DPP4 inhibitors have similarities such as sustained glucose lowering, minimal side effects, and weight neutrality. Differences include binding characteristics, with some binding longer to DPP4. Vildagliptin may provide better fasting glucose control due to maintaining overnight GLP1 levels. Vildagliptin has proven efficacy and safety in Ramadan fasting and has shown cardiovascular safety in clinical trials and real-world evidence, with no increased risk of heart failure unlike some other DPP4 inhibitors.

1. Presentation Name Presenter:
Are all DPP4 inhibitors the
same?

2. Presentation Name Presenter:
DPP4 inhibitors: What are the similarities?
• Sustained glucose lowering
• Minimal incidence of hypoglycemia and other side effects
• Weight neutrality
Diabetes Ther 2014; 5:1–41

3. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
• Differences in DPP4 inhibition
• Any differences in efficacy?
• Usage in Ramadan
• CV outcome & effect on QTC
• Usage in renal impairment

4. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
Differences in DPP4 inhibition
DPP4 inhibitors such as vildagliptin tend to covalently bind to the DPP4
enzyme – thus binding for a longer time – this may result in a better
control on glycaemic variability

5. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
Any differences in efficacy?

6. Presentation Name Presenter:
6
Vildagliptin vs. sitagliptin - Better circadian glycaemic control
Diabetes Metab. 2012; 38: 359 – 66
OPTIMA study. N=38 T2DM patients inadequately controlled on metformin (HbA1c 6.5 – 8%) were
randomized to 2 groups (vildagliptin 50 mg BID or sitagliptin 100 mg OD) and followed for 8 weeks.
130.6 131
118.5
129.4
112
114
116
118
120
122
124
126
128
130
132
Vildagliptin Sitagliptin
Blood
glucose
(mg/dL)
Mean 24-hour blood glucose
reading
Baseline Week 8
*
*p=0.01; ^p=0.02
917
872
1139
958
0
200
400
600
800
1000
1200
Vildagliptin Sitagliptin
Minutes
Time spent in the ideal# range
Baseline Week 8
^
# 70 – 140 mg/dL
DPP4 inhibitors: What are the differences?
Any differences in efficacy?

7. Presentation Name Presenter:
Superior FPG reduction of vildagliptin vs. sitagliptin and saxagliptin
N=208 T2DM patients inadequately controlled on dual therapy metformin and either glimepiride, acarbose or
pioglitazone; HbA1c 7.5 – 10%) were randomized to 3 groups (vildagliptin 50 mg BID or sitagliptin 100 mg OD or
saxagliptin 5 mg OD) and followed for 24 weeks.
-43.92
-26.82
-32.94
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Vildagliptin Sitagliptin Saxagliptin
Fasting
Plasma
Glucose
(mg/dL)
Comparison of DPP-4 inhibitors added to T2DM
patients uncontrolled on dual drug therapy
-17.1 mg/dL; p<0.01
-10.98 mg/dL; p<0.01
Diabetol Metab Syndr. 2014; 6: 69
Similar HbA1c reductions
Numerically highest with vildagliptin but statistically
non-significant
Vildagliptin
-1.34%
Sitagliptin
-1.07%
Saxagliptin
-1.21%
DPP4 inhibitors: What are the differences?
Any differences in efficacy?

8. Presentation Name Presenter:
Superior HbA1c reduction vs. sitagliptin and linagliptin
N=535 T2DM patients inadequately (HbA1c >7%) controlled on insulin therapy plus oral drugs (metformin or acarbose) were
randomized to 3 groups (vildagliptin 50 mg BID or sitagliptin 100 mg OD or linagliptin 5 mg OD) and followed for 12 weeks.
FPG and 2hPPG reductions were
significantly higher with vildagliptin vs.
sitagliptin
Vildaglipti
n
20.71U
Sitagliptin
27.34U
Linagliptin
24.81U
Diabetol Metab Syndr. 2015; 7: 91
-1.33
-0.84 -0.81
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Vildagliptin Sitagliptin Linagliptin
HbA1c
(%)
Comparison of DPP-4 inhibitors added to T2DM
patients uncontrolled on insulin therapy
66.27% * 52.73% 55.49%
Percentage of patients who achieved HbA1c <7%
*p<0.05 for both comparisons; $ p=0.000 for both
comparisons
$
Lower mean insulin dose in vildagliptin
vs. sitagliptin and linagliptin
P=0.000
P=0.007
DPP4 inhibitors: What are the differences?
Any differences in efficacy?

