ueda2013 dpp-4 inhibitors “vildagliptin” -d.mesbah

1. DPP-4 Inhibitors
“Vildagliptin”
Between Guidelines and New
Evidence
Mesbah Said Kamel
MD

2. 2
Diabetes in Egypt
1-http://www.who.int/diabetes/facts/world_figures/en/index2.html accessed 13-3- 2012
2-http://www.diabetesatlas.org/map cited 10-5-2011
3-The IDF Diabetes Atlas 5th Edition
4- IDF atlas 2012
In 2012: 7.5 million patients are diagnosed diabetic in Egypt
*
*
*
* Number of diabetic patients in millions
1 2 3
*
4

3. 3
aHbA1c ≤6.5%.
HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.
Liebl A, et al. Diabetologia. 2002; 45: S23–S28.
• In the CODE study of a European cohort of over 7000 patients with
T2DM, ONLY 31% of patients had adequate glycaemic control
Patientswithadequateglycaemic
control(%)
Approximately 70% of patients with T2DM do not
reach HbA1c goals

4. 4
Impact of Uncontrolled Diabetes
p<0.001 age-adjusted death rates for linear trend.
Khaw K-T, et al. BMJ 2001; 322:1-6.
6
0
1
2
3
4
5
RelativeriskOfMortality
HbA1C %
 5 5.0-5.4 5.5-6.9 7
Diabetes Mellitus as Cardiovascular Disease Equivalent
Mortality risk is doubled with ≥7% HbA1c

5. The question now is not
whether to target
postprandial, fasting blood
sugar, or HbA1c but when,
how, and to what goals?

6. 6
Legacy effect: early glycaemic control is key to
long-term reduction in complications
Bad legacy effect
Achieving glycaemic control late in the disease, after a prolonged
period of poor control, does not improve long-term risk of
macrovascular complications2
Long-standing, preceding hyperglycaemia accounted for
the high rate of complications at baseline in VADT3
UKPDS=UK Prospective Diabetes Study; VADT=Veterans Affairs Diabetes Trial.
1Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589.
2Duckworth W, et al. N Engl J Med. 2009; 360: 129–139;
3Del Prato S. Diabetologia. 2009; 52: 1219–1226.
Good legacy effect
Early, strict glycaemic control brings benefits,
reducing the long-term risk of microvascular and macrovascular
complications (UKPDS1)

8. Recent Guidelines
Recommend Patients Centered
Approach for Better Control

9. 9

10. The General Goal is
<7% in most patients
to reduce the
incidence of
microvascular disease
More stringent HbA1c targets might be
considered in selected patients (with short
disease duration, long life expectancy, no
significant CVD) if this can be achieved without
significant hypoglycemia or other adverse
effects of treatment
6.0– 6.5%
less stringent HbA1c goals are appropriate for
patients with a history of severe hypoglycemia,
limited life expectancy, advanced complications
especially CVD and extensive co morbid
conditions
7.5–8.0% or even
slightly higher
Individualized Goal

11. 11

12. 12

13. 13
T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–
Individualized Treatment

14. 14
Current Oral Therapies do not Address
Islet Cell Dysfunction
Islet Dysfunction
Inadequate
glucagon
suppression
(-cell
dysfunction)
Progressive
decline of β-cell
function
Insufficient
Insulin secretion
(β-cell
dysfunction)
Sulfonylureas
Glinides
TZDs
Metformin
TZDs
Ins. Resistance
(Impaired insulin action)
TZD= Thiazolidinedione; T2DM= Type 2 Diabetes Mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24-S40

15. 15
Islet Cells are Targets for Incretin Hormones
GLP-1=Glucagon-Like Peptide-1
Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940; Wang Q, et al. Diabetologia. 2004;47:478-487.
Incretin Response
Food
intake
α-Cell
β-Cell
Islet
Incretin

