Presented by Dr. A B M Kamrul Hasan in CME of Endocrinology Department, BSMMU on 30th October, 2013

1. WELCOME
to
CME PROGRAM

2. VILDAGLIPTIN IN THE MANAGEMENT
OF TYPE 2 DM
Presenter:
DR. A.B.M. KAMRUL HASAN
MD Final Part (E&M)
Department of Endocrinology
BSMMU

3. DM: GLOBAL BURDEN
• One of the greatest challenges faced by the modern
world is diabetes mellitus and its consequences
• Once considered a disease of the West, diabetes is
now a global health problem
• The prevalence of diabetes is rapidly rising all over
the globe at an alarming rate

4. DM: GLOBAL BURDEN
Prevalence (%)
DM and IGT: World Prevalence and projection
2010 and 2030
9
8
7
6
5
4
3
2
1
0
8.4
7.9
7.8
6.6
2010
2030
DM
IGT
DM and IGT
International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009.
Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

5. DM: GLOBAL BURDEN
DM and IGT: World prevalence and projection- 2010 and 2030
Number of people
(millions)
500
472
439
400
300
344
285
2010
200
2030
100
0
DM
IGT
DM and IGT
International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009.
Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

6. Top 10 countries for numbers of diabetes in 2010 and 2030
(population aged 20-79 years)
2010
Country
2030
No. of DM
(millions)
No. of DM
(millions)
Country
1
India
50.8
87.0
India
1
2
China
43.2
62.6
China
2
3
USA
26.8
36.0
USA
3
4
Russian
Federation
9.6
13.8
Pakistan
4
5
Brazil
7.6
12.7
Brazil
5
6
Germany
7.5
12.0
Indonesia
6
7
Pakistan
7.1
11.9
Mexico
7
8
Japan
7.1
10.4
Bangladesh
8
9
Indonesia
7.0
10.3
Russian
Federation
9
10
Mexico
6.8
8.6
Egypt
10
International Diabetes Federation. The Diabetes Atlas. 4th ed. Brussels: 2009.
Shaw JE et al. Diabetes Res Clin Pract. 2010;87:4-14.

7. Major Metabolic Defects in Type 2 Diabetes
Decreased
pancreatic
insulin secretion
Peripheral insulin
resistance in muscle
and fat tissue
Deficient incretin
hormones
response
Increased
hepatic glucose
output

8. Recent research has implicated at least 5 other
pathophysiological defects intimately involved in the
development of T2DM
• Decreased incretin effects from GIT
• Dysregulated pancreatic α-cell activity
• Lipotoxicity
• Maldaptive kidney responses
• Central neurotransmitter dysfunction

9. Pathophysiology of T2DM
Insulin secretion
Incretin
effect
glucagon
secretion
Hyperglycemia
Hepatic
glucose
production
Neurotransmitter
dusfunction
DeFronzo R. Diabetes 2009;58:773-95.
Lipolysis
glucose
reabsorption
Glucose uptake

10. Traditional current oral therapies do not address
all islet cell dysfunction
Pancreatic Islet Dysfunction
Insulin Resistance
(Impaired insulin action)
Inadequate
glucagon
suppression
( -cell
dysfunction)
Metformin
TZDs
Insufficient Insulin
secretion
(β-cell
dysfunction)
Sulfonylureas
Glinides
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
Progressive
decline of β-cell
function

11. Traditional current oral therapies do not address
all islet cell dysfunction
Pancreatic Islet Dysfunction
Insulin Resistance
(Impaired insulin action)
Inadequate
glucagon
suppression
( -cell
dysfunction)
Metformin
TZDs
Insufficient Insulin
secretion
(β-cell
dysfunction)
Progressive
decline of β-cell
function
GLP-1
DPP-4 inhibitors
Sulfonylureas
GLP-1
DPP-4 inhibitors
Glinides
GLP-1
DPP-4 inhibitors
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.