9. Presentation Name Presenter:
Possible reasons for better FPG control with vildagliptin
Vildagliptin dosing
BID
Evening dose of
vildagliptin
Maintains
overnight GLP-1
levels
Prolonged
inhibition of
glucagon
Controls HGP, hence
fasting glucose levels
Maintaining overnight GLP1 levels
might help in better control of fasting
plasma glucose levels

10. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
• Differences in DPP4 inhibition
• Yes. Binding characteristics vary among DPP-4 inhibitors. Agents that bind to
DPP4 longer might help in reducing glycaemic variability
• Any differences in efficacy?
• Fasting glucose reduction with vildagliptin seems to be superior to other DPP4
inhibitors. This may possibly be due to overnight maintenance of GLP1 levels.
• Usage in Ramadan
• CV outcome & effect on QTC
• Usage in renal impairment

11. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
Usage in Ramadan

12. Presentation Name Presenter:
Patients fasting during Ramadan
Increased risk
of
hypoglycaemia
Increased risk
of
hyperglycaemia
Increased risk
of acute
complications
Limited drug
options
Thus, management in patients who fast during
Ramadan
• An efficacious drug with less safety
concerns

13. Presentation Name Presenter:

14. Presentation Name Presenter:
Vildagliptin: Proven efficacy and safety in T2DM patients who fast
during Ramadan
VildagliptIn expeRience compared wiTh sulphonylUreas obsErved (VIRTUE) during Ramadan
N=1333 type 2 diabetes patients (~8% were from India) treated with vildagliptin vs. sulphonylurea either as
monotherapy or add-on to metformin with an HbA1c<8.5%. Duration was ~16 weeks Int J Clin Pract. 2013; 67: 957 – 63
~3.5 fold reduction in risk of hypoglycaemia… …. while not compromising on HbA1c reduction
36
123
0
20
40
60
80
100
120
140
Vildagliptin Sulphonylurea
Number
of
patients
Patients with ≥1 hypoglycaemic
event
↓~3.5
X
-0.26%
P<0.001
-0.24
0.02
-0.3
-0.25
-0.2
-0.15
-0.1
-0.05
0
0.05
Vildagliptin Sulphonylurea
HbA1c
(%)
Change in HbA1c
Modest weight loss
-0.63, p<0.001)
Medication changes in
preparation of
Ramadan
~10% 20.2%
Vildagliptin SU
vs.

15. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
• Differences in DPP4 inhibition
• Yes. Binding characteristics vary among DPP-4 inhibitors. Agents that bind to
DPP4 longer might help in reducing glycaemic variability
• Any differences in efficacy?
• Fasting glucose reduction with vildagliptin seems to be superior to other DPP4
inhibitors. This may be possibly due to overnight maintenance of GLP1 levels.
• Usage in Ramadan
• DPP4 inhibitors such as vildagliptin have been demonstrated to be a safe and
efficacious agent in type 2 diabetes patients who fast during holy month of
Ramadan
• CV outcome & effect on QTC
• Usage in renal impairment

16. Presentation Name Presenter:
• Sitagliptin, saxagliptin, alogliptin have demonstrated cardiovascular safety
• Saxagliptin (and to some extent alogliptin) showed an increased risk of heart failure
hospitalizations
• Sitagliptin demonstrated cardiovascular as well as heart failure safety
• Vildagliptin cardiovascular safety data also demonstrated similar benefits
DPP4 inhibitors: What are the differences?
CV Safety

17. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
Sitagliptin CV Outcome - TECOS
Sitagliptin is cardiovascular safe

