Insulin Sensitizers for Improving the Endocrine and Metabolic Profile in Overweight Women With PCOS

Chuan Xing; Chunzhu Li; Bing He

Disclosures

J Clin Endocrinol Metab. 2020;105(9) 

In This Article

Discussion

This is the first NMA comparing efficacy and safety of both monotherapy and combinations of different insulin sensitizers in overweight PCOS. Many studies suggest that, in obese PCOS patients, metabolic abnormalities related to insulin resistance and obesity are more important than androgen excess in the mechanism of anovulation in PCOS.[33] Metformin, which has insulin-lowering effects by ameliorating insulin sensitivity in liver and peripheral tissues, is the most widely used drug for regulating metabolic and endocrine disorders in PCOS, and it can, in turn, improve ovarian steroidogenesis and decrease circulating androgen level. These changes offer benefits that targets both cardiometabolic disorders and reproductive abnormalities.[34] TZDs such as pioglitazone and rosiglitazone have also been shown to be effective in improving insulin resistance and hyperandrogenemia, as well as ovulation rate and menstrual cyclicity in PCOS, and GLP-1 receptor agonists such as exenatide and liraglutide are novel therapeutic options for the treatment of obesity, particularly in women with PCOS who display impaired first- and second-phase insulin secretion.[34] Our results showed that metformin combined with GLP-1 receptor agonists was superior to monotherapy in improving SHBG and AND; in addition, it had better effects on reducing FT and FG when compared with GLP-1 receptor agonists alone. Metformin combined with TZDs was associated with better effects on increasing SHBG and promoting the recovery of menstruation than metformin. We did not observe a difference between metformin, GLP-1 receptor agonists, and TZD monotherapy in terms of menstrual frequency, hyperandrogenemia, FINS, and WC improvement; whereas, TZDs were inferior to metformin in decreasing BMI.

Menstrual disorders and symptoms of sterility occur in approximately 98% of women with PCOS.[35] Metformin may improve menstrual cyclicity and ovulation; moreover, it may also amplify the effects of ovulation-inducing drugs or androgen-lowering medications.[36] Other studies have shown that pioglitazone and GLP-1 receptor agonists could also restore menstrual cycles and induce ovulation.[37,38] We confirmed that all these interventions were effective; in addition, both TMA and NMA demonstrated that metformin combined with TZDs was more effective than metformin alone and the SUCRA curve illustrated that metformin combined with TZDs was the best intervention for promoting menstrual recovery.

For the improvement of hyperandrogenemia, metformin can reduce androgen secretion from thecal cells and adrenal glands of women with PCOS while stimulating SHBG production, modulating LH discharge, and attenuating the ovarian androgen response to gonadotropin stimulation by reducing circulating insulin and androgen levels, thus reducing FT concentration.[39,40] Both animal experiments and clinical research have shown that GLP-1 receptor agonists can reduce serum testosterone concentration in PCOS,[41,42] and TZDs were found to repress androgen biosynthesis in thecal cells.[43] Both TMA and NMA showed no significant difference among metformin, GLP-1 receptor agonists, and TZDs in improving TT, FT, and SHBG, which was in accordance with our previous study.[44] However, the meta-analysis done by Niafar et al found that TT decreased significantly after 3 months of GLP-1 receptor agonists treatment,[42] and Li et al found that TZDs were superior to metformin in reducing FT after 12 weeks of treatment.[45] Our results were not consistent with those of Niafar et al and Li et al, which may be due to the fact that the inclusion criteria limited weight and age, so our finding was more suitable for overweight adult PCOS. No previous meta-analysis had compared the difference between the combination of 2 insulin sensitizers and monotherapy in improving hyperandrogenemia. Our TMA revealed that both metformin combined with TZDs and metformin combined with GLP-1 receptor agonists were superior to metformin alone in improving TT and SHBG, while metformin combined with GLP-1 receptor agonists was superior to GLP-1 receptor agonists alone in improving TT, FT, and SHBG. The NMA showed similar results in improving FT and SHBG. The SUCRA curve revealed that metformin combined with GLP-1 receptor agonists was the best intervention for improving FT and SHBG. However, for decreasing TT, NMA showed no significant difference between the 5 interventions. The difference between TMA and NMA was likely due to the insufficient statistical power, because only 2 to 4 RCTs were included in each direct pairwise analysis. Because of the limitation of measurement technology, it is often difficult to accurately determine the concentration of FT, so free testosterone index (FAI) is often preferred to evaluate the level of active androgen production in vivo.[46] Unfortunately, only 3 studies reported the changes of FAI, so it was impossible to carry out meta-analysis since the number was too small. Elkind-Hirsch et al[15] found that compared with metformin, metformin combined with exenatide significantly reduced FAI, while Jensterle et al[18,19] found no significant FAI difference between metformin and liraglutide. Although the role of AND in evaluation of PCOS was unclear, it is sometimes elevated in PCOS.[47] Both TMA and NMA revealed that metformin combined with GLP-1 receptor agonists was more effective than metformin or GLP-1 receptor agonists alone.