12. Pharmacologic Targets of Current Drugs Used in
the Treatment of T2DM
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
Glinides
Increase insulin secretion from
pancreatic -cells
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.
Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.
Thiazolidinediones
Decrease lipolysis in adipose
tissue, increase glucose
uptake in skeletal muscle and
decrease glucose production
in liver
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption

13. Pharmacologic Targets of Current Drugs Used in
the Treatment of T2DM
GLP-1 analogues
Improve pancreatic islet glucose sensing, slow
gastric emptying, improve satiety
DPP-4 inhibitors
Prolong GLP-1 action leading to improved
pancreatic islet glucose sensing, increase
glucose uptake
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
Glinides
Increase insulin secretion from
pancreatic -cells
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226.
Ahrén B, Foley JE. Int J Clin Pract 2008; 62: 8-14.
Thiazolidinediones
Decrease lipolysis in adipose
tissue, increase glucose
uptake in skeletal muscle and
decrease glucose production
in liver
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption

14. What is Incretin?
•
Incretins are gut hormones that enhance
glucose stimulated insulin secretion
•
Incretin effect designates amplification of
insulin secretion following oral glucose load

15. NATURAL INCRETINS
Two types:
1. Glucose dependent insulinotropic polypeptide (GIP)
2. Glucagon like peptides (GLPs) -GLP-1
These two hormones are rapidly degraded by an
enzyme DPP-4

16. GLP-1 and GIP are the 2 major incretins in human
• Both are peptide hormones
(30 and 42 amino acids)
• Secreted from endocrine
cells in the small intestinal
mucosa
• GLP-1: distal, L-cells
(mainly ileum, colon)
• GIP: proximal, K-cells
(mainly duodenum)
• Released in response to
meal ingestion
GLP-1 positive endocrine Lcells in human small intestine

17. WHAT IS DPP-4?
• Dipeptidyl Peptidase-4 (DPP-4) is an enzyme found
free in the circulation and tethered to endothelium
and epithelial cells in most tissues, especially in the
intestinal mucosa
• It clears and inactivates GLP-1 and GIP with in few
minutes
• It cleaves the N-terminal dipeptide from peptides.

18. GLP-1: an incretin hormone with multiple direct
effects on human physiology
α
β
Pancreas
Brain
Satiety
Intestine
β
Glucose-dependent
insulin secretion
β
Insulin synthesis
α
Glucose-dependent
glucagon secretion
GLP-1
Stomach
Gastric
emptying
Heart
Cardioprotection
Liver
Glucose
production
Cardiac function
L-cells secrete GLP-1
degraded by DPP-4
Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131–57

19. EFFECTS OF GLP-1 & GIP

20. THE PROBLEM
 Because of very short half life (1-2 min) therapeutic efficacy is
challenged
 This led to idea of producing drugs that act as analogue or
receptor agonist but longer half life
 Another idea was to develops drugs that inhibit DPP-4
enzyme responsible for breakdown of GLP-1 or GIP
 Thus one group of drugs is called incretin mimetics and
the other group is known as incretin enhancers

21. NEW THERAPIES: INCRETIN SYSTEM
Ingestion
of food
GI tract
Release of
active incretins
GLP-1 and GIP
X
Exenatide
Gliptin
Inactive
GLP-1
Pancreas
DPP-4
enzyme
Inactive
GIP
Beta cells
Glucose
depende
 Insulin
nt
(GLP-1and
GIP)
 Glucose
uptake by
peripheral tissue
 Blood glucose in
fasting and
postprandial states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
 Hepatic
glucose
production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

22. SITES OF ACTION OF GLIPTINS

23. INCRETIN MIMETICS AND DPP-4 INHIBITORS:
MAJOR DIFFERENCES
Properties/effect
Incretin mimetics
DPP-4 inhibitors
Mechanism of stimulation of insulin
secretion exclusively through GLP-1
effect
Yes
Unknown
Restitution of insulin secretion (2
phases)
Yes (exenatide)
Yes
Hypoglycaemia
No
No
Inhibition of gastric emptying
Yes
Marginal
Effect on body weight
Weight loss
Weight neutral
Side effects
Nausea
None observed
Administration
Subcutaneous
Oral
Gallwitz. Eur Endocr Dis. 2006

24. DIPEPTIDYL PEPTIDASE - 4 INHIBITORS
Drugs belonging to this class:
• Sitagliptin (FDA approved 2006)
• Vildagliptin (EU approved 2008)
• Saxagliptin (FDA approved 2009)
• Linagliptin (FDA approved 2011)

25. 25

26. VILDAGLIPTIN: PHARMACOKINETICS
• Rapidly absorbed (tmax <2 hours) & highly
bioavailable (85%) after oral administration
• Low plasma protein binding (9%)
• Plasma half life 1.5 - 4.5 hours
• Majority (approx. 69%) undergo renal metabolism to
inactive metabolites