18. Presentation Name Presenter:
Vildagliptin Cardiac safety
Study Design
18
40
studies
meta-
analysis
Phase
3 & 4
studies
≥12 -
>104
weeks
17446
patients
Composite of
• Non-fatal MI
• Non-fatal stroke
• CV death
Primary
outcome
• Non-fatal MI
• Non-fatal stroke
• CV death
• HF events*
Secondary
outcomes
*new onset or hospitalization for
worsening HF
Diabetes Obes Metab. 2015; 17: 1085 – 92
All events
were
independently
adjudicated
^36% placebo, 33% SU, 10% TZD, 15% metformin, 6%
others
Vildagliptin
N=9599
Comparator^
N=7847
Patient distribution Mean values
Age
57 years
HbA1c
8.1%
Diabetes
duration
5.5 years

19. Presentation Name Presenter:
Vildagliptin cardiac safety
No increased risk of cardiovascular events
19
*new onset or hospitalization for
worsening HF
Diabetes Obes Metab. 2015; 17: 1085 – 92
MACE composite
Primary endpoint
Myocardial
infarction
Stroke
CV Death
HF events*
No increased risk of new onset HF or
hospitalization for worsening HF
RR 1.08 (non significant)
• No increased risk of cardiovascular events
• No increased risk of new or worsening HF ^
^saxagliptin study showed an increase in heart failure
hospitalisation

20. Presentation Name Presenter:
Vildagliptin Cardiac safety
No increased risk of worsening heart failure
20
VIVIDD
The
Vildagliptin In
Ventricular
Dysfunction
Diabetes
VIVIDD Poster presentation at ADA 2014 (San Francisco)
No increased risk
in worsening of
CHF events
(18 vs. 17.6%,
p=0.939)
No increased risk
in hospitalization
due to CHF
(10.2 vs. 8%,
p=0.552)
Vildagliptin vs. placebo
N=254 T2DM patients with NYHA Class I-III CHF randomized to vildagliptin or placebo and followed up for 52 weeks.
1-year study of
vildagliptin in
T2DM patients
with NYHA
Class I – III
CHF
Incidence of
HF
hospital-
isation
Outcomes
Study
Details

21. Presentation Name Presenter:
Randomised Controlled Trials (RCT) & Real World Evidence (RWE):
Complementing Each Other
Randomized Controlled Trials
Advantages Disadvantages
Robust method to
validate efficacy
Restriction of patient
numbers
Randomisation helps to
eliminate confounders
Strict inclusion and
exclusion criteria
hence results not
generalizable to larger
population
Minimum bias Limited time to follow
up
Data of large number of patients
included from electronic health
records
Yields answers relevant to broader
population of patients
Better predictor of how drugs
perform in real world settings and
how would they affect patient’s life
Real World Evidence
Complements RCTs in proving that
the results of RCTs are applicable to
real world population

22. Presentation Name Presenter:
Real world evidence on cardiovascular safety of Vildagliptin vs
other NIADs
Diabetes Obes Metab. 2017:19;1473-8.
N= 738054; Study assessed CV safety of vildagliptin (patient year exposure 28330) vs other non-
insulin antidiabetes agents (NIADs) using real world data from 5 European electronic healthcare
databases
Across the five nations (UK, Germany, France, Denmark, Sweden),
no increased risk of CV events was observed with vildagliptin vs
other non-insulin antidiabetic agents
No increased risk of CHF was observed with vildagliptin vs. other
non-insulin antidiabetic agents

23. Presentation Name Presenter:
DPP4 inhibitors and risk of hospitalization due to HF: evidence from real-world settings
Vildagliptin and Saxagliptin vs Sitagliptin
Vildagliptin: Reduced risk of heart failure hospitalization
N=239669 type 2 diabetes patients (>20 years) who initiated DPP-4 inhibitors (sitagliptin, saxagliptin or
vildagliptin) were identified from National Health Insurance (NHI) database and followed for one year from
drug initiation Int J Cardiol 2016;220:14-20
0. 1 10.0 100.0
0.01
Reference Sitagliptin
1.0
Hazard ratios for hospitalization due to heart failure comparing vildagliptin and
saxagliptin with sitagliptin as reference
Vildagliptin
Saxagliptin
0.82 (0.75 – 0.90)
1.00 (0.92 – 1.08)
Vildagliptin is associated with modestly reduced risk of HHF vs. Sitagliptin

