The diabetes drug metformin has a lot of friends and foes. It never fails to amaze us when people try to either put a medicine on a pedestal or have the FDA ban it. Most drugs have both benefits and risks, pros and cons, plusses and minuses. Metformin is no exception. Why is metformin a miracle for some and a menace for others?
Metformin vs. Long COVID:
There is a growing body of research to suggest that metformin might reduce the risk of long COVID (Lancet Infectious Diseases, Oct. 2023):
“Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe.”
A study in Clinical Infectious Diseases (May 1, 2024) also produced promising results:
“Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)…The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo.
“The antiviral response is consistent with the statistically significant and clinically relevant effects of metformin in preventing clinical outcomes: severe COVID-19 (emergency department visit, hospitalization, or death) through day 14, hospitalization or death by day 28, and the diagnosis of long COVID. The magnitude of effect on clinical outcomes was larger when metformin was started earlier in the course of infection at <4 days from symptom onset, with metformin reducing the odds of severe COVID-19 by 55% and of long COVID by 65%.”
An even more recent study (Diabetes Care, Sept. 17, 2024) seems to confirm this benefit:
“Studies show metformin use before and during SARS-CoV-2 infection reduces severe COVID-19 and postacute sequelae of SARS-CoV-2 (PASC) in adults. Our objective was to describe the incidence of PASC and possible associations with prevalent metformin use in adults with type 2 diabetes mellitus (T2DM).”
PASC is doctorspeak for long COVID. Here is what the researchers reported:
“Prevalent metformin use is associated with a slightly lower incidence of death or PASC after SARS-CoV-2 infection…These data are consistent with other observational analyses showing prevalent metformin is associated with favorable outcomes after SARS-CoV-2 infection in adults with T2DM [type 2 diabetes].”
Metformin vs. Aging:
Research suggests that this very old medication appears to promote healthy aging and protect muscle cells from atrophying after inactivity due to illness or injury (Aging Cell, July 24, 2023).
A study in male monkeys adds to this finding (Cell, Sept. 12, 2024):
“In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research…The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability…Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.”
Downsides of Metformin:
But some people cannot tolerate the GI side effects of metformin. There is also concern that the drug might increase the risk for birth defects (Annals of Internal Medicine, March 29, 2022).
Some researchers are also exploring metformin for its anti-cancer, immunoregulatory and anti-aging activity. Research suggests it may even work against HIV/AIDS (Nature Immunology, March 25, 2021). Moreover, there are some intriguing data on metformin against prostate cancer (Biomedical Research International, Oct. 8, 2021).
A Short Metformin History:
Metformin is the most popular diabetes drug in the world. Over 18 million Americans swallow it daily. Metformin is prescribed by itself or in combination with other blood glucose-lowering medicines. It is one of the most affordable medications for type 2 diabetes on the market.
Metformin really got its start centuries ago. That’s because during the middle ages European healers used the French lilac plant (Galega officinalis) to treat a wide range of conditions. This was long before diabetes was identified.
There are lots of popular names for Galega officinalis besides French lilac. It is also known as goat’s rue, galega, Spanish sainfoin, professor-weed or Italian fitch. It was used to treat symptoms that might have been caused by diabetes such as bladder problems, constipation, fluid retention (edema), blood disorders and fevers. In medieval times people also soaked their tired, sore feet in a goat’s rue solution.
Metformin for Modern Times:
Researchers discovered that this herb could lower blood sugar in animals in the 1920s. French regulators first approved metformin for the treatment of diabetes in 1957 under the name Glucophage (glucose eater). It took US regulators much longer to consider metformin a miracle, if they ever did. The FDA gave the drug the green light in 1994.
Pharmaceutical manufacturers have developed a lot of pricey new medications to lower blood sugar. But metformin is still a mainstay, and researchers are exploring a number of new uses for this very old drug.
Metformin: A Miracle Muscle Protector?
