What is the role of GLP-1 (Glucagon-like peptide-1) receptor agonists in the treatment of Polycystic Ovary Syndrome (PCOS)?

GLP-1 Receptor Agonists in PCOS Treatment

Liraglutide and semaglutide are the preferred GLP-1 receptor agonists for PCOS management, particularly in patients with obesity and metabolic dysfunction, though current evidence remains low to very low quality and these agents should be combined with resistance training to preserve lean body mass. 1

Agent Selection and Efficacy

Longer-acting GLP-1 RAs demonstrate superior clinical benefits compared to shorter-acting formulations:

• Semaglutide produces the greatest weight loss (3.47-6.5 kg), followed by liraglutide (0.3-3.38 kg), while exenatide twice daily shows minimal benefit (+0.3 to -2.96 kg). 1
• Exenatide twice daily does not confer significant benefits over metformin and causes more adverse events, making it a poor choice for PCOS. 1
• Liraglutide at 3 mg dosing optimizes weight loss, though many studies used suboptimal lower doses. 1
• Semaglutide appears most potent but has only one small pilot study in PCOS patients, limiting definitive recommendations. 1, 2

Metabolic and Reproductive Benefits

Weight loss correlates directly with metabolic and reproductive improvements:

• GLP-1 RAs improve insulin sensitivity more effectively than metformin (SMD -0.40,95% CI -0.74 to -0.06). 3
• BMI reduction of -1.65 kg/m² and testosterone reduction of 0.29 nmol/L occur after 3 months of liraglutide treatment. 4
• Combined GLP-1 RA plus metformin therapy produces greater weight loss and more favorable endocrine/metabolic outcomes than monotherapy. 5
• A subset of obese PCOS patients with insulin resistance (HOMA-IR >2) and metabolic syndrome show particularly robust response to liraglutide (BMI decrease 2.13 kg/m² vs 0.62 kg/m² with metformin). 6

Critical Implementation Requirements

Physical activity, specifically resistance training, must accompany GLP-1 RA treatment:

• Liraglutide alone causes greater lean body mass loss than placebo. 1
• When combined with lifestyle interventions including resistance training, lean body mass is preserved. 1, 2
• This combination approach is essential for weight maintenance and optimal outcomes. 2

Adverse Events and Tolerability

All GLP-1 RAs consistently produce more adverse events than controls, including metformin:

• Common gastrointestinal effects include nausea, vomiting, diarrhea, and abdominal pain. 1, 7
• Longer-acting agents (liraglutide, semaglutide) offer improved adherence, glycemic effects, and tolerance compared to exenatide. 1
• For patients with IBS, start semaglutide at 0.25 mg weekly and increase by 0.25 mg every 4 weeks as tolerated. 7
• Monitor for pancreatitis, gallbladder disease, and acute kidney injury. 7

Evidence Quality and Research Gaps

Current recommendations are limited by inadequate trial quality:

• Most studies used 12-week protocols, insufficient to demonstrate changes in hirsutism and fertility outcomes. 1, 2
• Evidence quality is low to very low certainty due to small sample sizes and high risk of bias. 1
• No data exist for adolescents or non-obese PCOS patients. 1, 8
• Urgent need for high-quality, multicenter trials of semaglutide incorporating reproductive, metabolic, and psychological outcomes. 1, 2

Clinical Algorithm

For obese PCOS patients (BMI ≥30 kg/m²):

1. First-line: Combined oral contraceptives remain standard for those not seeking pregnancy. 2
2. For weight management: Consider liraglutide 3 mg or semaglutide (preferred over exenatide).
3. Particularly strong consideration for patients with insulin resistance (HOMA-IR >2), metabolic syndrome, or cardiovascular risk factors. 9, 6
4. Always combine with resistance training program. 1, 2
5. Consider adding metformin for enhanced metabolic benefits. 5

For non-obese PCOS patients:

• Insufficient evidence to recommend GLP-1 RAs as first-line therapy. 8
• If metabolic abnormalities present, liraglutide or semaglutide preferred over exenatide. 8

Common Pitfalls

• Using exenatide twice daily instead of longer-acting agents results in inferior outcomes and more adverse events. 1
• Prescribing GLP-1 RAs without concurrent resistance training leads to excessive lean body mass loss. 1
• Using suboptimal liraglutide doses (<3 mg) reduces efficacy. 1
• Expecting meaningful clinical benefits from short 12-week treatment courses. 1, 2