were similar in a lifestyle that combined metformin and lifestyle modifications to the metformin or lifestyle alone groups.
In fact, the two adjustments may have contradictory effects on diabetes. First, metformin reduces blood glucose levels. But exercise tends to increase levels of glucagon, the hormone that deals with low blood sugar. When the two are combined, glucagon concentrations become significantly higher as the body tries to compensate for the effect of metformin. Second, by increasing the heart rate, metformin has the potential to lower some patients’ selected exercise intensity, which means it could lead to the prescription of lower exercise workloads than are commonly recommended.
So, the combination of exercise and metformin, both common prescriptions for diabetics, is likely less effective at lowering the glycemic response to a meal than metformin alone. There have also been studies out of Taiwan showing that metformin taken by diabetics for long periods of time (12 years or longer) can nearly double the risk of Alzheimer’s and Parkinson’s.
There have even been a handful of reports of metformin-induced hepatotoxicity (toxicity in the liver). In a case of nonalcoholic liver disease, metformin was pegged as the cause of jaundice, nausea, fatigue, and unintentional weight loss, two weeks after initiating treatment, due to abnormalities in liver enzymes caused by the drug. Another case involved a 73-year old Japanese woman who experienced fatigue, jaundice, nausea, vomiting, anorexia, and abdominal pain due to severe hepatotoxicity that resulted from metformin.
I recently asked Dr. Dallas Clouatre, a well-established author and consultant in the alternative and complementary medicine and nutrition field and my guest on the podcast episode How Low-Fat Diets Make You Fat, about his thoughts on metformin, and here’s what he had to say:
“My thoughts on metformin are that it is interesting but over-hyped. Keep in mind that it works primarily on the liver (30% of glucose clearance from meals) and not on the peripheral tissues (70% of glucose clearance). It likely does promote a longer ‘health span’ given that lowering insulin and IGF-1 along with mTOR, typical of caloric restriction and of those who naturally live to extreme old age, is usually a good thing. Of course, any item that keeps insulin levels low along with keeping blood glucose in the low-normal range will lower mTOR. Downsides of metformin include reduced efficacy with advancing age, reduced efficacy with prolonged use, and GI-tract issues in some individuals. Given that rehabilitation of the mitochondrial electron transport Complex I is a normal function of a good night’s sleep, for me, it is difficult to suggest the chronic intake of a drug that works by gumming up a natural process of the body.”
So Where Does This All Leave Metformin?
Despite the 20 years of positive clinical observations on metformin, these recent studies and the information above, in my opinion, have called its efficacy and overall health benefits into question.
Perhaps it’s time to broaden the horizons and look to natural alternatives that can have very similar antidiabetic, blood sugar stabilizing and longevity-enhancing effects, including many of the natural strategies and compounds I discuss in my articles “How To Biohack Your Blood Sugar Levels” and “5 Simple Steps You Can Take To Live Longer, Banish Blood Sugar Swings & Massively Enhance Energy Levels.“, including:
- Strength training…
- Pre-breakfast fasted cardio performed frequently…
- Post-prandial walks…
- Low-level physical activity or standing/treadmill workstations at work…
- And most notably, plants, herbs and spices…
So that you can equip your cupboard with compounds that can safely and naturally support your blood sugar levels, I'd like to expound on that last category of plants, herbs and spices.
Let’s begin with Ceylon cinnamon. Cinnamon has a long history both as a spice and as a medicine, and it’s unique healing abilities come from the essential oils found in its bark, which contain three active components called cinnamaldehyde, cinnamyl acetate, and cinnamyl alcohol. The cinnamaldehyde in cinnamon helps prevent unwanted clumping of blood platelets, which makes cinnamon anti-inflammatory.
In one study, the antioxidant effects of a cinnamon extract in people with prediabetes decreased a marker of oxidative stress by fourteen percent. Participants took 250 mg of cinnamon extract, twice per day, for twelve weeks. This is significant considering that chronic inflammation and oxidative stress plays a role in nearly every chronic disease, including diabetes.
Cinnamon also mimics the effects of insulin, which increases insulin sensitivity, making insulin more efficient at shuttling glucose into cells. Five grams of cinnamon is all you need to do this while also reducing total plasma glucose response. Effects last twelve hours. Cinnamon also reduces fasting blood glucose, total cholesterol, and triglycerides, and it increases HDL cholesterol. And the best type of cinnamon to use? Approximately the equivalent of 2 teaspoons of organic Ceylon cinnamon per day will suffice (it is important that the cinnamon is indeed of the Ceylon variety). I like to buy it in bulk.
