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DPP 4 Inhibitors

Role of Evogliptin


Conceptual Evolution of Incretins
Iso-glycaemic profiles

Incretin effect
Insulin concentration

Glucose given orally

Glucose given intravenously

to achieve the same profile

0 10 20 30 40 50 60 70 80 90
Normal Glucose Homeostasis: Role of Incretins
In response to meals, incretin Fat Increased
1 hormones (GIP and GLP-1)
are increasingly released from Glucose
the small intestine Uptake

Insulin Secretion

GI Tract β Indirect Glucose

Incretin Effect Pancreas suppression
α of glucagon

Glucagon Secretion
Pancreatic cells
Incretins (GIP/GLP-1)
2 respond to high
levels of incretins
β Pancreatic beta cell
α DPP-4 enzymes Decreased
Pancreatic alpha cell
3 break down incretins Glucose

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4.

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.
2. Drucker DJ. Cell Metab. 2006;3:153-165.
T2DM: Role of Incretins
In adults with T2DM, Fat Impaired
1 incretins are released,
but the incretin-mediated Glucose
effects are diminished Uptake

DPP-4 Insulin Secretion


GI Tract β Less indirect

Diminished suppression Hyperglycemia
Incretin Effect α of glucagon

Glucagon Secretion
Incretin action on
Incretins (GIP/GLP-1) 2 pancreatic cells is
β Pancreatic beta cell
α Pancreatic alpha cell Increased

1. Kim W et al. Pharmacol Rev. 2008;60:470-512.

2. Drucker DJ. Cell Metab. 2006;3:153-165.
Postprandial GLP-1 Levels in Patients
With T2D
Normal glucose tolerance
20 Impaired glucose tolerance
* * * * T2D
GLP-1† (pmol/L)

15 *


0 60 120 180 240
Time (min)

Postprandial GLP-1 levels are decreased in patients

with T2D
J Clin Endocrinol Metab. 2001;86:3717-3723.
DPP-4 Inhibition And Incretin Activity:
Insulin/Glucagon Ratio in T2DM

 Insulin
Further impaired
response Hyperglycemia
islet function
Glucose diminished

 Glucagon

DPP-4 inhibitor
 Insulin

Improved islet Improved
function glycemic control
Glucose prolonged

 Glucagon

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus

Adapted from Unger RH. Metabolism. 1974; 23: 581–593; Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
What are incretins?
Gastric Inhibitory Polypeptide

• Secreted by the K cells of the proximal gut. However, type 2

diabetes patients are resistant to its action (high blood level),
making it a less attractive therapeutic target.
What are incretins?
Glucagon-like peptide-1 (GLP-1)

• a 30-amino acid peptide secreted in response to the oral ingestion

of nutrients by L cells, primarily in the ileum and colon.
• There are GLP-1 receptors in islet cells and in the central nervous
system, among other places.
• GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-
IV) .
Physiology of GLP-1 secretion and action on
GLP-1 receptors in different organs and tissues
GLP-1 actions
• GLP-1 suppresses glucagon secretion in normal and
hyperglycaemic states
• At hypoglycemic range glucogon rises despite high levels of GLP-1
• Delays gastric emptying
• GLP-1 has access to brain areas involved in satiety, appetite, food
intake and energy expenditure
• More than 65mg% of glucose is necessary for GLP-1 to augment
insulin release
• Improvements in insulin biosynthesis, induction of neogenesis and
proliferation of beta cells and prevention of apoptosis induced by
toxic factors –Rodent models
• Trans differentiation of exocrine pancreatic ductal cells into beta
• Induces expression of Pdx1 in pancreas
Physiological Actions of GLP-1
• GIP-Incretin effect in healthy subjects
• GLP-1 minor physiologic role
• Retains insulinotropic actvity in T2 DM
• Incretin effect contributed between 27.6% to 62.9%to overall
increments in C-peptide levels
Inhibition of DPP-4 Increases Active GLP-


GLP-1 GLP-1 t½=1–2 min



(>80% of pool)
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.

