THE TWENTY YEARS JOURNEY OF

VILDAGLIPTIN FROM CLINICAL TRIALS

TO REAL WORLD EVIDENCE

John MF Adam

Division of Endocrinology and Metabolism

Department of Internal Medicine,
Faculty of Medicine, Hasanuddin University, Makassar
 Therapy considerations for patients with type 2 diabetes

Key considerations for pharmacological therapy include:1

Cost,
Efficacy Hypoglycaemia Weight Side effects comorbidities,
(HbA1c)
pt. preference

Diabetes Guidelines recommendations for pharmacological agents1,2

Initial drug therapy: Combination drug therapy:

• If metformin cannot be used as • When metformin fails to achieve or
initial drug therapy (contraindicated maintain glycaemic goals, another
or not tolerated), another oral agent agent should be added
can be chosen

HbA1c=haemoglobin A1c; Pt=patient

1American Diabetes Association. Diabetes Care 2014;37(Suppl 1):S14–80; 2Inzucchi et al. Diabetes Care 2012;35:1364–79
 The challenge of blood glucose control in diabetes
mellitus

Hypoglycaemia /
weight gain

HbA1c
control

HbA1c=haemoglobin A1c

Jacob et al. Diabetes Obes Metab 2007;9:386–93; Khunti & Davies. Diabetes Obes Metab 2010;12:474–84;
Wright et al. J Diabetes Complications 2006;20:395–401
 The challenge of blood glucose control in diabetes
mellitus

Hypoglycaemia / HbA1c
weight gain control

HbA1c=haemoglobin A1c

Jacob et al. Diabetes Obes Metab 2007;9:386–93; Khunti & Davies. Diabetes Obes Metab 2010;12:474–84;
Wright et al. J Diabetes Complications 2006;20:395–401
 Metformin SU TZD DPP - 4 SGLT2-
Innhibitors Innhibitors

Reduced A1c better than the new oral anti - diabetics

Therapy for Diabetes Mellitus and Related Disorders, 6th ed. In: Umierrez GE (ed). American
Diabetes Association 2014
 Pharmacokinetics and pharmacodynamics of DPP-4
inhibitors

Generic Metabolism Excertion DPP-4 inhibition

name
Vildagliptin Hydrolyzed Renal (22% as > 80 %, 12 hours
(Galvus) to inactive parent, 55% as postdose
metabolisme inactive metabolite
Sitagliptin Not apreciably Renal (~80% > 80%, 24 hours
(Januvia) metabolized unchanged) postsode
Saxagliptin Hepatic to active Renal (12-29% ~70%, 24 hours
(Onglyza) metabolite as parent, 21-52 postdose
as active matabolite
Linagliptin Not apreciably Billiary (> 70% ~70%, 24 hours
(Trajenta) metabolized unchanged as postdose
parent)

Aschner P. Dipeptidyl-peptidase 4 inhibitors. In: Umierrez GE (ed). Therapy for Diabetes Mellitus
and Related Disorders, 6 th ed. American Diabetes Association 2014; 387-400
 CARDIOVASCULAR EFFECT

Aloglitpin EXAMINE
Saxagliptin SAVOR
Sitagliptin TECOS
Vildagliptin ??????

Preferable : Combination therapy

with Metfomin
 ALGORITMA ADA / EASD - 2018
Healthy eating, weight control, increased physical activity, and diabetes education
Mono
Metfomin
therapy
Efficacy’ High
Hypo risk Low risk
Weight Neutral / loss
Side effects GI / lactic acidosis
Side costs’ Low

If HbA1c target not achieved after ~3 months of monotherpay, proceed to 2-drug combintaion (order not meant to
denote any specific preference-choice dependent on a variety of patient- and disease-specififc factors):

Metfomin Metfomin Metfomin Metfomin Metfomin Metfomin

+ + + + + +
Dual Sub TZD DPP-4 inhibitor SGLT2 inhibitor GLP-1 RA Insulin basal
therapy
Efficacy’...........High ................. High .................... Intermediate......Intermediate............ High............ Highets
Hypo risk..........Moderate risk ...Low risk................Low risk.............Low risk.................. Low risk...... High risk
Weight.............Gain...................Gain .....................Neutral..............Loss..........................Loss............Gain
Side effects......Hypoglycemia....Edema, HF, fxs.....Rare..................GU, dehydration..... GI............... Hypoglycemia
Side costs’.......Low.....................Low .....................High...................High..........................High...........Variable