24. Presentation Name Presenter:
Risk of hospitalization for HF among T2DM patients initiating DPP4 inhibitors
No significant difference in the risk of hospitalization due to HF and
incidence of first HHF events among different DPP4 inhibitors
Diabetes Obes Metab 2017;19:1416-24
N=127,555 retrospective analysis of hospitalization due to HF or incidence of first HHF in
T2DM patients initiating DPP4 inhibitors or SU alone or in combination with metformin
P-value not significant between groups

25. Presentation Name Presenter:
DPP4 inhibitors and their cardiovascular safety
Sitagliptin
TECOS: No increased risk of CV events and heart failure hospitalization
Saxagliptin
SAVOR TIMI: No increased risk of CV events. However, an increased risk of
heart failure hospitalization was observed with saxagliptin
Vildagliptin
Meta-analysis: No increased risk of CV events as well as new or worsening HF
Real world evidence: No increased risk of CV events including the risk of CHF

26. Presentation Name Presenter:
The danger of QTc prolongation

27. Presentation Name Presenter:

28. Presentation Name Presenter:

29. Presentation Name Presenter:
QTc prolongation- Teneligliptin vs Moxifloxacin

30. Presentation Name Presenter:
Other DPP4 inhibitors
J Clin Pharmacol. 2009 Aug;49(8):937-46. doi: 10.1177/0091270009337511.
A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular
repolarization in healthy subjects.
Bloomfield DM1, Krishna R, Hreniuk D, Hickey L, Ghosh K, Bergman AJ, Miller J, Gutierrez
MJ, Stoltz R, Gottesdiener KM, Herman GA, Wagner JA.
Curr Med Res Opin 2011;27:1453-63
Vildagliptin
Sitagliptin
Linagliptin
Saxagliptin

31. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
• Differences in DPP4 inhibition
• Yes. Binding characteristics vary among DPP-4 inhibitors. Agents that bind to
DPP4 longer might help in reducing glycaemic variability
• Any differences in efficacy?
• Fasting glucose reduction with vildagliptin seems to be superior to other DPP4
inhibitors. This may be possibly due to overnight maintenance of GLP1 levels.
• Usage in Ramadan
• DPP4 inhibitors such as vildagliptin have been demonstrated to be a safe and
efficacious agent in type 2 diabetes patients who fast during holy month of
Ramadan
• CV outcome & effect on QTC
• DPP4 inhibitors such as sitagliptin and vildagliptin have demonstrated CV
safety, HF safety; unlike teneligliptin all major DPP4 inhibitors do not show QT
prolongation
• Usage in renal impairment

32. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
Usage in renal impairment
Age and
diabetes: both
associated with
renal function
decline
At high risk of
hypoglycaemia
Limited drug
options
Traditional drugs
such as
metformin and
SU are not
preferred
Thus, management in patients with
renal impairment needs
• An efficacious drug with less
safety concerns

33. Presentation Name Presenter:
DPP 4 inhibitors in CKD
Drug Initial dose Dose adjustment for level of renal impairment
Mild
(CrCl ≥50
ml/min)
Moderate
(CrCl ≥30 to
<50 ml/min)
Severe
(CrCl<30
ml/min)
ESRD/
Dialysis
Sitagliptin 100 mg OD NDA 50 mg 25 mg 25 mg
Vildagliptin 50 mg BD NDA 50 mg OD 50 mg OD 50 mg OD
Saxagliptin 5 mg OD NDA 2.5 mg
2.5 mg
Caution
Should not
be used
Linagliptin 5 mg OD NDA NDA NDA NDA
Teneligliptin 20 mg OD NDA No data No data No data
Batin S & Majumdar S :Approach to management of hyperglycemia in a patient with Type 2 DM 7 CKD ; pg 155;Managing Diabetes &
Endocrine Conditions (Springer Healthcare Education)2017
NDA- No dose adjustment