Gliptins have a promising safety profile among antidiabetics

AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016

Profiles of anti-diabetic medications


The only anti-diabetic category without

any significant point for precaution

DPP4-I: Current Status
Gliptins: What we already know?

Efficacy in real life and in Baseline dependent

Efficacy Similar to other Indian patients is even HbA1c reduction,
OADs better Durability Data

Works in all stages of

diabetes, early, late,
with all drugs and with Placebo Like Safety Promise of Beta Cell
insulin Profile (Hypo, Weight) Regeneration

Seck et al, Int J Clin Pract. 2010 Apr;64(5):562-76, n=1172, 2 years

Barzilai et al, Current Medical Research & Opinion Vol. 27, No. 5, 2011, 1049–1058, Efficacy and tolerability of sitagliptin
monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial
Pharmacol Res. 2015 Oct;100:127-34. doi: 10.1016/j.phrs.2015.07.019. Epub 2015 Jul 23. Sitagliptin in type 2 diabetes mellitus:
Efficacy after five years of therapy.
DPP4-I: Current Place of Therapy
Indicated for the treatment of T2DM as a monotherapy/adjunct to
diet and exercise

• Favourable Clinical Efficacy

• Low risk of hypoglycemia
• Weight neutral
• Rare chances of Side effects

• Backed by extensive scientific evidence

Evogliptin (Suganon) 2015

Diabetes Care 2015;38(Suppl. 1): S1–S94.; Nutrition, Metabolism and Cardiovascular Diseases, vol. 20, no. 4, pp. 224–235, 2010.
A meta-analysis of 18 randomized studies 4,988 patients on DPP4
inhibition therapy and 3,546 patients on control treatment (other diabetic
treatments or placebo)

The relative risk for adverse CV events during follow-up was 52%
lower for DPP4 inhibitors compared to other therapies

Pooled safety studies for other individual DPP4 inhibitors have shown
decreases in risk for major adverse CV events, 57% with saxagliptin,
66% with linagliptin, and 48% with alogliptin

DPP4 inhibitors are safe from a CV standpoint and may possibly

decrease risk of adverse CV events
Am J Cardiol 2012;110:826 – 833
Indianapolis, US, 19 July, 2018 – CARMELINA® (CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with type 2
diabetes at high vascular risk) met its primary endpoint, defined as time to first occurrence of cardiovascular death, non-fatal myocardial infarction or non-
fatal stroke (3-point MACE), with linagliptin demonstrating similar cardiovascular safety compared to placebo.

Linagliptin demonstrates long-term cardiovascular safety in adults with T2DM

(DPP-4 Inhibitor)
• Evogliptin (DA-1229) is a piperazine derivative
• Selective, potent and reversible inhibitor of DPP-4a
• Extensively studied in-vitro & in-vivo animal models for its efficacy and
• Evogliptin has been studied in a RCTs Phase II study and two Phase III
studies in South Korean patient with Type 2 DMb
• Drug has low potential for interaction with other co-administered drugsb
• Evogliptin is approved in South Korea (Dong-A) in 2nd October 2015 & also
in Azerbaijan as Monotherapy and in combination with metformin
• Approved by DCGI to manufacture and market the drug on 28.08.2018.

(a) Wu D, et al. Diabetes Obes Metab. 2014 Jan;16(1):30-7. (b) McCormack PL. Drugs. 2015 Nov;75(17):2045-9.
Evolving DPP4 Inhibitors

Are all DPP4I Equal?

DPP 4 Enzyme with the Binding Site

S2 Extensive S2 S1 S1’ S2’

DPP4 Enzyme

Binding with S1 and S2 is Binding to additional sites

considered as fundamental like S1’, S2’ or S2
binding and required to extensive produces more
produce DPP4 inhibition. inhibition of DPP4

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

Are all DPP4I Equal?


S2 Extensive S2 S1 S1’ S2’

DPP4 Enzyme

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

Are all DPP4I Equal?

