Transcript GLP-1 - The 6th Arab Diabetes Forum In Collaboration with Egyptian

Treatment of type 2 diabetes:
•Are we on the road?
By
Abbas Orabi
1
A lot of guidelines!!
DDG (Germany)9
HbA1c < 6.5%
IDF (Western Pacific Region)7
HbA1c ≤ 6.5%
CDA (Canada)4
HbA1c ≤ 7%
ADA (US)1
HbA1c < 7%
AACE (US)2
HbA1c ≤ 6.5%
(UK)5
NICE
HbA1c 6.5–7.5%
EASD
HbA1c < 6.5%
Australia8
HbA1c ≤ 7%
IDF (Global)3
HbA1c < 6.5%
ALAD (Latin America)6
HbA1c < 6–7%
Guidelines recommend target HbA1c as near to normal as safely possible
1ADA.
Diabetes Care 2007; 30 (Suppl. 1):S4–S41.
Diabetes Road Map Task Force, 2005. Available at: www.aace.com/meetings/consensus/odimplementation/roadmap.pdf
3IDF Clinical Guidelines Taskforce, 2005. Available at: www.idf.org/webdata/docs/IDF%20GGT2D.pdf.
4CDA. 2
Can J Diabetes 2003; 27 (Suppl. 2):S1–S152. 5NICE, 2002. Available at: www.nice.org.uk. 6ALAD. Rev Asoc Lat Diab 2000; 8 (Suppl. 1):101–167.
7Asian-Pacific Type 2 Diabetes Policy Group, 2005. Available at: www.idf.org/webdata/docs/T2D_practical_tt.pdf. 8NSW Health Department, 1996
9www.deutsche-diabetes-gesellschaft.de
2ACE/AACE
Current management often fails to achieve
glycaemic targets
CHINA
(CODIC-2)1
HbA1c <7.5%
Latin America
(DEAL)3
HbA1c <7%
EUROPE
(CODE-2)5
HbA1c <6.5%
43%
32% 68%
31%
57%
CANADA 69%
(DICE)2
HbA1c ≤7%
49%
US
(NHANES)4
HbA1c <7%
69%
37%
51%
63%
3
1Xingbao
C. Chinese Health Economics 2003; Ling T. China Diabetic Journal 2003. 2Harris SB, et al. Diabetes Res Clin
Pract 2005;70:90–97. 3Lopez Stewart G, et al. Rev Panam Salud Publica 2007;22:12–20.
4Saydah SH, et al. JAMA 2004;291:335–342. 5Liebl A, et al. Diabetologia 2002;45:S23–S28.
Most Patients with T2DM Do Not Achieve HbA1c Goals
Percentages of Adults with HbA1c <7.0% in NHANES III
(1988–1994) and NHANES 1999–2000
60
NHANES III (n=1218)
44.3%
US Adults (%)
50
NHANES 1999–2000 (n=404)
37.0%
40
30
20
10
0
HbA1c Level <7.0%
HbA1c=hemoglobin A1c
Adapted from Saydah SH, et al. JAMA. 2004; 291: 335–342.
4
Progression of Hyperglycemia in T2DM
(Retrospective Analysis)
8.0
Sulfonylurea
Metformin
Thiazolidinedione
7.8
HbA1c (%)
7.6
7.4
7.2
7.0
6.8
6.6
6.4
3
6
9
12
15
18
21
24
27
30
33
36
39 42
45
48
Time (months)
Riedel AA, et al. Diabetes. 2006; 55 (Suppl 1): A132.
5
Abnormal Pancreatic Islet Function Determines the Development of
IGT and T2DM in the Setting of Insulin Resistance
Age, lifestyle,
environmental factors
Insulin resistance
Normal islet
function
NGT
Abnormal
islet function
IGT / T2DM
IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus
Adapted from Ahrén B, et al. Diabetes Obes Metab. 2005; 7: 2–8.
6
Traditional Current Oral Therapies Do Not Address
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
Sulfonylureas
Glinides
TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3 (Suppl 1): S24–S40.
7
Why do beta cells fail?
8
The need for new therapies!
9
10
11
In 1902, Bayliss and Starling proposed
that intestinal mucosa contains a
hormone that stimulates the exocrine
secretion of the pancreas ("Secretin").
However, oral administration of extracts
of intestinal mucosa failed to help several
patients with type 1 diabetes.
12
In 1939–1940, based on their studies,
Leow et al. concluded that the existence
of incretins was “questionable.” No
further research in this area was
performed for about thirty years.
13
In 1939–1940, based on their studies,
Leow et al. concluded that the existence
of incretins was “questionable.” No
further research in this area was
performed for about thirty years.
14
In 1970, GIP was isolated and sequenced
from intestinal mucosa (JC Brown).
Originally named gastric inhibitory peptide,
GIP was renamed glucose-dependent
insulinotropic peptide in 1973 after Brown
and Dupre showed that GIP stimulates
insulin secretion.
15
However, initial research could not
establish its utility as a treatment for
diabetes. The anglerfish proglucagon
peptide was sequenced in 1982 by Lund
and co-workers. The human Proglucagon
gene was cloned in 1983 by G. Bell, et al.,
and the human proglucagon sequence
was subsequently deduced.
