Mechanism of Action of Sitagliptin

Introduction

Sitagliptin is an oral dipeptidyl peptidase‑4 (DPP‑4) inhibitor used to manage type 2 diabetes mellitus (T2DM). It improves glycemic control by enhancing incretin hormone activity, leading to increased insulin secretion and decreased glucagon release in a glucose-dependent manner.

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Step-by-Step Mechanism of Action

1. Inhibition of DPP‑4 enzyme
   Sitagliptin selectively inhibits the DPP‑4 enzyme, which normally degrades incretin hormones.
2. Increased incretin levels
   The inhibition of DPP‑4 prolongs the activity of glucagon-like peptide‑1 (GLP‑1) and glucose-dependent insulinotropic polypeptide (GIP).
3. Enhanced insulin secretion
   Elevated incretin levels stimulate insulin release from pancreatic β-cells in a glucose-dependent manner.
4. Suppression of glucagon
   GLP‑1 also suppresses glucagon secretion from pancreatic α-cells, reducing hepatic glucose output.
5. Improved glycemic control
   These actions together lead to reduced fasting and postprandial blood glucose without causing hypoglycemia.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral
Bioavailability	~87%
Protein Binding	~38%
Metabolism	Minimal; primarily renal excretion
Half-life	~12 hours
Excretion	Primarily renal (unchanged drug)

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Clinical Uses

• Monotherapy or add-on therapy in type 2 diabetes mellitus
• Often used in combination with metformin, sulfonylureas, or insulin

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Adverse Effects

• Nasopharyngitis
• Headache
• Upper respiratory tract infections
• Rare: pancreatitis, hypersensitivity reactions, joint pain

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Comparative Analysis

Agent	Mechanism	Dosing	Hypoglycemia Risk
Sitagliptin	DPP‑4 inhibitor	Once daily	Low
Saxagliptin	DPP‑4 inhibitor	Once daily	Low
Liraglutide	GLP‑1 receptor agonist	Once daily	Moderate
Metformin	Reduces hepatic glucose production	Twice daily	Minimal

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MCQs

1. Sitagliptin inhibits which enzyme?
   a) SGLT2 b) DPP‑4 c) α-glucosidase d) CYP3A4
   Answer: b) DPP‑4
2. Sitagliptin’s primary mechanism involves:
   a) Enhancing insulin sensitivity b) Increasing insulin secretion via incretins c) Inhibiting glucose absorption d) Stimulating glucagon
   Answer: b) Increasing insulin secretion via incretins
3. GLP‑1 and GIP are degraded by:
   a) CYP enzymes b) Amylase c) DPP‑4 d) Pepsin
   Answer: c) DPP‑4
4. Sitagliptin lowers blood glucose by:
   a) Inhibiting SGLT2 b) Blocking insulin degradation c) Increasing hepatic glucose output d) Enhancing insulin and reducing glucagon
   Answer: d) Enhancing insulin and reducing glucagon
5. Risk of hypoglycemia with sitagliptin monotherapy is:
   a) High b) Moderate c) Low d) Guaranteed
   Answer: c) Low
6. Excretion route for sitagliptin is primarily:
   a) Biliary b) Renal c) Pulmonary d) Salivary
   Answer: b) Renal
7. Dosing adjustment is required in:
   a) Hepatic impairment b) Mild asthma c) Renal impairment d) Gout
   Answer: c) Renal impairment
8. Sitagliptin’s main benefit over sulfonylureas is:
   a) Once-weekly dosing b) Weight gain c) No hypoglycemia d) Stronger glucose control
   Answer: c) No hypoglycemia
9. It increases levels of:
   a) Cortisol b) Insulin-independent glucose uptake c) GLP‑1 and GIP d) Adrenaline
   Answer: c) GLP‑1 and GIP
10. Common side effect of sitagliptin is:
    a) Pancreatitis b) Nasopharyngitis c) Weight loss d) Diarrhea
    Answer: b) Nasopharyngitis

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FAQs

1. Does sitagliptin cause hypoglycemia?
Not when used alone; risk increases with insulin or sulfonylureas.

2. Can it be used in renal impairment?
Yes, but dose adjustment is required based on creatinine clearance.

3. Does it aid in weight loss?
It is generally weight neutral.

4. Is it safe in elderly patients?
Yes, but renal function should be monitored.

5. How long does it take to show effect?
Glycemic improvement is usually observed within a few weeks of initiation.

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References

• PubMed: Pharmacology of Sitagliptin
• DrugBank: Sitagliptin
• FDA Label: Januvia (Sitagliptin)
• StatPearls: DPP-4 Inhibitors
• PMC: Incretin-based therapies