Pharmacokinetics of all DPP4 inhibitors and efficacy in type 2 diabetes

5.  These are antidiabetic drugs that improve glycaemic control without causing
weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes
mellitus (T2DM).
 The eight available DPP-4 inhibitors, includes:
Alogliptin
Anagliptin
Gemigliptin
Linagliptin
Saxagliptin
Sitagliptin
Teneligliptin
Vildagliptin

6.  Dipeptidyl peptidase-4 inhibitors
may be classified into:
 Peptidomimetic (i.e., sitagliptin,
teneligliptin, vildagliptin,
saxagliptin, and anagliptin)
 Non-peptidomimetic (i.e., alogliptin
and linagliptin) subtypes (Fig).

7. Table 1 Clinical pharmacokinetic and pharmacodynamics properties of selective DPP-4 inhibitors
Continue..

8. Table 1 (continued)

9. DPP-4 inhibitors suppress the enzymatic activity of DPP-4, resulting in an increase in incretin levels (GLP-1 and
GIP), which subsequently inhibit glucagon release and glucose production in the liver and increase insulin
secretion and glucose uptake in skeletal muscle. Consequently, it leads to a decrease in blood glucose level. GLP-
1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide.

10. • Alogliptin selectively inhibits DPP-4 with an IC50 of 7 nmol/L and has exhibited more than 14 000-fold
selectivity over the related serine proteases DPP-8 and DPP-9.
• Anagliptin Potent inhibitor for DPP-4, with an IC50 of 3.4 nmol/L.
• Gemigliptin is a potent, competitive, reversible, long-acting DPP-4 inhibitor (IC50 = 16 nmol/L) with over 3000-
fold selectivity over other DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase, and cathepsin G
• Linagliptin has greater potency than other DPP-4 inhibitors (IC50 = ~1 nmol/L for linagliptin vs 19, 62, 50 and
24 nmol/L for sitagliptin, vildagliptin, saxagliptin and alogliptin, respectively.
• Teneliigliptin with IC50 of 1.75 nmol/L
• Vildagliptin is a potent, competitive, and reversible inhibitor for DPP-4, with an IC50 of 3.5 nmol/L.
Diabetes, Obesity and Metabolism 13: 7–18, 2011

11.  ALOGLIPTIN - Takeda Pharmaceuticals (Osaka, Japan), FDA approval January 2013
 Alogliptin selectively inhibits DPP-4 with an IC50 of 7 nmol/L and has exhibited more
than 14 000-fold selectivity over the related serine proteases DPP-8 and DPP-9.
 Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition
of DPP-4 within 2–3 h after dosing.
 Single doses of alogliptin from 25 to 800 mg produced peak DPP-4 inhibition ranging
from 93.3% to 98.8%.
 FDA of the US approved the drug in three formulations: as a standalone, in combination
with metformin (Kazano) or with pioglitazone (Oseni).
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

12.  ANAGLIPTIN- was developed by Sanwa Kagaku Kenkyusho Co. (Mie, Japan) and
approved by the PMDA of Japan in September 2012.
 Potent inhibitor for DPP-4, with an IC50 of 3.4 nmol/L
 oral dose of 100 mg in healthy subjects were 98.2 % recovered within 168 h, with
73.2% in urine and 25.0% in faeces
 Peak plasma is achieved within 1.8 hr of postdose
 Mean fraction of the dose absorbed was > 73%.
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

13.  GEMIGLIPTIN- LG Life Science (Seoul, Korea) and Double-Crane
Pharmaceutical Co. (Beijing, China).
 Approval from Korea Food & Drug Administration in June 2012.
 Gemigliptin is a potent, competitive, reversible, long-acting DPP-4 inhibitor (IC50
= 16 nmol/L) with over 3000-fold selectivity over other DPP-2, DPP-8, DPP-9,
elastase, trypsin, urokinase, and cathepsin G
 At oral dose of ≥ 200 mg of gemigliptin inhibited plasma DPP-4 activity by > 80%
over a 24-h dosing interval in healthy subject.
 Gemigliptin exhibited linear kinetic properties over the range of 50–400 mg
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

14.  LINAGLIPTIN – Develop by Tradjenta & Trajenta;was approved by the FDA in May
2011
 It is used as a monotherapy or in combination with metformin (Jenadueto).
 Linagliptin has greater potency than other DPP-4 inhibitors (IC50 = ~1 nmol/L for
linagliptin vs 19, 62, 50 and 24 nmol/L for sitagliptin, vildagliptin, saxagliptin and
alogliptin, respectively)
 peak plasma concentrations of linagliptin occurred at approximately 1.5 h postdose.
 Linagliptin shows modest oral bioavailability, but is rapidly absorbed.
 The absolute bioavailability of linagliptin is around 30%.
 Following oral administration, the majority (about 90%) of linagliptin is excreted
unchanged.
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

15.  SAXAGLIPTIN (Onglyza); co-developed by Bristol-Myers Squibb and AstraZeneca was
approved by the FDA in July 2009.
 It is also used in combination with metformin (Kombiglyze XR).
 Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the
2.5–400 mg dose range.
 Single oral dose of 5 mg saxagliptin, the mean plasma t½b for saxagliptin and its active
metabolite was 2.5 and 3.1 h, respectively
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

