Semaglutide

Overview

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk. Originally approved for type 2 diabetes management under the brand name Ozempic (2017), it later received FDA approval for chronic weight management as Wegovy (2021). An oral formulation, Rybelsus, is also available for diabetes treatment.

The peptide represents a significant advancement in metabolic therapy, demonstrating unprecedented weight loss results in clinical trials - with participants losing an average of 15-17% of body weight in the STEP trials.

Mechanism of Action

Semaglutide mimics the effects of endogenous GLP-1, a hormone released from the gut after eating:

• Glucose-dependent insulin secretion: Stimulates pancreatic beta cells to release insulin only when blood glucose is elevated
• Glucagon suppression: Reduces glucagon secretion from alpha cells, decreasing hepatic glucose output
• Gastric emptying delay: Slows stomach emptying, prolonging feelings of fullness
• Appetite regulation: Acts on hypothalamic receptors to reduce hunger and increase satiety
• Cardiovascular effects: Demonstrates cardioprotective benefits through mechanisms still being studied

The 94% amino acid homology with native GLP-1, combined with structural modifications (Aib at position 8, C18 fatty acid chain), results in extended half-life and enhanced receptor binding.

Research Summary

Key Clinical Trials

STEP Program (Semaglutide Treatment Effect in People with Obesity)

• STEP 1 (n=1,961): 2.4mg weekly resulted in 14.9% mean weight loss vs 2.4% placebo at 68 weeks
• STEP 2 (n=1,210): Diabetic patients achieved 9.6% weight loss
• STEP 3 (n=611): Combined with intensive behavioral therapy, 16% weight loss achieved
• STEP 4 (n=902): Continuation study showed weight regain upon discontinuation

SUSTAIN Program (Diabetes focus)

• Demonstrated HbA1c reductions of 1.5-1.8% across multiple trials
• SUSTAIN-6 showed 26% reduction in major cardiovascular events

Published Efficacy Data

Pharmacokinetics

Common Protocols

Note: The following represents protocols studied in clinical trials. This is not medical advice.

FDA-Approved Dosing (Wegovy for weight management)

• Week 1-4: 0.25mg once weekly
• Week 5-8: 0.5mg once weekly
• Week 9-12: 1.0mg once weekly
• Week 13-16: 1.7mg once weekly
• Week 17+: 2.4mg once weekly (maintenance)

Diabetes Dosing (Ozempic)

• Start: 0.25mg weekly for 4 weeks
• Increase: 0.5mg weekly
• Maximum: 1mg or 2mg weekly depending on response

The gradual titration is essential for tolerability, allowing the GI system to adapt and minimizing nausea.

Administration

Injection Sites

• Abdomen (preferred, 2+ inches from navel)
• Thigh (front, outer area)
• Upper arm (back, fleshy area)

Injection Guidelines

• Same day each week (can vary by ±2 days)
• Rotate injection sites
• May be administered with or without food
• Room temperature preferred for comfort
• Refrigerate pens at 2-8°C (36-46°F)
• After first use, can store at room temperature (up to 30°C/86°F) for 56 days

Side Effects

Common (>10% incidence)

• Nausea (44%)
• Diarrhea (30%)
• Vomiting (24%)
• Constipation (24%)
• Abdominal pain (20%)

These GI effects typically diminish after 4-8 weeks and are why titration is recommended.

Less Common (1-10%)

• Headache
• Fatigue
• Dizziness
• Dyspepsia
• Injection site reactions

Serious (Rare)

• Pancreatitis (0.3%)
• Gallbladder disease (2.6%)
• Acute kidney injury (rare)
• Hypoglycemia (mainly with sulfonylureas/insulin)

Boxed Warning

• Risk of thyroid C-cell tumors observed in rodents
• Contraindicated in patients with personal/family history of MTC or MEN2

Interactions

Contraindications

• Personal/family history of medullary thyroid carcinoma (MTC)
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
• Known hypersensitivity to semaglutide

Drug Interactions

• Insulin/sulfonylureas: Increased hypoglycemia risk
• Oral medications: Delayed absorption due to slowed gastric emptying
• Levothyroxine: Monitor thyroid function
• Warfarin: Monitor INR more frequently

Precautions

• History of pancreatitis
• Diabetic retinopathy
• Renal impairment
• Hepatic impairment

Community Insights

The following represents aggregated reports from online communities and should not be considered medical advice or verified claims.

Commonly Reported Experiences

• Initial nausea often described as "worst in weeks 2-6"
• Many report significant reduction in food noise/cravings
• "Ozempic face" - some report facial volume loss with significant weight loss
• Sleep improvements reported alongside weight loss
• Alcohol tolerance often significantly reduced

Practical Tips Shared

• Taking dose at bedtime may help manage nausea
• Staying well-hydrated appears important
• Small, frequent meals better tolerated than large meals
• Some report better tolerance with compounded versions

Concerns Discussed

• Weight regain upon discontinuation is common
• Cost and insurance coverage issues
• Long-term effects still being studied

References

1. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. [PMID: 33567185]

2. Davies M, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). Lancet. 2021;397(10278):971-984. [PMID: 33667417]

3. Rubino D, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance (STEP 4). JAMA. 2021;325(14):1414-1425. [PMID: 33755728]

4. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. [PMID: 27633186]

5. FDA Label - Wegovy (semaglutide) injection. Reference ID: 4809616.

6. Novo Nordisk. Ozempic Prescribing Information. 2023.