16. 16
HGO= Hepatic Glucose Output
Adapted from Unger RH. Metabolism. 1974;23:581.
 Insulin
 Glucagon
IMPROVED
GLYCEMIC CONTROL
Incretin
Activity
Prolonged
Improved islet
function
DPP-4 Inhibitor
 Insulin
 Glucagon
HYPERGLYCEMIA
Incretin
Response
Diminished
Further impaired
islet function
T2DM
Blocking DPP-4 can Improve Incretin
Activity and Correct the Insulin/Glucagon
Ratio in T2DM

17. 17

18. Role of Vildagliptin in
Glycemic Management

19. 19
Vildagliptin add-on to metformin:
study design and objective
Objective: to demonstrate superior HbA1c reduction with vildagliptin
+ metformin vs metformin monotherapy
Target population: T2DM on maximal dose of metformin;
HbA1c 7.5–11%
HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.
*Patient number refers to primary intention-to-treat population.
Bosi E, et al. Diabetes Care. 2007; 30: 890–895.
n=130: Placebo + metformin
n=143: Vildagliptin 50 mg twice daily + metformin
n=143: Vildagliptin 50 mg once daily + metformin
24 weeks
Metformin
>1500 mg
(monotherapy,
stable dose)
4 weeks
N=416*

20. 20
Vildagliptin produces clinically meaningful,
decreases in A1C & FPG as add-on therapy to metformin.
Placebo + metformin (n=130)
Vildagliptin 50 mg twice daily + metformin (n=143)
Vildagliptin 50 mg once daily + metformin (n=143)
FPG=fasting plasma glucose; HbA1c=hemoglobin A1c.
*P <0.001; **P=0.003 vs placebo; ***P <0.001 vs placebo.
Primary intention-to-treat population.
Bosi E, et al. Diabetes Care. 2007; 30: 890–895.
7.2
7.4
7.6
7.8
8.0
8.2
8.4
8.6
−4 0 4 8 12 16 20 24
Time (Weeks)
MeanHbA1c(%)
−0.7% vs placebo
−1.1% vs
placebo
*
*
Duration: 24 weeks
Vildagliptin add-on
to metformin
Time (Weeks)
MeanFPG(mmol/L)
−4 0 4 8 12 16 20 24
8
9
10
11
−0.8 vs placebo
= - 30.6mg/dL
**
***
Duration: 24 weeks
Vildagliptin add-on
to metformin
Add-on Treatment to Metformin (2.1 g Mean Daily)
Reduction in HbA1c Reduction in FPG
−1.7 vs
placebo

21. 21
Vildagliptin: Enhances β-cell Function and Improves
PPG when Metformin Alone is not Sufficient
AUC=area under the curve; ISR=insulin secretion rate;
met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin.
*P ≤0.001 vs PBO.
Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.
Diabetes Care. 2007; 30: 890–895.
Vilda 50 mg twice daily + met (n=57)
β-cell Function
Placebo-adjusted
values
AdjustedMeanChangein
ISRAUC/GlucoseAUC
* *
5.2
5.7
0.0
2.0
4.0
6.0
8.0
10.0
AdjustedMeanChangein
2-hPPG(mmol/L)
*
*
-1.9
-2.3
-3.0
-2.0
-1.0
0.0
Vilda 50 mg once daily + met (n=53)
Duration: 24 weeks
Vilda add-on to met
2-h PPG
Placebo-adjusted
values
-41.4mg/dL
-34.2mg/dL

22. 22
Initial combination of vildagliptin and metformin
in drug-naïve patients is effective across the hyperglycemia spectrum
~9.9%
96
Change from BL to EP
~8.7%
285
Overall*
>9%
High BL Open-label
Sub-studyb
MeanChangeinHbA1c(%)
≥10%
~10. 6%
35
~9.2%
201
>8%
Subgroups by BL HbA1ca
*P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen.
Intent-to-treat population. aRaw mean change from baseline;
bLS (least-square) mean change from baseline. BL=baseline; EP=end point;
HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin.
Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515;
a Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1.
Vilda 100 mg once daily** + met 2000
mg daily open-label sub-study (P
<0.001 vs BL)d
High-dose vilda + met (50/1000 mg twice daily)c
BL mean=
n =
>11%
~12. 1%
86
*
Duration: 24 weeks
Vilda + met vs mono
Overall
At
Goal
< 7%

