GLP-1 receptor agonist

**Mechanism/Physiology:** GLP-1 (glucagon-like peptide-1) is an incretin secreted by intestinal L cells (ileum/colon) after meals. It binds the GLP-1 receptor (Gs-coupled GPCR → ↑cAMP) on pancreatic beta cells, enhancing glucose-dependent insulin release (the "incretin effect": oral glucose gives a greater insulin response than IV glucose). Native GLP-1 is degraded within minutes by DPP-4, so agonists are engineered to resist DPP-4 degradation (e.g., albumin binding, fatty-acid acylation, Fc fusion). DPP-4 inhibitors (-gliptins) instead raise endogenous GLP-1 modestly.

**Effects:** - ↑ Glucose-dependent insulin secretion (beta cells) - ↓ Glucagon secretion (alpha cells), in a glucose-dependent manner - ↓ Gastric emptying (can blunt postprandial glucose spikes and the absorption of oral drugs) - ↑ Satiety via hypothalamic and brainstem signaling, causing ↓ appetite and weight loss - ↓ HbA1c about 1-1.5% (or more, depending on agent)

**Agents:** - Exenatide (BID or weekly; derived from Gila monster saliva, exendin-4) - Liraglutide (daily; Victoza for T2DM, Saxenda for obesity) - Dulaglutide, semaglutide (weekly injectable; Ozempic for T2DM, Wegovy for obesity; oral Rybelsus for T2DM) - Lixisenatide - Tirzepatide is a dual GIP/GLP-1 receptor agonist (Mounjaro for T2DM, Zepbound for obesity/OSA) with greater weight loss.

**Clinical uses:** - Type 2 diabetes mellitus, especially with ASCVD, high ASCVD risk, obesity, or CKD - Chronic weight management (obesity, or overweight with comorbidity) - Cardiovascular benefit: liraglutide (LEADER), semaglutide (SUSTAIN-6, SELECT in non-diabetic obesity with CVD) and dulaglutide (REWIND) reduce MACE - Renal benefit: semaglutide reduces CKD progression in T2DM (FLOW) - Additional approved or studied uses include MASLD/MASH and obstructive sleep apnea (tirzepatide). Studies of heart failure with preserved EF and osteoarthritis also show benefit.

**Adverse effects:** - GI (most common): nausea, vomiting, diarrhea, constipation. These are dose-related and attenuate over time, so titrate slowly. Severe vomiting can cause volume depletion and AKI. - Acute pancreatitis (stop the drug if suspected, and do not restart) - Cholelithiasis/cholecystitis (associated with rapid weight loss) - Thyroid C-cell tumor risk (boxed warning, seen in rodents): contraindicated in personal or family history of medullary thyroid carcinoma and in MEN2 - Hypoglycemia, mainly when combined with sulfonylureas or insulin - Diabetic retinopathy complications with rapid glucose lowering (semaglutide, SUSTAIN-6) - Delayed gastric emptying: aspiration risk with anesthesia or sedation (hold per perioperative guidance), and gastroparesis concerns - Injection-site reactions

**Contraindications/cautions:** Personal or family history of MTC, MEN2, history of pancreatitis (caution), severe gastroparesis, and pregnancy (stop before conception; weight-loss agents are contraindicated). They are not indicated in type 1 DM and do not treat DKA.

**Board pearls:** - Benefits are weight loss, low hypoglycemia risk, and cardiovascular protection. Compare with SGLT2 inhibitors (also weight loss, with HF and CKD benefit but genital mycotic infections, euglycemic DKA, and UTIs), sulfonylureas (weight gain, hypoglycemia), and TZDs (weight gain, edema, HF). - A question vignette with a T2DM patient with obesity and established ASCVD points toward a GLP-1 RA or SGLT2 inhibitor. - If a patient on a GLP-1 RA develops severe epigastric pain radiating to the back, think pancreatitis (check lipase). - Mnemonic: "GLP-1 = Gut hormone, Lowers glucose, Promotes satiety."