27. VILDAGLIPTIN: PHARMACOKINETICS
• Negligible involvement
metabolism
of
CYP450
isoforms
in
• Most (85%) is eliminated via urine
• A dose of 50-100mg of vildagliptin provides:
o Almost complete inhibition of DDP-4
approximately 12 hours
o About 40% inhibition by 24 hours
for

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29. Secretion of incretins decreased in IGT and
T2DM
T2DM patients vs healthy individuals – following meal
20
GLP-1
2.5
2.0
P <0.001
1.5
1.0
0.5
0.0
Normal
GT
Impaired
GT
T2DM
GIP AUC (nmol/L*240 min)
GLP-1 AUC (nmol/L*240 min)
3.0
GIP
P=0.095
15
10
5
0
Normal
GT
Impaired
GT
GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; GT=glucose tolerance; T2DM=type 2 diabetes mellitus
Toft-Nielsen, et al. J Clin Endocrinol Metab 2001: 3717-3723.
T2DM

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32. Β-CELL FUNCTION CONTINUES TO DECLINE
REGARDLESS OF INTERVENTION IN T2DM
Sulfonylurea (n=511)
Progressive Loss of β-cell Function
Occurs prior to Diagnosis
100
Diet (n=110)
Metformin (n=159)
β-cell Function (%)*
80
60
40
20
0
–5
–4
–3
–2
–1
0
1
Years since Diagnosis
T2DM=type 2 diabetes mellitus
*β-cell function measured by homeostasis model assessment (HOMA)
Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
2
3
4
5
6

33. EFFECT OF VILDAGLIPTIN ON -CELL PRESERVATION AND
-CELL REGENERATION
Insulin
Vehicle
Vildagliptin
P <0.001
100
75
50
25
0
Vehicle
Vildagliptin
60 mg/kg/d
Apoptosis
2.5
2.0
1.5
P <0.05
1.0
0.5
0.0
Vehicle
Week 1
Vildagliptin decreased islet apoptosis
and increased -cell replication
Adapted from Duttaroy A, et al. Diabetes. 54 (suppl 1): A141.Abstract 572-P.
Vildagliptin
60 mg/kg/d
Total islet mass
% islet area x pancreatic weight (mg)
Replication
Apoptotic cells / islet area ( 105)
BrdU-positive cells / islet area ( 105)
Neonatal rat model of pancreatic islet growth
0.14
P <0.05
0.12
0.10
0.08
0.06
0.04
Vehicle
Vildagliptin
60 mg/kg/d
Week 3
Resulted in increased
insulin-positive islet mass

34. VILDAGLIPTIN ENHANCES ISLET CELL FUNCTION BY INCREASING
INSULIN AND DECREASING GLUCAGON SECRETION
OGTT 30 min after single oral dose of vildagliptin (100 mg)
75 g glucose
Insulin (pmol/L)
120
Placebo (n=16)
Vildagliptin 100 mg (n=15)
100
Dose
80
60
40
20
0
−90
−60
−30
0
30
60
90
120
150
180
210
240
270
300
−90
−60
−30
0
30
60
90
120
150
180
210
240
270
300
−90
−60
−30
0
30
60
90
120
150
180
210
240
270
300
Glucose (mmol/L)
22.5
17.5
12.5
7.5
Glucagon
(ng/L)
140
120
100
80
60
OGTT=oral glucose tolerance test
*P <0.01.
He YL, et al. J Clin Pharmacol 2007; 47: 633-641.
Time

35. VILDAGLIPTIN ENHANCES Β-CELL SENSITIVITY TO
GLUCOSE
Glucose sensitivity
Basal secretory tone
260
Secretion at 7 mM glucose
(pmol/min/m2)
Glucose sensitivity
(pmol/min/m2/mM)
75
70
65
60
55
50
240
220
200
180
45
-4 0 4
8 12 16 20 24 28 32 36 40 44 48 52
Time (weeks)
-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (weeks)
Vildagliptin 50 mg once daily
Placebo
Mari A, et al. J Clin Endocrinol Metab 2008; 93: 103-109.

