Teneligliptin

The emerging gliptin

Akshata Rao
Medical Services
Diabetes in Indian subcontinent

Retrieved from http://www.cadiresearch.org/topic/diabetes-indians/diabetes-in-the-indian-subcontinent

 Choice of agents in current use

Sulphonylureas
Insulin
Thiazolidinediones
Biguanides
Alpha-glucosidase inhibitors
Meglitinides
Each therapy has a drawback

Tripathi 2005, 5th Edition

Nature Reviews 2007 :6 :109-110
Pharmacology and Therapeutics 2010:125; 328-361
DPP-4 Inhibitors - A major addition
to Diabetes Armamentarium
Major DPP-4 inhibitors currently available :-

Sitagliptin

Vildagliptin

Saxagliptin

Linagliptin
 Teneligliptin – Novel and potent
addition to gliptin category
Approved by *Ministry of Health, Labour and Welfare (MHLW)
Japanese Pharmaceutical and Medical Devices Agency (PMDA) in
2012

Important features to be noted

Highest potency
Long half – life
Safety in renal patients
Safety in hepatic patients
Ministry of Health, Labour and Welfare (MHLW) Japanese Pharmaceutical and Medical
Devices Agency - Both are governing bodies which is responsible for final drug
approval in Japan Accessed from http://www.pmda.go.jp/files/000153594.pdf
 Teneligliptin – Structural features

Introduction of the ‘’anchor lock domain’’, which binds to the S2

extensive subsite - Higher potency and selectivity

Forms a stable gliptin-DPP-4 enzyme complex due rigid 5 ring “J

structure - Longer Half life

Carbonyl group derived from the peptide mimetic, forms a

hydrogen bond (strongest bond) DPP4 enzyme - Higher potency

Biochemical and Biophysical Research Communications 434 (2013) 191–196

 Unique binding capability

Effect on the outcome

1500 fold higher 5 fold higher

activity activity

Occupies a larger area of

2.08nm2 As compared to As compared to
Vildagliptin and Sitagliptin
Saxagliptin
Unique mode of excretion

Teneligliptin excreted
by two modes of
excretion i.e. by liver
and kidney . (Liver -
45.4% and kidney -
46.5%
 Teneligliptin Vs other gliptins –
Interaction with DPP-4 enzymes.

Journal of Diabetes Mellitus, 2016, 6, 113-131

Teneligliptin Vs other gliptins –
Pharmacokinetic comparison

Journal of Diabetes Mellitus, 2016, 6, 113-131

Teneligliptin in renally compromised patients
 In special
Safety and efficacy of teneligliptin: a novel population
(Renal
DPP-4 inhibitor for Impairment)

hemodialysis patients with type 2 diabetes.

Design Prospective, non-randomized study with 43 diabetic ESRD
patients ; Teneligliptin 20 mg/day (n=14) and Control group ( n=
29)
Control group treated with voglibose, vildagliptin, miglitol,
Meglitinides

Duration 28 weeks
Patient ESRD diabetic patients with Serum Creatinine levels*
characteristic (Teneligliptin group = 9.1mg/dl and Control group = 10.3 mg/dl
s
End-points Blood glucose levels , Glycated Albumin levels (GA) and
HbA1C(%)

Normal creatinine levels *- 0.6 to 1.2 milligrams (mg) per deciliter (dL) in adult males and 0.5 to 1.1
milligrams per deciliter in adult females Int Urol Nephrol (2014) 46:427–432
 Duration –
Teneligliptin significantly improves the glycemic states in 28 weeks

Diabetic ESRD patients

P<0.05 P<0.05

p = 0.057

Blood glucose decreased significantly in the teneligliptin group from 4 weeks

GA level in the teneligliptin group dropped significantly after 4 weeks
HbA1c in the teneligliptin group declined significantly from 8 weeks
Int Urol Nephrol (2014) 46:427–432
 Teneligliptin also improves glycemic states in patients
switching from conventional Oral Anti-Diabetic drugs

Blood glucose level decreased 21–60 mg/dl at 28 weeks after teneligliptin

administration. GA dropped 1.7–2.3 % by 28 weeks and HbA1c fell 0.3–0.8 % by 24
weeks.
Int Urol Nephrol (2014) 46:427–432
 Conclusion
• Teneligliptin is well tolerated, safe, and significantly improves glycemic
control in diabetic patients with ESRD.
• No serious side effects or hypoglycemia relating to teneligliptin is seen
during the study.
• Teneligliptin 20 mg is probably stronger than Vildagliptin 50 mg for
dialysis patients.
• Teneligliptin is expected to be a powerful DPP-4 inhibitor of ESRD.

