GLP-1 receptor agonists

**Mechanism:** GLP-1 is an incretin secreted by intestinal L cells (ileum/colon) after meals. Native GLP-1 is degraded within minutes by DPP-4. GLP-1 RAs are DPP-4-resistant analogs (or exendin-4 derivatives) that bind the GLP-1 receptor (a Gs-coupled GPCR, which raises cAMP) on: - Pancreatic beta cells: increase glucose-dependent insulin release. Hypoglycemia risk is low as monotherapy. - Pancreatic alpha cells: decrease glucagon. - Stomach: slow gastric emptying. - Hypothalamus/brainstem: increase satiety and decrease appetite, leading to weight loss. - Other effects: possible beta-cell preservation in animal models, and cardiovascular and renal benefits.

**Agents:** - Exenatide: derived from Gila monster (Heloderma suspectum) saliva exendin-4. Given BID or weekly (ER). - Liraglutide: daily. Brand names: Victoza (T2DM), Saxenda (obesity). - Semaglutide: weekly SC (Ozempic for T2DM, Wegovy for obesity), also oral (Rybelsus). - Dulaglutide: weekly. - Tirzepatide: dual GIP/GLP-1 agonist, weekly (Mounjaro, Zepbound). It produces greater weight loss and HbA1c reduction.

**Clinical uses:** - T2DM: HbA1c reduction of about 1–1.5% or more, often combined with metformin. - Obesity/overweight with comorbidities. - ASCVD risk reduction: liraglutide (LEADER), semaglutide (SUSTAIN-6, SELECT) and dulaglutide (REWIND) reduce MACE. Preferred in T2DM with established ASCVD or high risk, and in T2DM with CKD (semaglutide, FLOW trial). - Newer indications include MASLD/MASH (semaglutide), and tirzepatide for obstructive sleep apnea.

**Adverse effects:** - GI (most common): nausea, vomiting, diarrhea. Usually transient and dose-dependent, so titrate slowly. - Acute pancreatitis: avoid or discontinue if suspected. - Cholelithiasis/cholecystitis, especially with rapid weight loss. - Thyroid C-cell tumors in rodents (boxed warning): contraindicated in personal/family history of medullary thyroid carcinoma or MEN2. - Acute kidney injury, mainly from volume depletion due to vomiting/diarrhea. - Diabetic retinopathy complications with rapid glucose lowering (semaglutide, SUSTAIN-6). - Delayed gastric emptying: aspiration risk with anesthesia/sedation, and caution in gastroparesis. - Hypoglycemia, mainly when combined with insulin or sulfonylureas. - No significant weight gain, unlike insulin, sulfonylureas, and TZDs.

**Comparison with DPP-4 inhibitors (-gliptins):** DPP-4 inhibitors raise endogenous GLP-1 levels modestly. They are weight-neutral, oral, and less potent, and they have no proven cardiovascular benefit. Both classes carry a pancreatitis risk.

**Exam pearls:** - Incretin effect: oral glucose triggers more insulin release than IV glucose because of GLP-1 and GIP. - GLP-1 RA plus T2DM plus obesity or ASCVD is a classic best-next-step answer. - Classic contraindication vignette: MEN2 or medullary thyroid cancer (elevated calcitonin). - SGLT2 inhibitors are the other class with cardiorenal benefit, especially in HF and CKD. Their adverse effects are genital mycotic infections, UTI, euglycemic DKA, and Fournier gangrene.