When we don’t use our muscles, they lose strength quickly. That is especially true for older individuals, whose muscles take longer to recover from injury or disuse. Metformin may have an unexpected benefit for older people undergoing rehabilitation.
Researchers conducted a placebo controlled trial among 20 healthy men and women over 60 years old (Aging Cell, July 24, 2023). After two weeks of a run-in trial, they took five days of bed rest as if they had been injured or undergone surgery. Following that, they phased off their treatment over the next week.
Those taking metformin had less muscle atrophy and lower levels of inflammatory compounds in their bloodstreams. Moreover, they had fewer markers of aging in their muscle fibers and less collagen was deposited in the muscles during inactivity. People in the metformin group had a healthier biochemical profile in their muscles during recovery.
Metformin Against Inflammation:
The investigators note that metformin has anti-inflammatory properties, probably because in it inhibits NF-kappaB. They suggest that pre-treatment could improve muscle recovery after a period of enforced inactivity.
The senior author of this study, Dr. Micah Drummond, told the University of Utah Communications Department (July 25, 2023):
“In the case of aging, we know that there’s immune dysfunction. As you get older, it becomes harder for your body to clear senescent [aging] cells and they accumulate. That’s one reason recovery is much slower for the elderly after periods of disuse.
“We saw two things in our study. When participants took Metformin during a bed rest, they had less muscle atrophy. During the recovery period, their muscles also had less fibrosis or excessive collagen. That build-up can make it harder for the muscle to properly function.
“Metformin is cheap, effective and quite safe, so it’s exciting to see that we can use it to accelerate recovery for older individuals.”
Metformin a Miracle Against Aging?
Researchers analyzed data from more than 300,000 people who submitted health information and genetic samples to the UK Biobank (Lancet Healthy Longevity, July, 2023). The investigators examined gene expression and a variety of “biomarkers of ageing.”
They introduced their findings this way:
“Metformin, a first-line medication for type 2 diabetes in the general population, is increasingly recognised as having a potential protective effect against age-related diseases, and it has been proposed that metformin could promote healthy ageing. Observationally, metformin use is associated with a lower risk of mortality in different patient populations, although whether these associations are driven by confounding and immortal time bias remains unclear.”
They go on to suggest that metformin might provide protective effects against:
“…ageing-related diseases (ie, cardiovascular diseases, cancer, Alzheimer’s disease, and osteoarthritis).”
Their conclusion and interpretation of the data:
“This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity.”
That’s complicated! But the bottom line seems to be that metformin is exerting its anti-aging effects through pathways other than blood sugar control. That’s not to say glycemic (glucose) control is not important. It is! But it also appears that metformin is exerting its biological benefits through a variety of “pathways.”
Metformin a Miracle against Cancer?
One of the more intriguing lines of research is metformin’s activity against cancer. Both laboratory and epidemiological research demonstrate that metformin has anticancer activity against a number of malignancies.
A review in the journal Oncology Reviews (online, Feb. 26, 2021) notes that:
“Many epidemiologic analyses have reported that metformin may improve prognosis of patients with different types of malignancies and even may prevent tumor initiation. Evans et al. noted as first that patients who were treated with metformin had a low risk of developing cancer. Next, a lot of studies in T2D [type 2 diabetes] patients have shown that metformin therapy is correlated with a reduced risk of numerous malignancies such as prostate cancer, lung cancer, head and neck cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer and liver cancer.
“Among other things, there is also medical evidence that supports the benefits of metformin in patients with blood cancers. “
We suspect that if this drug were just discovered today, it would come with an enormous price tag and garner lots of attention. No doubt it would be regularly advertised on television. But metformin is dirt cheap because it is available generically.
Stomach Cancer:
A meta-analysis and systematic review of metformin “on Survival and Recurrence Rate of Gastric Cancer” after surgery in diabetic patients reveals some fascinating data (Journal of Gastrointestinal Cancer, Aug. 1, 2023):
The authors introduce their study this way:
“Gastric cancer (GC) is one of the most common worldwide cancers and causes of death. Various studies have investigated the effect of metformin on overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and recurrence rate in diabetic patients after gastrectomy, and their results have been contradictory.”
