If I had to name the medication I have prescribed more than any other in my career as a physician, it wouldn’t be insulin or Ozempic or even Synthroid — thyroid hormone in pill form. Hands down, it would be metformin. My patients often ask about metformin, too. They have heard from influencers focused on longevity that metformin may be the key to a long and healthy life.
In part this is because I treat people with Type 2 diabetes, and for decades metformin has been the foundation upon which all treatment regimens for Type 2 diabetes were built. But more than nearly any other drug, metformin has been studied for its potential to treat myriad diseases beyond the disease it was originally designed to treat.
From weight gain to cancer prevention to anti-aging, metformin has been evaluated as a possible therapy for much of what ails the human race. In a world where developing novel and jaw-droppingly expensive new drugs is typical, metformin is generic, cheap, and has a proven record for safety. It all sounds too good to be true. But what does the data say about metformin?
What is metformin?
Metformin is the only remaining drug in the class of biguanides, the first of which were discovered more than 100 years ago as the active ingredient in the traditional medication goat’s rue. Before metformin was used for its blood-sugar-lowering properties, it was studied as an antimalarial medication in the 1940s. Metformin was not approved for treating Type 2 diabetes in the United States until 1994, but it was preceded by two other biguanides — phenformin and buformin — that are no longer available.
Metformin has two mechanisms for lowering blood sugar, one we understand well and one we still do not understand. Metformin prevents stored blood sugar in the liver from being released inappropriately when someone is fasting, by inhibiting a key enzyme in this process. It also helps the body to be more sensitive to insulin, via an unknown mechanism.
The reason metformin is so broadly used to treat Type 2 diabetes is that it does not cause weight gain and may help with weight loss. When blood sugars are high, it is very effective at lowering them, but if blood sugars are normal, metformin will not lower them further. And it is the only medication other than insulin that targets high fasting blood sugars.
Researchers almost immediately began exploring metformin to treat diseases other than Type 2 diabetes, including weight loss, polycystic ovary syndrome (PCOS), infertility, and cancer prevention.
Metformin for weight loss
One of metformin’s big advantages over older medications for diabetes, including insulin, is that it helps people with Type 2 diabetes lose weight. So it didn’t take long for researchers to ask whether it might help non-diabetics lose weight too.
Compared with today’s blockbuster weight-loss medications, weight loss results with metformin are modest, but studies like this one show that patients taking it may lose up to 5% of their body weight. It does seem to be more effective for weight loss in patients with significant insulin resistance.
Furthermore, metformin has been shown to be effective in preventing weight gain, particularly among patients taking antipsychotic medications notorious for causing weight gain.
Metformin for PCOS
PCOS is a common syndrome affecting 5% to 7% of women during their reproductive years. While we don’t fully understand what causes PCOS, we know that in most cases, high insulin levels are present and are related to both the irregular menstrual periods and weight gain that many women with PCOS experience. As a result, metformin has been extensively studied as a treatment for PCOS.
When women have irregular periods, it is often because they aren’t ovulating regularly. Absent or infrequent ovulation is a hallmark of PCOS. Metformin has been shown to regulate ovulation in about 50% of women with PCOS. With regular ovulation comes regular periods.
Women with PCOS often also struggle with weight gain, and treatment with metformin has been shown to lead to modest but significant weight loss in women with PCOS. Interestingly, in a subset of women, metformin has been shown to lower testosterone levels — testosterone is a key driver of PCOS symptoms like acne and body hair growth. Because metformin can address so many of their symptoms, I reach for metformin frequently when treating women with PCOS.
Metformin for fertility
Because some women with PCOS struggle with infertility and because metformin has been shown to regulate ovulation in some women with PCOS, metformin has been studied as a treatment for infertility in women both with and without PCOS.
The hypothesis is that metformin can help induce ovulation. And it can, but when it comes to helping women become pregnant, it is not nearly as effective as other medications used to induce ovulation, like clomiphene and letrozole.
The study above suggested that when you give women both metformin and clomiphene, conception rates are increased compared with clomiphene alone. However, a subsequent meta-analysis did not find that adding metformin to Clomid (the brand name of clomiphene) improved pregnancy rates.
As a result, when infertility is related to absent or infrequent ovulation, other medications are preferred, though it is reasonable to add metformin to those medications if a woman has signs of insulin resistance.
