Table of Contents
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.
Stepwise Mechanism of Action of DPP-4 Inhibitors
- Inhibition of DPP-4 enzyme
DPP-4 inhibitors block the dipeptidyl peptidase-4 enzyme, which normally degrades incretin hormones like GLP-1 and GIP. - Prolonged action of incretin hormones
By preventing their breakdown, these drugs increase levels of active GLP-1 and GIP in the bloodstream. - 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. - Suppression of glucagon secretion
Incretins also reduce glucagon release from alpha cells, decreasing hepatic glucose output. - Improved glycemic control
The combined effects lead to better fasting and postprandial glucose regulation, without significant risk of hypoglycemia.
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%) |
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
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)
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) |
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
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.
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/