23. Vildagliptin Metformin
Combination Vs
SU/ Metformin

24. 24
HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.
Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386–393;
Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443;
Wright AD, et al. J Diabetes Complications. 2006; 20: 395–401.
Risks of Hypoglycaemia
Weight gain
and
hypoglycaemia
Bodyweight
HbA1c
Plasmaglucose
Decreasing HbA1c is associated with
increased risks of hypoglycaemia and
weight gain

25. 25
Risk Difference of Hypoglycemia with Different
Glucose-lowering Agents for T2DM
CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones.
Bolen S, et al. Ann Intern Med. 2007;147:386–399
Met vs Met + TZD
Weighted absolute risk difference
0.20.150.150.50
3 (1557)
5 (1495)
6 (2238)
8 (2026)
3 (1028)
5 (1921)
8 (1948)
9 (1987)
Studies
(participated)
0.00 (-0.01 to 0.01)
0.02 (-0.02 to 0.05)
0.03 (0.00 to 0.05)
0.04 (0.0 to 0.09)
0.08 (0.00 to 0.16)
0.09 (0.03 to 0.15)
0.11 (0.07 to 0.14)
0.14 (0.07 to 0.21)
Pooled effect
(95% CI)
SU vs repag
Glyb vs other SU
SU vs Met
SU + TZD vs SU
SU vs TZD
SU + Met vs SU
SU + Met vs Met
Drug 1 more harmfulDrug 1 less harmful

26. 26
Health and economical consequences of
hypoglycemia
26
Hypoglycemia
CV complications2
Weight gain by defensive eating3
Coma2
Car accident4
Hospitalization costs1
Dizzy turn unconsciousness2
Seizures2
Death6
Increased risk of dementia5
Quality of Life7
1. Jönsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193–198
2. Barnett AH. CMRO. 2010;26:1333–1342
3. Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541–548
4. Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 –140.
5. Whitmer RA, et al. JAMA. 2009;301:15655–1572
6. Zammitt NN, et al. Diabetes Care. 2005;28:2948–2961
7. McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436

27. 27
Pathophysiological cardiovascular consequences
of hypoglycaemia
CRP=C-reactive protein; IL-6=interleukin 6; VEGF=vascular endothelial growth factor.
Desouza CV, et al. Diabetes Care. 2010; 33: 1389–1394.
 VEGF  IL-6 CRP
 Neutrophil
activation
 Platelet
activation
 Factor VII
Blood coagulation
abnormalities
Sympathoadrenal response
Inflammation
Endothelial
dysfunction
 Vasodilation
Heart rate variability
Rhythm abnormalities Haemodynamic changes
 Adrenaline
 Contractility
 Oxygen consumption
 Heart workload
HYPOGLYCAEMIA

28. 28
*P=0.01; **P=0.02; ***P <0.01.
CL=confidence limit; HDL-C=high-density lipoprotein cholesterol.
Abraira C. Oral Presentation. Presented at the 68th Scientific Sessions of the American Diabetes Association; 6–10 June 2008, San Francisco, USA.
HR (Lower CL, Upper CL)
Risk of death
Lower Higher
Hypoglycemia
HbA1c
HDL-C
Age
Prior event
4.042 (1.449, 11.276)*
1.213 (1.038, 1.417)**
0.699 (0.536, 0.910)*
2.090 (1.518, 2.877)***
3.116 (1.744, 5.567)***
Hypoglycemia was a strong predictor of CV death
in VADT study
0 2 4 6 8 10 12
Hazard Ratio

29. Oral Pharmacologic Treatment of Type 2
Diabetes Mellitus:
(A clinical Practice Guideline From the
American College of Physicians)
Most diabetes medications had similar efficacy
and reduced HbA1c levels by an average of 1%
The guidelines essentially state that clinicians should use metformin
as a first-line agent to treat diabetes when diet and exercise are
insufficient, but they do not differentiate between the efficacy of
other diabetes treatments.
adapted from Ann Intern Med. 2012;156:218-231.
The preference from drug to drug will be based on safety and
tolerability

