Dipeptidyl peptidase inhibitors(DPP-IV): A deep insight

PRESENTED TO: DR.SASWATI SINHA, DR.SHARMILA CHATTERJEE
PRESENTED BY:
VISHNU.R.NAIR,
PHARM.D INTERN(AMRI HOSPITAL ACADEMIC TRAINEE),
NATIONAL COLLEGE OF PHARMACY, KERALA.

 DPP-IV inhibitors(also known as “GLIPTINS”)  represent a class of oral antidiabetics.
 Principle of action: “Drugs, that prolong incretin action”
Oral glucose intake
Causes release of “gut hormones”(incretins)
Increases glucose-induced insulin secretion
Thus
Oral glucose load  provokes higher insulin response (as compared to glucose given i.v)
Katzung B. Basic & clinical pharmacology. 14th ed. San Francisco: McGraw-Hill Education; 2018. Pg: 761-62.

 Incretins include:
a. GLP-1(Glucagon-like peptide-1)
b. GIP(Glucose-dependent insulinotropic peptide)
GLP-1
Infused in Type-2 DM
Reduces blood glucose levels Stimulates insulin release

GLP-1  shows “glucose-dependent action”:
a. Increases insulin release only when BGL is high
b. No effect in euglycemia
c. Lower risk of hypoglycemia (as compared to sulfonylureas).
Other effects of GLP-1 include:
a. Suppression of glucagon secretion
b. Reduced gastric emptying
c. Reduced apoptosis of human islets

d. GLP-1
Reduces “feeding” (via CNS mechanism)
Thus
Type-2 DM patients on GLP-1 therapy  tend to be less hungry!

DPP-IV Endopeptidase 24.11
Degrade GLP-1
Converted into inactive form, eliminated by kidney
Solutions
GLP-1 agonists(resist
enzymatic
degradation & renal
clearance)
DPP-IV
inhibitors(inhibit
DPP-IV enzyme,
prolonging GLP-1
activity)

DPP-IV inhibitors
Block DPP-IV
Prolong action of endogenously released GLP-1 & GIP
Increase insulin
secretion in
response to meals
Reduce glucagon
secretion

Whalen K, Feild C, Radhakrishnan R. Pharmacology(Lippincott Illustrated Reviews). 7th ed. Philadelphia: Wolters Kluwer; 2019. Pg:917

 Bioavailability: 85%
 Half-life: 12 hours
 Drug  undergoes renal excretion  requires dosage adjustment in renal dysfunction!
 Metabolite activity: Nil
 Dosage adjustment for renal dysfunction:
a. If GFR = 30-50 ml/min  dose : 50 mg OD
b. If GFR < 30 ml/min  dose: 25 mg OD.
 Can be given as either “monotherapy”/ in combination with metformin, TZDs or SUs.
Tripathi K. Essentials of Medical Pharmacology. 8th ed. New Delhi: Jaypee Brothers Medical Publishers; 2018. Pg: 297-98.

ADRs include:
a. Nasopharyngitis
b. URTIs
c. Headache
d. Acute pancreatitis
e. Severe hypersensitivity reactions
If the above PMS reports occur  discontinue drug immediately!!
Post marketing
surveillance
reports

Drug interactions:
a. Sitagliptin + OHAs  increased toxicity/effects of latter  monitor therapy!
b. Drug + ACE-Inhibitors  increased toxicity of latter  monitor therapy!
c. Drug + diuretics(loop, thiazide); corticosteroids  diminished hypoglycemic effect of
former  monitor therapy!
Contraindications:
a. Type-1 DM
b. DKA(Diabetic keto-acidosis)
c. Drug hypersensitivity.

Monitoring parameters:
a. Symptoms of pancreatitis
b. RFTs
c. HbA1C levels.
Therapeutic efficacy: Reduction of HbA1C by 0.5-1.0% observed.
Pregnancy category: “B”
Dose: 100 mg OD, orally.

Metabolite activity: Active
Half-life: 3.1 hours
Dosage adjustment required for renal impairment
Can be given as “monotherapy” or as “combination therapy” with biguanides,
TZDs & SUs
Therapeutic efficacy: reduction in HbA1C by 0.4-0.9%
Katzung B. Basic & clinical pharmacology. 14th ed. San Francisco: McGraw-Hill Education; 2018. Pg: 762.
Tripathi K. Essentials of Medical Pharmacology. 8th ed. New Delhi: Jaypee Brothers Medical Publishers; 2018. Pg: 298.