If HbA1c target not achieved after ~3 months of dual therpay, proceed to 3-drug combintaion (order not meant
to denote any specific preference-choice dependent on a variety of patient- and disease-specififc factors):

A1c < 9% consider monotherpy; A1c > 9% consider dual therapy; A1c > 10% consider combination injectable therapy
 ALGORITME PENATALAKSANAAN HIPERGLIKEMI
ADA 2018

1. Kadar A1C < 9.0% pilihan OAD monoterapi, pilihan

pertama METFORMIN

2. Kadar A1C > 9.0% sebaiknya segera dimulai dengan dual

terapi yaitu metformin dan obat pendam-
ping lainnya
a. ada ASCVD sebaiknya pilihan obat pendamping adalah obat
yang dapat menurunkan kejadian kardiovaskuler / mortalitas
(Empagliflozin, Canagliflozin)
b. tanpa ASCVD, obat pendamping lain seperti DPP-4 Inhibitor

3. Kadar A1C > 10% atau glukosa plasma sewaktu > 300 mg/dL,
sebaiknya KOMBINASI DENGAN INSULIN
 INHIBITION OF DPP – 4
INCREASES ACTIVE GLP-1
Meal
Insulin action GLP-1 as an
Intestinal secretagog, is glucose
GLP-1
release dependent
Active
GLP-1

DPP-4

DDP - 4 inhibitor GLP-1

inactive
(>80% of pool)

GLP-1 = Glucagon-Like Peptide-1; DPP-4= Dipeptidyl Peptidase-4

Adapted from Deacon CF, et
Rothenberg P, al. Diabetes.
et al. 1995;44:1126-1131.
Diabetes. 2000;49(suppl 1):A39.
EDGE: Study purpose and main objective
(Mean baseline A1c 8,2%) EDGE= Effectiveness of Diabetes
control vildaGliptin and vildagliptin-mEtformin

Study Purpose:
To assess the profile of vildagliptin and the fixed-dose combination of
vildagliptin/metformin relative to comparator oral anti-diabetic drugs (OADs)
in patients with type 2 diabetes in a real-world setting

Primary Objective:
To determine the proportion of patients on vildagliptin add-on dual therapy or
vildagliptin/metformin (fixed-dose) relative to comparator OAD dual therapy
responding (A1c drop >0.3%) to 12 months’ treatment without any of the
predefined tolerability issues:

➢peripheral edema, or
➢hypoglycemic events, or
➢discontinuation due to GI events, or
➢weight gain (>5%)

Mathieu C, et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: A real-life
worldwide observational study (EDGE). Int J Clin Pract. 2013 Oct;67(10):947-56.
 27 Countries participating in EDGE
Europe
Austria, Belgium, Czech Republic, Germany, Greece, Netherlands,
Portugal, Slovakia, Sweden, Bulgaria, Luxembourg, Russia

Total Enrolled Population: 45,868 East Asia

South Korea
Philippines
Latin America India
Mexico, Venezuela,
Argentina, Colombia,
Ecuador

Middle East
Jordan, Palestine, Lebanon,
Bahrain, Kuwait, Oman
United Arab Emirates
12
Adapted from Mathieu C, et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2
diabetes: A real-life worldwide observational study (EDGE). Int J Clin Pract. 2013 Oct;67(10):947-56.
 Study design (EDGE study)
• Multinational, multicenter, post-authorization, prospective, observational, cohort study
• EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin)
involved nearly 46,000 patients (intention-to-treat [ITT] population) from nearly 3,000
centres in 27 countries from Europe, Central and Latin America, Asia and the Middle
East

Vildagliptin add-on dual therapy or vildagliptin/metformin (fixed-dose)*

Monotherapy failure

Comparator OADs dual therapy **

Month 0 1 2 3 4 5 6 7 8 9 10 11 12
BL demography HbA1c HbA1c
HbA1c Weight Weight
Weight T2DM meds T2DM meds
T2DM meds AEs, SAEs AEs, SAEs