30. 30
Vildagliptin vs. glimepiride as add-on to
metformin: study design and objective
Study purpose: To demonstrate long-term efficacy and safety of add-on therapy with
vildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoing
metformin monotherapy
Interim analysis: To demonstrate non-inferiority of vildagliptin vs glimepiride at 1 year
Target population: Patients with T2DM inadequately controlled on stable metformin
monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%)
n=1393: Glimepiride up to 6 mg once daily + metformin
n=1396: Vildagliptin 50 mg twice daily + metformin
4 weeks
Metformin
HbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.* Randomised population.
Ferrannini E et al. Diabetes Obes Metab 2009; 11: 157–166.
1-year interim
analysis
N=2789*
104 weeks

31. 31
In patients uncontrolled with metformin monotherapy vildagliptin is as
effective as glimepiride over 1 year with low incidence of hypoglycaemia
and no weight gain
Glimepiride up to 6 mg once daily + metformin
Vildagliptin 50 mg twice daily + metformin
Number of
hypoglycaemic events
Patients with
1 hypos (%)
Number of severe
hypoglycaemic
events c
Incidence(%)
1389 1383 1389 1383 1389 1383n =
No.ofevents
No.ofevents
16.2
1.7 39
554
Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride
Mean HbA1c reduction a
Incidence of hypoglycaemia b
BL=baseline; CI=confidence interval
NI=non-inferiority; aPer protocol population ; bSafety population.
cGrade 2 or suspected grade 2 events.
*P <0.001; adjusted mean change from BL to Week 52,
between-treatment difference and P value were from
an ANCOVA model containing terms for treatment,
baseline and pooled centre.
Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.
MeanHbA1c(%)
0.0
6.5
6.7
6.9
7.1
7.3
7.5
-8 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
NI: 97.5%
CI (0.02, 0.16)
−0.4%
−0.5%
Time (weeks)
Adjustedmeanchangein
bodyweight(kg)fromBL
(BL mean ~88.8kg)
1117n = 1071
Change in body weight a

32. 32
Vildagliptin vs glimepiride as add on to metformin:
No severe hypoglycemic events at 2 years
Safety population; * any episode requiring the assistance of another party
Vilda= vildagliptin; Glim= glimepiride; Met= metformin
Matthews DR et al Diab Obes Metab. 2010; 12:780-789
Glim up to 6 mg qd + Met (n=1546)
Vilda 50 mg bid + Met (n=1553)
Number of
hypoglycemic
events
Number of
Severe hypo
events*
Patients with one
or more
hypoglycemic
events (%)
Incidence(%)
Numberofevents
Numberofevents
This hypoglycemic profile was maintained in patients > 65 years
Discontinuation
due to
hypoglycemia
0
Numberofevents

33. 33
Vildaglipin improves alpha cell sensitivity in both
hyper and hypoglycemia
-cell Response to
Hypoglycemia
(glucose clamp at 2.5 mmol/L)
Galvus (vildagliptin) 100 mg qd is not approved.
AUC=area under the curve; N=25 (completers population). *P=0.019; **P=0.039.
Ahrén B, et al. Poster 560-P. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA;
Thornberry NA, et al. Best Pract Res Clin Endocrinol Metab. 2009;23:479–486
Vildagliptin 100 mg once daily
Placebo
-cell Response to a
Standard Meal
**
ChangeinPlasma
Glucagon(ng/L) 0
10
20
30
40
50
60
+38%
IncrementalGlucagonAUC0-60
(ng/Lxmin)
-41%
0
200
400
600
800
1000
1200
*

