FPIN's Help Desk Answers

Alternatives to Metformin for Patients with PCOS


Am Fam Physician. 2016 Sep 1;94(5):378-379.

Clinical Question

What is the best insulin-sensitizing medication for patients with polycystic ovary syndrome (PCOS) who cannot tolerate metformin?

Evidence-Based Answer

Compared with placebo, thiazolidinediones (TZDs) decrease systolic blood pressure and fasting blood glucose and insulin levels while improving menstrual irregularities in women with PCOS. (Strength of Recommendation: A, based on a meta-analysis of randomized controlled trials [RCTs].) Metformin and TZDs have similar effects on pregnancy rates, ovulation, and menstrual frequency, but TZDs can cause weight gain and lower free testosterone and dehydroepiandrosterone (DHEA) levels to a greater degree, whereas metformin reduces body mass index (BMI) and serum triglyceride levels to a greater degree.

A 2012 systematic review of 44 RCTs (N = 3,992) evaluated metabolic and reproductive outcomes for insulin-sensitizing drugs, including metformin, rosiglitazone (Avandia), pioglitazone (Actos), and D-chiro-inositol (a dietary supplement involved in insulin signal transduction) in women with oligomenorrhea, subfertility, and PCOS (defined as meeting at least two of the 2003 Rotterdam consensus criteria).1 Only six of the 44 studies involved agents other than metformin; two studies used rosiglitazone (N = 100; 4 mg once or twice daily), two used pioglitazone (N = 70; 30 mg daily), and two used D-chiro-inositol (N = 327; 100 mg to 1,200 mg daily). Menstrual cycle regularity improved with rosiglitazone (odds ratio [OR] = 5.6; 95% confidence interval [CI], 2.2 to 14.2) and pioglitazone (OR = 8.9; 95% CI, 2.4 to 33.6) compared with placebo. Patients receiving rosiglitazone had a slightly lower systolic blood pressure (mean difference = −2.0 mm Hg; 95% CI, −4.0 to −0.05) compared with placebo. D-chiro-inositol was evaluated in two trials of obese women (mean BMI = 31 to 33 kg per m2) with PCOS diagnosed by oligomenorrhea, elevated testosterone level, or hirsutism. In these studies, D-chiro-inositol had no effect on ovulation

Address correspondence to Karen G. Bucher, DO, at karen.bucher@us.af.mil. Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


1. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. 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):CD003053.

2. Li XJ, Yu YX, Liu CQ, et al. Metformin vs thiazolidinediones for treatment of clinical, hormonal and metabolic characteristics of polycystic ovary syndrome: a meta-analysis. Clin Endocrinol. 2011;74(3):332–339.

3. Du Q, Yang S, Wang YJ, Wu B, Zhao YY, Fan B. Effects of thiazolidinediones on polycystic ovary syndrome: a meta-analysis of randomized placebo-controlled trials. Adv Ther. 2012;29(9):763–774.

Help Desk Answers provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group ( http://www.cebm.net/?o=1025).

The complete database of evidence-based questions and answers is copyrighted by FPIN. If interested in submitting questions or writing answers for this series, go to http://www.fpin.org or email: questions@fpin.org.

This series is coordinated by John E. Delzell Jr., MD, MSPH, Assistant Medical Editor.



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