The most rigorously trialled compound in the peptide space. Multiple large phase 3 randomized trials with cardiovascular outcome data.
Semaglutide is a long-acting copy of GLP-1, a hormone the gut releases after eating. It tells the pancreas to release insulin when blood sugar is high, slows how fast the stomach empties, and acts on appetite centres in the brain. The practical result is lower blood sugar and a strong reduction in how much food a person wants to eat. It was engineered to survive in the bloodstream for about a week, which is why it is dosed weekly rather than daily.
Semaglutide is a 31-amino-acid GLP-1 analogue with 94% sequence homology to native human GLP-1(7-37). Three modifications extend its half-life: Ala8 to Aib8 substitution confers resistance to dipeptidyl peptidase-4 (DPP-4) cleavage; Lys34 to Arg34 prevents mis-acylation; and a C18 fatty diacid is attached to Lys26 via a gamma-glutamyl/OEG spacer, producing high-affinity reversible albumin binding that reduces renal clearance. Agonism at the class B GPCR GLP-1R drives Gs-coupled adenylate cyclase activation, raising cAMP and activating PKA and Epac2 in pancreatic beta cells. This potentiates glucose-dependent insulin secretion, suppresses glucagon from alpha cells, and delays gastric emptying via vagal afferents. Central anorectic effects are mediated through GLP-1R populations in the hypothalamic arcuate nucleus and area postrema, which lie outside the blood-brain barrier.
Research areas
Community-specified data
Source note: Bump by 5 units / 2x/week. Start at intro dose 4 weeks. If nausea, split into 3rds 3x/week
Not medical guidance. These third-party figures have not been independently verified, clinically reviewed, or endorsed by DB Peptide. They may be inaccurate or unsafe and should not replace product labelling or advice from a qualified clinician.
Every protocol below is reproduced from a published study or approved labelling, with its source named. These are records of what was studied — not recommendations, and not a suggestion that any of them is appropriate for any person.
| Protocol as reported | Source |
|---|---|
| 0.25 mg weekly for 4 weeks, escalating in 4-week steps to a 2.4 mg weekly maintenance doseThe escalation schedule exists to limit gastrointestinal adverse events, which were the most common reason for discontinuation in trials. | STEP 1 trial protocol (Wilding et al., NEJM 2021) |
| 0.5 mg or 1.0 mg weekly maintenance in type 2 diabetes | SUSTAIN-6 trial protocol (Marso et al., NEJM 2016) |
| 2.4 mg weekly maintenance for cardiovascular risk reduction | SELECT trial protocol (Lincoff et al., NEJM 2023) |
Approved. Phase 3 complete across SUSTAIN, STEP and SELECT programmes; cardiovascular outcome trials reported.
3,297 patients with type 2 diabetes at high cardiovascular risk. Primary composite cardiovascular endpoint occurred in 6.6% on semaglutide vs 8.9% on placebo.
1,961 adults with overweight or obesity without diabetes. Mean body weight change of -14.9% vs -2.4% for placebo at week 68.
17,604 patients with established cardiovascular disease and overweight/obesity but without diabetes. 20% relative reduction in major adverse cardiovascular events over a mean 39.8 months.
Grade A requires multiple adequately powered randomized controlled trials in humans with consistent results. Semaglutide has three separate phase 3 programmes — SUSTAIN, STEP and SELECT — covering more than 25,000 randomized participants, plus reported cardiovascular outcome data.
Semaglutide is a single-receptor agonist acting only at GLP-1R. Tirzepatide is a dual agonist at both GIP and GLP-1 receptors. In the SURMOUNT-1 and SURPASS-2 trials, tirzepatide produced larger mean weight reductions, though the compounds have not been compared across every endpoint.
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6)
Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1)
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)
Discovery of the Once-Weekly Glucagon-Like Peptide-1 Analog Semaglutide
Medical disclaimer
This page is for informational and research purposes only. Nothing here constitutes medical advice. The compounds discussed are research chemicals. Consult a qualified clinician before starting any protocol.
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