ADRs:
a. URTI
b. UTI
c. Headache
d. Hypersensitivity reactions
e. High risk of heart failure!!!
High risk observed with
High levels of NT-pBNP
Renal impairment History of HF

Drug interactions: Same as that of sitagliptin.
Contraindications:
a. Same as that of sitagliptin
b. Heart failure(extra addition)
Monitoring parameters: Same as that of sitagliptin
Dose: 2.5-5 mg OD, orally.

 Usually given in combination with pioglitazone, metformin and sulfonylureas
 Therapeutic efficacy: If used as combination therapy  drug reduces HbA1C by 0.4-0.6%
 Drug  mainly excreted through bile  no dosage adjustment required in renal dysfunction!
 Drug interactions: Same as that of sitagliptin
 Contraindication: Same as that of sitagliptin
 Monitoring parameters: Same as that of sitagliptin(except RFT)
 Pregnancy category: “B”

ADRs:
a. Nasopharyngitis
b. Hypersensitivity reactions
c. Pancreatitis.
Dose: 5 mg OD, orally.

 Given in combination with metformin, pioglitazone and SUs
 Dosage adjustment  required for renal dysfunction
 Dosage adjustment for renal dysfunction:
a. If CrCl = 30-60 ml/min  dose: 12.5 mg OD
b. If CrCl = < 30 ml/min  dose: 6.25 mg OD
 Therapeutic efficacy: If used as combination therapy  reduction in HbA1C by 0.5-
0.6%
 Drug interactions: Same as that of sitagliptin.

 Contraindications: Same (in addition, heart failure)
 Monitoring parameters: Same(in addition, LFTs prior to starting treatment, and periodically
thereafter)
 Pregnancy category: “B”
 ADRs:
a. Hypersensitivity reactions
b. Hepatic failure
c. Pancreatitis.
 Dose: 25 mg OD, orally.

 Usually used as combination therapy
 Therapeutic efficacy: If used as combination therapy  lowers HbA1C by 0.5-1.0%
 Drug interactions: Same as that of sitagliptin
 Contraindications:
a. Pancreatitis f. DKA
b. Liver failure
c. Heart failure
d. Drug hypersensitivity
e. Type 1 DM

 Monitoring parameters:
a. Blood glucose levels
b. Lipid profile
c. HbA1C(Baseline & periodically thereafter)
d. LFTs
e. Symptoms of pancreatitis.
 Pregnancy category: Uncategorized  usage is not recommended.
 Dose: 50 mg, OD/BD, orally.

ADRs:
a. URTI
b. Nasopharyngitis
c. Dizziness
d. Headache
e. Hepatitis(rare).

 Patient counselling tips:
a. Can be taken with/without food
b. Avoid alcohol intake
c. Report to physician if the following occur:
Fatigue Right upper abdominal discomfort.
Anorexia
Dark urine

 Newer molecule
 Developed in Japan
 Long-lasting (> 24 hours) hypoglycemic effect
 With a single morning dose  post prandial blood glucose level is reduced significantly at all
3 meals of the day!
 Given either as “monotherapy” or as “combination therapy” with metformin ± SUs/ a TZD
 Metabolites  eliminated by both liver & kidney  no dose adjustment required in renal
dysfunction!
 Exercise caution, while using drug in patients with/ prone to QT-prolongation!
 Dose: 20 mg before breakfast daily  increase dose to 40 mg/day(if needed).

Sitagliptin
Saxagliptin
Alogliptin

DRUG DOSE
SITAGLIPTIN 100 mg, P/O, OD
SAXAGLIPTIN 2.5-5 mg, P/O, OD
LINAGLIPTIN 5 mg, P/O, OD
ALOGLIPTIN 25 mg, P/O, OD
VILDAGLIPTIN 50 mg, P/O, OD/BD
TENELIGLIPTIN 20 mg, P/O, OD(May increase to 40 mg/day if required)

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Dipeptidyl peptidase inhibitors(DPP-IV): A deep insight