Semaglutide | Peptide Research Hub

At a Glance

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk. It is FDA-approved under multiple brand names:

Ozempic (injectable, for type 2 diabetes)
Wegovy (injectable, for weight management)
Rybelsus (oral, for type 2 diabetes)

Semaglutide is one of the most extensively studied GLP-1 agonists, with large cardiovascular outcomes trials and real-world evidence.

⚠️ Prescription Medication: Semaglutide is an FDA-approved prescription drug. This dossier summarizes published research and is not a substitute for medical consultation.

Mechanism of Action

Semaglutide mimics the endogenous GLP-1 hormone with modifications for extended half-life (~7 days):

Appetite Suppression: Acts on hypothalamic GLP-1 receptors to reduce hunger and increase satiety
Gastric Emptying: Slows stomach emptying, promoting prolonged fullness
Insulin Secretion: Enhances glucose-dependent insulin release from pancreatic β-cells
Glucagon Suppression: Reduces glucagon secretion in a glucose-dependent manner

Structural Note: Semaglutide has 94% homology to native GLP-1 with key amino acid substitutions and a fatty acid side chain for albumin binding.

Evidence Summary

Weight Loss (STEP Trials)

High Confidence RCT ≤3 Years

The STEP (Semaglutide Treatment Effect in People with obesity) program included multiple Phase 3 trials:

STEP 1 (N=1,961):

Arm	Mean Weight Loss at 68 Weeks
Semaglutide 2.4 mg	-14.9%
Placebo	-2.4%

86% achieved ≥5% weight loss
69% achieved ≥10% weight loss
50% achieved ≥15% weight loss

Limitations: Industry-sponsored; lifestyle intervention in both arms; predominantly female (74%); high dropout in some studies.

[PMID: 33567185]

Type 2 Diabetes (SUSTAIN Trials)

High Confidence RCT 3-10 Years

The SUSTAIN program demonstrated:

HbA1c reductions of 1.5–1.8% vs. placebo
Superior to sitagliptin, exenatide, and insulin glargine in head-to-head trials
Durable glycemic control through 2 years

Cardiovascular Outcomes (SELECT Trial)

High Confidence RCT ≤3 Years

The SELECT trial (N=17,604) in patients with obesity and established CVD showed:

20% reduction in major adverse cardiovascular events (MACE)
Statistically significant reduction in CV death, non-fatal MI, and stroke
Benefits independent of diabetes status

[PMID: 37952131]

Safety & Unknowns

Common Adverse Events

Event	Incidence
Nausea	20–44%
Vomiting	15–25%
Diarrhea	15–30%
Constipation	10–20%
Abdominal pain	10–15%

GI effects typically peak during dose escalation and improve over time
Dose titration protocols reduce discontinuation rates

Warnings & Precautions

Thyroid C-cell tumors: Boxed warning based on rodent studies; contraindicated in personal/family history of MTC or MEN2
Pancreatitis: Rare but reported; discontinue if suspected
Gallbladder disease: Increased risk of cholelithiasis
Hypoglycemia: Risk when combined with insulin or sulfonylureas
Retinopathy complications: Reported in diabetic patients with rapid glycemic improvement

Regulatory Status

Region	Status
FDA	Approved (Ozempic 2017, Wegovy 2021)
EMA	Approved
WADA	Not prohibited

Key Studies

Year	Trial	Finding
2021	STEP 1	14.9% weight loss at 68 weeks
2023	SELECT	20% reduction in MACE
2017	SUSTAIN-6	CV safety established

Primary sources: [PMID: 33567185] [PMID: 37952131] [PMID: 27633186]

Tirzepatide: Dual GIP/GLP-1 agonist with greater weight loss
Liraglutide (Victoza/Saxenda): Earlier GLP-1 agonist, daily injection
Retatrutide: Triple agonist (investigational)

Changelog

Date	Change
2026-01-21	Initial dossier created