By Kym Campbell, BSc. | Updated September 30th, 2022
Metformin is one of the most commonly prescribed treatments for PCOS. But it shouldn’t be. In this article, I describe the failures and shortcomings of metformin treatment for PCOS. I also describe better alternatives. Chief among them are dietary interventions.
This is an evidence-driven perspective. But you can see how the consequences play out among women that take part in my free 30-Day PCOS Diet Challenge.
1. It Isn’t Recommended for PCOS
Metformin isn’t recommended for women with PCOS. Even if you have prediabetes. Unless you have a diabetes diagnosis, any use is “off-label”.
In 2003, Dr. Robert Barbieri authored a guide on the use of metformin for the treatment of PCOS [1]. Many prescribing physicians may still rely on this guidance.
But, by 2018, Barberi and his colleagues had changed their recommendations. Based on more recent data, they no longer recommend the use of metformin as a first-line therapy for any indication [2].
This is a mainstream medical view. You can refer your doctor to their review of the literature here.
2. Metformin is a Band-Aid Solution
Metformin is a band-aid solution for preventing diabetes. It only lowers your insulin levels as long as you’re taking it daily.
In 2002, the Diabetes Prevention Program Research Group quantified these benefits. They found that over 3 years, metformin reduced the incidence of newly developed diabetes cases by 31% [3]. But in a follow-up study, the majority of the benefit did not persist when the treatment was stopped [4]. This means that unless you make other changes, you’ll need to take metformin for life.
The same researchers compared metformin to a diet and lifestyle intervention. Their “lifestyle group” enrolled in a 24-week program focusing on diet and exercise. This group reduced their risk of type II diabetes by 58%. This was significantly better than the 31% achieved by the metformin group.
This supports what I see within the PCOS community. Many women that take part in my free 30-Day PCOS Diet Challenge take metformin. For those that can adapt to a PCOS diet, their insulin sensitivity improves dramatically. Over time, many of these women get key biomarkers back within normal ranges and stop taking this unnecessary drug.
3. It Doesn’t Help with Weight Loss
Many women are told that metformin helps with weight loss. That’s why “metformin weight loss PCOS” and “PCOS belly fat metformin” are such heavily searched terms on Google. A quick look at the scientific literature though shows disappointing weight loss results.
Metformin has been shown to cause weight loss in non-diabetic people. In one study, people with severe insulin resistance lost more weight than insulin-sensitive people [5]. These benefits were independent of age, sex, and BMI. But the results are different for women with PCOS.
In a 2017 meta-analysis, Morely and colleagues reviewed 42 metformin studies in women with PCOS. They found that metformin had a slight improvement in the distribution of excess body fat. This led to a small improvement in waist to hip ratio. But there was no effect on body weight overall [6].
Meta-analyses like these are the most powerful assessments of scientific evidence. Smaller (and older) metformin weight loss PCOS studies have shown a slight benefit [7]. But the size of the effect was small. When considering the entire body of evidence, metformin is unlikely to help you lose weight.
The impact of dietary change overshadows these gains. This is because diet is the best way to reverse insulin resistance. The right diet can also address chronic inflammation. This is another underlying mechanism driving PCOS weight gain. You can see this at play when PCOS women lose weight. Many of their other symptoms go away too.
4. Metformin Doesn’t Help Fertility (Much)
Infertility is the second most common reason women with PCOS are prescribed metformin. I was once one of them.
The 2017 review by Morley and colleagues found that metformin may improve live birth rates. But a previous review conducted in 2012 found no improvement [8]. The only difference between these studies was a trial by Finish researchers. This one study tipped the narrow balance in metformin’s favor [9]. With only four studies used to assess live birth rates, the quality of evidence is low. As the authors of the 2017 review note, “…Given the… evidence quality, the advantage offered by metformin remains difficult to interpret clinically.”
Even the Endocrine Society Clinical Practice Guidelines state that “[metformin] has limited or no benefit in treating hirsutism, acne, or infertility [10].”
These statements would be more definitive if metformin improved PCOS infertility in a meaningful way. Given the availability of better alternatives, the benefits need to be obvious before prescribing this drug. The women from my PCOS community provide powerful testimony to the use of diet over metformin. Here are some examples from my free 30-Day PCOS Diet Challenge.
5. Metformin Depletes Nutrients
There’s an abundance of evidence showing that metformin use is associated with decreased vitamin B12 status.
A study on older adults found that metformin use was the best predictor of vitamin B12 deficiency [11]. The larger the dose and the longer you use metformin, the lower your serum B12 levels are likely to be [12, 13]. This is because metformin impairs B12 absorption [14-18]. Given the importance of B12, this is bad news for women with PCOS. Pregnancy outcomes, vascular, cognitive, bone, and eye health may all be affected by a long-term sub-clinical deficiency [19, 20].