Gymnema Sylvestre is another potent herbal tactic for controlling glycemic variability. It has been used in traditional Ayurvedic medicine for thousands of years and has promising research around its ability to control blood sugar levels. Its blood sugar lowering effects are possibly due to it causing an increase in insulin secretion, which partially explains its ability to increase glucose utilization, with this also being due to it increasing the activities of enzymes responsible for utilization of glucose by insulin-dependant pathways. The increase in insulin secretion may be explained by Gymnema supplementation regenerating pancreatic islet beta cells, the cells responsible for sensing sugar in the blood and telling the pancreas to release the proper amount of insulin to maintain normal blood sugar levels. Gymnema also inhibits glucose absorption from the intestines and has been shown to lower serum cholesterol and triglycerides.
Gymnema Sylvestre extract administered to non-insulin-dependant type 2 diabetics at 400 mg per day for 18 months significantly reduced blood sugar, hemoglobin A1c and glycosylated plasma protein levels, with many participants lowering their diabetes medication and five participants ending with controlling blood sugar using Gymnema Sylvestre extract alone. The same reductions have occurred in people with type 1 diabetes, with Gymnema also allowing for a decrease in insulin requirements. The easiest way to use Gymnema Sylvestre is by taking one 400-600 mg capsule, standardized to contain 25 percent gymnemic acid, ten minutes before a carbohydrate containing meal.
Berberine, a compound derived from a variety of herbs including goldenseal and Oregon grape root, shows a variety of distinct benefits. It increases glucose uptake by the cells and improves insulin utilization by increasing glucose uptake pathways GLUT-4 and GLUT-1. Berberine also activates AMP-activated protein kinase (AMPK), with increased activation allowing for a reduction in fat storage, increased insulin sensitivity, reduction in cholesterol/triglyceride production, and suppression of chronic inflammation.
Berberine has also been shown to significantly reduce free fatty acids, high levels of which damage the pancreas and insulin production In one study, berberine significantly lowered fasting blood glucose, hemoglobin A(1c), triglyceride, and insulin levels in type 2 diabetics by increasing insulin receptor expression. It also improved liver function. Another study found that 500 mg of berberine taken twice per day by patients with type 2 diabetes lowered blood glucose, fasting insulin, and blood lipid levels and it was as effective at lowering blood glucose as metformin.
There’s a ton more research you can read here on berberine on everything from metabolic syndrome, PCOS, osteoporosis and much more. The standard dose of berberine HCL is 900-2,000mg a day, divided into three to four doses, taken with a meal.
What I Personally Use Daily To Regulate Blood Sugar
Since beginning to test my blood glucose continuously using a Dexcom G6 implanted in my abdomen (as I describe in detail in my last post on how to track ketones and glucose), I’ve experimented with taking THREE servings of Kion Lean each day. I’m taking two capsules before every meal, three times per day.
I realize six capsules a day is a lot, but I may actually continue this as a staple in my life extension and weight management protocol, and I’d highly recommend you try it, especially if you want to support your blood sugar levels.
Bitter melon has only positives, as far as I am concerned. It’s fresh on my mind, because like I mentioned, when I was in New York City, I had the pleasure of spending quite a bit of time with Chef David Bouley, a world-famous Japanese cuisine expert who frequently travels to Asia to study specific food consumption and dietary habits that allow locales such as Okinawa, Japan to be such longevity hotspots. And one of the large bags of tea he brought back with him and gave to me was comprised of the same compound they ate in copious quantities before nearly every meal – you guessed it – bitter melon extract.
But I already knew of bitter melon because I’ve personally been using it in the form of a potent tiny capsule I'll fill you in on shortly, and I've been using it to manage my postprandial blood glucose levels with potent efficacy for the three years.
Taxonomically known as Momordica charantia, bitter melon may be effective in controlling blood sugar levels and regulating blood pressure. Although the precise mechanism by which it works (whether it’s through regulation of insulin release or altered glucose metabolism and its insulin-like effect) is not known, bitter melon naturally contains antidiabetic compounds like charantin, vicine, and polypeptide-p, plus some other health-boosting components like antioxidants.
Bitter melon is a popular treatment for diabetes and similar conditions among the indigenous people of Asia, South America, India, and East Africa. As noted earlier, it’s known particularly well in Okinawa, Japan. Okinawa, like the Bama County, is one of the world’s “blue zones”, an area where the average lifespan is unusually long, and it’s also where some of the longest-lived people on the planet live.
In places like Okinawa, almost every part of the bitter melon has been used in traditional medicine, including the fruit, leaves, vines, seeds, and roots. It’s used to treat everything from microbial infections to digestive issues, stimulate menstruation, heal wounds, reduce inflammation and fevers, deal with hypertension, and it’s even been used as a laxative and emetic. It also activates cellular machinery to regulate energy production (particularly AMP-activated protein kinase) and the way fats are processed by the liver.
