Semaglutide

In simple words

Semaglutide is a copy of a natural satiety hormone made in the gut. It is studied for weight loss and heart protection; in large studies, people lost about 15% of their body weight.

What this molecule is

29 amino acids, a GLP-1 analog with an Aib8 substitution and a C18 fatty acid. 94% homology with native GLP-1. ~4114 Da.

Why it is studied

Semaglutide is the gold standard of drug treatment for obesity. STEP 1 (n=1961): −15% over 68 weeks. SELECT (n=17 604): −20% CVD risk. Oral form (OASIS 4, NEJM 2025): 25 mg/day ≈ injections.

How it works

GLP-1R agonist on pancreatic β-cells (↑insulin, ↓glucagon), in the hypothalamus (↓appetite via the ARC), and in the brainstem (↓nausea). Slows gastric emptying. Long action through albumin binding. Neuroprotection via GLP-1R in the hippocampus.

Doses used in studies

Studies used the SEMAPLUS titration schedule: weeks 1–4 — 0.25 mg/week; weeks 5–8 — 0.5 mg; weeks 9–12 — 1.0 mg; weeks 13–20 — 1.7 mg; weeks 21+ — 2.4 mg (if tolerated). Administration once weekly SC (abdomen/thigh/arm).

Combined with in studies

• Metformin — insulin resistance
• Tirzepatide — at a plateau — switch, not combine
• MOTS-c — mitochondrial priming
• GHK-Cu — skin during weight loss

Level of evidence

Level A Human clinical trials. There are randomized controlled trials (RCTs), or the compound has been approved by a regulatory agency. The most reliable level. FDA-approved (Wegovy 2021, Ozempic 2017). 7 years of safety data.

Important to know

Honest caveat: Contraindicated with a history of medullary thyroid cancer. Nausea 40%, vomiting 24%. Pancreatitis is rare but requires amylase/lipase monitoring. After discontinuation, 60% of the weight returns within 1 year (STEP 4).

Studies in PubMed

1. Once-Weekly Semaglutide in Adults with Overweight or Obesity. (N Engl J Med, 2021)
2. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. (N Engl J Med, 2023)
3. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. (JAMA, 2021)
4. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. (Nat Med, 2024)
5. Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. (N Engl J Med, 2025)