Metformin vid PCOS

Fråga: Vi har flera patienter på vår vårdcentral som står på Metformin insatt via privata gynekologer för att främja viktnedgång vid PCOS. Har nyligen fått frågan från en patient om det fungerar, men jag kunde inte svara på det. Finns det någon visad effekt av Metformin på vikten hos dessa patienter, hur fungerar det isåfall och vilka är nackdelarna?

Svar: Sammanfattning
Insulin resistance is believed to play an intrinsic role in the pathogenesis of Polycystic ovary syndrome (PCOS). In meta-analyses, metformin decreased BMI and weight modestly at 24 weeks of treatment. The efficacy of treatment beyond 24 weeks has not been evaluated in clinical trials. There is insufficient data to determine if the risk profile for metformin is different in patients with PCOS as compared to patients with diabetes.
Svar
Insulin resistance is believed to play an intrinsic role in the pathogenesis of polycystic ovary syndrome (PCOS) (1). Obesity is common in women with PCOS and weight loss is a primary therapy in PCOS.

Recently, a systematic review and meta-analysis published 2018 by Wang FF et al (1) compared the effects of the interventions used to induce weight loss in women with PCOS and overweight/obesity. The meta-analysis included 23 randomized clinical trials. Metformin was compared with placebo in 11 studies (n=249). These studies had small sample sizes varying from 14 to 122. Participants received a dosage of metformin ranging from 1.5 to 2 g/day for 12 or 24 weeks. Over 50% of the trials examining metformin recommended lifestyle modifications such as dieting and exercise. Most of the studies (7/11) had diabetes/impaired fasting glucose as exclusion criteria. Metformin intervention was evaluated for a maximum 24 weeks. In studies with a duration of 12 weeks, there was a non-significant reduction of body weight (-2.60 kg [95% CI -6.74, 1.54]) compared with placebo. In studies with a duration of 24 weeks, there was a significant reduction (-1.04 kg [95% CI -2.07, -0.01]). When both 12-weeks and 24-weeks studies were combined, the results showed a significant reduction of body weight for metformin compared with placebo (-1.37 kg [95% CI -1.56, -1.17]). Compared with the placebo, metformin intervention thus led to a significant decrease in weight. However, the magnitude of weight reduction was significantly lower than other interventions evaluated (liraglutide, orlistat). According to the authors it was not possible to calculate the mean percentage weight loss, but results from some of the included studies show a relatively modest effect. After 12 weeks therapy with 1.5 g metformin the mean weight loss was -4.69% ± 1.3% (2) to -5.04% ± 0.67% (3). The meta-analysis concluded that 12 weeks of metformin treatment is not effective, and that treatment should be continued for at least 24 weeks.

In an older meta-analysis from 2015, the authors compared the effect of metformin+lifestyle intervention or metformin alone, with placebo+lifestyle intervention (4). This analysis included 12 randomized, controlled trials of a total of 608 women with PCOS, most of which were overweight or obese. The included studies were small, with the number of participants ranging from 14-156, and they partly overlapped with the study by Wang FF et al. Metformin+lifestyle intervention was associated with a greater BMI reduction compared with placebo+lifestyle intervention at 6 months of treatment (-0.73 kg/m2 [95% CI -1.14, -0.32]. There was no significant difference between metformine alone and placebo+lifestyle intervention.

We have found one prospective cohort study of the effects of 24 months of metformin treatment in 119 overweight and normal-weight women with PCOS (5). This study found that metformin decreased BMI at 6 months, but there was no further significant changes in BMI after this time frame where a steady-state was maintained till 24 months. The absolute reduction of BMI was not presented.

Metformin is typically associated with gastrointestinal adverse reactions (such as nausea, diarrhea, abdominal pain) and lactic acidosis (6). Due to limited data, it is not possible to determine if the risk profile is different in patients with PCOS compared with patients with diabetes.

The Swedish Society for Obstetrics and Gynecology (Svensk förening för obstetric och gynekologi) states in a 2008 guideline for the treatment of PCOS that metformin has no effect on body weight in this patients group (7). The refer to a study by Tang et al (included in both meta-analyses described above), but appear to have left out other studies.

1. Wang FF, Wu Y, Zhu YH, Ding T, Batterham RL, Qu F, Hardiman PJ. Pharmacologic therapy to induce weight loss in women who have obesity/overweight with polycystic ovary syndrome: a systematic review and network meta-analysis. Obes Rev. 2018 Jul 31.
2. Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. J Clin Endocrinol Metab 2005; 90: 729–733.
3. Ghandi S, Aflatoonian A, Tabibnejad N, Moghaddam MH. The effects of metformin or orlistat on obese women with polycystic ovary syndrome: a prospective randomized open-label study. J Assist Reprod Genet 2011; 28: 591–596.
4. Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015 Sep-Oct;21(5):560-74.
5. Yang PK, Hsu CY, Chen MJ, Lai MY, Li ZR, Chen CH, Chen SU, Ho HN. The Efficacy of 24-Month Metformin for Improving Menses, Hormones, and Metabolic Profiles in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2018 Mar 1;103(3):890-899.
6. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2010 Jun;1(3):117-28.
7. Polycystiskt ovarialsyndrom (PCOS), Svensk förening för obstetric och gynekologi, 2008. https://www.sfog.se/natupplaga/nr583ec963ad-d97d-45b7-a7f0-975614972f81.pdf