Alogliptin, linagliptin

S2 Extensive S2 S1 S1’ S2’

DPP4 Enzyme

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


Sitagliptin, Teneligliptin,

S2 Extensive S2 S1 S1’ S2’

DPP4 Enzyme

• Evogliptin
• Binds S1, S2, and S2 extensive binding sites
• Noncovalent binding
• 6,000 times higher potency compared to human DPP-VIII and DPP-IX
• 20,000 times greater potency compared to human DPP-I,II

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

Phase I Study
• Study design:
– A dose block-randomized, double-blind, placebo-controlled, single/multiple
dosing, dose escalation study
• Part I: Single Ascending Dose Study
• Part II: Multiple Ascending Dose Study
• Pharmacokinetics:
– Dose dependent increase in AUC0 – 24 and Cmax
– T1/2 = 32.5 – 39.8 hours
– No Food Effect
• Pharmacodynamics:
– Dose dependent DPP4 inhibitory activity
• Safety Observation:
– Safe in all dose range in both SAD and MAD.
– All AEs were mild in severity

2.5, 5, 10 mg/ day dose levels were selected for Phase 2 study
Clin Ther. 2012 Sep;34(9):1986-98.

Evogliptin: PK: Conclusions from Phase I

• The absolute bioavailability of Evogliptin was 50.24%
• Evogliptin reached its plasma concentration peak at 3.0 to 5.5 hours
following a single oral dose
• Plasma DPP-4 inhibition rapidly surpassed 80% in less than an hour
after administration.
• The terminal elimination half-life (t1/2) of evogliptin was 32.5-39.8
• The pharmacokinetics of DA-1229 were unchanged by food
• Evogliptin reached a steady-state concentration within 3 days and
accumulated only a small amount with an accumulation index of
DA-1229 was well tolerated within the dose range of 1.25 to 60 mg.

Clinical Therapeutics/Volume 34, Number 9, 2012


Evogliptin: PK: Conclusions from Phase I

• According to in vitro studies, evogliptin is not an inducer of cytochrome
P450 (CYP) 3A4 nor an inhibitor of CYP1A2, 2C9, 2C19, 2D6, or 3A4,
although its metabolism is primarily mediated by CYP3A4
• The renal clearance (15.0-16.8 L/h) and fraction excreted unchanged
in urine (27%–34%) of evogliptin.
• No dose adjustment was required because urinary excretion is not the
major pathway for the elimination of evogliptin

Drug Design, Development and Therapy 2014:8 1709–1721

Xueying Tan & Jingbo Hu (2016): Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes, Expert Opinion on
Pharmacotherapy, DOI:10.1080/14656566.2016.1183645
Evogliptin: Novel PD
• ↑ the PP GLP-1 levels by 1.5- to 2.4-
fold Evogliptin improved (Animal Data)
• Insulin sensitivity
• ↓ the PPG levels to 20%–35%
• Delay the onset of DM
• The DPP-IV inhibition increased in a • ↑ β-cell replication and
dose-dependent manner, and neogenesis
remained >80% over 24 hours • Renal protective effect
• Improve hepatic steatosis

IC 50
Drug Design, Development and Therapy 2014:8 1709–1721
Evogliptin: Favourable Pharmacokinetics

DPP4 I t1/2 (hrs) Dosing Excretion

Vildagliptin 1.5-4.5 BID Renal

Sitagliptin 8-24 OD Renal
Saxagliptin Parent: 2-4, OD Renal
Metabolite: 3-7
Alogliptin 12-21 OD Renal
Linagliptin 10-40 OD Biliary
Teneligliptin 24.2 OD Renal & hepatic
Evogliptin 32-39 OD Hepatic & lesser
by renal