For glucose metabolism, metformin can inhibit the gluconeogenesis of hepatic glycogen, increase glucose uptake and utilization by the peripheral tissues, and improve hepatic insulin sensitivity in patients with PCOS.[47] Guo found that GLP-1 receptor agonists can directly increase insulin sensitivity in fat, muscle, and liver tissues.[48] Moreover, metformin can potentially enhance the effect of GLP-1 receptor agonists.[36] Treatment with TZDs has been shown to improve peripheral insulin sensitivity and enhance insulin effects on skeletal muscle and adipose tissue without any direct effect on pancreatic insulin secretion.[37] Both TMA and NMA revealed that metformin combined with GLP-1 receptor agonists was superior to GLP-1 receptor agonists in improving FG. Moreover, the SUCRA curve illustrated that metformin combined with GLP-1 receptor agonists was the best intervention for improving FG. Our NMA showed no significant difference between any of the 5 interventions in decreasing fasting insulin.

Obesity is a basic feature of 60% to 70% women with PCOS, and a loss of 5% to 10% of body weight has been shown to improve reproductive and metabolic outcomes in these women.[49] Metformin may normalize appetite in obese women with PCOS and it may also enhance the expression of GLP-1 receptors.[50,51] GLP-1 receptor agonists bind with the receptor in the arcuate nuclei of the hypothalamus to inhibit appetite, increase the sensation of satiety, and reduce food intake, in addition to delaying gastric emptying and bowel movements and reducing body weight.[52,53] TMA showed that the combination of metformin and GLP-1 receptor agonists was better than metformin alone and metformin combined with GLP-1 receptor agonists was ranked best among the 5 regimens for WC reduction. Moreover, both TMA and NMA revealed that TZDs were inferior to metformin, which was consistent with the previous study,[45] and the negative effect of TZDs on weight may be related to the fluid retention and increased appetite.[54]

Unfortunately, only a few of the 14 studies included in our analysis studied improvements in ovulation and hirsutism, so it is impossible to form a NMA. Wang et al[27] and Li[22] revealed that, compared with metformin, metformin combined with TZDs could significantly increase ovulation rate. Elkind-Hirsch et al[15] found that metformin combined with GLP-1 receptor agonists was superior to GLP-1 receptor agonists and metformin alone in increasing ovulation rate. In terms of improving hirsutism and acne, Wang et al,[27] Jensterle et al,[18] and Ortega-Gonzalez et al[24] revealed that metformin, GLP-1 receptor agonists, TZDs, and metformin combined with TZDs could significantly improve hirsutism, but there were no statistical differences among the interventions. Ortega-Gonzalez et al[24] found that both metformin and TZDs could significantly improve acne, and Liang et al[23] showed that acne scores decreased significantly after 12 weeks of treatment with (in descending order) metformin, TZDs, and metformin combined with TZDs.

In terms of adverse events, the most common adverse effects of the pharmacologic therapies were headache and abdominal pain with metformin, GLP-1 receptor agonists, and TZDs; hypoglycemic events and gastrointestinal side effects (such as nausea, heartburn, vomiting, and diarrhea) were common with the combination of metformin and GLP-1 receptor agonists. Both GLP-1 receptor agonists and TZDs may cause insomnia, and GLP-1 receptor agonists may cause rash at the injection site and constipation; drug-specific adverse reactions associated with TZDs include mastopathy, muscle cramping, and peripheral edema. Most of the adverse effects were mild and resolved after a few weeks of treatment. Only rash at the injection site of GLP-1 receptor agonists was serious, causing 1 participant to withdraw from the trial.[18]

This is the first NMA comparing efficacy and safety of both monotherapy and combinations of different insulin sensitizers in the management of overweight women with PCOS. The application of the NMA adds the ability to address the comparisons that are not powered in the TMA. All the original studies used a randomized controlled study design, which greatly reduced the likelihood of recall and selection bias. Since no prior meta-analysis has focused on the improvement of menstrual frequency, hyperandrogenemia, glucose metabolism, and obesity-related parameters simultaneously, our study is more complete.

The present study has several limitations. First, very few clinical studies have been conducted on overweight women with PCOS, and still fewer studies met the inclusion criteria of the current analysis. Most studies included had small sample sizes, and "grey literature" was not included, causing high heterogeneity and possible selection bias. Second, publication bias may exist, since studies with significant results are more likely to be published. However, we have attempted to address this issue by retrieving all the available studies, and we created funnel plots to assess any bias that may have arisen from this source. Third, the study populations differed, including European, Asian, and American populations. Fourth, the studies using GLP-1 receptor agonists compared with metformin could not adopt a blinding method. Fifth, the dosing regimens and follow-up durations were not consistent among the different studies, which may have affected the clinical efficacy. Finally, the methodology was limited in some studies, and the units of the evaluation indices were not the same. However, the conclusions and limitations of this study may provide some directions for the design of new trials.

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