Semaglutide (Ozempic / Wegovy / Rybelsus)

Semaglutide is a 31-amino-acid synthetic GLP-1 receptor agonist with 94% sequence homology to human GLP-1. Its CAS number is 910463-68-2, and its molecular weight is 4,113.64 Da. Developed by Novo Nordisk, it has become the most prescribed weight loss medication in history and holds the distinction of being the first obesity drug proven to reduce cardiovascular events. The molecule's design solves the core problem with native GLP-1: it is degraded within minutes by DPP-4 enzymes. Semaglutide achieves a 7-day half-life through two modifications. First, an alpha-aminoisobutyric acid (Aib) substitution at position 8 makes it resistant to DPP-4 cleavage. Second, a C-18 fatty diacid chain attached to Lys26 via a linker enables binding to serum albumin, sharply reducing renal clearance. The result is a once-weekly injection that maintains therapeutic levels continuously. The STEP trial program established semaglutide's efficacy for weight management. STEP 1 (NEJM 2021, PMID: 33567185) enrolled 1,961 adults with obesity and showed 14.9% mean weight loss at 68 weeks versus 2.4% on placebo. STEP 5 (Nature Medicine 2022, PMID: 36216945) demonstrated that this weight loss was sustained through 104 weeks. The more recent STEP UP trial led to FDA approval of Wegovy HD (7.2 mg) in March 2026, achieving approximately 21% weight loss. The SELECT trial (NEJM 2023, PMID: 37952131) was the big one: 17,604 participants with established cardiovascular disease and overweight/obesity but without diabetes received semaglutide 2.4 mg or placebo. Semaglutide reduced major adverse cardiovascular events by 20% (HR 0.80, P<0.001). This led to FDA approval of the MACE risk reduction indication for Wegovy, making it the first and only weight loss medication with a proven cardiovascular benefit. Semaglutide is available in multiple formulations. Ozempic (injectable, for T2D) was approved December 2017. Rybelsus (oral tablets, for T2D) was approved September 2019 as the first oral GLP-1 agonist, using a SNAC absorption enhancer to achieve approximately 1% oral bioavailability. Wegovy (injectable, for weight management) was approved June 2021. Wegovy HD (7.2 mg) was approved March 2026, and oral Wegovy tablets (25 mg) were approved December 2025. The compounding landscape has changed a lot. Semaglutide was removed from the FDA drug shortage list in February 2025, ending the broad compounding latitude that had existed during the shortage. Compounding remains legal under 503A and 503B pathways with documented medical necessity, but the shortage-based justification is gone. Novo Nordisk has pursued litigation against some compounders, and the FDA has issued warning letters. Meanwhile, Novo Nordisk launched a direct-to-patient self-pay program at $199-349/month, narrowing the gap with compounded pricing. Side effects are predominantly gastrointestinal and dose-dependent: nausea (20-44%), diarrhea (10-30%), vomiting (5-25%), and constipation (10-24%). These typically improve during the first weeks at each dose level. Serious warnings include a boxed warning for thyroid C-cell tumors (observed in rodents, unknown human relevance), pancreatitis, gallbladder disease, and acute kidney injury secondary to dehydration. Patients scheduled for surgery should discuss discontinuation timing with their provider due to delayed gastric emptying and aspiration risk.