They attempted to resolve the controversy. Here are their results after reviewing nine studies including 245,387 patients with gastric cancer.
“The use of metformin in diabetic patients with GC [gastric cancer] can be associated with improved OS [overall survival], CSS [cancer-specific survival], RFS [recurrence-free survival], and reduced recurrence rate after gastrectomy, especially in the Asian population.”
Breast & Colorectal Cancer:
Two large population-based studies show that people who take metformin are less likely to develop breast or colorectal cancer (Diabetes Research and Clinical Practice, May 22, 2020).
Melanoma, Endometrial & Bone Cancer:
A review of the medical literature reveals that metformin users appear protected in part from melanoma, endometrial cancer and bone cancer as well (Frontiers in Endocrinology, April 16, 2020). In addition, the drug has benefits for the liver, the kidneys and the cardiovascular system.
Prostate Cancer:
A reader recently asked this question:
“You recently answered a question from a man taking metformin following his prostate cancer treatment. I am puzzled. What does a diabetes drug have to do with prostate cancer?”
Researchers have noted that people with type 2 diabetes who were taking metformin were less likely to develop cancer. That observation prompted studies showing that metformin has anticancer activity.
A systematic review and meta-analysis involving 27 studies and 123,212 participants found that people taking metformin had better prostate cancer outcomes (Biomedical Research International, Oct. 8, 2021). This link was especially strong if men received radiation therapy.
Statins and Metformin:
Among more than 12,000 men with high-risk prostate cancer, the use of metformin in combination with a statin significantly reduced their risk of dying from prostate cancer (Cancer Medicine, April 2020). Other investigators conducted test tube research showing synergistic effects of metformin and curcumin (the active ingredient in the spice turmeric). This combination helped put the brakes on prostate cancer cells (Nutrition and Cancer, July 13, 2020).
A few other combination therapies also feature metformin. In one study of mice, scientists found that a combination of metformin with certain probiotics had beneficial effects on colorectal cancer (Cancers, July 10, 2020).
Esophageal Cancer and Lymphoma:
Research suggests that metformin might also play a role against esophageal cancer and large B-cell lymphoma (Clinical Cancer Research, July 9, 2020; Cancer & Metabolism, July 6, 2020).
A systematic review and meta-analysis published in Postgraduate Medical Journal (Nov. 1, 2022) concluded:
“Metformin is associated with a reduced risk of OC [oesophageal cancer]. More well-designed studies are still needed to further elaborate on these associations.”
Esophageal cancer is is a very nasty disease. Anything that could lower the risk for this kind of malignancy is welcome.
Is Metformin a Miracle for PCOS?
Cancer is not the only condition for which metformin appears helpful. Women with polycystic ovary syndrome (PCOS) often have insulin resistance, even though they may not have type 2 diabetes. PCOS can affect fertility as well as quality of life, and metformin can help women with this condition ovulate (Fertility and Sterility, Sep. 2017).
Is Metformin a Miracle for Longevity?
Anti-aging researchers are also looking at the potential for metformin to extend healthy life spans. Preliminary animal research has produced promising results (Cold Spring Harbor Perspectives in Medicine, March 2016).
There are studies that suggest metformin doesn’t just help improve glucose metabolism. It reduces inflammation, helps reduce oxidative damage and diminishes cellular aging.
A review of the anti-aging activity of metformin offers this summary (Cell Metabolism, July 7, 2020):
“In conclusion, there is extensive epidemiological, basic science, and clinical data highlighting the effectiveness of metformin in targeting several age-related morbidities in humans. Studies in model organisms and cell lines provide compelling evidence on metformin’s beneficial effects against crucial pathways in aging.”
