Exenatide, Dapagliflozin, or Phentermine/Topiramate Differentially Affect Metabolic Profiles in Polycystic Ovary Syndrome

Karen E. Elkind-Hirsch; N. Chappell; Ericka Seidemann; John Storment; Drake Bellanger


J Clin Endocrinol Metab. 2021;106(10):3019-3033. 

In This Article

Abstract and Introduction


Context: Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms.

Objective: The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and coadministered (EQW/DAPA), DAPA/extended-release (ER) metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS.

Methods: Nondiabetic women (n = 119; aged 18–45 years) with a body mass index (BMI) greater than 30 and less than 45 and polycystic ovary syndrome (National Institutes of Health criteria) were randomly assigned in a single-blinded fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000 mg XR daily), or PHEN (7.5 mg)/TPM (46 mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures, and body composition evaluated by dual-energy x-ray absorptiometry (DXA). Oral glucose tolerance tests were conducted to assess glycemia and mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI), and lipid profiles were measured in the fasting sample.

Results: EQW/DAPA and PHEN/TPM resulted in the most loss of weight and total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI, and IS. Reductions in fasting glucose, testosterone, FAI, and BP were seen with all drugs.

Conclusion: Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.


Polycystic ovary syndrome (PCOS) is one of the most common gynecological disorders, and it arises from multifactorial contributions including genetic, epigenetic, and environmental factors.[1–3] The growing body of evidence linking PCOS to an inherited resistance to insulin action, aggravated by lifestyle problems such as obesity, poor diet, and physical inactivity has led to trials of diabetic therapies in patients with PCOS.[4–6] Currently, a number of antidiabetes medications have been approved that facilitate weight loss and improve the underlying insulin resistance. Glucagon-like peptide-1 (GLP-1) agonists (GLP-1RAs) comprise a novel class of antidiabetic medications with multiple beneficial metabolic effects, including glucose-dependent stimulation of insulin secretion (IS), suppression of postprandial glucagon, inhibition of glucose production, enhanced glucose disposal, and slowing of gastric emptying in patients with type 2 diabetes mellitus (T2DM).[7] In addition to improving glucose tolerance, this class of drugs enhances satiety and weight loss. There are a limited number of studies that have evaluated the effect of GLP-1RAs in individuals without diabetes. In a 160-week study, 2254 prediabetic participants were randomly assigned to receive the GLP-1RA liraglutide vs placebo; liraglutide induced greater weight loss than placebo at week 160 (–6% vs −1.9%) in individuals with prediabetes.[8] Clinical trials of GLP-1RA therapy in the treatment of excess body weight (BW) in women with PCOS showed that both liraglutide and exenatide were effective in weight reduction either as monotherapy or in combination with metformin (MET).[9,10] Elkind-Hirsch et al further demonstrated that exenatide treatment significantly improved first-phase insulin responses to oral glucose administration in obese PCOS women.[10] However, while GLP-1RAs have been associated with moderate weight loss, their use is limited by the need for administration by injection and gastrointestinal side effects.

Another newly approved class of glucose-lowering medications, sodium–glucose cotransporter 2 inhibitors (SGLT2i) afford modest weight loss. These agents can be administered orally and increase glycosuria, which also produces an osmotic diuresis that, in part, contributes to blood pressure (BP) reduction and calorie loss leading to weight loss. These drugs have been shown to be effective when used as monotherapy and as add-on therapy to other diabetes medications.[12] Studies of these agents in the prediabetic population have been quite limited. A 12-week, randomized, controlled trial was performed with dapagliflozin (DAPA) at a dose of 10 mg daily in 24 individuals with metabolic syndrome that demonstrated significant decreases in BW, body mass index (BMI), waist circumference (WC), fasting glucose, and uric acid.[13] In another study of obese adults without diabetes, DAPA plus once-weekly exenatide (EQW) dual therapy produced sustained reductions in BW, prediabetes, and systolic blood pressure (SBP) over 52 weeks.[14] Studies of these drugs in PCOS patients are also limited. In a recent trial there was improvement in anthropometric parameters and body composition in overweight and obese women with PCOS after 12 weeks of treatment with the SGLT2i empagliflozin compared to MET, although no changes were seen in hormonal or metabolic parameters.[15] An advantage of the SGLT2i over existing treatments is the weight loss seen with SGLT2i is similar to that seen with GLP-1RAs, and may be more acceptable because they are oral agents.

In the present study we measured the effects of 24 weeks of treatment with EQW once-weekly and DAPA (dual therapy or each alone), combination DAPA/MET extended release (XR) (DAPA/MET), and phentermine topiramate XR (PHEN/TPM) on metabolic profiles and body composition in obese, nondiabetic women with PCOS. The potential therapeutic effects of EQW/DAPA, EQW, DAPA, and DAPA/MET have never been evaluated in the subpopulation of obese nondiabetic women with PCOS. This is the first report comparing the efficacy of a GLP-1RA and SGLT2i, in combination and alone, SGLT2i plus MET vs a comparator weight loss medication in this patient population.