36. VILDAGLIPTIN ENHANCES Α-CELL SENSITIVITY
TO GLUCOSE
Vildagliptin
24
Placebo
24
Vilda wk 0 (50 mg twice daily, n=14)
Vilda wk 12 (50 mg twice daily, n=14)
22
Glucagon (pmol/L)
22
Glucagon (pmol/L)
Placebo wk 0 (n=14)
Placebo wk 12 (n=14)
20
18
16
*
14
*
8.0
12.0 16.0
18
16
14
*
12
4.0
20
*
20.0 24.0
Glucose (mmol/L)
wk=week; vilda=vildagliptin
*P <0.05 vs wk 0.
Data on file, Novartis Pharmaceuticals, LAF237A2344.
12
28.0
4.0
8.0
12.0
16.0 20.0
Glucose (mmol/L)
24.0 28.0

37. VILDAGLIPTIN ENHANCES INSULIN SENSITIVITY
Duration: 6 weeks
Vildagliptin vs placebo
Hyperinsulinemic euglycaemic clamp
7.0
*
Glucose Rd (mg/kg•min)
6.5
6.1
Mean Rd difference=0.7 mg/kg•min
6.0
5.5
Insulin infusion 80 mU/m2•min
5.4
Vildagliptin 50 mg twice daily (n=16)
Placebo (n=16)
5.0
4.5
4.0
Rd=rate of disappearance
*P <0.05.
Azuma K, et al. J Clin Endocrinol Metab 2007; [Epub].

38. Vildagliptin improves postprandial lipid and
lipoprotein metabolism
Plasma TG
Chylomicron TG
0.8
4.0
Before vilda, week 0 (n=13)
0.6
3.0
mmol/L
mmol/L
3.5
2.5
2.0
0.4
0.2
1.5
1.0
−1 0 1 2 3 4 5 6 7 8
0.0
−1 0 1 2 3 4 5 6 7 8
Chylomicron apo B-48
Chylomicron cholesterol
0.08
0.50
0.06
0.20
0.10
0.00
−1 0 1 2 3 4 5 6 7 8
Time (h)
TG=triglycerides; vilda=vildagliptin
Matikainen N, et al. Diabetologia 2006; 49: 2049-2057.
mmol/L
mg/L
0.40
0.30
Vilda 50 mg twice daily,
week 4 (n=15)
0.04
0.02
0.00
−1 0 1 2 3 4 5 6 7 8
Time (h)

39. VILDAGLIPTIN ENHANCES Β-CELL FUNCTION AND
INSULIN SENSITIVITY OVER 52 WEEKS
Patients on stable metformin therapy
300
0.050
0.045
Adaptation
index
*
*
*
0.040
0.035
0.030
0.025
275
*
*
250
225
200
0 12 24
52
Time (week)
0 12 24
52
Time (week)
nmolC-peptide · mmolglucose-1 ·
mL-1 · m-2
Insulin
sensitivity
mL · min-1 · m -2
pmol/L 30 min/(mmol/L)
Insulin
secretion
14
12
*
*
10
8
6
0 12 24
Time (week)
Vildagliptin 50 mg daily / metformin
Placebo / metformin
*P <0.05 vs placebo; †P <0.01 vs placebo.
Adapted from Ahrén B, et al. Diabetes Care 2005; 28: 1936–1940.
†
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52. COMPARISON OF OADs

53. VECTOR: Results 1
• Hypoglycaemic events (HE)
•
No patients treated with Vildagliptin experienced hypos including no severe
events, compared with 34 hypos in 15 patients, including one severe event with SU
–
53
Mean between-group difference in patients who experienced at least one HE was –41·7% (p = 0·0002)
1.
VECTOR. doi:10.1185/03007995.2011.579951

54. VECTOR: Results1
• HbA1c
•
1.
Vildagliptin significantly lowered HbA1c (7·7% to 7·2%) versus SU (7·2% to 7·3%) postRamadan. The between group difference being −0·5% (p = 0·0262)
VECTOR. doi:10.1185/03007995.2011.579951

55. VECTOR: Results1
• Adherence
•
The mean number of missed doses was markedly lower with Vildagliptin than with
SU (0·2 vs 7·6; between-group difference −7·4 doses; p = 0·0204). That is, on
average, patients had 7 fold more missed doses with SUs than Vildagliptin
 Only 1 patient in the
Vildagliptin group missed
at least one dose,
compared with 10 patients
in the SU group
1.
VECTOR. doi:10.1185/03007995.2011.579951

56. Vildagliptin Vs Other DPP-4i

57. Vildagliptine Vs. Sitagliptine & Sexagliptine:
Powerful 1.1% reduction in HbA1c
Superior HbA1c reduction data from 2 separate studies with different baseline HbA1c values2

58. Vildagliptine Vs. Sitagliptine:
Longer duration of DPP-4 binding & increased Active GLP 1 than sitagliptin
Tight substrate-like binding of
galvus leads to potent DPP-4
inhibition
Greater increases in active GLP-1
levels with GALVUS compared
with sitagliptin is likely due to
tighter and longer-lasting
binding