16
However, the entire GLP-1 molecule had
no effect on insulin levels. It was found
that only one specific sequence of GLP-1
has insulinotropic effect: GLP-1 amide. It
is rapidly inactivated to GLP-1by DPP-4
with a plasma half-life of only 1–2 minutes.
17
18
Incretins
19
The two main candidate molecules
that fulfill criteria for an incretin are
glucagon-like peptide-1 (GLP-1) and
Gastric inhibitory peptide (aka
glucose-dependent insulinotropic
peptide or GIP). Both GLP-1 and GIP
are rapidly inactivated by the enzyme
dipeptidyl peptidase-4 (DPP-4)
20
The Incretins
GLP-1: Glucagon-like Peptide-1
H A E G T F T S D V S S Y L E G Q A
A
K
A
K
F
L
R
I
V
E
W
G
G
GIP: Glucose-dependent Insulinotropic Peptide
A
E G T F I S D Y S I A M D K I H
Q
K K G K
A L L W N V F D Q
D
N
W
Q
K
T Q
I
N
H
Y
Amino acids shown in orange are homologous with the structure of glucagon.
21
21
GLP-1 and GIP are Synthesized and Secreted from the Gut in
Response to Food Intake
L-cell
(ileum)
ProGIP
Proglucagon
GLP-1 [7–37]
GLP-1 [7–36 NH2]
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1
Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.
GIP [1–42]
K-cell
(jejunum)
22
22
DPP-4
Enzymatic cleavage of GLP-1 by
DPP-4 inactivates GLP-1
GLP-1
30
1 2 3
Des-HA-GLP-1 (inactive)
1 2
3
30
Two possible solutions to utilize GLP-1 action therapeutically:
1) Long-acting DPP-4 resistant GLP-1 analogues / incretin
mimetics
2) DPP-4 inhibitors / incretin enhancers
Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994
23
1. Glucose-dependent stimulation of
insulin secretion
2. Postprandial suppression of
glucagon secretion
3. Slowing of gastric emptying
4. Decrease of appetite, increase of
satiety
Drucker DJ. Diabetes Care. 2003;26:2929-2940.; Perley MJ, Kipnis DM. J Clin Invest. 1967;46:1954-1962.;Nauck M, et al.
Diabetologia. 1986;29:46-52.
24
Mechanisms of GLP-1 action:
Role of incretins in plasma glucose regulation
Meal-induced secretion of GLP-1
↓ ß-cell stress
Increased satiety
Decreased appetite
↑ ß-cell
response
ß-cells:
Stimulation of glucose
dependent insulin secretion
25
α-cells:
↓ postprandial
glucagon secretion
Liver:
↓ glucagon decreases
hepatic glucose production
Stomach:
slowing of gastric emptying
Modified from Flint A, et al. J Clin Invest. 1998;101:515-520.; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.;
Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Drucker DJ. Diabetes. 1998;47:159-169.
Insulin release :
It involves 3 main steps :
1. Translocation of insulin granules.
2. Docking of insulin granules.
3. Fusion of insulin granules.
26
The motive force to propel granules along the
microtubules is provided by the interaction
between :
Filamentous
actin
ATP
Phosphorylated
myosin
+
Ca+
Granule transport
It gives the force but not the way
27
Ca+ is essential for almost all steps
involved in insulin release, thus factors
increasing intracellular Ca+ will augment
insulin release.
Mechanisms involved in increasing intracytoplasmic Ca+ :
 Ca-influx from outside.
 Inhibition of Ca-reuptake by
intracellulas stores.
Ca++ Store
x
 Increased Ca-sensitivity.
28
Increased intracellular Ca+ is essential for
granules translocation and fusion hence release
of insulin.
ATP-sensitive
K+ channel
Glucose
GLUT2
Voltage-gate
Ca channel
6
X
Fusion
Glucose
2
Glucokinase
K retention
4
3
Depolarization
5
1
G-6-P
Ca+
ATP
Translocation
Each B-cell contains up to 500 Ca channels
29
The potentiating effect of GLP-1 is mediated
through activation of adenyl cyclase :
GLP-1
Adenyl cyclase
ATP
C-AMP
Ca2+ uptake into stores
PKA
Cyclosolic Ca2+
Ca2+ sensitivity
Insulin
Release
30
Insulin Secretion Increases Dramatically in Response to
Oral Glucose Ingestion
Oral Glucose Tolerance Test
150
400
50 g glucose
300
Insulin (pmol/L)
Glucose (mg/dL)
200
100
50
100
0
0
-30
0
30
60
90 120 150 180 210
Time (min)
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
31
200
-30
0
30
60
90 120 150 180 210
Time (min)
Proof of a Gastrointestinal ‘Incretin Effect’: Different
Responses to Oral vs. IV Glucose
200
400
150
300
Insulin (pmol/L)
Glucose (mg/dL)
OGTT and Matched IV Infusion
100
50
100
0
0
-30
0
30
60 90 120 150 180 210
Time (min)
Oral
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.
