GLP-1 Receptor Agonists in Obesity Management: Balancing Efficacy and Adverse Effects

GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide (Ozempic, Wegovy), liraglutide (Saxenda), exenatide (Byetta), and dulaglutide (Trulicity), have revolutionized obesity management by promoting satiety, delaying gastric emptying, and facilitating significant weight loss. These agents, originally developed for type 2 diabetes (T2D), are now pivotal in addressing the global obesity epidemic, a key risk factor for diabetes. However, their widespread use necessitates a thorough understanding of associated risks, as detailed in the 2025 meta-analysis, Meta-Analysis of Risks and Adverse Effects of GLP-1 Receptor Agonists (Metaanálisis de los Riesgos y Efectos Adversos de los Agonistas de los Receptores GLP-1).

Key Findings on Adverse Effects

The meta-analysis, encompassing 30 studies (20 randomized controlled trials and 10 observational studies), evaluated GLP-1 RAs in adults with T2D and obesity over short-term (12-24 weeks), medium-term (24-52 weeks), and long-term (>52 weeks) durations. The following adverse effects were quantified:

  • Gastrointestinal (GI) Disturbances: The most common side effects, with nausea affecting 20-40% of patients, vomiting 10-20%, diarrhea 15-30%, and constipation 5-10%. These are dose-dependent and typically transient, though severe cases contribute to treatment discontinuation in some patients.
  • Pancreatitis: Incidence ranges from 1-3%, with a heightened risk compared to placebo, manifesting as severe abdominal pain radiating to the back. This aligns with prior reports linking GLP-1 RAs to pancreatic inflammation.
  • Thyroid Risks: A small increase in medullary thyroid carcinoma risk was noted, particularly with liraglutide and semaglutide, though absolute incidence remains low. This necessitates caution in patients with a family history of thyroid neoplasms.
  • Receptor Desensitization: Long-term use (beyond 12 months) showed evidence of reduced efficacy due to GLP-1 receptor desensitization, a concern for sustained therapeutic benefit.
  • Rebound Effect: Approximately 30% of patients experienced significant weight regain post-discontinuation, alongside potential glycemic dysregulation, highlighting the need for structured withdrawal strategies.
  • Mood Alterations: Rare but serious, depression and suicidal ideation were reported, particularly in patients with pre-existing mental health conditions, underscoring the importance of psychological monitoring.
  • Chronic Inflammation: Data remain inconclusive, with some studies suggesting anti-inflammatory benefits and others showing no significant change in inflammatory markers.

Clinical Implications

For healthcare professionals within the IATPD network, these findings emphasize the dual nature of GLP-1 RAs: potent tools for obesity and diabetes management, yet accompanied by risks that demand careful oversight. The high incidence of GI side effects, while manageable with gradual dose escalation, impacts patient adherence. More severe risks—pancreatitis, thyroid neoplasms, and mood changes—require baseline screening (e.g., pancreatic enzyme levels, thyroid function tests) and ongoing surveillance. The rebound effect and desensitization further complicate long-term use, suggesting a need for adjunctive therapies or periodic treatment breaks to maintain efficacy.

Recommendations for Practice

Drawing from the meta-analysis conclusions, the following strategies can optimize GLP-1 RA use:

  1. Patient Selection: Assess history of pancreatitis, thyroid disease, and mental health disorders before initiation.
  2. Monitoring: Regularly evaluate GI tolerance, pancreatic symptoms, thyroid function, and psychological well-being.
  3. Dose Management: Start with low doses, titrating slowly to minimize GI distress.
  4. Discontinuation Planning: Implement gradual tapering and post-treatment follow-up to reduce rebound weight gain and glycemic shifts.
  5. Research Needs: Further studies are critical to clarify long-term thyroid and pancreatic risks, desensitization mechanisms, and inflammation effects.

Access the Full Analysis

The complete meta-analysis, Meta-Analysis of Risks and Adverse Effects of GLP-1 Receptor Agonists, provides a robust evidence base for refining clinical approaches to GLP-1 RA therapy. It is available for review here: Link to Document.

Call to Action

As the IATPD continues to lead in diabetes prevention and treatment, integrating these insights into practice will enhance patient outcomes. Share your strategies and join the discussion, send us an email ([email protected]).