Semaglutide

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes and chronic weight management. It is a modified version of human GLP-1 with 94% amino acid homology, engineered for extended duration of action through specific structural modifications.

Development and Approval

Semaglutide was developed by Novo Nordisk and represents an advancement over earlier GLP-1 agonists like liraglutide. The compound received FDA approval in 2017 for type 2 diabetes (Ozempic) and in 2021 for chronic weight management (Wegovy).

In 2019, Rybelsus became the first GLP-1 receptor agonist available in oral form, representing a significant advancement in peptide drug delivery.

Chemical Structure

Semaglutide is based on the structure of human GLP-1 (7-37) but incorporates several modifications to extend its half-life:

Key Modifications

• Position 8: Alanine replaced with α-aminoisobutyric acid (Aib) – provides resistance to DPP-4 degradation
• Position 34: Lysine replaced with arginine
• Position 26: Attachment of a C-18 fatty di-acid chain via a glutamic acid spacer – enables albumin binding

These modifications result in a half-life of approximately 7 days, allowing for once-weekly dosing.

Mechanism of Action

Semaglutide works by mimicking the effects of the naturally occurring incretin hormone GLP-1:

Glycemic Effects

• Glucose-dependent insulin secretion: Stimulates insulin release when blood glucose is elevated
• Glucagon suppression: Reduces glucagon secretion in a glucose-dependent manner
• Beta-cell preservation: May help maintain pancreatic beta-cell function

Weight Loss Effects

• Appetite reduction: Acts on hypothalamic GLP-1 receptors to decrease hunger
• Gastric emptying: Slows stomach emptying, promoting satiety
• Food reward: May reduce cravings and food reward signaling

Cardiovascular Effects

Clinical trials have demonstrated cardiovascular benefits independent of glucose control:

• Reduction in major adverse cardiovascular events (MACE)
• Potential improvements in blood pressure
• Beneficial effects on lipid profiles

Clinical Uses

Type 2 Diabetes (Ozempic)

Semaglutide is approved as an adjunct to diet and exercise for glycemic control in adults with type 2 diabetes. Clinical trials demonstrated:

• HbA1c reductions of 1.5-1.8%
• Weight loss of 4-6 kg
• Cardiovascular risk reduction (SUSTAIN-6 trial)

Chronic Weight Management (Wegovy)

At higher doses (2.4 mg weekly), semaglutide is approved for chronic weight management in adults with:

• BMI ≥30 kg/m² (obesity), or
• BMI ≥27 kg/m² (overweight) with weight-related comorbidities

The STEP clinical trial program showed average weight loss of 15-17% of body weight over 68 weeks.

Dosing

For Type 2 Diabetes (Ozempic)

For Weight Management (Wegovy)

Side Effects

Common Side Effects

• Nausea (most common, typically transient)
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Injection site reactions

Serious Considerations

• Pancreatitis: Rare but serious; discontinue if suspected
• Gallbladder disease: Increased risk with rapid weight loss
• Thyroid C-cell tumors: Boxed warning based on rodent studies
• Hypoglycemia: Risk increased when combined with sulfonylureas or insulin

Contraindications

• Personal or family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• History of serious hypersensitivity to semaglutide

Comparison with Other GLP-1 Agonists

Related Compounds

• Tirzepatide – Dual GIP/GLP-1 agonist
• Liraglutide – Earlier GLP-1 agonist
• GLP-1 – Native incretin hormone
• Weight Loss Peptides – Overview category

References

1. Marso SP, et al. "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes." N Engl J Med. 2016.
2. Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." N Engl J Med. 2021.
3. FDA Prescribing Information: Ozempic (semaglutide) injection. Novo Nordisk. 2023.
4. Knudsen LB, Lau J. "The Discovery and Development of Liraglutide and Semaglutide." Front Endocrinol. 2019.