PUPC Conference Coverage

Navigating the Expanding Benefits and Long-Term Side Effects of GLP-1 Receptor Agonists

Anthony Calabro, MA

Key Highlights

  • GLP-1 receptor agonists (RAs) demonstrate durable benefits in weight loss, glycemic control, and cardiometabolic outcomes.
  • Gastrointestinal (GI) side effects are the most common long-term adverse events and can be managed with targeted strategies.
  • Evolving guidance suggests careful consideration for holding GLP-1 RAs before procedures due to slowed gastric emptying.
  • GLP-1 RAs show promise in secondary indications such as addiction treatment, sleep apnea, and metabolic dysfunction-associated steatohepatitis (MASH).

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) continue to gain prominence in the management of type 2 diabetes and obesity due to their favorable long-term efficacy and emerging ancillary benefits. In her Practical Updates in Primary Care presentation1, Leigh Perreault, MD highlights the persistent GI side effects, recent guidance on peri-procedural management, and evidence supporting their broader therapeutic potential, including cardiovascular benefit and organ protection.

Dr Perreault detailed the established safety profile of GLP-1 RAs, which includes more than 2 decades of use. Given rising clinical adoption and expanded indications, understanding the long-term tolerability and systemic effects of these agents is critical.

Gastrointestinal side effects—particularly nausea, vomiting, and diarrhea—were found to persist in a subset of patients. Although bothersome, these can be effectively managed with dose adjustments and patient education strategies.

“There is also guidance in terms of managing the side effects, specifically the three E’s: educate, explain, and escalate to an appropriate dose,” Dr Perreault said in her PUPC presentation.

Clinicians should educate their patients about the potential for mild to moderate GI side effects, as well as explain to them that they should be mindful to avoid eating when they are not hungry. Dr Perreault also noted that dose escalation is primarily for patient tolerability. While dosages generally increase after 4 weeks, in clinical practice, a discussion between the clinician and the patient should take place before any escalations occur, Dr Perreault explained.

Dr Perreault reviewed several studies, which showed the potential advantages of GLP-1 RAs include cardiometabolic improvements, with substantial reductions in major adverse cardiovascular events (MACE) reported in patients with type 2 diabetes (T2D). For example, she noted a study by Lincoff and colleagues2, which demonstrated cardiovascular protection in patients with obesity as well, even in the absence of diabetes. Additionally, GLP-1 RAs have been shown to prevent kidney function decline, reduce hospitalizations for heart failure, and improve sleep apnea indices. Emerging evidence suggests possible roles in treating addictions and reducing MASH activity, with Dr Perreault noting that Loomba and colleagues3 showed favorable liver-related outcomes. Finally, Dr Perreault cited diabetes prevention data from Jastreboff and colleagues4, which indicated a 93% risk reduction in high-risk individuals.

Of note, GLP-1 RAs are associated with slowed gastric emptying, prompting revised pre-procedure recommendations by anesthesiology societies. This has led to evolving guidance on when to hold therapy before surgery. Although suicidal ideation has surfaced in isolated reports, robust studies have not confirmed a causal link.

“The first GLP-1 RA (exenatide) was approved 20 years ago, and post-marketing surveillance has not revealed new warnings,” Dr Perreault concluded. “And regarding the GI side effects, which are by far the most common long-term side effects, there are tips and tricks to manage this. So remember, explain, educate, and then dose escalate accordingly.”

Reference
1. Perreault L. Digging Deeper Series: Accessibility to GLP-1 Drugs and Long-Term Side Effects. Presented at Practical Updates in Primary Care. May 7, 2025.
2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
3. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024;391(4):299-310. doi:10.1056/NEJMoa2401943
4. Jastreboff AM, le Roux CW, Stefanski A, et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. N Engl J Med. 2025;392(10):958-971. doi:10.1056/NEJMoa2410819