32
200
-30
IV
0
30
60 90 120 150 180 210
Time (min)
The Role of Incretins in T2DM
33
The Incretin Effect is Impaired in T2DM Leading to
Reduced Insulin Production
Plasma Glucose (mg/dL)
240
180
90
0
0
C-Peptide (nmol/L)
T2DM
(n=8)
60
120
30
IV Glucose
Oral Glucose
20
10
*
* *
*
* *
*
*
0
180
90
0
0
60
120
180
0
60
120
Time (min)
180
30
20
10
0
0
60
120
Time (min)
180
*P <.05
Adapted from Nauck M, et al. Diabetologia. 1986;29:46-52.
34
(n=14)
240
180
C-Peptide (nmol/L)
Plasma Glucose (mg/dL)
NGT
Meal
20
*
* *
*
*
*
GLP-1 (pmol/l)
15
*
NGT
IGT
10
*
T2DM
5
0
0
60
*P<0.05 T2DM vs NGT
Toft-Nielsen
et al. J Clin Endocrinol Metab. 2001
35
120
Time (min)
180
240
IGT=impaired glucose tolerance; NGT=normal glucose tolerance
16
Glucose (mmol/l)
T2DM
12
T2DM + GLP1
8
Controls
4
Breakfast
Lunch Snack
0
2200
Rachman et al. Diabetologia. 1997
36
0200
0600 1000
1400
Clock time (hours)
1600
Control
+ GLP-1
Day 1
Day 3
Day 5
Farilla
et al. Endocrinology. 2003
37
β-Cell mass
β-Cell proliferation
30
12
8
4
Proliferating β-cells (%)
P<0.01
P<0.05
2.0
1.5
1.0
0.5
Control
GLP-1
treated
Farilla
et al. Endocrinology. 2002
38
20
P<0.001
10
0
0
0
Apoptotic β-cells (%)
2.5
16
β-Cell mass (mg)
β-Cell apoptosis
Control
GLP-1
treated
Control
GLP-1
treated
39
Galvus
Vildagliptin
40
Galvus : A Potent and Selective DPP-4 Inhibitor
H
HO
N
O
N
N
 Highly selective DPP-4
inhibitor that acts like a
substrate
 Has a high affinity for
the human enzyme
 Reversible inhibition
X-ray crystallographic structure of
vildagliptin (green) bound to the active site
(yellow) of human DPP-4
DPP-4=dipeptidyl peptidase-4
41
Galvus : what do we know so far? Chemical
structures of DPP-4 inhibitors
Competitive inhibitors
F
Noncovalent
F
Substrates acting as inhibitors
NH2 O
N
N
F
N
N
CF3
Sitagliptin1
O
H3 C
Noncovalent
O
N
CN
Covalent
(cyanopyrr
olidine)
N
NC
N
O HHO
Vildagliptin
N
N
NH 3+ PhCO 2-
Alogliptin3
1Januvia
Prescribing Information. http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed January 2010.
BF, et al. Poster 0788 presented at EASD 2006.
3Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29.
4Onglyza Prescribing Information. http://packageinserts.bms.com/pi/pi_onglyza.pdf. Accessed January 2010.
Ahren B et al, Diab Obes Metab 2011 "Accepted Article"; doi: 10.1111/j.1463-1326.2010.01321.x
2Burkey
Vildagliptin: Pharmacokinetics
 Rapid absorption after oral administration (tmax 0.5–1.5 hours)1
 Dose-dependent, highly selective, rapid, and reversible DPP-4
inhibition1
 Bioavailability >80%, no food effect2
 Very low protein binding (9%)
 Metabolism2,3
– hydrolysis
– major metabolite is pharmacologically inactive
– does not inhibit / induce or utilize P450 (CYP)
 Excretion:85% excreted in urine (mostly as inactive metabolite), 15%
in feces3
 No drug-drug interaction with commonly prescribed agents4-7
DPP-4=dipeptidyl peptidase-4; tmax=time of maximum concentration.
1He Y-L, et al. J Clin Pharmacol. 2007; 47: 633–641; 2Ristic S, Bates PC. Drugs Today (Barc). 2006; 42: 519–531;
3Henness S, Keam SJ. Drugs. 2006; 66: 1989–2001; 4He Y-L, et al. J Clin Pharmacol. 2008; 48: 89–95;
5He Y-L, et al. J Clin Pharmacol. 2007; 47: 998–1004; 6He Y-L, et al. Curr Med Res Opin. 2007; 23: 1131–1138;
7Ayalasomayajula SP, et al. Curr Med Res Opin. 2007; 23: 2913–2920.
Galvus Enhances GLP-1 Levels in Patients
with T2DM
Meal
Active GLP-1 (pmol/L)
16.0
Placebo (n=16)
*
Vildagliptin 100 mg (n=16)
*
*
12.0
*
*
*
*
*
**
8.0
*
*
*
4.0
0.0
17:00
20:00
GLP-1=glucagon-like peptide-1
*P <0.05
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
23:00
02:00
Time
05:00
08:00
Galvus: Enhances Insulin Sensitivity
Duration: 6 weeks
Vildagliptin vs placebo
Hyperinsulinemic Euglycemic Clamp
7.0
Glucose Rd (mg/kg/min)
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Rd=rate of disappearance
*P <0.05
Azuma K, et al. Diabetes. 2007 (submitted).