Metformin vs. HIV/AIDS:
A new study by researchers at the University of North Carolina at Chapel Hill suggests that metformin may slow replication of HIV in T cells (Nature Immunology, March 25, 2021). Instead of attacking the virus directly, metformin makes it harder for HIV to multiply inside cells. It does this by interfering with energy production.
It is always nice when experimental evidence is confirmed in a clinical setting. Although the research is preliminary, there is some suggestion that people with HIV who were taking metformin for their type 2 diabetes had substantially lower levels of HIV in their bloodstreams. This discovery may offer new insights into ways to treat HIV/AIDS.
The Dark Side of Metformin:
Despite all of the optimism about future uses for metformin, the drug has downsides. People starting families will want to review the latest study regarding birth defects.
Metformin and Birth Defects:
A study in the Annals of Internal Medicine links this drug with birth defects in male infants (March 29, 2022). The data come from Denmark, where medical registries tracked 1.1 million births between 1997 and 2016.
Men who took metformin in the three months before the babies were conceived were more likely to have offspring with abnormalities. Specifically, 5.2 percent of these babies had some type of birth defect, compared to 3.3 percent of those whose fathers did not take metformin. This difference is 1.4 times higher.
Genital defects were very rare. However, they were three times as common among baby boys whose fathers had taken metformin. The totals were 0.9 percent among exposed infants and 0.24 percent among unexposed newborns. If the fathers had taken metformin the previous year, there was no impact on their sons. Only the prior three months, when sperm were being formed, seemed to make a difference. The scientists call for further research to confirm their findings and clarify the mechanism.
Diarrhea from Metformin:
Birth defects are just one possible risk of taking metformin. Readers and listeners have noted that it can cause severe digestive distress. Here is what we heard from one listener. Others have reported different adverse reactions.
Q. I am suffering from such severe diarrhea I am sometimes afraid to leave the house. Bad gas and bouts of abdominal pain add to my misery. Could the metformin I take for diabetes be responsible? My doctor says my symptoms are not from my medicine.
The Prevacid I take for my heartburn isn’t helping enough to justify the expense. I am also experiencing pain and tingling in my toes.
Hopefully, a remedy like cinnamon will help me control my blood sugar. What foods can help with my gas and heartburn? Please send me some information.
A. Metformin can cause diarrhea, nausea, heartburn, flatulence and stomachache. Acid-suppressing drugs like lansoprazole (Prevacid), omeprazole (Prilosec) or esomeprazole (Nexium) won’t solve the problem completely and may interfere with absorption of vitamin B12. Cinnamon shouldn’t be substituted for your diabetes drug, but it may be helpful.
Metformin and Vitamin B12 Depletion:
Metformin can interfere with vitamin B12 absorption. As a result, people may experience nerve problems, confusion and digestive difficulties. Because this vitamin is crucial for nerve function, deficiency can contribute to numbness, tingling or pain of the toes, feet or fingers, trouble walking, memory problems, depression, confusion and burning tongue.
One reader shared this experience:
Q. Thank you for writing about the side effects of metformin. I have been on it for at least 15 years, and now I am starting to have trouble with numbness and tingling, usually at night. Horrific leg and foot cramps are depriving me of much needed sleep. Could metformin be causing these problems?
A. Your doctor should be monitoring your vitamin B12 level. Metformin can deplete the body of this crucial nutrient, especially if taken over a long period of time.
In addition to the symptoms mentioned above, vitamin B12 deficiency can cause balance problems, weakness, numbness and tingling in hands and feet, burning tongue and depression. Another problem with long-term metformin use is low magnesium (American Journal of Clinical Nutrition, June 2024). This could contribute to the nighttime cramps troubling you.
Another reader writes in defense of cinnamon:
“I have had type 2 diabetes for 12 years and started taking two cinnamon capsules with my supper about three months ago. My pre-breakfast blood glucose reading that used to average 155 mg/dl is now averaging 120. Cinnamon works!