59. Vildagliptine Vs. Sitagliptine:
Vildagliptin
Sitagliptin
•Efficacy in add on to metformin:
1.1% HbA1C reduction vs
•Efficacy in add on to metformin:
0.7% HbA1C reduction
•Skin reaction not observed
•Hypersensitivity reaction observed in
post marketing
•Durability over 02 years
•Durability 01 year
Recent Advancement of Vildagliptin Labeling:
•No more Caution in CHF
•Recommended in moderate to severe renal impairment also

60. VILDAGLIPTIN APPROVED IN EU FOR T2DM
PATIENTS WITH MODERATE OR SEVERE RENAL
IMPAIRMENT

61. VILDAGLIPTIN APPROVED IN EU FOR T2DM
PATIENTS WITH MODERATE OR SEVERE RENAL
IMPAIRMENT
• Renal impairment affects approximately 25 percent
of patients with T2DM
• Majority of currently available medications are not
recommended, contraindicated or have to be taken
with caution in this population

62. VILDAGLIPTIN APPROVED IN EU FOR T2DM
PATIENTS WITH MODERATE OR SEVERE RENAL
IMPAIRMENT
• 24-week, multi-center, randomized, double-blind, parallelgroup, placebo-controlled study (n=515) assessed the safety
and tolerability of vildagliptin (50 mg qd) in patients with type
2 diabetes and moderate or severe renal impairment
• The trial showed that vildagliptin had a similar safety profile
to placebo in these patients6 and resulted in significant
improvements in glycemic control when added to existing
anti-diabetic therapy

63. TIME COURSE OF HBA1C DURING RESCUE-FREE
TREATMENT IN PATIENTS WITH MODERATE RI

64. TIME COURSE OF HBA1C DURING RESCUE-FREE
TREATMENT IN PATIENTS WITH MODERATE RI

65. Overall summery of AEs by Rx &
severity of RI

66. Summery of common AEs by Rx &
severity of RI

68. VILDAGLIPTIN IN HEPATIC IMPAIRMENT
• The effect of impaired hepatic function on the
pharmacokinetics of vildagliptin was studied in subjects with
mild, moderate, and severe hepatic impairment based on the
Child-Pugh scores (ranging from 6 for mild to 12 for severe) in
comparison to subjects with normal hepatic function.
• The exposure to vildagliptin (100 mg) after a single dose in
subjects with mild and moderate hepatic impairment was
decreased (20% and 8%, respectively), while the exposure to
vildagliptin for subjects with severe impairment was increased
by 22%.

69. VILDAGLIPTIN IN HEPATIC IMPAIRMENT
• The maximum change (increase or decrease) in the
exposure to vildagliptin is ~30%, which is not
considered to be clinically relevant
• There was no correlation between the severity of
hepatic function impairment and changes in
exposure to vildagliptin

70. VILDAGLIPTIN IN HEPATIC IMPAIRMENT
• The use of vildagliptin is not recommended in
patients with hepatic impairment including patients
with a pre-treatment ALT or AST > 2.5x the upper
limit of normal

71. VILDAGLIPTIN IN HEPATIC IMPAIRMENT
• Liver function should be monitored quarterly
in the first year and periodically thereafter
• Vildagliptin should be stopped if ALT rises 3
times upper normal limit

72. TAKE HOME MESSAGE
• Incretins are gut hormones that enhance glucose
stimulated insulin secretion
• Amplification of insulin secretion following oral
glucose load- “incretin effect”
• This effect is severely reduced or lost in type 2 DM

73. TAKE HOME MESSAGE
• Biologic incretins are ineffective in clinical use
because of short half-life
• Therapeutic benefit is obtained by DPP-4 resistant
GLP-1 analogue and DPP-4 enzyme inhibitors
• Incretin based therapy has shown a new pathway
of treatment of T2DM, with a promise for weight
loss and β cell generation

74. TAKE HOME MESSAGE
• Gliptins are weight neutral and does not cause
hypoglycaemia
• Gliptins may increase beta cell mass in human
• Vildagliptin is safe and effective in type 2
diabetic patients with moderate to severe
renal impairment

75. Acknowledgement
• Prof. Md. Fariduddin
Chairman & Course Co-ordinator,
Department of Endocrinology, BSMMU
• Dr. M.A. Hasanat
Associate Prof,
Department of Endocrinology, BSMMU
• Novartis Pharma, Bangladesh

76. Thank You All
76