*
6.1
Vildagliptin 100 mg daily (n=8)
5.4
Placebo (n=8)
Galvus : Suppresses Glucagon Secretion
20
Meal
Placebo (n=16)
Delta Glucagon (ng/L)
10
Vildagliptin 100 mg (n=16)
0
−10
−20
*
−30
*
−40
−50
*
*
*
−60
17:00
*
*
*
20:00
23:00
*P <0.05 vs placebo
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
02:00
Time
*
05:00
08:00
Galvus Comprehensive Clinical Development Program
Initial combo
SU add-on with TZD
Insulin add-on
TZD add-on
Metformin add-on vs SU
Initial combo with metformin
Metformin add-on vs TZD
Metformin add-on vs placebo
OAD combo
Prediabetes
Diet and
exercise
Insulin mono
OAD mono
In IFG
Insulin combo
Mono vs placebo
Mono head to head
vs metformin
Mono head to head
vs acarbose
In IGT
22,000 patients enrolled in completed
clinical trails on Galvus.
60,000 patients (ongoing trails)
Mono head to head
vs rosiglitazone
IFG=impaired fasting glucose; IGT=impaired glucose tolerance; 47
OAD=oral antidiabetic drug; SU=sulfonylurea; TZD=thiazolidinedione
Galvus
as Monotherapy
48
Vildagliptin Dose-ranging Study: Design and
Objective
Design: a 24-week, double-blind, randomized, placebo-controlled,
parallel-group study
Objective: to demonstrate superior HbA1c reduction of vildagliptin
versus placebo
Target population: drug-naïve patients with T2DM; HbA1c 7.5–10%
n=88: Vildagliptin 50 mg once daily
n=83: Vildagliptin 50 mg twice daily
N=354
n=91: Vildagliptin 100 mg once daily
Drug-naïve
n=92: Placebo
2 weeks
HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus
Pi-Sunyer FX, et al. Diabetes Res Clin Pract 2007; 76: 132-138.
24 weeks
49
Vildagliptin Monotherapy: Reductions in HbA1c
over 24 Weeks
Mean HbA1c (%)
9.0
Vilda 50 mg once daily (n=84)
Vilda 50 mg twice daily (n=79)
Vilda 100 mg once daily (n=89)
PBO (n=88)
8.6
8.2
7.8
*
**
**
7.4
7.0
-4
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (weeks)
HbA1c=hemoglobin A1c; PBO=placebo; vilda=vildagliptin
Primary intention-to-treat population. *P=0.01; **P <0.001 vs placebo.
Pi-Sunyer F, et al. Diabetes Res Clin Pract 2007; 76: 132-138.
50
Galvus as an
Add-on to Metformin
51
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%
n=143: Vildagliptin 50 mg once daily + metformin
N=416*
Metformin
>1500 mg
(monotherapy,
stable dose)
n=143: Vildagliptin 50 mg twice daily + metformin
n=130: Placebo + metformin
4 weeks
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.
24 weeks
52
Vildagliptin Add-on to Metformin: Effective HbA1c
Reduction at 24 Weeks
Duration: 24 weeks
Vilda add-on to met
Add-on Treatment to Metformin (2.1 g Mean Daily)
Change in HbA1c (%)
Mean Difference vs PBO
BL ~8.4%
BL=baseline; HbA1c=hemoglobin A1c; met=metformin;
PBO=placebo; vilda=vildagliptin.
Primary intention-to-treat population.
*P <0.001 difference vs PBO.
Bosi E, et al. Diabetes Care. 2007; 30: 890–895.
-0.7
*
*
Vilda 50 mg once daily + met (n=143)
Vilda 50 mg twice daily + met (n=143)
53
Vildagliptin Add-on to Metformin: Effect on Blood Pressure in
Hypertensive Patients (SBP >140 mmHg and DBP >90 mmHg)
Duration: 24 weeks
Vilda add-on to met
Add-on Treatment to Metformin (2.1 g Mean Daily)
DBP
Change from BL (mmHg)
n=
57
SBP
59
57
59
*
*
Vilda 50 mg twice daily + met
PBO + met
*
BL=baseline; DBP=diastolic blood pressure; met=metformin; PBO=placebo; SBP=systolic blood pressure; vilda=vildagliptin. *P <0.05 vs BL.
Bosi E, et al. Presented at ADA Annual Meeting; June 22–26, 2007; Chicago, IL. 2165-PO.
54
Vildagliptin Add-on to Metformin: Significantly Lowers
HbA1c over 52 Weeks
Duration: 52 weeks
Vilda add-on to met
Vilda 50 mg daily + met (extension, ITT n=42)
PBO + met (extension, ITT n=29)
Vilda 50 mg daily + met (core, ITT n=56)
8.4
PBO + met (core, ITT n=51)
HbA1c (%)
8.0
P <0.0001
 –1.1 ± 0.2%
7.6
P <0.0001
7.2
6.8
−4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Week
n refers to ITT population.
HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin.
Adapted from Ahrén B, et al. Diabetes Care. 2004; 27: 2874–2880.