34. 34
DPP-4TZDMET AGI
MET
Dual therapy Dual therapy
TZD
Glinide or SU
MET +
GLP-1
or
DPP-4
AACE / ACE Diabetes Algorithm for Glycemic
Control: HbA1c Goal <6.5%*
Monotherapy
Triple therapy
MET +
MET +
Triple therapy
+
+ SU
+ TZD
Drug-naive Under treatment
Symptoms No symptoms
GLP-1 or DPP-4
TZD
Glinide or SU
GLP-1 or DPP-4
Colesevelam
AGI
MET
TZD
MET
+
+
+
HbA1c 6.5–7.5%** HbA1c 7.6–9.0%
+
Insulin + other agent(s) Insulin + other agent(s)
Insulin
+ other
agent(s)
Insulin
+ other
agent(s)
Robard HW, et al. Endocr Pract. 2009; 15: 540–559. *May not be appropriate for all patients; **For patients with diabetes and
HbA1c <6.5%, pharmacologic Rx may be considered.
GLP-1
or DPP-4
GLP-1 or
DPP-4
TZD
+ TZD
+ SU
GLP-1
or DPP-4
TZD
GLP-1
or DPP-4
GLP-1 or DPP-4
or TZD
Glinide or SU
Lifestyle modification
HbA1c >9.0%

35. Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5

36. 36
Addition of Vildagliptin 50 mg twice daily to T2DM Patients
nonresponsive to Combination Metformin+SU :
Study Design :
 Uncontrolled Type 2 Diabetes Mellitus patients with mean HbA1c of
9.30 ± 1.38 .
 Vildagliptin (50 mg bid) was prescribed for at least 6 months to
patients whose combination therapy with Metformin (1,700-2,550
mg/day) and a sulphonylurea − either gliclazide MR (30-90 mg/day),
glibenclamide (10-20 mg/day) or glimepiride (4 mg/day) − was not
able to maintain HbA1c levels < 7% .
 Patients who achieved HbA1c levels < 7% after the addition of
Vildagliptin were labeled responsive, whereas those who did not
were considered nonresponsive.
Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5

37. 37
A statistically significant reduction in FPG (-45mg/dL) and
HbA1c(-1.6%) levels after the addition of Vildagliptin
Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5
Results of patients achieved HbA1c levels
< 7%
-2.21 %-63mg/dL
Overall Reduction

38. 38
T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–

39. Vildagliptin added to once or twice daily
insulin regimens improves glycemic control
without
increasing risk of hypoglycemia and weight
gain in patients with type 2 diabetes

40. 40
Study Design
 Patients with T2DM, HbA1c of ≥7.5% and ≤11.0%, fasting plasma glucose
(receiving a stable dose (≤1 U/kg/day) of basal long-acting, intermediate-
acting or pre-mixed insulin by daily injection(s), with (60%)or without (40%)
stable metformin treatment (≥1500 mg daily), for at least 12 weeks were
randomised in a 1:1 ratio to receive either vildagliptin 50 mg bid or placebo.
W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

41. 41
Baseline Demographic
• There were no clinically relevant changes in insulin dose at study
end (–1.10 U/day and –0.19 U/day in the vildagliptin and placebo
groups, respectively).
W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

42. 42
Results: Statistically significant sustained reduction
in HbA1c of -0.7% vs placebo after 24 weeks
W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

43. Vildagliptin is well
studied as add on to
insulin
Fonseca V et al. Vildagliptin Plus Insulin in T2DM … Horm Metab Res 2008 ; 40: 427 – 430

44. 44
-0.5
-0.7
-0.2
-0.1
-0.8
-0.6
-0.4
-0.2
0.0
Vildagliptin Add-on to Insulin: Significant Reduction
in HbA1c and Fewer Hypoglycemic Events
>65 Years Mean BL = 8.4%Overall Mean BL = 8.4%
ChangeinHbA1c(%)
Add-on Treatment to Insulin
140
**
149 42 41n =
*
Duration: 24 weeks
Add-on to insulin:
vilda vs PBO
PBO + insulin
Vilda 50 mg twice daily
+ insulin
PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.
Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
No. of Hypoglycemic Events No. of Severe Hypoglycemic Events
0
40
80
120
160
200
0
2
4
6
8
10
No.ofSevereEvents
113
185
0
6
*
**
No.ofEvents

45. 45Ved P, Shah S, Indian J Endocrinol Metab. 2012 Mar;16 Suppl 1
Significant Decrease in Hba1c and Insulin Dose When
Vildagliptin Is Added to Insulin