Metformin for preventing Type 2 diabetes
Some of the most compelling data for metformin outside of treating Type 2 diabetes is for preventing it. Having a family history of Type 2 diabetes, a personal history of gestational diabetes, prediabetes, impaired fasting glucose, and impaired glucose tolerance all put patients at a high risk for developing Type 2 diabetes.
Upward of 8% of adults have Type 2 diabetes, and the disease brings with it significant additional health risks. And treating diabetes is expensive. Preventing it is worthwhile.
A Cochrane review that includes data from more than 6,000 study subjects found that metformin is superior to placebo and to diet and exercise in preventing Type 2 diabetes in high-risk individuals. The authors note that metformin was not superior to intensive lifestyle change.
I would argue that while it may be feasible to maintain intensive lifestyle change for the duration of a clinical trial, many people will struggle to maintain that level of change indefinitely. So metformin may be a more practical option for many.
A study of women with a history of gestational diabetes and signs of disordered glucose metabolism found that metformin was so effective at preventing Type 2 diabetes, you only needed to treat five women with metformin to prevent one case of Type 2 diabetes. Compare that with statins, where you would need to treat 49 people to prevent a single cardiovascular event.
Metformin for cancer
One very active area of metformin research is in cancer prevention. It was first observed that patients with Type 2 diabetes had lower incidences of some cancers. A review of cancer incidence in patients with Type 2 diabetes showed a reduction of about 30% in both cancer incidence and in mortality from cancer among patients taking metformin.
We think metformin may prevent some cancers by modifying how our cells use energy. But does metformin prevent cancer in non-diabetic patients? There are a number of observational studies suggesting that it does. In particular, there is evidence that metformin may be beneficial in preventing or treating lung cancer, colorectal cancer, prostate cancer, breast cancer, and pancreatic cancer.
Metformin’s impact on various types of cancer continues to be an active area of research. ClinicalTrials.gov lists more than 100 ongoing trials of metformin in cancer. Many trials thus far have been observational, but randomized controlled trials are underway.
Metformin for anti-aging
Perhaps the most touted use of metformin is to prevent aging. This makes sense. While not all of us will get diabetes, PCOS, or even cancer, we will all get older. And, to paraphrase George Carlin, while getting older is better than the alternative, most of us would be happy to get older more slowly or at least with as little pain as possible.
Numerous retrospective studies have been published regarding metformin’s purported anti-aging properties. A review from the journal Gerontology notes that metformin’s effects on cell metabolism that may prevent cancer may also prevent aging. Studies in animals have demonstrated that metformin extends lifespan. And we know that metformin can prevent diabetes — a disease that significantly affects lifespan — in patients with insulin resistance and prediabetes. Data from MILES (Metformin in Longevity Study) showed that metformin does impact cellular pathways that affect lifespan in humans. But thus far, the data on metformin and aging in humans isn’t definitive.
Though it hasn’t begun enrolling as of this writing, the TAME (Targeting Aging with Metformin) trial may provide us with more definitive data regarding the efficacy of metformin in preventing aging. The randomized controlled trial seeks to enroll 3,000 participants in sites across the U.S. However, because metformin is a generic medication, there is no big pharmaceutical company looking to foot the bill for the trial, and the investigators are still looking for funding.
Metformin may not be the fountain of youth, but taking it may provide benefits even for healthy people. There are some people who should not take metformin or who should be closely supervised by a doctor, including people with chronic kidney disease or heart failure and those over age 80. It can cause some significant gastrointestinal side effects, but many people tolerate it without issue.
The bottom line
- Metformin is an inexpensive and safe medication with a long track record for effectively treating Type 2 diabetes.
- Metformin has been shown to decrease the risk of developing Type 2 diabetes in high-risk individuals; result in a modest amount of weight loss in patients without diabetes but with significant insulin resistance; regulate ovulation in some women with PCOS; and reduce the incidence of cancer in people with Type 2 diabetes.
- Metformin may reduce the incidence of some types of cancer in people without Type 2 diabetes and may slow aging, but we need more data to know for sure.
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Sooo… what are the chances of getting my gynecologist to put me on it for weight loss? I’ve found it almost impossible to lose weight since perimenopause started. I’ve gained 15 pounds in 3 years, but am not in Ozempic territory (my BMI is 25.2). Metformin sounds too good to be true!
It certainly can’t hurt to ask! Though you may need to consult an endocrinologist with more experience in prescribing it.