55
Head-to-head Study: Vildagliptin vs glimepiride in
Add-on to Metformin – results from a 2-year study
Study purpose: To show that vildagliptin added to metformin is non-inferior to glimepiride
in reducing HbA1c levels from baseline over 2 years inT2DM inadequately controlled
with metformin monotherapy in a randomized, double-blind, multicenter study
Interim analysis: to demonstrate non-inferiority of vildagliptin vs glimepiride at 2 year
Target population: patients with T2DM inadequately controlled on a stable metformin
monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%)
n=1562: Vildagliptin 50 mg twice daily + metformin
N=3118
Metformin
n=1566: Glimepiride up to 6 mg once daily + metformin
2-year interim
analysis
4 weeks
*.
Diabetes, Obesity and Metabolism 12: 780–789, 2010.
Volume 12 No. 9 September 2010
104weeks
56
Vildagliptin produced similar glucose control Compared
with Glimepiride
Add-on to Metformin – results from a 2-year study
Mean change in HbA1c (%)
(BL ~7.3%)
Both treatments showed similar efficacy in HbA1c reduction
from baseline to week 104.
*.
Diabetes, Obesity and Metabolism 12: 780–789, 2010.
Volume 12 No. 9 September 2010
57
Vildagliptin Vs Glimepiride:
Hypoglycemic Events in Add-on to Metformin Treatment
Duration: 104weeks
Add-on to met:
vilda vs glim
n=
Patients with
>1 Hypos (%)
1562
1566
*.
Diabetes, Obesity and Metabolism 12: 780–789, 2010.
Volume 12 No. 9 September 2010
Number of
Hypoglycemic
Events
1562
Study
discontinuation
1566
1562 1566
Vildagliptin 50 mg twice daily + metformin
Glimepiride up to 6 mg once daily + metformin
(p < 0.001).
58
Changes in body weight
•Mean change inbody weight
(kg)
(p < 0.001).
Body weight decreased slightly with Vildagliptin −0.3 kg.
With a modest effect in lipid parameters.
*.
Diabetes, Obesity and Metabolism 12: 780–789, 2010.
Volume 12 No. 9 September 2010
59
Galvus Is a Unique
Molecule
60
Compared to other DPP-4 inhibitors, Galvus offered The
greatest reduction in HbA1c1
Meta-analysis summarizing the current evidence on therapies affecting the GLP-1 pathway including 63 randomized controlled clinical
trials from 12 to 52 weeks duration, with the primary endpoint of change from baseline HbA1c, published between January 1 1990 and 31
December 2009.
References: 1. Aorda V. et al. Meta-Analysis of the efficacy of GLP-1R Agonists and DPP-4 inhibitors for treatment of Type 2 Diabetes
Mellitus. European Association for the Study of Diabetes 48th Annual Meeting. Stockholm, Sweden, September 10-24, 2010.
61
Compared to other DPP-4 inhibitors, Galvus offered The
greatest reduction in fasting glucose1
Meta-analysis summarizing the current evidence on therapies affecting the GLP-1 pathway including 63 randomized controlled clinical
trial from 12 to 52 weeks duration, with the primary endpoint of change from baseline HbA1c, published between January 1 1990 and 31
December 2009.
References: 1. Aorda V. et al. Meta-Analysis of the efficacy of GLP-1R Agonists and DPP-4 inhibitors for treatment of Type 2 Diabetes
Mellitus. European Association for the Study of Diabetes 48th Annual Meeting. Stockholm, Sweden, September 10-24, 2010.
62
63
Study Objective:
To evaluate the efficacy of sitagliptin vs. vildagliptin 50
mg twice daily on daily blood glucose fluctuations in
patients with type 2 diabetes that was inadequately
controlled by metformin.
R. Marfella et al. / Journal of Diabetes and Its Complications 21 Jan (2009)
64
Procedure:
• Forty-eight-hour continuous subcutaneous glucose
monitoring (CSGM) was performed in patients treated with
metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a
period of 3 months.
• The mean amplitude of glycemic excursions (MAGE) was
used for assessing glucose fluctuations during the day.
• During a standardized meal, glucagon-like peptide-1 (GLP1), glucagon, and insulin were measured.
R. Marfella et al. / Journal of Diabetes and Its Complications 21 Jan (2009)
65
Comparison of plasma GLP-1 levels following
3 Months’ treatment with vildagliptin or sitagliptin
Retrospective analysis of patients on
sitagliptin (N=20) or vildagliptin (N=18)
Vildagliptin 50 mg
twice daily + metformin (N=18)
Sitagliptin 100 mg
once daily + metformin
30
Intact GLP-1 (pmol/L)
(N=20)
25
20
15
10
5
0
-20 0 15 30 60 90 120 180
Breakfast
240 300 0 15 30 60 90 120
Lunch
180
240 300
0 15 30 60 90 120 180
240 300 min
Dinner
GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group,
Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients.
Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010..