European Journal of Medicinal Chemistry 74 (2014) 1-32, Endocr J. 2015;62(1):13-20; Metabolic Syndrome and Obesity: Targets and Therapy 2013:6
Phase II study
• Study Title:
–A randomized, double-blind, placebo-
controlled, therapeutic exploratory clinical trial
to investigate the efficacy and safety of DA-
1229 after oral administration in patients with
type 2 diabetes who have inadequate
glycaemic control on diet and
• Objective:
– To evaluate efficacy and safety of DA-1229
and determine the optimal dose.
• Study design:
– Randomized, double-blind, placebo-controlled,
parallel-group, fixed-dose, multi-center, dose
finding design, setting 3 dose groups of DA-
1229 (2.5mg, 5mg and 10mg).
– Patients randomized 158
Diabetes Metab Res Rev 2015; 31: 295–306.
Baseline characteristics of study participants
according to treatment groups

Diabetes Metab Res Rev 2015; 31: 295–30

Hb1Ac Reduction
0.7 0.66
0.6 0.56
Placeb Evo Evo 5 Evo 10
o 2.5 mg mg mg
0.09 0.56 0.66 0.61
Hb1Ac Reduction

In a phase II trial involving sitagliptin

(100 mg daily), the mean HbA1c was
significantly reduced by approximately
0.55% compared with the placebo after
12 weeks of treatment.
In a 12-week phase II trial of vildagliptin
(100 mg daily), a 0.53% reduction in the
mean HbA1c after 12 weeks of
treatment was observed
Diabetes Metab Res Rev 2015; 31: 295–30
Dose selection for Phase III study:

• Efficacy End Points:

– Primary efficacy endpoint: Change in HbA1c from baseline to
week 12
– The placebo-adjusted reduction in HbA1c was 0.47, 0.57
and 0.53% at doses of 2.5mg, 5mg and 10mg,

• 5 mg dose group showed highest reduction in HbA1c

values among other groups.

• Evogliptin was safe and well tolerated

5 mg dose is selected for Phase III study

Diabetes Metab Res Rev 2015; 31: 295–306.
Incidence of treatment-emergent adverse events
and adverse drug reactions

There were no hypoglycaemic events. and there were no clinically

significant findings with respect to vital signs, ECG or laboratory tests.

5 mg dose is selected for Phase III study

Phase III Study
• Two Phase III studies conducted in Korea
– Monotherapy
• No of patients: 160
• Design: Placebo controlled study
• Treatment duration: 24 weeks

– Combination therapy
• No of patients: 222
• Design: Sitagliptin controlled with
background metformin therapy
• Treatment duration: 24weeks
Phase III study: Evogliptin Monotherapy in
Patients with T2DM

In this randomized, double-blind, placebo-controlled, parallel-

group, multicentre, 160 patients with T2D were assigned to either
evogliptin 5 mg or placebo for 24 weeks.

Diabetes Obes Metab. 2017;19:1681–1687.

Study participants

Diabetes Obes Metab. 2017;19:1681–1687

Baseline demographics and characteristics of the
study participants

Diabetes Obes Metab. 2017;19:1681–1687

Changes of HbA1c from baseline to week 24

• The mean HbA1c significantly decreased from 7.20% at baseline to 6.97%

in the evogliptin group.
• The mean HbA1c level increased modestly in the placebo group.
• The mean change in HbA1c was significantly greater in the evogliptin group
than in the placebo group (−0.23% vs 0.05%; P < .0001)

Diabetes Obes Metab. 2017;19:1681–1687

The secondary efficacy endpoints
• The proportion of patients achieving

HbA1c <6.5%: significantly higher in the

evogliptin group than in the placebo group

(33.3% vs 15.2%; P = 0.008)

• Mean change in FPG increased in both

groups, a numerically greater increase

was seen with placebo compared with

evogliptin (0.008 mmol/L in the evogliptin

group and 0.401 mmol/L in the placebo


Diabetes Obes Metab. 2017;19:1681–1687

Adverse drug reactions
One asymptomatic
hypoglycaemic episode was
reported in the evogliptin
group, but this episode was
not suspected to be related
to treatment.
No clinically meaningful
emerged regarding the
laboratory analyses or vital

• Treatment-emergent AEs were reported by 33.3% of the patients in the evogliptin group and 35.0% of
the patients in the placebo group
• Four adverse drug reactions (constipation, diarrhoea, hypersensitivity and hyperglycaemia) were
suspected to be related to evogliptin.
• No serious AEs occurred with evogliptin, and one serious AE (tendon rupture) was reported in one
placebo recipient.