Unfortunately, many women are not informed of this risk.
Other vitamins and minerals may also be affected by metformin. This includes vitamin B1, folic acid, vitamin D, and magnesium [21]. Nutrient supplementation is recommended for people taking metformin. This is particularly important for women that are trying to conceive.
As I explain in my article Vitamin D for PCOS, this nutrient, in particular, should be at the top of the list for most people.
6. Side Effects Are Common
In one study, approximately 88% of people experienced metformin side effects [22]. The most common side effects include diarrhea, heartburn, nausea, abdominal pain, bloating, and retching [23].
When I polled my PCOS support Facebook group, 78% reported adverse effects. Here’s what some of the respondents said.
“I was violently sick and couldn’t eat, everyone thought I had morning sickness so I had to stop taking it”.
“It made me super sick and it was a terrible experience”.
“I was always sick to my stomach on it”.
“I had numerous side effects, tiredness, nauseous, headaches, pain in my abdomen.”
“the metformin I started taking for fertility made me bleed for over 20 days and I had to go to urgent care due to anemia.”
Metformin also has other less common side effects. There have been many case studies of metformin causing liver injury [24-26]. Studies on rats also suggest an increased risk of Alzheimer’s disease [27].
The take-home here is that metformin may be a safer drug, but it’s not without its risks.
7. There Are Better Alternatives
The effectiveness of alternatives to metformin for PCOS is one of the biggest reasons not to take this drug.
A combination of myo-inositol and d-chiro-inositol, like that used in Ovasitol for PCOS, shows the most promise. For example, a 2021 meta-analysis compared inositol supplements to metformin. This study showed that a combined inositol supplement was many times more effective than metformin at improving menstrual frequency [28].
A 2019 meta-analysis compared the insulin-sensitizing effects of myo-inositol and metformin. Straight myo-inositol was found to be as good as metformin. Myo-inositol also performed as well as metformin when it came to improving testosterone levels, body mass index, and more [11].
The natural herb, berberine, also shows great potential in patients with PCOS. Trials show that it can improve insulin resistance, blood lipids, and ovulation [29-32]. One meta-analysis suggests that berberine is as effective as metformin for improving insulin sensitivity [33].
Like inositol supplements, berberine is generally well-tolerated. This means fewer side effects and less disruption to your everyday life. It’s important to keep in mind though, that berberine is not safe during pregnancy.
Of course, the best alternative to metformin for PCOS is changing how you eat. Metformin’s health benefits come from its anti-inflammatory and antioxidant properties [34]. Its alteration of the gut microbiome is also key to its effectiveness [35-37]. Both of these mechanisms are affected by diet.
A PCOS diet reduces inflammation and improves gut health. It can also reverse insulin resistance. By addressing the underlying causes of PCOS, the right diet can displace the need for metformin. It also improves other PCOS symptoms at the same time.
The Bottom Line
It’s hard to justify metformin treatment for PCOS. Experts in the field no longer recommend its use as a first-line therapy for PCOS patients. Even for PCOS women with diabetes, metformin is a band-aid solution with better alternatives.
Metformin doesn’t provide meaningful weight loss results. Nor does it significantly improve fertility. Metformin depletes important nutrients and has significant side effects. Ovasitol and berberine perform just as well but are much better tolerated.
A PCOS diet is the most important step though for improving insulin regulation and fertility. A PCOS diet can displace the need for metformin and can further improve other PCOS symptoms.
Get started on the right track today by downloading this free 3-Day Meal Plan. Or sign up for my next free 30-Day PCOS Diet Challenge.
Author
Since 2010, Kym Campbell has used evidence-based diet and lifestyle interventions to manage her PCOS. After getting her symptoms under control and falling pregnant naturally, Kym now advocates for dietary change as part of any PCOS treatment plan. Combining rigorous science and clinical advice with a pragmatic approach to habit change, Kym is on a mission to show other women how to take back control of their health and fertility. Read more about Kym and her team here.
Co-Authors
This blog post has been critically reviewed to ensure accurate interpretation and presentation of the scientific literature by Dr. Jessica A McCoy, Ph.D. Dr McCoy has a master’s degree in cellular and molecular biology, and a doctorate in reproductive biology and environmental health. She currently serves as a University professor at the College of Charleston, South Carolina.
This blog post has also been medically reviewed and approved by Dr. Sarah Lee, M.D. Dr. Lee is a board-certified Physician practicing with Intermountain Healthcare in Utah. She obtained a Bachelor of Science in Biology from the University of Texas at Austin before earning her Doctor of Medicine from UT Health San Antonio.
References
1Barbieri, R.L., Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol, 2003. 101(4): p. 785-93.