66
Comparison of plasma glucagon levels following
3 Months’ treatment with vildagliptin or sitagliptin
Retrospective analysis of patients on
sitagliptin (N=20) or vildagliptin (N=18)
Vildagliptin 50 mg
twice daily + metformin (N=18)
Plasma Glucagon (mg/dL)
90
Sitagliptin 100 mg once
daily + metformin (N=20)
80
70
60
50
40
30
20
-20 0 15 30 60 90 120 180
Breakfast
240 300 0 15 30 60 90 120
180
Lunch
*P <0.05 vs vildagliptin group; Plasma levels during 24-h sampling comprising three
standardized meals after 3 months of treatment in type 2 diabetic patients.
Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009.
240 300
0 15 30 60 90 120 180
240 300 min
Dinner
67
Results

over a 3-month study period; nevertheless, the effects on glucose
fluctuations over a day, as estimated from MAGE:
indexes that:
reflect that the reduction in daily execration of blood
glucose level was more pronounced in the Galvus
than in the sitagliptin group
• This result from a significantly better daily GLP-1
inhibition profile for Galvus, which could be responsible
for a MAGE within a shorter range.
R. Marfella et al. / Journal of Diabetes and Its Complications 21 Jan (2009)
68
Conclusion
 This may be a potential mechanism for the different effects on
glucose fluctuations over a daily period observed in bid Galvustreated diabetic patients.
Since glucose variations over time, linked to daily fluctuations of
glucose, are associated with an activation of oxidative stress, the
main mechanisms that lead to chronic diabetic complications.
The present data suggest that the DPP-4 inhibition therapy should
target: not only reducing HbA1c, PPG, and mean hyperglycemia but
also flattening acute glucose fluctuations over a daily
period
R. Marfella et al. / Journal of Diabetes and Its Complications 21 Jan (2009)
69
SUMMARY
 Galvus is a Potent and highly Selective DPP-4
Inhibitor.
 Galvus is effective across all hyperglycemia spectrum.
 Galvus monotherapy reduce HbA1c over 24
Weeks 1.1% as a result of reduction of FPG
 Galvus Effective up to 2 years in controlled monotherapy
studies.
70
SUMMARY
• Galvus added to Metformin is as effective as
Glimepiride in reducing HbA1c levels from baseline over
2 years
• Galvus has a dual benefits of reduced hypoglycaemia
risk, without weight gain.
•
Galvus reduces prandial glucagon levels, and increase
insulin secretion
• Galvus had improved β-cell function and insulin
resistance.
Ahren B, Foley JE, Ferrannini E et al
Diabetes, Obesity and Metabolism 12: 780–789, 2010.
Volume 12 No. 9 September 2010
71
Thanks
Backup slides
Safety Profile of Vildagliptin
Large Database Allows for Robust Safety Assessments
Highest exposure on vildagliptin
50 mg twice daily
Vildagliptin
50 mg qd
Total PBO
Total comp
50 mg bid
All-study safety (excluding open-label) population
Patients (N)
2049
6116
1470
6210
Mean duration (weeks)
31.9
62.4
26.0
54.7
Exposure (SYE)
1254
7314
734
6513
All-study safety (including open-label) population
Patients (N)
2206
6159
1470
7082
Mean duration (weeks)
32.8
62.3
26.0
49.4
Exposure (SYE)
1385
7351
734
6705
bid=twice daily; comp=all comparators; PBO=placebo; qd=once daily; SYE=subject-year exposure.
Data on file, Novartis Pharmaceuticals.
Incidence of Reported Common AEs (>5%) in any Pooled Group by
Preferred Term
Vildagliptin
Preferred term
50 mg qd
50 mg bid
Total PBO
Total comp
2049
6116
1470
6210
1253 (61.2)
4225 (69.1)
923 (62.8)
4288 (69.0)
Nasopharyngitis
6.6
9.4
7.3
8.5
Headache
5.0
7.0
3.6
6.0
Dizziness
4.9
6.4
4.8
7.4
Back pain
4.0
5.8
2.7
5.2
Upper respiratory tract
infection
4.1
5.2
4.4
4.1
Diarrhea
2.4
5.6
3.3
6.7
Hypertension
2.7
4.9
2.2
5.1
Tremor
3.5
3.0
4.2
7.6
Hyperhidrosis
2.7
2.8
3.5
6.8
Hypoglycemia
2.0
1.7
3.5
5.8
N
Any AE, n (%)
AEs=adverse events; bid=twice daily; comp=all comparators; PBO=placebo; qd=once daily. All-study safety (excluding open-label) population.
Data on file, Novartis Pharmaceuticals.
Low Risk of Hypoglycemic Events in Add-on to Metformin
Vildagliptin 50 mg qd + met
Hypoglycemia Incidence in
Add-on Metformin
Vildagliptin 50 mg bid + met
Placebo + met
Glimepiride + met
14
Pioglitazone* + met
Incidence (%)
12
9.2
10
8
6
4
2
0.6
0.8
2
340
23
3021
0.3
0
0
n=
N=
1
354
bid=twice daily; glim=glimepiride; met=metformin; pio=pioglitazone; qd=once daily.
Up to 24-week add-on to metformin population. *Pioglitazone 30 mg once daily.
Data on file, Novartis Pharmaceuticals.