REQUIRED OPTIONAL REQUIRED

DATA COLLECTION OPPORTUNITIES

*Vildagliptin cohort: T2DM patients newly initiating vildagliptin as add-on dual therapy or newly initiating vildagliptin/metformin (fixed-dose) from non-
vildagliptin monotherapy
**Comparator OAD cohort: T2DM patients newly initiating therapy with oral anti-diabetic therapies other than vildagliptin (defined as SU, metformin, TZDs,
metiglinides, α-glucosidase inhibitors) as add-on dual therapy except as add-on to vildagliptin, other DPP-4 inhibitors, or GLP-1 mimetics/analogues
AE = adverse event; BL = baseline; OAD = oral anti-diabetic drug; T2DM = type 2 diabetes mellitus; TZDs = thiazolidinediones

Mathieu C, et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: A
real-life worldwide observational study (EDGE). Int J Clin Pract. 2013 Oct;67(10):947-56.
 The EDGE Study
One of the largest T2DM observational studies ever conducted in a real-world setting
12-month observational, multicenter, post-authorisation, prospective cohort study, which included
45,868 patients from 27 countries worldwide

Overall HbA1c reductions Patients who achieved HbA1c <7%,

Vildagliptin n = 29759; Comparators n = 16078 without hypoglycaemia and weight gain
Patients at goal (HbA1c <7%)
HbA1c drop (%) 40.0%
0 35.1%
-0.2 Vildagliptin Comparators
30.0%
-0.4 23.2%
-0.6 20.0%
-0.8
-1 10.0%
-0.99
-1.2
-1.19 0.0%
-1.4
BL 8.17% BL 8.16% Vildagliptin Comparators

BL=baseline
OAD comparators used: metformin, SU, TZD, AGI, glinide; other DPP-4 inhibitors and GLP-1 analogues are excluded
Adapted from Mathieu C, et al, Int J Clin Pract 2013;67:947-56
 Vildagliptin as add-on metformin in real-life setting:
-1.1% HbA1c reduction
Broadly consistent with the decrease seen in randomized controlled trial settings

Vildagliptin was consistently effective Vildagliptin as add-on metformin

in reducing HbA1c 24-week-therapy
12-month-therapy in real-life setting in randomized controlled trial settings
(Baseline 8.17±1.3%)1 (Baseline 8.4±0.1%)2

Consistent efficacy

1 EDGE Study. Mathieu C, et al, Int J Clin Pract 2013;67:947-56

2 Bosi E, et al, Diabetes Care 2007;30:890–5
 Conclusions EDGE
➢ Under "real-life" conditions more patients responded in the
vildagliptin as compared with comparator as measured by a
composite endpoint assessing efficacy and tolerability

➢ In this large "pragmatic" trial vildagliptin provided glucose control

(A1c -1.1%) consistent with previous randomized clinical trials

➢ Overall adverse events were under-reported if compared to an

"explanatory trial" but consistent with those seen in other "real-life
studies"

➢ Overall adverse events were not different between vildagliptin and

comparator and consistent with those seen in vildagliptin clinical
program.

EDGE Study. Mathieu C, et al, Int J Clin Pract 2013;67:947-56

 VILDAGLIPTIN RAMADAN
STUDIES (Mean baseline A1c was 7,4%)
 VIRTUE: Objectives

– VildagliptIn expeRience compared wiTh

sulfonylUreas obsErved during Ramadan
– To assess the effect of vildagliptin compared with SUs
on hypoglycemia in Muslim patients fasting during
Ramadan in a real-world setting, using a large
population of patients from the Middle East and Asia
– To assess changes in body weight, safety and treatment
compliance for both therapies

SU = sulphonylurea

Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
VIRTUE: data from >1300 fasting T2DM patients pooled
from 10 countries

T2DM = Type 2 diabetes mellitus

Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
 VIRTUE: Numbers of patients from participating countries

