The foundation of GLP-1RAs began in the 1980s when Jean-Pierre Raufman studied Gila monster venom and discovered its pancreatic effects. In 1992, John Eng isolated exendin-4, a stable GLP-1-like peptide in the venom, and patented it after his employer declined interest. Amylin Pharmaceuticals synthesized exenatide (Byetta) from exendin-4, which gained FDA approval in 2005 as the first GLP-1RA. This breakthrough spurred further innovations, including Novo Nordisk’s liraglutide (fatty-acid-modified for prolonged action) and semaglutide (weekly dosing). Research into GLP-1’s insulin-stimulating fragment (GLP-1) by Svetlana Mojsov and others in the 1980s laid the groundwork for understanding its therapeutic potential. 

1. Type 2 Diabetes

First-line therapy for managing hyperglycemia, especially in patients with atherosclerotic cardiovascular disease (ASCVD), heart failure, or obesity.

2. Obesity

Approved for chronic weight management in adults with BMI ≥30 or ≥27 with comorbidities (e.g., hypertension).

3. Cardiovascular Disease

Reduce major adverse cardiovascular events (e.g., heart attack, stroke) in high-risk patients. Recent FDA approvals include Wegovy (semaglutide) for cardiovascular risk reduction in overweight/obese individuals.

4. Obstructive Sleep Apnea

Zepbound (tirzepatide) recently approved for moderate-severe cases in adults with obesity.

5. Non-Alcoholic Fatty Liver Disease (NAFLD)

Improve liver fat, inflammation, and fibrosis; semaglutide in Phase III trials for NASH.

6. Polycystic Ovary Syndrome (PCOS)

Off-label use to improve insulin sensitivity, hyperandrogenism, and menstrual irregularities 

• Gastrointestinal: Nausea (up to 50% of users), vomiting, diarrhea, constipation, bloating, and stomach pain. These symptoms are often dose-dependent and typically improve over time.

 • Other: Injection site reactions, headache, fatigue, dizziness, and nasopharyngitis.

Serious Risks

 • Pancreatitis: Linked to a ninefold higher risk compared to older weight-loss drugs, though absolute risk remains low (<1% per year).

 • Gastroparesis: Delayed stomach emptying, increasing aspiration risk during anesthesia.

 • Bowel obstruction: Reported with higher relative risk (fourfold increase).

 • Gallbladder issues: Inflammation or stones, particularly with rapid weight loss.

 • Kidney injury: Often secondary to dehydration from vomiting/diarrhea.

 • Thyroid tumors: Boxed FDA warning for thyroid C-cell tumors (preclinical rodent data; human risk unclear). 

• Renal impairment: Avoid exenatide in severe cases (creatinine clearance <30 mL/min); monitor hydration in others.

 • Hypoglycemia: High risk when combined with sulfonylureas/insulin; monitor blood glucose closely.

 • Pancreatitis: Discontinue if severe abdominal pain occurs.

 • Surgery: Stop 3–7 days before anesthesia to reduce aspiration risk.

 • Hydration: Ensure adequate fluid intake to prevent dehydration from GI side effects.

 • Gallbladder disease: Monitor for symptoms (e.g., jaundice, upper abdominal pain). 

www.pnas.org/doi/10.1073/pnas.2415550121 

www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00155/full  

www.ilmeridian.com/newsroom/glp-1-agonists.html?utm_ 

www.goodrx.com/classes/glp-1-agonists/glp-1-side-effects?utm_ 

www.hcplive.com/view/four-facts-remember-prescribing-glp-1-agonist?utm_ 

www.ncbi.nlm.nih.gov/books/NBK551568/ 

https://www.nature.com/articles/s41392-024-01931-z

myendoconsult.com/learn/mechanism-of-action-of-glp-1-agonists/