2Barbieri, R.L.E., D.A., Metformin for treatment of the polycystic ovary syndrome. UpToDate, 2018.
3Knowler, W.C., et al., Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002. 346(6): p. 393-403.
4Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care, 2003. 26(4): p. 977-80.
5Seifarth, C., B. Schehler, and H.J. Schneider, Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes, 2013. 121(1): p. 27-31.
6Morley, L.C., et al., Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev, 2017. 11(11): p. Cd003053.
7Nieuwenhuis-Ruifrok, A.E., et al., Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Hum Reprod Update, 2009. 15(1): p. 57-68.
8Tang, T., et al., Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev, 2012(5): p. Cd003053.
9Morin-Papunen, L., et al., Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab, 2012. 97(5): p. 1492-500.
10Legro, R.S., et al., Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2013. 98(12): p. 4565-92.
11Laird, E.J., et al., Voluntary fortification is ineffective to maintain the vitamin B12 and folate status of older Irish adults: evidence from the Irish Longitudinal Study on Ageing (TILDA). Br J Nutr, 2018. 120(1): p. 111-120.
12Aroda, V.R., et al., Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab, 2016. 101(4): p. 1754-61.
13Ting, R.Z., et al., Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med, 2006. 166(18): p. 1975-9.
14Bauman, W.A., et al., Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care, 2000. 23(9): p. 1227-31.
15Kozyraki, R. and O. Cases, Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders. Biochimie, 2013. 95(5): p. 1002-7.
16Wulffelé, M.G., et al., Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med, 2003. 254(5): p. 455-63.
17Quadros, E.V., Advances in the understanding of cobalamin assimilation and metabolism. Br J Haematol, 2010. 148(2): p. 195-204.
18Reinstatler, L., et al., Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care, 2012. 35(2): p. 327-33.
19O’Leary, F. and S. Samman, Vitamin B12 in health and disease. Nutrients, 2010. 2(3): p. 299-316.
20Rogne, T., et al., Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data. Am J Epidemiol, 2017. 185(3): p. 212-223.
21Wakeman, M. and D.T. Archer, Metformin and Micronutrient Status in Type 2 Diabetes: Does Polypharmacy Involving Acid-Suppressing Medications Affect Vitamin B12 Levels? Diabetes Metab Syndr Obes, 2020. 13: p. 2093-2108.
22Florez, H., et al., Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. Postgrad Med, 2010. 122(2): p. 112-20.
23Bouchoucha, M., B. Uzzan, and R. Cohen, Metformin and digestive disorders. Diabetes Metab, 2011. 37(2): p. 90-6.
24Hashmi, T., Probable hepatotoxicity associated with the use of metformin in type 2 diabetes. BMJ Case Rep, 2011. 2011.
25Saadi, T., et al., Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review. Int J Gen Med, 2013. 6: p. 703-6.
26Zheng, L., Metformin as a Rare Cause of Drug-Induced Liver Injury, a Case Report and Literature Review. Am J Ther, 2016. 23(1): p. e315-7.
27Picone, P., et al., Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates. Aging (Albany NY), 2016. 8(8): p. 1718-34.
28Zhao, H., et al., Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis. Reprod Health, 2021. 18(1): p. 171.
29Ju, J., et al., Efficacy and safety of berberine for dyslipidaemias: A systematic review and meta-analysis of randomized clinical trials. Phytomedicine, 2018. 50: p. 25-34.
30Rondanelli, M., et al., Polycystic ovary syndrome management: a review of the possible amazing role of berberine. Arch Gynecol Obstet, 2020. 301(1): p. 53-60.
31Wei, W., et al., A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol, 2012. 166(1): p. 99-105.
32Xie, L., et al., The Effect of Berberine on Reproduction and Metabolism in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Control Trials. Evid Based Complement Alternat Med, 2019. 2019: p. 7918631.
33Li, M.F., X.M. Zhou, and X.L. Li, The Effect of Berberine on Polycystic Ovary Syndrome Patients with Insulin Resistance (PCOS-IR): A Meta-Analysis and Systematic Review. Evid Based Complement Alternat Med, 2018. 2018: p. 2532935.
34Dehkordi, A.H., et al., Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. Journal of Renal Injury Prevention, 2018.
35Wu, H., et al., Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med, 2017. 23(7): p. 850-858.
36Weersma, R.K., A. Zhernakova, and J. Fu, Interaction between drugs and the gut microbiome. Gut, 2020. 69(8): p. 1510-1519.
37Lee, C.B., et al., The Relationship between the Gut Microbiome and Metformin as a Key for Treating Type 2 Diabetes Mellitus. Int J Mol Sci, 2021. 22(7).