Pancreatitis was not reported in this study. Diabetes Obes Metab. 2017;19:1681–1687

• Evogliptin 5 mg monotherapy significantly decreased HbA1c and was well

tolerated in patients with T2D inadequately controlled on diet and exercise.

• The results from the present study suggest that patients with T2D with
modest hyperglycaemia may be good candidates for evogliptin

• Evogliptin 5 mg once daily provides a new option for clinicians in the

management of T2D.

Diabetes Obes Metab. 2017;19:1681–1687

Phase III study: Evogliptin in Combination with
Metformin in Patients with T2DM

This trial consisted of a 24-week multicentre, randomized, double-blind,

double-dummy, active-controlled study and a 52-week open label
extension study to assess the efficacy and safety of evogliptin

Diabetes Obes Metab. 2017;19:654–663.

Study setting and design

Those participants, who completed the 24-week treatment period, gave their
consent to receive another extended 28 weeks of open label treatment with 5
mg evogliptin qd. In the extended study, patients visited the site every 7 weeks
(at weeks 31, 38, 45 and 52).

Diabetes Obes Metab. 2017;19:654–663.

Study participants
Baseline, results at week 24 and changes in results from
baseline for HbA1c, fasting plasma glucose, mean daily

Diabetes Obes Metab. 2017;19:654–663.

Changes of HbA1c from baseline to week 24

Evogliptin and sitagliptin decreased the HbA1c level after treatment during 24
weeks (−0.59% ± 0.61% and −0.65% ± 0.61%, respectively; all P < 0.0001)

Diabetes Obes Metab. 2017;19:654–663.

Changes of HbA1c from baseline

After the 52-week treatment period, evogliptin caused a persistent

decrease in the level of HbA1c (-0.44 +/-0.65%, P < .0001)

Diabetes Obes Metab. 2017;19:654–663.

The secondary efficacy endpoints

• Evogliptin and sitagliptin decreased FPG (-0.60 ± 1.11 mmol/L

and -0.59 ± 1.47 mmol/L, respectively; all P < .0001) and MDG (-
0.92 ± 1.60 mmol/L and -1.30 ± 1.71 mmol/L, respectively; -all P <
.0001) levels from baseline through week 24

• After 52 weeks, the evogliptin/evogliptin group exhibited a

persistent decrease in FPG (-0.38 ± 1.19 mmol/L; P = .0048) and
MDG (-1.00 ± 1.69 mmol/L; P < .0001).

MDG: Mean Daily Glucose. Diabetes Obes Metab. 2017;19:654–663.

Adverse drug reactions
• AE: nasopharyngitis (7.2%), dyspepsia (4.5%), diarrhea and
pruritus (3.8%, each)
• In general, both treatments were well tolerated, with incidences and
types of adverse events comparable between the two groups.
• Hypoglycaemic events, mostly mild, were reported in 0.9% of
patients treated with evogliptin and in 2.8% of patients treated with
sitagliptin for 24 weeks.
• All fasting lipid parameters, which included total cholesterol, LDL-C,
HDL-C, TG and FFA, did not change significantly after 24 weeks of
evogliptin treatment nor after 52 weeks of evogliptin/ evogliptin

Diabetes Obes Metab. 2017;19:654–663

• Evogliptin 5 mg added to metformin therapy effectively improved
glycaemic control and was non-inferior to sitagliptin and well tolerated
in patients with type 2 diabetes mellitus that was inadequately
controlled by metformin alone.

