Mechanism of Action of Semaglutide

Introduction

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) used for type 2 diabetes mellitus (T2DM) management and chronic weight management. It mimics endogenous GLP‑1 to improve glycemic control and promote weight loss through central appetite suppression and delayed gastric emptying.

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Step-by-Step Mechanism of Action

1. Activation of GLP‑1 receptors
   Semaglutide binds to GLP-1 receptors on pancreatic β-cells, α-cells, brain satiety centers, and gastrointestinal tissue.
2. Glucose-dependent insulin secretion
   It enhances insulin release from β-cells when blood glucose is elevated.
3. Suppressed glucagon secretion
   By binding receptors on α-cells, it inhibits glucagon release during hyperglycemia.
4. Delayed gastric emptying
   Slows gastric motility, reduces postprandial glucose spikes, and promotes early satiety.
5. Appetite suppression and weight loss
   Activates satiety centers in the hypothalamus, leading to reduced caloric intake and weight loss.
6. Cardiovascular and renal benefits
   Improves endothelial function, reduces inflammation, and decreases albuminuria—contributing to cardiovascular and renal protection.

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Pharmacokinetic Parameters

Parameter	Value
Route	Subcutaneous weekly injection
Bioavailability	~89%
Time to Peak (Tmax)	1–3 days
Protein Binding	>94%
Metabolism	Proteolysis; minimal CYP involvement
Half-life	~165–184 hours (7 days)
Excretion	Metabolites excreted in urine and feces

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Clinical Uses

• Glycemic control in type 2 diabetes
• Chronic weight management in obesity and overweight (with risk comorbidities)

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Adverse Effects

• Gastrointestinal: nausea, vomiting, diarrhea, constipation
• Risk of pancreatitis (rare)
• Possible gallbladder disease (e.g., cholelithiasis)
• Mild injection-site reactions
• Contraindicated in individuals with personal or family history of medullary thyroid carcinoma or MEN2

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Comparative Analysis

Agent	Receptor Duration	Dosing Interval	Weight Effect
Semaglutide	Long-acting	Weekly injection	Significant weight loss
Liraglutide	Short-acting	Daily injection	Moderate weight loss
Dulaglutide	Long-acting	Weekly injection	Moderate weight loss

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MCQs

1. Semaglutide activates which receptor?
   a) DPP‑4 b) GLP‑1 c) GIP d) SGLT2
   Answer: b) GLP‑1
2. Primary effect on β-cells is:
   a) Glucose-independent insulin release
   b) Glucose-dependent insulin release
   c) Increased glucagon release
   d) Reduced insulin synthesis
   Answer: b) Glucose-dependent insulin release
3. It delays:
   a) Gastric emptying
   b) Bile secretion
   c) Renal filtration
   d) Insulin action
   Answer: a) Gastric emptying
4. A central effect of semaglutide is:
   a) Increased appetite
   b) Appetite suppression
   c) Blood pressure increase
   d) Cognitive enhancement
   Answer: b) Appetite suppression
5. The half-life allows dosing:
   a) Daily b) Weekly c) Monthly d) Daily BID
   Answer: b) Weekly
6. A potential rare adverse effect is:
   a) Hypoglycemia b) Pancreatitis c) Hepatorenal syndrome d) Constipation
   Answer: b) Pancreatitis
7. It is contraindicated in patients with:
   a) Type 1 diabetes b) Medullary thyroid carcinoma c) Hyperthyroidism d) Hypothyroidism
   Answer: b) Medullary thyroid carcinoma
8. Protein binding is approximately:
   a) 50% b) 75% c) >94% d) 100%
   Answer: c) >94%
9. Effects on heart and kidneys include:
   a) Increased albuminuria b) Vascular protection c) Fluid retention d) Increased LDL
   Answer: b) Vascular protection
10. Compared to liraglutide, semaglutide dosing is:
    a) Daily b) Weekly c) Monthly d) BID
    Answer: b) Weekly

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FAQs

1. How often is semaglutide administered?
It’s given once weekly via subcutaneous injection.

2. Does it cause hypoglycemia?
Hypoglycemia risk is low when used alone but increases if combined with insulin or sulfonylureas.

3. How much weight loss can be expected?
On average, patients lose 5–15% of body weight over several months.

4. Should thyroid function be monitored?
Side effects on thyroid are rare but avoid in those with medullary thyroid carcinoma or MEN2.

5. Is it safe in patients with renal impairment?
Semaglutide requires no dose adjustment in mild-to-moderate renal impairment.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
• KD Tripathi. Essentials of Medical Pharmacology
• DrugBank: Semaglutide pharmacology summary
• StatPearls: GLP-1 receptor agonists
• PubMed review: Semaglutide cardiovascular and weight benefits