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 mediate Others mediated
d
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
• Atazanvir
… Except for saxagliptin
• 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.
