Exenatide, Metformin, or Both for Prediabetes in PCOS: A Randomized, Open-label, Parallel-group Controlled Study

Abstract

Context: Up to 40% of patients with polycystic ovary syndrome (PCOS) have prediabetes; an optimal pharmacotherapy regimen for diabetes prevention in PCOS is yet to be established.

Objective: To evaluate clinical efficacy of exenatide (EX), metformin (MET), or combination (COM) for prediabetes in PCOS.

Design: Randomized, open-label, parallel-group controlled trial.

Setting: Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine.

Patients: PCOS with prediabetes (fasting plasma glucose 5.6-6.9 mmol/L and/or 2 hour post glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]). A total of 150 out of 183 eligible enrollees completed the study.

Intervention: EX (10-20μg daily), MET (1500-2000 mg daily), or COM (EX plus MET) for 12 weeks.

Main outcome measures: Sustained remission rate of prediabetes (primary endpoint, a normal OGTT after 12 weeks of treatment followed by 12 weeks of washout on no drug treatment) along with anthropometric, hormonal, metabolic, and pancreatic β-cell function parameters (secondary endpoints) and potential mechanisms were assessed.

Results: Impaired glucose tolerance was found the dominant prediabetes phenotype. Overall sustained prediabetes remission rate was 50.7%. Remission rate of COM group (64%, 32/50) or EX group (56%, 28/50) was significantly higher than that of the MET group (32%, 16/50) (P = .003 and .027, respectively). EX was associated with superior suppression of 2-hour glucose increment in OGTT. A 2-step hyperglycemic clamp study revealed that EX had led to higher postprandial insulin secretion than MET, potentially explaining the higher remission rate.

Conclusions: Compared with MET monotherapy, EX or COM achieved higher rate of remission of prediabetes among PCOS patients by improving postprandial insulin secretion.

Trial registration: ClinicalTrials.gov NCT03352869.

Keywords: exenatide; metformin; polycystic ovary syndrome; prediabetes.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Study schema (A) and patient flowchart (B). EX, exenatide; MET, metformin.

Figure 2.

(A) Remission rate of patients treated with MET, EX, or COM. (B) Percentage suppression of 2-hour glucose increment by each treatment. Two-hour glucose increments at baseline (before treatment) in each group were set to 100%. (C) The SIOGTT among patients treated with MET, EX, or COM. (D) Serum insulin levels at 2-hour post 75 g of oral glucose in patients treated with MET, EX, or COM.

Figure 3.

(A) Study protocol of the 2-step hyperglycemic clamp study: During step 1 of the study, plasma glucose level was acutely raised and maintained at 12 mmol/L by an initial 50% dextrose bolus followed by 20% glucose infusion. After 90 minutes, 20% glucose was withdrawn, allowing plasma glucose to return to baseline. A 75-g of oral glucose was then administered to induce incretin. Forty minutes later, step 2 of the clamp study was started by 50% dextrose bolus followed by 20% glucose infusion to raise and maintain plasma glucose level at 12mmol/L for another 90 minutes. Plasma insulin concentrations were measured at 2-minute intervals during the first 10 minutes, then at 10 minute intervals during the remaining 80 minutes of each step of the clamp. (B) The average relative insulin concentrations (baseline insulin concentrations at time of zero of clamp study were set to 100) at each time points during the 2-step clamp for both groups. Asterisks indicate time points when insulin concentrations were statistically different between the 2 groups. (C)AUC of phase 1 (0-10 minutes) and phase 2 (10-90 minutes) insulin secretion during the two-step hyperglycemic clamp study. P values of the differences between the 2 groups are indicated.