46. 46
Vildagliptin is the only DPP-4i Shows
Comparable Efficacy to GLP-1As
Of 362 potential RCTs (≥12 weeks’ duration in T2DM), 80 were eligible for inclusion*
Mean baseline HbA1c ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4
inhibitor studies)
The highest maintenance doses† of GLP-1RAs and DPP-4 inhibitors evaluated were associated
with changes from baseline in mean HbA1c of –1.1% to –1.6% and 0.6% to –1.1%, respectively
From Aroda VR, et al. Clin Ther 2012;34:1247–1258
*The majority of studies (85%) included ≥90 patients per treatment arm; †approved or tested: exenatide (10 µg bid), exenatide (2 mg qw),
liraglutide (1.8 mg qd), alogliptin (25 mg qd), linagliptin (5 mg qd), saxagliptin (5 mg qd), sitagliptin (100 mg qd), vildagliptin (50 mg bid)
GLP1-RA=GLP-1 receptor agonists; RCTs=randomized controlled trials
Exenatide BID
Exenatide QW
Liraglutide
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Vildagliptin
Mean HbA1c difference (95% CI)
–1.10 (–1.22 to –0.99)
–1.59 (–1.70 to –1.48)
–1.27 (–1.41 to –1.13)
–0.69 (–0.85 to –0.84)
–0.60 (–0.75 to –0.46)
–0.68 (–0.78 to –0.57)
–0.67 (–0.75 to –0.60)
–1.06 (–1.48 to –0.64)
–2.0 –1.5 –1.0 –0.5
HbA1c change (%)
Mean FPG difference (95% CI)
–1.16 (–1.35 to –0.97)
–2.12 (–2.28 to –1.96)
–1.82 (–2.07 to –1.57)
–0.97 (–1.27 to –0.67)
–1.04 (–0.59 to –0.49)
–0.73 (–0.95 to –0.50)
–0.87 (–0.98 to –0.77)
–1.57 (–2.23 to –0.90)
–2.5 –2.0 –1.5 –1.0 –0.5
FPG change (mmol/L)

47. 47
Vildagliptin treatment improves insulin sensitivity
4.0
4.5
5.0
5.5
6.0
6.5
7.0
Duration: 6 weeks
Vildagliptin vs
placebo
GlucoseRd(mg/kg•min)
Placebo (n=16)
Vildagliptin 50 mg twice daily (n=16)
Insulin infusion 80 mU/m2•min
Mean Rd difference=0.7 mg/kg•min
Rd=rate of disappearance.
*P <0.05.
Azuma K, et al. J Clin Endocrinol Metab. 2008; 93: 459–464.
*6.1
5.4
Hyperinsulinemic Euglycemic Clamp

48. 48
 Reduced glucose toxicity: which is true for all drugs that
reduce FPG
 Reduced glucagon during meals: increases
insulin/glucagon ratio in the liver which is true for all GLP-1
based therapies
 Reduced lipo-toxicity as determined by improved insulin
mediated glucose oxidation in muscle
 Due to reduced stored TG in muscle & liver
 Due to decreased fasting lipolysis in fat cells which is
also true for TZDs
 Improvement of inflammatory markers
 Increase GLUT4 protein expression
Vildagliptin is associated
with reduced insulin resistance Due to
Ahrén B, Schweizer A, Dejager S, Villhauer EB , Dunning BE, Foley JE. Mechanisms of Action of DPP-4 Inhibitors in Humans. Diabetes Obesity &
Metabolism, 13: 775–783, 2011.

49. 49
Rizzo et al 2012 Conclusions
• Nitrotyrosine levels correlated with MAGE (p<0.001) and PPG
(p=0.004)
• MAGE and PPG levels correlated with fasting plasma IL-6, IL-
18,TNFα, and inflammation score (p<0.001*)
• Activation of oxidative stress and increased activity of the innate
immune system can be reduced by the control of acute glucose
swings over a daily period in type 2 diabetics
• Despite similar plasma fasting hyperglycemia, HbA1c and
postprandial glucose, vildagliptin was associated with a greater
amelioration of MAGE and reduction of nitrotyrosine and
proinflammatory cytokines
Rizzo, et al Diabetes Care. 2012 Oct;35(10):2076-82.