189
2045
0
280
No Increased Risk for Adjudicated CV Events,
Relative to All Comparators*
Incidences and Odds Ratios for
Adjudicated CV Events by Treatment
Risk Ratio
Vildagliptin
n / N (%)
Reference
n / N (%)
M-H RR
(95% CI)
Vilda 50 mg qd# 10 / 1393 (0.72)
14 / 1555 (0.90)
0.88 (0.37–2.11)
Vilda 50 mg bid# 81 / 6116 (1.32)
80 / 4872 (1.64)
0.84 (0.62–1.14)
0.1
1
Vildagliptin better
10
Vildagliptin worse
#Meta-analysis
of vildagliptin 50 mg bid data vs all comparators according to the methodology set by the US Food and Drug
Administration‡ [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)].
AEs=adverse events; bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin.
#Vs comparators (all non-vildagliptin treatment groups). All-study safety population.
‡Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, U.S. Department
of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.
Schweizer A, et al. DOM 2010 in press.
Vildagliptin Not Associated with Increased Risk for
Infections
Odds Ratio
Vildagliptin
All
comparators
Peto odds ratio
n / N (%)
n / N (%)
(95% CI)
Infections / infestations
Vilda 50 mg qd* 356 / 1502 (23.07)
432 / 1662 (26.0)
0.88 (0.75–1.04)
Vilda 50 mg bid* 2099 / 6116 (34.3) 1697 / 4872 (34.8)
1.04 (0.96–1.13)
0.1
1
Vildagliptin better
10
Vildagliptin worse
bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin.
*Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.
Ligueros-Saylan M, et al. DOM 2010 in press
79
No Increased Risk for Pancreatitis-related AEs
Odds Ratio
Vildagliptin
All comparators
Peto odds ratio
n / N (%)
n / N (%)
(95% CI)
Pancreatitis events
Vilda 50 mg qd*
2 / 1502 (0.13)
4 / 1662 (0.24)
0.76 (0.15–3.89)
Vilda 50 mg bid*
7 / 6116 (0.11)
9 / 4872 (0.18)
0.70 (0.26–1.88)
0.01
0.1
1
Vildagliptin better
10
100
Vildagliptin worse
AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin.
*Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.
Ligueros-Saylan M, et al. DOM 2010 in press
80
No Increased Risk for Hepatic AEs and SAEs vs
Comparators
Vildagliptin
Reference
Peto odds ratio
n / N (%)
n / N (%)
(95% CI)
Odds Ratio
Hepatic AEs
Vilda 50 mg qd*
15 / 1502 (1.00) 14 / 1662 (0.84) 1.29 (0.61–2.70)
Vilda 50 mg bid* 83 / 6116 (1.36) 84 / 4872 (1.72) 0.87 (0.64–1.19)
Hepatic SAEs
Vilda 50 mg qd*
2 / 1502 (0.13)
2 / 1662 (0.12) 1.08 (0.15–7.76)
Vilda 50 mg bid*
6 / 6116 (0.10)
5 / 4872 (0.10) 1.13 (0.35–3.67)
0.01
0.1
1
10
100
AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily;
SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators
Vildagliptin better
Vildagliptin worse
(all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.
According to the Prescribing information, vildagliptin should not be used in patients with
hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN).
Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should
be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.
Ligueros-Saylan M, et al. DOM 2010 in press
81
DPP-8/-9 Selectivity and Galvus
Vildagliptin is Not Associated with Previously Reported Toxicities in Rodents
• In a 13-week, preclinical study vildagliptin plasma levels were high enough to
inhibit DPP-8 and -9 Burkey et al 2008
Vildagliptin dose:
Mice: up to 1500 mg/kg/day
Rats: up to 900 mg/kg/day
• Previously DPP-8 and -9 inhibition had been associated with toxicity in rats
and mice Lankas et al 2005
Lankas et al 2005
Selective Dual DPP-8/-9 Inhibitor
Burkey et al 2008
Vildagliptin
2-week toxicity* findings in rats and mice
13-week toxicity*** findings in rats and mice
In rats:
In mice:
Alopecia
Thrombocytopenia
Reticulocytopenia
Enlarged spleen
Mortality
NO toxicities described by Lankas et al
observed with vildagliptin
Mortality**
Even at very high doses of vildagliptin (that exceed concentrations needed to inhibit
DPP-8/-9), the toxicities ascribed to selective DPP-8/-9 inhibition were NOT observed
*Toxicities in rats at 10–100 mg/kg/day; **Mortality in mice observed at 100 mg/kg/day (incidence 1/12) and at 300 mg/kg/day (100% incidence, 24/24);
***Doses of vildagliptin used: up to 900 mg/kg/day in rats and 1500 mg/kg/day in mice.
Burkey BF, et al. Diabetes Obes Metab. 2008; 10: 1057–1061.
Lankas GR, et al. Diabetes. 2005. 54: 2988–2994.
Incidence of Drug Discontinuation in Mild Renal Impairment is Lower in
Vildagliptin- vs Comparator-treated Patients
Normal Renal
Function
Mild Renal
Impairment
Vildagliptin 50 mg qd
Vildagliptin 50 mg bid
7.6
Total comparators
6.5
5.9
Total placebo
5.7
5.0
4.0
3.6
Incidence (%)
2.9
Events=
N=
54
1338
212
4232
33
927
248
4217
38
665
118
1802
15
511
145
1918
bid=twice daily; qd=once daily.
