Mechanism of Action of Semaglutide (Ozempic/Wegovy)

Introduction

Semaglutide (Ozempic for diabetes; Wegovy for obesity) is a GLP‑1 receptor agonist used for type 2 diabetes mellitus management and chronic weight loss. It mimics the incretin hormone glucagon‑like peptide‑1 (GLP‑1), leading to improved glycemic control, reduced appetite, delayed gastric emptying, and favorable effects on cardiovascular risk.

---

Step-by-Step Mechanism of Action

1. GLP‑1 receptor activation
   Semaglutide binds to GLP‑1 receptors on pancreatic β‑cells and brain centers, mimicking endogenous GLP‑1.
2. Glucose-dependent insulin secretion
   Receptor activation increases cAMP in β‑cells, enhancing insulin release when blood glucose is elevated.
3. Glucagon suppression
   It inhibits glucagon secretion from α‑cells, reducing hepatic glucose production.
4. Delayed gastric emptying
   Acting on GLP‑1 receptors in the gut and brain delays gastric emptying, prolonging satiety and reducing postprandial glucose spikes.
5. Appetite reduction and weight loss
   Central effects on the hypothalamus and brain stem decrease appetite and caloric intake, promoting weight loss.
6. Potential cardiovascular benefits
   GLP‑1 receptor effects on endothelial and cardiac tissues may improve vascular health and reduce risk of major cardiovascular events.

---

---

Pharmacokinetic Parameters

Parameter	Value
Route	Subcutaneous injection, weekly (Ozempic) or weekly/higher doses for Wegovy
Bioavailability	~80–90%
Time to Peak (Tmax)	~1–3 days
Half-life	~7 days
Metabolism	Proteolytic degradation; no CYP involvement
Excretion	Urine (~3%), feces (~5%), remainder via metabolism

---

Clinical Uses

• Primary treatment of type 2 diabetes mellitus to reduce HbA₁c
• Chronic weight management in obesity or overweight individuals with risk factors
• Reduces risk of major adverse cardiovascular events in high-risk diabetic patients

---

Adverse Effects

• Common: nausea, diarrhea, constipation, vomiting
• Less common: injection-site reactions, headache, dizziness
• Rare risk: pancreatitis; monitor for gallbladder disease
• Caution: use in patients with a history of medullary thyroid carcinoma or MEN2

---

Comparative Analysis

Agent	Receptor Target	HbA₁c Reduction	Weight Loss	Administration Frequency
Semaglutide	GLP‑1 agonist	1.5–2.3%	10–17%	Weekly injection
Liraglutide	GLP‑1 agonist	~1.0–1.5%	~7–10%	Daily injection
Exenatide	GLP‑1 agonist	~0.8–1.1%	~3–5%	Twice daily or weekly

---

MCQs (15)

1. Semaglutide primarily acts on which receptor?
   a) GIP receptor b) GLP‑1 receptor c) Insulin receptor d) DPP‑4 receptor
   Answer: b) GLP‑1 receptor
2. It enhances insulin secretion in a _____ manner.
   a) Glucose-dependent b) Constant c) Glucose-independent d) Time-dependent
   Answer: a) Glucose-dependent
3. It suppresses which hormone?
   a) Somatostatin b) Glucagon c) Ghrelin d) Cortisol
   Answer: b) Glucagon
4. Typical onset of gastric emptying delay is:
   a) Within minutes b) Within hours c) After weeks d) No effect
   Answer: b) Within hours
5. Semaglutide injection frequency is:
   a) Daily b) Weekly c) Monthly d) As-needed
   Answer: b) Weekly
6. A rare but serious adverse effect to monitor is:
   a) Hypoglycemia b) Pancreatitis c) Hyperthyroidism d) Nephrolithiasis
   Answer: b) Pancreatitis
7. It is contraindicated in patients with:
   a) Type 1 diabetes b) Medullary thyroid carcinoma c) Obesity d) Hypertension
   Answer: b) Medullary thyroid carcinoma
8. Compared to exenatide, semaglutide yields:
   a) Less weight loss b) More weight loss c) Higher injection frequency d) Less HbA₁c reduction
   Answer: b) More weight loss
9. Half-life of semaglutide is approximately:
   a) 24 hours b) 3 days c) 7 days d) 15 days
   Answer: c) 7 days
10. Excretion involves:
    a) High renal elimination b) Only feces c) Metabolism and minimal excretion d) Biliary excretion
    Answer: c) Metabolism and minimal excretion
11. An added cardiovascular benefit was shown in:
    a) SUSTAIN trials b) DPP‑4 studies c) RAAS inhibitor trials d) REM sleep studies
    Answer: a) SUSTAIN trials
12. Weight loss percentage ranges from:
    a) 1–5% b) 5–10% c) 10–17% d) 20–25%
    Answer: c) 10–17%
13. A significant GI side effect is:
    a) Increased appetite b) Nausea c) Insomnia d) Hypertension
    Answer: b) Nausea
14. Semaglutide metabolism involves:
    a) CYP3A4 b) Proteolysis c) Renal enzymes only d) Conjugation
    Answer: b) Proteolysis
15. An advantage over liraglutide is:
    a) Lower efficacy b) Higher weight loss c) Daily dosing d) Less frequent injection
    Answer: d) Less frequent injection

---

FAQs

1. Does semaglutide cause weight loss in non-diabetic patients?
   Yes—it’s approved for chronic weight management under Wegovy, showing 10–17% loss.
2. How soon does glycemic control improve?
   HbA₁c reduction is often seen within 4–8 weeks.
3. Can semaglutide be combined with insulin?
   Yes—with adjustment; monitor for hypoglycemia.
4. Is cardiovascular benefit proven?
   Yes—major trials showed reductions in cardiovascular events in diabetic patients.
5. Does semaglutide need dose titration?
   Yes—gradual dose escalation helps improve tolerance, especially GI.

---

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• DrugBank: Semaglutide pharmacology summary
• StatPearls: Semaglutide in diabetes and obesity
• PubMed: SUSTAIN trials glycemic and cardiovascular outcomes
• PubMed: Wegovy weight loss evidence

---