50. 50
Greater reduction of MAGE with Vildagliptin
treated patients within 3 months
P=NS vs BL
P=,0.001
M. ROSARIA et al Diabetes Care. 2012 : 35(10):2076-82.
BL: Baseline
MAGE=Mean Amplitude of Glycemic Excursion
39%

51. 51
Vildagliptin: Significantly reduces Inflammatory mediators,
Oxidative stress compared with other DPP-4 inhibitors
Pro-inflammatory cytokines
IL-6 (pg/ml)
Oxidative stress
Nitrotyrosine µmol/L
*p<0.001 vs baseline
*p < 0.01 *p < 0.01
Vildagliptin
SitagliptinRizzo, et al Diabetes Care. 2012 Oct;35(10):2076-82.
¥ p<0.001 vs sitagliptin
¥ ¥
BL: 0.43 BL: 0.42BL: 2.47

52. 52
Management challenges can lead to cautious
prescribing in the elderly
1. Market research, data on file, Novartis.
2. schweizer A, et al. Diabetes Obes Metab. 2011; 13: 55–64
Hypoglycaemia
Other factors
Glycaemic targets
Managementchallenges
Frequently and marked unawareness of
hypoglycemia in older patients, leading to more
frequent and severe episodes. 2
The presence of numerous comorbidities
and a high prevalence of polypharmacy, and
increased risk for drug–drug interactions.
And very limited availability of clinical trial data,
especially in the very elderly subgroup 2
There is a difficult balance to strike between
HbA1c levels and safety.1

53. 5353

54. 54
Vildagliptin: very elderly patients from
pooled analysis
Pooled safety and efficacy analysis of all randomised, double-blind
studies that:
• Dosed vildagliptin 50 mg twice daily
• Included patients ≥75 years
• Duration ≥24 weeks
• 10 studies were included seven Mono-therapy and three add on , total
n=12,326
No. patients receiving vildagliptin
<75 years ≥75 years
Safety
population
5984 132
Monotherapy Add-on therapy Monotherapy Add-on therapy
Efficacy
population
2303 910 62 25
Vildagliptin is approved for 50 mg once or twice daily in combination with metformin or a TZD,
and vildagliptin 50 mg once daily in combination with a sulfonylurea.
Schweizer A, et al. Diabetes Obes Metab. 2011; 13: 55–64.

55. 55
Vildagliptin Monotherapy in Patients ≥ 75 years:
Efficacious Without Hypoglycemia
BL
< 75 years
8.7
≥ 75 years
8.3
-2
-1
0
MeanchangefromBL(%)
HbA1c
#
*
*
≥ 75 years < 75 years
Any
events
0.0 % 0.3 %
Severe
events
0.0 % 0.0 %
Hypoglycemic events ##
#Pooled monotherapy efficacy population up to Week 24 (7 studies; n=62 (≥ 75 years) and n=2303 (< 75 years)); ##Monotherapy (excluding
open-label) safety population up to Week 24 ((n=71 (≥ 75 years) and n=2553 (< 75 years)); unadjusted mean changes; *p<0.05 vs baseline;
BL= baseline Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.
-2
-1
0
MeanchangefromBL(mmol/L)
FPG #
*
*
BL
< 75 years
10.5
≥ 75 years
9.7
-0.9
-1.2
-1.1
-1.2
Vildagliptin 50 mg twice daily
< 75 years
≥ 75 years
20mg/dL 22mg/dL

56. 56
≥50% of elderly patients achieving a target HbA1c
A1C ≤7% in monotherapy
Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.
T2DM in older individuals is known to be associated with relative
hyperglucagonaemia and elevated postprandial glucose.
Vildagliptin treatment appears to address both these defects

57. 57
-2
-1
0
MeanchangefromBL(kg)
BL
< 75 years
86.1
≥ 75 years
74.9
Body weight #
* -0.9
-0.4
#Pooled monotherapy efficacy population up to Week 24 (7 studies; n=62 (≥ 75 years) and n=2303 (< 75 years)); ##Monotherapy (excluding
open-label) safety population up to Week 24 ((n=71 (≥ 75 years) and n=2553 (< 75 years)); unadjusted mean changes; *p<0.05 vs baseline;
BL= baseline. Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.
Vildagliptin did not induce weight gain in older or
younger patients as monotherapy
Vildagliptin did not induce weight gain
This modest weight loss may explain the positive trends seen for blood
pressure and the fasting lipid profile.

