Mechanism of Action of DPP-4 Inhibitors

Introduction

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors, commonly referred to as gliptins, are oral antidiabetic drugs that enhance the action of incretin hormones, especially GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). They help regulate postprandial and fasting blood glucose levels in patients with type 2 diabetes mellitus.

Commonly used DPP-4 inhibitors include:

• Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin

These agents are known for being weight-neutral and having a low risk of hypoglycemia.

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Stepwise Mechanism of Action of DPP-4 Inhibitors

1. Inhibition of DPP-4 enzyme
   DPP-4 inhibitors block the dipeptidyl peptidase-4 enzyme, which normally degrades incretin hormones like GLP-1 and GIP.
2. Prolonged action of incretin hormones
   By preventing their breakdown, these drugs increase levels of active GLP-1 and GIP in the bloodstream.
3. Increased insulin secretion (glucose-dependent)
   Elevated GLP-1 and GIP enhance insulin release from pancreatic beta cells, but only in the presence of elevated blood glucose.
4. Suppression of glucagon secretion
   Incretins also reduce glucagon release from alpha cells, decreasing hepatic glucose output.
5. Improved glycemic control
   The combined effects lead to better fasting and postprandial glucose regulation, without significant risk of hypoglycemia.

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Pharmacokinetic Parameters of DPP-4 Inhibitors

Drug	Half-life	Metabolism	Excretion
Sitagliptin	~12 hours	Minimal hepatic	Renal (~80%)
Saxagliptin	~2.5 hours (active metabolite ~3 hrs)	CYP3A4/5	Renal/Fecal
Linagliptin	>100 hours	Minimal (enterohepatic recycling)	Biliary/Fecal
Vildagliptin	~3 hours	Hepatic (hydrolysis)	Renal (~80%)

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Clinical Uses of DPP-4 Inhibitors

• Type 2 diabetes mellitus (monotherapy or combination with metformin, sulfonylureas, or SGLT2 inhibitors)
• Effective in elderly, overweight, or renal-compromised patients (e.g., linagliptin)
• Used when hypoglycemia and weight gain are concerns

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Adverse Effects of DPP-4 Inhibitors

• Nasopharyngitis, headache, upper respiratory symptoms
• Pancreatitis (rare but serious)
• Joint pain (FDA warning)
• Allergic reactions – rash, urticaria
• Heart failure risk (with saxagliptin and alogliptin – use cautiously in CHF)

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Comparative Analysis: DPP-4 Inhibitors vs GLP-1 Agonists

Feature	DPP-4 Inhibitors	GLP-1 Receptor Agonists
Route of administration	Oral	Injectable
Weight effect	Neutral	Weight loss
Hypoglycemia risk	Low	Low
GLP-1 levels	Moderate increase	Supraphysiological increase
Side effects	Mild	GI upset (nausea, vomiting)

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Practice MCQs

Q1. DPP-4 inhibitors increase the levels of which hormones?
a. Insulin and cortisol
b. GLP-1 and GIP ✅
c. Glucagon and insulin
d. Leptin and ghrelin

Q2. The action of DPP-4 inhibitors is:
a. Glucose-independent
b. Glucose-dependent ✅
c. Long-acting sulfonylurea
d. Non-hormonal

Q3. Sitagliptin works by:
a. Inhibiting glucose absorption
b. Stimulating insulin receptors
c. Inhibiting DPP-4 enzyme ✅
d. Blocking SGLT2

Q4. Which of the following is an advantage of DPP-4 inhibitors?
a. Weight gain
b. Severe hypoglycemia
c. Weight neutrality ✅
d. Increased appetite

Q5. GLP-1 causes all EXCEPT:
a. Increased insulin secretion
b. Delayed gastric emptying
c. Glucagon suppression
d. Decreased insulin degradation ✅

Q6. Which drug is excreted mainly via bile and feces?
a. Sitagliptin
b. Saxagliptin
c. Linagliptin ✅
d. Vildagliptin

Q7. A rare but serious side effect of DPP-4 inhibitors is:
a. Hepatic failure
b. Pancreatitis ✅
c. Retinopathy
d. Anemia

Q8. Saxagliptin should be used with caution in:
a. Liver cirrhosis
b. Congestive heart failure ✅
c. Hyperthyroidism
d. Hyperuricemia

Q9. Which enzyme do DPP-4 inhibitors inhibit?
a. CYP3A4
b. DPP-4 ✅
c. HMG-CoA reductase
d. Na⁺/K⁺ ATPase

Q10. What is the role of GIP in glucose regulation?
a. Stimulates insulin secretion ✅
b. Inhibits beta cells
c. Causes lipolysis
d. Promotes glucagon release

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FAQs

Q1: Can DPP-4 inhibitors be used in type 1 diabetes?
No. They require functional beta cells and are only approved for type 2 diabetes.

Q2: Do DPP-4 inhibitors cause weight gain?
No. They are weight neutral, making them ideal for overweight patients.

Q3: Are they safe in renal impairment?
Yes. Linagliptin is preferred as it requires no dose adjustment in renal failure.

Q4: Do DPP-4 inhibitors cause pancreatitis?
There have been rare reports, so caution is advised in patients with a history of pancreatitis.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• ADA Guidelines
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK500008/