16.  SITAGLIPTIN is the first DPP-4 inhibitor developed by Merck & Co. , approved
by the FDA in October 2006.
 50 mg sitagliptin and 500 or 1000 mg metformin was approved by FDA in April
2007.
 Sitagliptin markedly and dose-dependently inhibited ~80% of plasma DPP-4
activity over 24 h.
 Peak plasma concentrations occurring 1–4 h postdose.
 Single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin
was 8.52 µmol/L per h, Cmax was 950 nmol/L, and apparent t½ß was 12.4 h.
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

17.  TENELIGLIPTIN was developed by Mitsubishi Tanabe Pharma (Osaka, Japan)
and gained approval from the PMDA of Japan in September 2012.
 Teneligliptin significantly inhibited human plasma DPP-4 and recombinant
human DPP-4 activity, with IC50 of 1.75 nmol/L and 0.889 nmol/L (Ki = 0.406
nmol/L), respectively.
 In human, teneligliptin is metabolized to five metabolites, M1, M2, M3, M4, and
M5, which all show some DPP-4 inhibitory activity.
 Plasma Cmax on oral administration of 10 or 20 mg once daily for 4 weeks was
125.0 and 274.5 ng/mL, respectively, with a Tmax of 1.0 h in both groups and a
mean t1/2b of 20.8 and 18.9 h, respectively
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

18.  VILDAGLIPTIN, gained approval from the European Medicines Agency (EMEA)
in February 2008.
 Its approval in the US is still pending. In the meantime, the EMEA has also
approved a combination use of vildagliptin with metformin (brand name:
Eucreas).
 Vildagliptin is a potent, competitive, and reversible inhibitor for DPP-4, with an
IC50 of 3.5 nmol/L.
 Its oral bioavailability was 85%, peak plasma concentrations 1.7 hr, plasma
protein binding 9.3% , mean volume of distribution (Vss) was 70.5 L
 Following oral administration of [14C] vildagliptin, ~85% of the dose was excreted
into the urine and 15% of the dose is recovered in the faecesClinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024

20.  1768 patients receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily for 26 week.
 25 mg alogliptin group (n = 128) had a reduction of - 0.6% HbA1C, with 44% of HbA1C ≤ 7.0% at
week 26.
 Alogliptin 12.5 and 25 mg have significant improvements of HbA1C and fasting plasma glucose
(FPG) compared to placebo at week 26

21.  A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin
twice daily or placebo (n=39).
 100 mg and 200 mg shows reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%,
respectively).
 Placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %.
 >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg
and 200 mg anagliptin, respectively.
Endocrine Journal 2015, 62 (5), 449-462

22.  145 T2DM patients treated with 50,100 or 200 mg gemigliptin for 12 week.
 All three doses of gemigliptin significantly reduced the HbA1C from baseline
compared to the placebo group (- 0.06 vs - 0.98, - 0.74 and - 0.78% in the placebo
and 50, 100 and 200 mg groups, respectively)

23.  336 T2DM patients treated with 5 mg once daily linagliptin for 24 week.
 47.1 % Patients treated with linagliptin achieve a reduction in HbA1c of ≥0.5% vs
placebo arm 19.0%.
 Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs.
placebo
 Monotherapy with linagliptin produced a significant, clinically meaningful and
sustained improvement in glycaemic control
Diabetes Obes Metab. 2011 Mar;13(3):258-67.

24. No evident association between the application of saxagliptin and the incidence of
gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin
lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe
cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, and
worsening renal function, the patients still need to be cautious to initiate the
saxagliptin treatment.

25.  Metanalysis of 14 trials containing 3415 people taking sitagliptin at range of 25
mg – 200 mg daily.
 Sitagliptin lowers HBA1c by 0.7% in sitagliptin versus placebo trials.
 Cochrane review show that the drug is well tolerated, causes no hypoglycaemia
and is weight neutral. No specific signals of concern for the safety of sitagliptin
have so far arisen in the pooled database.
Clinical Medicine: Therapeutics 2009: 1

26.  324 T2DM patients were treated with placebo, 10 mg, 20 mg, or 40 mg
teneligliptin for 12 week.
 10, 20, and 40 mg teneligliptin reduced the HbA1C levels 0.77%, 0.80%, and
0.91%, respectively.

27.  632 T2DM were treated with 50 mg qd, 50 mg bid, or 100 mg qd for 24 week.
 HbA1c reduced to greater extent in patients receiving vildagliptin 50 mg qd
(Delta=-0.8+/-0 .1%), 50 mg bid (Delta=-0.8+/-0.1%), or 100 mg qd (Delta=-0.9+/-
0.1%,for all groups VS. placebo).
 Vildagliptin monotherapy decreases HbA1c in drug-naïve patients without weigh
gain and is well tolerated with minimal hypoglycemia.
Horm Metab Res. 2007 Mar;39(3):218-23.

28.  DPP-4 inhibitors are distinctive in their metabolic properties, excretion,
recommended dosage, and daily dosage, and head-to-head clinical trials
comparing the various DPP-4 inhibitors are scarce, the available data regarding
indirect comparisons suggest that all available DPP-4 inhibitors have nearly the
same efficacy and safety profile.
 The DPP-4 inhibitors represent a highly promising, novel class of oral agents for
the treatment of type 2 diabetes. Their novelty lies in their dual action on a- and
b-cell function, leading to an improved profile of glucagon and insulin secretion
patterns after meal.
Clinical and Experimental Pharmacology and Physiology (2015) 42, 999–1024