Int Urol Nephrol (2014) 46:427–432

Teneligliptin in Indian patients
 Study of Anti-hyperglycemic Activity of Teneligliptin in Patients of T2DM

Design Uncontrolled, open label, observational study with patients who

were uncontrolled on metformin were selected. Teneligliptin 20
mg/day was added to current treatment.
Duration 12 weeks
Patient Patients of T2DM attending OPD of Dhanashree Hospital, Pune
characteristic were included in the study after obtaining informed written
s consent
End-points Fasting blood sugar level, Post prandial blood sugar level and
HbA1C (%)

Indian J Pharmacol. 2015 Dec; 47(Suppl 1): S57–S177.

Teneligliptin Vs other gliptins
 Impact of teneligliptin on oxidative
stress and endothelial function in type 2
diabetes patients with chronic kidney
disease: a case–control study
Design Open-label, prospective, randomized study with 45 diabetic CKD
patients who received sitagliptin for at least 12 months were
randomized to either continue sitagliptin (n = 23) or switch to
teneligliptin (n = 22)

Duration 24 weeks
Patient type 2 diabetes with (HbA1c) >6.5 %, CKD (eGFR) <60
characteristic mL/min/1.73 m2 or microalbuminuria >30 mg/g Cr] [14], and
s treatment with sitagliptin for 1 year or longer
End-points HbA1c, eGFR, or urinary albumin excretion levels, endothelial
function by reactive hyperaemia index (RHI), reactive oxygen
metabolites (ROMs) measured by the d-ROMS test

Cardiovasc Diabetol (2016) 15:76

 Results

Baseline After 3 months

Fasting blood 172.4 124.5
glucose (mg/dl)
Post prandial blood 225.5 176.4
glucose
HbA1C (%) 9.5 8.6

Conclusion:
Teneligliptin can be considered as an effective alternative for
add-on treatment in patients of T2DM uncontrolled on
metformin monotherapy.
Cardiovasc Diabetol (2016) 15:76
Results

Cardiovasc Diabetol (2016) 15:76

 Results

Changes in RHI Changes in d-ROMs

Cardiovasc Diabetol (2016) 15:76

 Conclusion

• Teneligliptin exhibits beneficial effects on both oxidative stress and

endothelial function in Japanese patients with type 2 diabetes and CKD.
• Teneligliptin exhibits beneficial effects on both oxidative stress and
endothelial function in Japanese patients with type 2 diabetes and CKD.
• The antioxidative effect of Teneligliptin is brought about by the sulphur
atom present in the molecule

Cardiovasc Diabetol (2016) 15:76

 Efficacy of linagliptin and teneligliptin for
glycemic control in type 2 diabetic
patients with chronic kidney disease:
assessment by continuous glucose
monitoring; a pilot study
Design randomized and crossover in design in 13 type 2 diabetes
patients with CKD treated with teneligliptin at 20 mg/day or
linagliptin at 5 mg/day for 6 days then switched to the other
agent for another 6 days.)

Duration 12 days
Patient type 2 diabetes patients with CKD who maintained glycosylated
characteristic hemoglobin (HbA1c) levels at <9 % by diet and exercise and had
s estimated glomerular filtration rates (eGFRs) \60 ml/min 1.73
m2.

End-points Mean amplitude of glucose excursions (MAGE)

Diabetology International pp 1-7 First online: 09 March 2016

 Results

no significant
difference
between the
two groups
(p = 0.05).

Twenty-four-hour mean sensor Mean amplitude of glycemic excursions

glucose levels before treatment and
after 6 days of treatment with
linagliptin/ teneligliptin in 13
patients.
(MAGE) before treatment and after 6 days
treatment with linagliptin/teneligliptin.
Values are mean ± standard deviation.
**P<0.01, vs before treatment

Diabetology International pp 1-7 First online: 09 March 2016

 Conclusion

• In type 2 diabetes patients complicated by CKD, the effects of treatment

with linagliptin and teneligliptin on CGM-based MAGE were comparable.
• Because both agents significantly reduced the 24-h mean sensor glucose
levels and AUC 180 but did not increase the incidence of hypoglycemia,
they have comparable efficacy and safety in type 2 diabetes patients
complicated by CKD.