Country Vildagliptin SU
n (%) n (%)
Bangladesh 50 (7.3) 49 (7.8)
Egypt 124 (18.1) 126 (20.0)
India 58 (8.5) 51 (8.1)
Pakistan 121 (17.7) 121 (19.2)
Indonesia 23 (3.4) 19 (3.0)
UAE 79 (11.5) 48 (7.6)
Lebanon 172 (25.1) 152 (24.1)
Kuwait 12 (1.8) 17 (2.7)
Oman 31 (4.5) 22 (3.5)
Saudi Arabia 14 (2.0) 26 (4.1)
All* 684 (100.0) 631 (100.0)

*18 patients excluded, as they were not treated with a medication of interest
SU = sulphonylurea

Al-Arouj M, et al. Abstract accepted for presentation at American Diabetes Association 73 rd Scientific
Sessions, June 21–25, 2013, Chicago, USA;
 VIRTUE: prospective, multinational ‘real-world’ study design

Two patient cohorts:

Patients on
stable diabetesvildagliptin plus metformin† or vildagliptin monotherapy*
treatment (1:1)
SU plus metformin† or SU monotherapy*

Data collection Data collection

opportunity 1 opportunity 2
-6 weeks to day prior Fasting period End of study
to start of fasting approx. 4 weeks

6 weeks before Start of fasting End of fasting 6 weeks after

fasting period period fasting

Observational period of approximately 16 weeks

†single pill combination allowed when available

*if applicable, as per local approved prescribing information
SU=sulphonylurea

Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
21
 VIRTUE study: Fewer Hypoglycaemic Events with Vildagliptin
Compared To SUs

Patients with ≥1 hypoglycaemic event Patients with grade 2

hypoglycaemic events
P<0.001‡ P=0.053‡
123 ~3.5
(19.8%) -fold

Patients (n) with grade 2

hypoglycaemic event

hypoglycaemic event
Patients (n) with ≥1

36
(5.4%)
4

Vildagliptin (n=669†) SU (n=621†)

†Number of patients with a post baseline assessment of hypoglycaemic events. hypoglycemia defined as grade 1 (mild): reported symptoms by the patient
and/or blood glucose measurement of <3.9 mmol/L (70 mg/dL) or grade 2 (severe): need for third party assistance ‡Fisher’s exact test
SU = sulphonylurea
Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
22
 VIRTUE: HbA1c Changes

Mean change in HbA1c (%) pre- to post-Ramadan

0.5
Mean change in HbA1c
from baseline (%)

0.02
0

–0.24 –0.26
P<0.001‡
–0.5

–1 Vildagliptin (n=485†) SUs (n=417†) Between-treatment

difference

†Thewithin and between treatment differences were based only on patients with HbA1c levels
assessed at both baseline and end of study. ‡Two-sample t test
SU = sulphonylurea; HbA1c = haemoglobin A1c
Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
23
 VIRTUE: Changes in Body Weight

Mean reduction in body weight (kg) pre- to post-Ramadan

0
Mean body weight change

–0.13
from baseline (kg)

–0.5

–0.63
–0.76 P<0.001‡
–1

–1.5

–2 Vildagliptin (n=659†) SUs (n=590†) Between-treatment

difference

†The mean change in body weight and the between treatment difference were based only on patients
with body weight assessments at both baseline and end of study. ‡Two-sample t test
SU = sulphonylurea

Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
24
 VIRTUE: Conclusions
•A large study assessing the relative benefit of DPP4 inhibitor in
Muslim patients with T2DM fasting during Ramadan

•A significant and clinically relevant ~3.5 fold lower incidence of

hypoglycaemic events with vildagliptin versus SU treatment was
reported during fasting

•Vildagliptin therapy was associated with significantly fewer patients

experiencing hypoglycemia compared with SU therapy in a large
representative cohort fasting muslim patients with T2DM. This
outcome is meaningful in the context of good glycaemic and weight
control in vildagliptin-treated patients who fasted in this study

SU = sulphonylurea; DPP4 = dipeptidyl peptidase 4; T2DM= type 2 diabetes mellitus

Al Arouj M., et al. Int J Clin Pract. 2013; doi 1111/ijcp 12243
Conclusion

Vildagliptin demonstrated its efficacy in lowering HbA1c

and achieving glycemic control better than sulphonylureas
with less risk of hypoglycemia and weight gain, which
makes vildagliptin a wise option for T2DM management
during Ramadan fasting
Europe, September 2017