Diabetes Obes Metab. 2017;19:654–663

Alkem Phase III Trial in Indian patients

A multicenter, randomized, double-blind, double dummy study comparing the

efficacy and safety of Evogliptin with Sitagliptin in patients with type 2 diabetes
mellitus receiving background therapy with Metformin

Subject Disposition

Failure(N=227 )
d (N=184)

Evogliptin 5 mg Sitagliptin 100

(N=92 ) mg (N=92 )

Completed Completed
(N=82) (N=82)

* 20 patients - Patient’s Voluntary Withdrawal of Consent (19), 1 Patient wrongly randomised


Primary Efficacy Parameter - HbA1c change at

Week 12

Evogliptin 5 mg Sitagliptin 100 mg

N=75 N=75

Baseline 8.33 ± 0.82 8.35 ± 0.67 0.905

Visit 6/ wk 12
7.96 ± 1.24 8.03 ± 1.23
(Mean change from 0.751
(-0.37) (-0.32)

p-value 0.0035 0.0177

95% CI for treatment difference estimate (-0.374: 0.330) NI margin: 0.35

14 - Rescue (2), major deviation (12) – IP noncompliance

Secondary Efficacy Parameter – HbA1c change at

Week 24

Evogliptin 5 mg Sitagliptin 100 mg p-value

Baseline 8.33 ± 0.82 8.35 ± 0.67 0.905

Visit 9/ Week 24
7.78 ± 1.22 7.86 ± 1.15
(Mean change from 0.654
(-0.55) (-0.48)

p-value 0.0001 0.0009


HbA1c change at Week 12 & 24








Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -0.37 -0.55
Sitagliptin -0.32 -0.48

Subjects achieving HbA1c < 7% at the Week 24

Parameter Evogliptin 5 mg Sitagliptin 100 mg P-value

No. of patient (%) at week

20 (26.7 %) 15 (20.0 %) 0.3344

Proportion of patients

30 26.7
25 20
Week 24 - Visit 9
Evogliptin 26.7
Sitagliptin 20

FPG change at Week 12 & Week 24 from baseline

Evogliptin 5 mg Sitagliptin 100 mg p-value

Baseline Visit 162.13 ± 60.82 174.54± 63.41 0.225

Visit 6/ Week 12
(Mean change from -19.08 -24.74 0.470
p-value 0.0271 0.0084
Visit 9/ Week 24
(Mean change from -22.96 -33.58 0.820
p-value 0.0040 0.0006

FPG change at Week 12 & Week 24 from baseline






Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -19.08 -22.96
Sitagliptin -24.74 -33.58

PPG change at week 12 & 24 from baseline






Week 12 - Visit 6 Week 24 - Visit 9
Evogliptin -21.45 -25.4
Sitagliptin -28.12 -19.35

Body Weight by Visit

Evogliptin Sitagliptin
75 • 66.23 ± 12.26 Scree • 69.10 ±
ing ning • 13.77
Visit 2 • 66.17 ± 12.19 Visit 2
70 13.78
69.12 ±
Visit69.13 • 66.2569.12
± 12.0969.03 68.92
Visit68.823 68.78 68.7
Mean Weight

65Visit 4
66.17 66.25
• 66.31 ± 12.15
66.31 66.02 66.02 69.03 ±
65.77 65.88
Visit 4
Visit 5 • 66.02 ± 12.17 • 13.41
68.92 ±
Visit 5
• 66.02 ± 11.98 • 13.36
Visit 6 Visit 6
Visit 9 • 65.90 ± 11.91 Visit 9
• 13.55
68.71 ±
50 No Significant weight change noted across both the
Screening( Week 0 - Week 2 -
* Values represent Mean± SD groups
Week 4 - Week 8 - Week 12 - Week 16 - Week 20 - Week 24 -
Visit 1) Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9

No effect on body weight seen in both the groups


• Two hypoglycemia events were reported during the study; 1 event
each in evogliptin and sitagliptin groups. Both events were mild and
unlikely to be related to the study drug.
• AE was dyslipidaemia (evogliptin: 6 events in 6 [6.5%] patients;
sitagliptin: 5 events in 5 [5.4%] patients), and most of these events
were reported to be unrelated to the study drug.

