DPP-4 inhibitors

in Type 2 Diabetes

dr. Sutomo Tanzil, MSc, SpFK

dr. Ayeshah A. Rosdah, MBiomedSc
Dr. Drs. Sonlimar Simangunsong
dr. Msy Syarinta Adenina
ADA, 2015
Overview
Dipeptidyl peptidase-4 (DPP4)
 An enzyme
 Encoded by the DPP4 gene
 Responsible for the degradation of incretins (glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP)
 DPP-4 inhibitors prolong the action of endogenously
released GLP-1 and GIP via competitive inhibition
 A number of neuropeptides, growth factors, cytokines, and
chemokines are potential DPP-4 substrates
 Drug Development

FDA Approval:
 Sitagliptin
 Sitagliptin (2006, Januvia )
 Sitagliptin + Glucophage (2007)
 Vildagliptin (not approved in USA)
 Saxagliptin
 Saxagliptin (Onglyza)
 Saxagliptin +/- metformin, sulfonylurea,
thiazolidinedione
 Linagliptin (2011, Tradjenta)
 Alogliptin (2013)
Mechanism of Action
 Insulinotropic  Glucose Glucagon
effect suppression

GLP-1 GLP-1 GLP-1

Others mediated Others mediated Others mediated

Adapted from Horowitz et al (2016)

 Inactive
metabolites

DPP-4
GLP-1

 appetite  glucose
uptake
 insulin
 glucagon

 glucose
 gastric poduction
emptying
 Inactive
DPP-4
metabolites
inhibitor
GLP-1

 appetite
DPP-4
 glucose
uptake
 insulin
 glucagon

 glucose
 gastric poduction
emptying
Pharmacokinetics
 Rapidly absorbed after oral administration
 Peak plasma concentration  1- 4 hours

 Oral bioavailability >87%

 Except linagliptin  due to 1st pass metabolism in liver
 But linagliptin is very selective and has long half-life
 able to inhibit 95% DPP-4 activity in 24-hour dosing interval

 Elimination primarily via renal excretion

 Vildagliptin and saxagliptin  renal, liver
 Linagliptin  mainly liver
 Different profiles of DPP-4 Inhibitors

Characteristics Sitagliptin Vildagliptin Saxagliptin Alogliptin Linagliptin

Dose (mg/day) 1 x 100 2 x 50 1x5 1 x 12,5-25 1x5

Half-life Long Short Short Long Very long

Active
- - Yes - -
metabolites
Renal
*
excretion
Dose
adjustment in
25-50 mg - 2,5 mg - -
renal
insufficiency
Drug interaction - - Yes** - -

* Main elimination via hepatobiliary route

**Need dose adjustment to 2,5 mg/day for use with CYP3A4 inhibitors (e.g.
ketoconazole)
 DPP-4 inhibitor in Indonesia

Tablets Duration

Vildagliptin (Galvus) 50 12-24 hours

Sitagliptin (Januvia) 25, 50, 100 mg 24 hours

Saxagliptin (Onglyza) 5 24 hours

Linagliptin (Trajenta) 5 24 hours

Perkeni, 2015
CONTRAINDICATION
• Hipersensitivity
• DM type 1
• Ketoacidosis

WARNING
• Elderly (reduced renal and liver function)
• Pregnancy
• Breastfeeding
Side Effects / Adverse Effects

 Headache, nausea
 Hypersensitivity
 Minor hypoglycaemia
 A small increase in neutrophil count
(~200 cells/µL)

 Upper respiratory tract infection

 Heart failure (sitagliptin)
 Pancreatitis (sitagliptin)
DRUG INTERACTION

 Only slightly metabolized by cytochrome P450

 Therefore minimal drug interaction!

• Ketoconazole
• Itraconazole
 … Except for saxagliptin • Atazanvir
• Indinavir
 CYP3A4/5 inihibitors increase saxagliptin • Saquinavir
• Nelfinavir
in plasma • Ritonavir
 Therefore need dose reduction to 2,5 mg/day • Nefazodone
• Telithromycin
• Clarithromycin
Blood Glucose

 ↓ 0.5-1.4% (HbA1c ---various clinical trials)

 ↓ 15-30 mg/dl (Fasting Plasma Glucose )

 ↓ 34-50 mg/dl (Post-prandial Glucose)

 Comparison with Metformin
METFORMIN DPP-4 inhibitor
 Post-prandial glucose

 Fasting glucose

Hypoglycemia ± ±

Gastrointestinal symptoms ±
Risk of use in patients renal Severe Reduce dosage
insufficiency

Risk in liver failure Severe ±

Weight gain ±

Drug-drug interactions ± ±
Pros

• Does not cause nausea or vomiting or weight loss

• Minimal side effects

• Practical use (once daily)

 Limitation
 Long-term safety of DPP-IV inhibitors
 DPP-IV can metabolize a wide range of peptides

 The potency of the DPP-IV inhibitors may be limited by the

amount of endogenous production of GLP-1.
 Conflicting evidence regarding GLP-1 secretion in diabetic patients

 DPP-4 inhibitors (monotherapy) were only slightly less effective

than sulfonylureas and as effective as metformin and
thiazolidinediones in regard to reducing blood glucose

 Pricing….?
Conclusion
Conclusion
Conclusion
 May be used for monotherapy
 Equally effective as metformin
 Still inferior compared to sulfonylurea 3 months cannot
reach HbA1c target
 Preventive Measures
 Check HbA1c
 Per 12 weeks  If target is not achieved  combine with
other oral antidiabetic agents

 Check kidney function (before and during therapy)

 creatinine, low GFR  sign of renal insufficiency
 May have to reduce dose

 Check liver function (before and during therapy)

 Precaution: increase of AST, ALT > 2,5x (especially in
vildagliptin
 May have to reduce/stop medication
Thank you.