Semaglutide is a GLP-1 receptor agonist developed by Novo Nordisk. It is FDA-approved as Ozempic (for type 2 diabetes) and Wegovy (for chronic weight management). Semaglutide is a modified analog of human GLP-1 with 94% structural homology, engineered with a fatty acid chain that binds to albumin, extending its half-life to support once-weekly dosing. In the STEP clinical trial program, semaglutide 2.4 mg weekly produced average weight loss of approximately 15-17% of body weight. While surpassed by tirzepatide in head-to-head trials, semaglutide remains a highly effective and well-established weight loss peptide with an extensive safety record.
Notes
Semaglutide has the most extensive clinical evidence of any GLP-1 agonist for weight loss. The SELECT cardiovascular outcomes trial demonstrated a 20% reduction in MACE events, making it the first obesity treatment to show cardiovascular benefit. Compounded semaglutide is available while branded supply shortages persist.
Semaglutide is a potent and selective GLP-1 receptor agonist. It mimics endogenous GLP-1, a gut-derived incretin hormone that: (1) stimulates glucose-dependent insulin secretion from pancreatic beta cells, (2) suppresses glucagon secretion, (3) slows gastric emptying, and (4) acts on hypothalamic appetite centers to reduce hunger and increase satiety. The appetite suppression is mediated through direct action on GLP-1 receptors in the arcuate nucleus and other hypothalamic regions, fundamentally reducing "food noise" and cravings.
Semaglutide is modified with a C18 fatty di-acid chain at position 26 (Lys) and an amino acid substitution at position 8 (Aib for Ala) and position 34 (Arg for Lys), conferring albumin binding and DPP-4 resistance. Subcutaneous bioavailability is approximately 89%. Peak plasma concentration occurs at 1-3 days post-injection. The 7-day half-life supports weekly dosing. Steady state is reached after 4-5 weeks. Metabolism is through proteolysis; not dependent on CYP enzymes. Elimination is renal and fecal.
Typical Dose
Subcutaneous: Start at 0.25 mg weekly for 4 weeks, then 0.5 mg for 4 weeks, then 1 mg for 4 weeks, then 1.7 mg for 4 weeks, and finally 2.4 mg weekly (Wegovy dosing schedule). For diabetes (Ozempic): maximum is 2 mg weekly. Compounded versions may use custom titration.
Frequency
Once weekly, on the same day each week.
Administration
Subcutaneous injection in the abdomen, thigh, or upper arm. Rotate injection sites. An oral formulation (Rybelsus) also exists but has much lower bioavailability and requires specific administration conditions.
Half-Life
7 days (approximately 168 hours)
Contraindications
No PCT required. Semaglutide does not affect the HPTA or sex hormone production. For weight maintenance, a gradual taper or long-term maintenance dose is recommended, as weight regain is common (approximately two-thirds of lost weight within one year of discontinuation in clinical trials).