Drug- Interaction study

• Drug Drug Interaction (DDI) study with Metformin:
– Objective: To evaluate DDI between Evogliptin and Metformin by
comparing PK/PD, safety and tolerability after multiple dosing of
Evogliptin plus Metformin to multiple dosing of either of Evogliptin alone
or Metformin alone.
– Study design: A randomized, open-label, three-treatment, three-period,
six-sequence, crossover study
– No of Subjects: 36 healthy subjects

Result: Co-administration of multiple doses of Evogliptin and metformin

did not alter the pharmacokinetics of either drugs.
DDI Study with Clarithromycin and Rifampicin

Comparison of Evogliptin (S) with or without Clarithromycin (CAM)

Comparison of Evogliptin (S) with or without Rifampicin (RFP)

Evogliptin is unlikely to cause interactions with other drugs acting as a

substrate of cytochrome enzymes

Study in Renal Dysfunction

• Renal Impairment Study:
– Objective: To evaluate PK and tolerability of Evogliptin in subjects with
renal impairment by comparing to those in subjects with normal renal
– Study design: A single dose, open-label, parallel-group study
– N= 32 (mild to severe renal dysfunction)
– GMR (90% CIs) of Cmax and AUClast were 1.52 and 1.98 for severe
renal impairment and 1.32 and 1.8 for moderate renal impairment
– Concentration was found Safe in Phase I Multiple Dose study
Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal
Disease (MDRD) formula: normal, ≥ 90 mL/min; mild, 60 – 90 mL/min; moderate, 30
– 60 mL/min; and severe, 15 – 30 mL/min.
Dosage adjustment of Evogliptin is not required in patients with renal dysfunction

The drug was found safe in all grade of kidney dysfunction

No clinical experience of Evogliptin in patients with end-stage renal impairment requiring
dialysis, administration of Evogliptin is not recommended in such patients.
Diabetes Obes Metab. 2017 Feb;19(2):294-298, PI of Sugano
No clinically
changes were
observed by
testing, ECG,
of vital signs
or physical

Diabetes Obes Metab. 2017 Feb;19(2):294-298

Animal Studies

Life Sci. 2012 Jan 2;90(1-2):21-9.

Overall plasma lipid levels stayed lower and hepatic lipid accumulation was
drastically suppressed by evogliptin treatment

Moreover, reduction in plasma non-esterified fatty acids supported the

improvement of insulin resistance by evogliptin treatment
Conclusively, our findings suggest that evogliptin treatment
ameliorates fatty liver by increasing insulin sensitivity and suppressing
Recent clinical trials with evogliptin

• Phase IV Clinical Trial to Investigate the Effect on Blood

Glucose of Evogliptin in Patients With Type 2 Diabetes
(EVERGREEN) (n=207)
– Evogliptin 5mg Group: Administration with Evogliptin 5mg for 0-24 weeks.
– Liniagliptin 5mg Group: Administration with linagliptin 5mg for 0-12
weeks, and with Evogliptin 5mg for 13-24 weeks
– Study completed in March 2018 – Results will be available in Dec 2018
– Abstract Presented in IDF-WPR 2018 Conference


Abstract Presented

Mean change in HbA1c in evogliptin and FPG concentration in evogliptin and

linagliptin groups linagliptin groups at baseline and at week 12

Hypoglycemic events, mostly mild, were reported in 1.98% of patients with evogliptin and 4.76% of patients with linagliptin for 12weeks.
Salient features of Evogliptin
 Highly Selective for DPP-4 (More than 1,000-fold selective against total 170 off-target
enzymes and receptors)

 Highly Potent (IC80 = 4nM; Sitagliptin: 80nM)

 Comparable efficacy to Sitagliptin & Linagliptin

 Weight neutral

 Minimal potential of drug interactions

 Safe in patients with renal dysfunction

 Two RCT: head to head comparison with linagliptin*

 Decreased hepatic steatosis & normalized liver enzymes, Potential benefits in NAFLD
and NASH#

*: result are not available in public domain # Preclinical data