58. 58
Cardiovascular endpoint studies with
Vildagliptin are ongoing, but so far a variety
of markers have been already used to
assess cardiovascular benefits of
Vildagliptin
This data may have off- label information
Endothelial
Dysfunction
Blood
Pressure
Lipid
Profile

59. Vildagliptin Improves
Endothelium-Dependent
Vasodilatation in Type 2 Diabetes
Pleun C.M. van Poppel, Diabetes Care. 2011 Sep;34(9):2072-7.
Four weeks treatment with vildagliptin
improves endothelium-dependent
vasodilatation in subjects with type 2
diabetes.
This observation might have favorable
cardiovascular implications.
This data may have off- label information

60. 60
Vildagliptin: Mean Change in BP in T2DM Patients
with SBP >140 mmHg and DBP >90 mmHg
-7.5
-9.1
-4.2
-5.3
-10.0
-5.0
0.0
DBP SBP
BL=baseline; BP=blood pressure; DBP=diastolic blood pressure; met=metformin;
SBP=systolic blood pressure; T2DM=type 2 diabetes; vilda=vildagliptin
*P <0.05 vs met.
Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.
ChangefromBL(mmHg)
n= 89 53 150 84
BL= 94 94 149 150
*
*
Duration: 52 weeks
Vilda vs met
Met 1000 mg twice daily
Vilda 50 mg twice daily
This data may have off- label information

61. 61This data may have off- label information
Am J Cardiol 2012;110:826 – 833

62. Safety of Vildagliptin

63. 63
In meta – analysis of 38 clinical trials include more
than 14.000 patients
Vildagliptin shows no increased risk of:
 Pancreatitis-related AEs
 ALT / AST or Bilirubin elevation
 Renal AEs and SAEs in patients with normal renal
function and mild renal impairment patients
 Infection and skin related adverse events
vs. comparators (placebo, insulin and other OAD)
Ligueros-Saylan et al. DIABETES, OBESITY AND METABOLISM Volume 12 No. 6 June 2010

64. 64
The incidence of any hepatic or renal AE was also
lower with vildagliptin than with comparators
Age ≥ 75 years
N (%)
Age < 75 years
N (%)
Vilda 50 mg
bid
Comparators Vilda 50 mg
bid
Comparators
Hepatic safety
Any hepatic
AE
1 (0.8) 2 (1.2) 84 (1.4) 91 (1.5)
ALT or AST ≥
3× ULN
0 (0.0) 1 (0.6) 51 (0.9) 40 (0.6)
Renal Safety
AEs in mild
renal
impairment
51 (62.2) 67 (68.4) 1216 (70.7) 1278 (70.2)
AEs : adverse events, ULN: upper limit of normal, ALT: Alanine aminotranferease , AST : aspartate aminotransferase
Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.

65. 65
Today’s Conclusion
• Approximately 70% of patients with T2DM do not reach HbA1c
goals
• Achieving early glycemic control may generate a good legacy
effect. Patients initially received intensive therapy had a lower
incidence of any complication
• Vildagliptin produces extra clinically meaningful, decreases in A1C
-1.1%when added to metformin
• Vildagliptin is as effective as mostly common used SU with low risk
of hypoglycemia and without severe hypoglycemic events
• Vildagliptin improves beta and Alpa cell function
• Vildagliptin safety is well established in a meta-analysis of 38
clinical trials with about 14.000 patients and with very elderly
patients.

66. 66
1. Glucagon suppression
2. GLP-1 raising
3. MAGE reduction
4. DPP-4 activity inhibition during 24 hrs
Differentiate Vildagliptin as Best-in-class efficacy
to support -1.1% A1C reduction message.
Vilda stronger efficacy in 4 dimension: