Short-term Combined Treatment with Exenatide and Metformin for Overweight/Obese Women with Polycystic Ovary Syndrome

Short-term Combined Treatment with Exenatide and Metformin for Overweight/Obese Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by chronic anovulation, hyperandrogenism, polycystic ovary morphology, obesity, and insulin resistance (IR). Obesity significantly contributes to reproductive and metabolic abnormalities in PCOS patients. Weight loss has been shown to help women with PCOS resume spontaneous menstruation, reduce circulating androgen levels, and improve glucose and lipid metabolism. Even a modest weight loss of 5% can yield these benefits. However, lifestyle modifications such as increased exercise and dietary changes, although effective, are often challenging for patients to maintain. Metformin (MET), an insulin sensitizer, is commonly used alongside lifestyle changes to treat PCOS. While MET improves insulin sensitivity, reduces androgen levels, increases ovulation rates, and enhances glucose tolerance, its effects on weight loss are often unsatisfactory.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of anti-diabetic agents that enhance insulin secretion and promote islet B cell proliferation. These agents have demonstrated efficacy in improving IR and impaired glucose tolerance, and they are associated with weight loss due to delayed gastric emptying and increased satiety. Short-acting exenatide and long-acting liraglutide have been used in PCOS treatment, showing significant weight loss and improved glucose metabolism. Combined treatment with a GLP-1 receptor agonist and MET has been found superior to monotherapies in improving menstrual cyclicity, insulin sensitivity, and weight loss. However, these combined therapies typically require frequent subcutaneous administration. Exenatide once-weekly (QW) is the newest GLP-1 receptor agonist, offering a convenient dosing regimen with reduced injection frequency. Despite its advantages, there are no reported studies on the effect of exenatide QW on PCOS patients.

This study aimed to explore the therapeutic effects of exenatide QW combined with MET on body weight, metabolic, and endocrinological parameters in overweight/obese women with PCOS. The hypothesis was that the combination of exenatide QW and MET would be more effective in inducing weight loss and improving IR in PCOS patients compared to MET alone.

The study was an open-label, prospective, randomized, outpatient clinical trial conducted over 12 weeks. Fifty overweight/obese women with PCOS, diagnosed via the Rotterdam criteria, were randomized into two treatment groups: MET monotherapy (500 mg three times a day) or combination therapy (COM) (MET 500 mg three times a day plus exenatide 2 mg QW). The primary outcomes were anthropometric changes associated with obesity, while secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein (CRP).

Forty patients (80%) completed the study. The COM therapy was superior to MET monotherapy in reducing weight, body mass index (BMI), and waist circumference. Patients in the COM group lost an average of 3.8 ± 2.4 kg compared to 2.1 ± 3.0 kg in the MET group. BMI and waist circumference decreased by 1.4 ± 0.87 kg/m² and 4.63 ± 4.42 cm in the COM group, respectively, compared to 0.77 ± 1.17 kg/m² and 1.72 ± 3.07 cm in the MET group. Additionally, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET. Mild to moderate gastrointestinal reactions were the most common adverse events in both groups.

The study demonstrated that combined therapy with exenatide QW and MET was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects. The findings suggest that exenatide QW could be a valuable addition to the treatment regimen for PCOS, particularly for patients struggling with weight management and insulin resistance.

The baseline characteristics of the participants were similar between the two groups. The mean age was 28.17 ± 4.40 years in the MET group and 30.10 ± 4.52 years in the COM group. The mean weight was 79.25 ± 10.75 kg in the MET group and 84.14 ± 12.82 kg in the COM group. BMI was 30.62 ± 3.42 kg/m² in the MET group and 31.51 ± 4.20 kg/m² in the COM group. Waist circumference was 96.18 ± 8.56 cm in the MET group and 98.94 ± 10.77 cm in the COM group. Hip circumference was 105.75 ± 5.85 cm in the MET group and 108.66 ± 8.12 cm in the COM group. Total testosterone levels were 0.76 ± 0.23 ng/mL in the MET group and 0.73 ± 0.28 ng/mL in the COM group. Dehydroepiandrosterone sulfate (DHEAS) levels were 257.91 ± 110.81 mg/dL in the MET group and 259.96 ± 111.71 mg/dL in the COM group. Fasting plasma glucose (FPG) levels were 5.19 ± 0.45 mmol/L in the MET group and 5.18 ± 0.55 mmol/L in the COM group. OGTT 2-h glucose levels were 7.11 ± 1.58 mmol/L in the MET group and 7.79 ± 1.67 mmol/L in the COM group. Fasting insulin levels were 20.01 ± 7.35 mIU/mL in the MET group and 23.47 ± 12.77 mIU/mL in the COM group. OGTT 2-h insulin levels were 144.08 ± 71.34 mIU/mL in the MET group and 177.28 ± 81.14 mIU/mL in the COM group. Homeostasis model assessment of insulin resistance (HOMA-IR) values were 4.41 (3.91–5.28) in the MET group and 4.91 (3.05–6.79) in the COM group. Homeostasis model assessment of β-cell function (HOMA-β) values were 228.19 (169.70–326.51) in the MET group and 240.65 (194.84–345.03) in the COM group. Quantitative insulin sensitivity check index (QUICKI) values were 0.31 (0.30–0.31) in the MET group and 0.30 (0.29–0.32) in the COM group. Matsuda index scores were 2.03 (1.71–2.37) in the MET group and 1.83 (1.56–2.85) in the COM group. Total cholesterol (TC) levels were 5.18 ± 0.84 mmol/L in the MET group and 4.77 ± 0.74 mmol/L in the COM group. Triglyceride (TG) levels were 1.60 (1.02–2.65) mmol/L in the MET group and 1.34 (0.97–1.96) mmol/L in the COM group. High-density lipoprotein cholesterol (HDL-c) levels were 1.16 ± 0.24 mmol/L in the MET group and 1.18 ± 0.24 mmol/L in the COM group. Low-density lipoprotein cholesterol (LDL-c) levels were 3.40 ± 0.67 mmol/L in the MET group and 3.06 ± 0.59 mmol/L in the COM group. Apolipoprotein A1 (ApoA1) levels were 1.26 ± 0.13 g/L in the MET group and 1.26 ± 0.15 g/L in the COM group. Apolipoprotein B (ApoB) levels were 1.04 ± 0.19 g/L in the MET group and 0.95 ± 0.14 g/L in the COM group. Free fatty acid (FFA) levels were 659.33 ± 206.62 mmol/L in the MET group and 592.29 ± 223.02 mmol/L in the COM group. High-sensitivity C-reactive protein (hsCRP) levels were 2.24 (1.45–5.34) mg/L in the MET group and 3.74 (1.86–9.05) mg/L in the COM group.

After 12 weeks of treatment, significant reductions in weight, BMI, and waist circumference were observed in both groups, with greater reductions in the COM group. The mean weight loss was 3.8 ± 2.4 kg in the COM group compared to 2.1 ± 3.0 kg in the MET group. BMI decreased by 1.4 ± 0.87 kg/m² in the COM group and 0.77 ± 1.17 kg/m² in the MET group. Waist circumference decreased by 4.63 ± 4.42 cm in the COM group and 1.72 ± 3.07 cm in the MET group. Hip circumference decreased significantly only in the COM group (2.56 ± 3.64 cm). Total testosterone levels decreased significantly in both groups, with no significant difference between treatments. DHEAS levels did not change significantly in either group. FPG, OGTT 2-h glucose, and OGTT 2-h insulin levels decreased significantly in the COM group but not in the MET group. The Matsuda index, reflecting systemic insulin sensitivity, improved significantly in the COM group but not in the MET group. HOMA-IR, HOMA-β, and QUICKI values did not change significantly in either group. HDL-c, ApoA1, and TG levels increased significantly in both groups, while TC levels increased significantly only in the MET group. LDL-c, ApoB, and FFA levels did not change significantly in either group. HsCRP levels did not change significantly in either group.

The most common adverse events were mild to moderate gastrointestinal reactions, including nausea, diarrhea, bloating, vomiting, headache, stomachache, constipation, and fatigue. The incidence of nausea was 40% in the MET group and 44% in the COM group. Diarrhea occurred in 44% of the MET group and 36% of the COM group. Injection site reactions, such as itching and induration, were common in the COM group but did not lead to treatment discontinuation.

In conclusion, this study provides preliminary evidence that the combination of exenatide QW and MET is superior to MET monotherapy in reducing body weight, BMI, waist circumference, and improving blood glucose and insulin levels in overweight/obese women with PCOS, with acceptable short-term side effects. However, the study’s small sample size, open-label design, and short duration limit the generalizability of the results. Larger, long-term randomized clinical trials are needed to further evaluate the efficacy and cost-effectiveness of exenatide QW in the treatment of PCOS.

doi.org/10.1097/CM9.0000000000001712

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