“I also eat oatmeal with ground flax seed and oat bran for breakfast and my cholesterol is perfect. I take metformin, glyburide and Actos.”
Metformin Side Effects:
Digestive Tract Challenges:
- Upset stomach (indigestion/heartburn)
- Gas/flatulence
- Diarrhea
- Nausea/vomiting
- Loss of appetite, metallic taste
- Cramps
Headache
Rash
Liver toxicity
Weakness
Lactic Acidosis:
Most worrisome is lactic acidosis. Palpitations, rapid pulse, low blood pressure, lethargy and severe nausea/stomach pain could signal this rare medical emergency.
Metformin a Miracle? Not for These People:
We have heard from many visitors to this website that metformin caused serious complications:
Carol developed severe GI problems while taking metformin:
“I lost 40 pounds when on Metformin, and it caused such severe diarrhea that I couldn’t leave the house. Ultimately, a substitute doctor happened to see my records and called to tell me to stop taking metformin immediately and see a kidney specialist as soon as possible.”
Jackie also experienced serious side effects while taking metformin:
“I was prescribed metformin when I developed type 2 diabetes (after being put on statins due to family history of heart disease). I experienced severe diarrhea as well as swelling of feet and ankles and a severe itchy rash. Reported all side effects to doctor. Was told they would subside once my body got used to the medication. It never did.
“The doctor prescribed 800 mg ibuprofen 4 x day for swelling, sent me to dermatologist for rash, and told me to use OTC meds and learn to live with diarrhea.
“I was on metformin for about three years, until my kidneys began failing. Doctor sent me to kidney specialist who took me off metformin and all NSAIDS. My kidney function improved immediately, but I had to go on insulin. My question is: Why do doctors ignore warning signals clearly printed on prescribing literature and simply prescribe another risky medication to mask troubling (even dangerous) side effects?”
We suspect Jackie’s kidney problems resulted at least in part from the large dose of ibuprofen she took for three years. Even smaller doses can damage the kidneys.
Kay’s digestive problems kept her trapped in her home:
“I started taking metformin to keep my blood sugar in the normal range because another med I was taking put my blood sugar thru the roof.
“The result was continuous stomach upset and violent diarrhea. I could no longer leave the house safely without taking meds for the diarrhea. There were accidents. I tried it with food. The slow release form was no help. Then my potassium started dropping.
“My doc prescribed another drug. It is low-priced and effective. After 6 weeks the diarrhea has stopped.
“There is no reason to take a drug that causes this many problems and chains you to your home. No responsible doctor should make you suffer. Change meds or change doctors.”
Greg developed lactic acidosis, a potentially life-threatening metformin complication:
“Metformin worked well for me, for about 10 years. It always caused me some stomach discomfort and flatulence. Then in November, 2016, I ended up in the hospital with severe vertigo and test results showing high levels of lactic acid. My doctor suspected lactic acidosis and took me off the drug. I’ve now found that none of the newer drugs work as well, and I’ve been started on insulin to get control of my blood sugar levels.”
So, Is Metformin a Miracle or a Menace?
It is neither. Like so many medicines, it can be beneficial for many and dangerous for others. You can learn more about metformin side effects at this link:
Metformin (Glucophage) Side Effects & Complications
Metformin is a first line treatment for type 2 diabetes. It can be tough on the digestive tract. Could it also have anti-cancer activity and prolong life?
Sometimes old drugs can be repurposed for new conditions. The inexpensive drug metformin might be the best example of this principle.
If you would like to learn more about metformin as well as other approaches for treating type 2 diabetes, here is a link to our eGuide: Preventing & Treating Diabetes.
You will also want to read about metformin formulations that are not contaminated with nitrosamines at this link.
Which Metformin is OK and Which is on the FDA’s Problem List?
The FDA admits that several metformin diabetes formulations contain a probable carcinogen. Which metformin is OK? How would you know?
Share your own experience with metformin in the comment section below.