34. Presentation Name Presenter:
34
Vildagliptin in Renal impairment
Proven clinical efficacy & safety across the spectrum of renal disease
Diabetes Obes Metab. 2011; 13: 947 – 54
N=525 type 2 diabetes patients (~15% were from India) with moderate (eGFR30 - <50 ml/min/ 1.73m2) or severe (eGFR
<30 ml/min/ 1.73m2) renal impairment and having inadequately HbA1c control (HbA1c 6.5 – 10%) were randomized to
either vildagliptin or placebo and followed for 24 weeks and then for additional 28 weeks (total 1 year)
*p<0.0001
-0.5
-0.6
-0.65
-0.6
-0.55
-0.5
-0.45
-0.4
-0.35
-0.3
-0.25
Moderate RI Severe RI
Vildagliptin
–
placebo
HbA1c
difference
(%)
Baseline
7.9%
Baseline
7.7%
*
*
Similar incidence of severe hypoglycaemia in
patients with moderate as well as severe RI
Benefits are retained even in the 1 year study
1.2
1.6
1.6
2.1
0
0.5
1
1.5
2
2.5
Moderate RI Severe RI
Percentage
of
patients
Incidence of hypoglycemia
Vildagliptin Placebo

35. Presentation Name Presenter:
A promising therapeutic option for T2DM patients with end stage renal disease
Type 2 diabetes patients with end stage renal disease (ESRD) undergoing peritoneal dialysis (n=10) or
hemodialysis (N=5) and treated with 50 mg OD vildagliptin were analysed retrospectively for 6 months
*p<0.05 vs baseline value
Diabetes Ther 2013; 4:321-9
-0.6
-0.5
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Peritoneal dialysis Hemodialysis
Change
in
HbA1c
(%)
Baseline
6.8%
Baseline
6.0%
-3.4
-2.1
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
Peritoneal dialysis Hemodialysis
Change
in
glycated
albumin
(%)
*
Baseline
19.6%
Baseline
21.8%
Vildagliptin in Renal impairment

36. Presentation Name Presenter:
DPP4 inhibitors: What are the differences?
• Differences in DPP4 inhibition
• Yes. Binding characteristics vary among DPP-4 inhibitors. Agents that bind to
DPP4 longer might help in reducing glycaemic variability
• Any differences in efficacy?
• Fasting glucose reduction with vildagliptin seems to be superior to other DPP4
inhibitors. This may be possibly due to overnight maintenance of GLP1 levels.
• Usage in Ramadan
• DPP4 inhibitors such as vildagliptin have been demonstrated to be a safe and
efficacious agent in type 2 diabetes patients who fast during holy month of
Ramadan
• CV outcome & effect on QTC
• DPP4 inhibitors such as sitagliptin and vildagliptin have demonstrated CV
safety, HF safety; unlike teneligliptin all major DPP4 inhibitors do not show QT
prolongation
• Usage in renal impairment
• Linagliptin doesn’t require any dose adjustment in renal impairment; vildagliptin
50 mg od dose has been evaluated in severe renal impairment as well as
ESRD patients

37. Presentation Name Presenter:
Take Home Messages
• Though DPP4 inhibitors have a similar class effect in glucose lowering, all of them
do not work similarly in all patient types
• Vildagliptin is known to have a strong fasting plasma glucose reduction, probably
due to sustained overnight GLP1 levels
• DPP4 inhibitors are known to be one of the safest agents for type 2 diabetes
patients who fast during Ramadan; vildagliptin has been extensively studied in
Ramadan patients
• Sitagliptin and vildagliptin have demonstrated cardiovascular as well as heart failure
safety
• Linagliptin doesn’t need dose adjustment in type 2 diabetes patients with renal
impairment; vildagliptin 50 mg od has demonstrated efficacy and safety in severe
renal impairment as well as ESRD patients