Centuries of oral consumption have demonstrated that bitter melon is both safe and effective. And on top of all those other conditions, according to a number of animal studies, it can even reduce insulin resistance and protect against diet-induced hyperglycemia and hyperinsulinemia. It should be noted, though, that commercially-sold varietals are not nearly as effective as wild bitter melon. One study observed the effects of bitter melon on diabetic rats. Specifically, they used an aqueous extract powder of fresh, unripe melons, and found that a dose of 20 mg per kilogram of body weight reduced fasting blood glucose levels by 48%.
Part of the reason bitter melon is so darn effective is likely its effect on GLP-1 secretion. GLP-1 is glucagon-like peptide-1, a peptide released from what are called L-cells, which increase in density along the length of the intestines. It helps to raise insulin levels as a part of the incretin effect, a hormonal response that effects insulin secretion following oral glucose ingestion. A study was done to examine the role of bitter melon extract in this process, and found that through bitter taste receptors and/or a PLC β 2-signaling pathway, the melon stimulated GLP-1 release, which contributes, at least in part, to the antidiabetic activity of bitter melon through the incretin effect.
Now, before you think that by supplementing your diet with bitter melon, your insulin levels will get too high, it’s important to note that insulin levels that are regulated by GLP-1 are either reduced or, in some cases, completely absent in people suffering from diabetes. Considering that, and the fact that GLP-1 has an extremely short half-life due to rapid inactivation, it’s not likely that your insulin levels will become abnormally high by using the melon. In all likeliness, your insulin count will rise and settle at a relatively normal level. However, further studies will need to be performed to confirm this.
And there’s more.
Bitter melon, specifically a wild species called Momordica charantia Linn var. abbreviata ser., can also regulate inflammation due to various diseases. Wild bitter melon and bitter melon extracts were used in a study to inhibit macrophage activity, which is a part of your natural immunological response to stress, disease, and tears in body tissues. The lipopolysaccharide (LPS)-stimulated macrophages that were targeted responded to both extracts, but especially to the wild variety of the melon, resulting in much-reduced inflammation.
As you may already know, insulin resistance is closely related to chronic inflammation induced by things like tumor necrosis factor-α (TNF- α), a compound that seeks out and destroys cancerous cells. But before jumping into the importance of TNF- α, you should memorize this chemical: triterpene 5β, 19-epoxy-25-methoxy-cucurbita-6.23-diene-3β, 19-diol – or, for short, EMCD. It’s purified from a wild species of bitter melon that was thought to activate AMP-activated protein kinase (AMPK), which itself is thought to repress TNF- α-induced inflammation.
When it was tested alongside a compound extracted from green tea that’s also reported to be anti-inflammatory, EMCD showed more obvious anti-inflammatory activity, but not by activating AMPK. It actually inhibited the activation of the IkB kinase, an important aspect of pro-inflammatory signaling, and thus, the melon extract mitigated inflammation tied to diabetes. Since inflammation is connected to shorter life spans and greater risk of conditions like cardiovascular diseases, you should definitely look into adding wild bitter melon to your diet or supplement cabinet as an anti-inflammatory strategy too.
Want more interesting reading on bitter melon extract? Check out these links:
- Going WILD with Bitter Melon for Blood Sugar Support
- Is the Metabolic Syndrome a Consequence of Aging?
- Aging and the Mitochondria
So how does wild bitter melon promote fat burning, liver health (and of course, anti-aging)? The answer involves caloric restriction and insulin.
Wild bitter melon is health-promoting. For example, it has been found that extracts of the wild bitter melon activate cellular machinery to regulate energy production (technically AMPK-activated protein kinase) and the way that fats are handled by the liver. Activation of this metabolic pathway is important to aging. It is sometimes referred to as “exercise in a bottle” because activation of AMPK is an aspect of the benefits derived from exercise. The effect of an extract from the wild genotype of bitter melon has proved to be more powerful than others on the market and much more consistent in producing positive results.
So in summary, I'm not a huge fan of metformin, but I am a huge fan of strength training and physical activity to manage blood sugar levels for both health and longevity. For regulating my blood sugar levels, I personally consider bitter melon extract to be at the top of my list.
For me personally and based on my own continuous blood glucose testing levels I discuss in my article “The Best Way To Test For Ketosis & Track Your Blood Glucose”, bitter melon works like gang-busters to regulate blood sugar levels after my evening carbohydrate-laden meal – and with more frequent dosing at three times per day is keeping my daily average blood sugar levels in the 70-89 range consistently. All my clients already pop two capsules of Kion Lean prior to any carbohydrate-rich meal, and I do too, for the past four years. It just works.
Do you have questions, thoughts or feedback for me about metformin or managing blood sugar? Leave your comments below and I will reply!