Diabetology International pp 1-7 First online: 09 March 2016

 In special

Pharmacokinetics and safety of population

(Hepatic

teneligliptin in subjects with hepatic

impairment)

impairment
Objective – To determine the pharmacokinetic and safety of single oral
administration of therapeutic doses of 20 mg Teneligliptin in subjects
with mild and moderate hepatic impairment as compared to healthy
subjects
Design Open label , non-randomised parallel group study (8 subjects in
each group)
Healthy
Mild hepatic impairment
Moderate hepatic impairment
Evaluatio All Teneligliptin Pharmacokinetic parameters and safety
n parameters
paramete
rs

Clinical Pharmacology in Drug Development

Volume 3, Issue 4, pages 290–296, July/August 2014
 Teneligliptin well-tolerated by patients with
hepatic impairment
Parameter Group Ratio of 90% CI (%)
Geometric mean

AUC 0-∞ Mild 145.85 122.13-174.17

Moderate 159.41 133-190.37

FDA-recommended “dose-adjustment” boundary of 200%

The AUC for Teneligliptin is within the dose adjustment limit set by FDA
No dose adjustment required for patients with mild to moderated hepatic
impairment

Clinical Pharmacology in Drug Development

Volume 3, Issue 4, pages 290–296, July/August 2014
 In special
Teneligliptin improves left ventricular diastolic population
(Cardiac
function and endothelial function patients)

in patients with diabetes.

Major findings of the study

An additional treatment with

Teneligliptin improved Left ventricular
diastolic function and endothelial
function.

Teneligliptin treatment exerts cardio-

protective effects in T2DM patients
with LV dysfunction at an early stage.

An increase in the serum levels of

adiponectin* after 3 months of
Teneligliptin treatment is seen

adiponectin*- adiponectin plays a role of antiatherosclerotic, antidiabetic, and anti-inflammatory effects

A high plasma level of adiponectin leads to a decrease in cardiovascular events Heart Vessels. 2015 Aug 13.
 In special

Effects of teneligliptin on PDMPs and PAI-1

population
(Cardiac
patients)
in patients with diabetes on hemodialysis

International Journal of General Medicine 2016:9 65–71

 Future research on possible benefits of
Teneligliptin
Obesity
Title of the study
The novel DPP-4
inhibitor teneligliptin prevent
s high-fat diet-induced
obesity accompanied with
increased energy expenditure
in mice.
Teneligliptin improves
metabolic abnormalities in a
mouse model of
postmenopausal obesity.
Year of Publishing Teneligliptin effects
Eur J Adipocyte hypertrophy and
Pharmacol. 2014 hepatic steatosis induced by
Jan 15;723:207-15 a high-fat diet were
suppressed by teneligliptin.
J Endocrinol. 2015 Teneligliptin effectively
Oct;227(1):25-36. ameliorated the
characteristics of metabolic
abnormalities associated
with postmenopausal
obesity.. Hepatic steatosis
was also markedly improved.
 Future research on possible benefits of
Teneligliptin
Non-alcoholic Fatty Liver disease
Title of the study Year of Publishing Teneligliptin effects

The Dipeptidyl Peptidase-4 Int J Mol Sci. 2015
Inhibitor Teneligliptin
Attenuates Hepatic
Lipogenesis via AMPK
Activation in Non-Alcoholic
Fatty Liver Disease Model
Mice
 Serum alanine
aminotransferase and
Dec; 16(12): intrahepatic triglyceride
29207–29218. levels were significantly
decreased in teneligliptin-
treated mice (p < 0.05).
 Teneligliptin increased
hepatic expression levels of
phosphorylated AMP-
activated protein kinase
(AMPK) protein.
Teneligliptin – Road ahead
Teneligliptin –Clinical trial in cardiac patients

The trial is expected to be completed by June 2019

Retrieved from https://clinicaltrials.gov/ct2/show/NCT02449330
 Tenegliptin – Dosage and Administration
• Indication
• Oral Teneligliptin is approved as an add-on for treatment of adults
with type 2 diabetes mellitus patients who have not responded
adequately to treatment with diet and exercise or addition of other
anti-diabetic agents such as biguanides, sulfonylureas,
thiazolidinediones, glinides, α-glucosidase inhibitors or insulin.
• Dosage
• The recommended dosage of Teneligliptin is 20 mg once daily.
• Teneligliptin may be administered irrespective of food, preferably
before breakfast.
• It is advisable to uptitrate the dosage to 40 mg once daily in patients
who do not achieve adequate glycemic control as required.

Journal of Diabetes Mellitus, 2016, 6, 113-131

 Precautions while administering Teneligliptin

• Teneligliptin should be used with caution in patients with severe hepatic

impairment & those with heart failure (NYHA Class III - IV), because of a
lack of clinical experience in these populations.
• Teneligliptin should not be used in patients with history of pancreatitis.
If the patient is already on sulfonylurea & addition of gliptin is
considered, in such cases the dose of sulfonylurea should be halved &
then up-titrated as required to reduce the risk of hypoglycaemia.
• There may be chances of hypoglycemia on co-administration of
Teneligliptin with insulin & hence dosage reduction may be required

Journal of Diabetes Mellitus, 2016, 6, 113-131

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