Number of patients with severe renal impairment was too small to be equally represented on this graph. All-study safety (excluding open-label)
population.
Data on file, Novartis Pharmaceuticals.
Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940
84
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
GLP-1 analogues e.g.:
•
Exenatide (Byetta®)
•
Liraglutide (Victoza®)
Injectables
Drucker.
Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
85
DPP- 4 inhibitors e.g.:
•
•
Sitagliptin (Januvia®)
Vildagliptin (Galvus®)
Oral agents
86
Sitagliptin - Januvia®
(MSD)
Vildagliptin - Galvus ® (Novartis)
Saxagliptin - Onglyza® (BMS/AZ)
87
Alogliptin
(Takeda/OSI)
Carmegliptin
(Roche)
Linagliptin
(BI)
Gosagliptin
(Pfizer)
Dutogliptin
(Phenomix/Forest)
Melogliptin
(Glenmark)
AMG-222
(Amgen/Servier/ Alantos)
LC15-0444
(LG Life Sciences)
ABT-279
(Abbott)
Opportunities in the
DPP-4 class exist in
the following areas
Side Effects: well-tolerated,
no weight gain
Safety: low risk of
hypoglycaemia
DPP-4 inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
88
Combination therapy Metformin / DPP-4 Inhibitors:
Addressing the 3 Core Defects of Type 2 Diabetes
DPP-4 inhibitors
improve
markers of β-cell
function and
increases insulin
synthesis and
release
β-Cell
Dysfunction
Insulin
Resistance
Metformin acts as an
insulin sensitiser
(liver>muscle/fat)
DPP-4 inhibitors
indirectly
reduces
HGO through
suppression of
glucagon from α
cells
Metformin significantly
decreases HGO by directly
targeting the liver to decrease
gluconeogenesis and
glycogenolysis
Hepatic Glucose
Overproduction
HGO=hepatic glucose overproduction.
89 P et al. Diabetes Care. 2006;29:2632–2637; Abbasi F et al. Diabetes Care. 1998;21:1301–1305; Inzucchi SE. JAMA 2002;287:360–372;
Aschner
Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33; Zhou G et al. J Clin Invest. 2001;108:1167–1174.
Vildagliptin: A Potent and Selective DPP-4 Inhibitor
H
HO
N
O
N
N
 Highly selective DPP-4
inhibitor that acts like a
substrate
 Has a high affinity for
the human enzyme
 Reversible inhibition
X-ray crystallographic structure of
vildagliptin (green) bound to the active site
(yellow) of human DPP-4
DPP-4=dipeptidyl peptidase-4
90
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
120
Insulin
(pmol/L)
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
22.5
Glucose (mmol/L)
17.5
12.5
7.5
140
Glucagon
(ng/L)
120
100
80
60
OGTT=oral glucose tolerance test
*P <0.01.
He YL, et al. In press.
Time
91
Vildagliptin Enhances GLP-1 Levels in Patients
with T2DM
Meal
Active GLP-1 (pmol/L)
16.0
Placebo (n=16)
*
Vildagliptin 100 mg (n=16)
*
*
12.0
*
*
*
*
*
**
8.0
*
*
*
4.0
0.0
17:00
20:00
GLP-1=glucagon-like peptide-1
*P <0.05
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
23:00
02:00
05:00
08:00
Time
92
Vildagliptin Suppresses Glucagon Secretion
20
Meal
Placebo (n=16)
Delta Glucagon (ng/L)
10
Vildagliptin 100 mg (n=16)
0
−10
−20
*
−30
*
−40
−50
*
*
*
−60
17:00
*
*
*
20:00
23:00
*P <0.05 vs placebo
Balas B, et al. J Clin Endocrinol Metab. 2007; Epub ahead of print.
02:00
*
05:00
08:00
Time
93
Vildagliptin: Enhances Insulin Sensitivity
Duration: 6 weeks
Vildagliptin vs placebo
Hyperinsulinemic Euglycemic Clamp
7.0
Glucose Rd (mg/kg/min)
6.0
*
6.1
Vildagliptin 100 mg daily (n=8)
5.4
Placebo (n=8)
5.0
4.0
3.0
2.0
1.0
0.0
Rd=rate of disappearance
*P <0.05
Azuma K, et al. Diabetes. 2007 (submitted).
94
GLP-1 Restores Insulin and Glucagon Responses in a
Glucose-Sensitive Manner in Patients with T2DM
N=10
Glucose (mg/dL)
C-Peptide (nmol/L)
300
30
3.0
GLP-1 infusion
GLP-1 infusion
250
2.5
200
2.0
150
1.5
GLP-1 infusion
25
*
*
*
*
20
*
*
15
*
*
*
*
100
Glucagon (pmol/L)
10
1.0
*
*
*
0
–30 0
*
*
50
*
5
0.5
*
*
*
30 60 90 120 150 180 210 240
0.0
–30 0
30 60 90 120 150 180 210 240
Time (Min)
GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus
*P <0.05
†GLP-1(7–36 amide) infused at 1.2 pmol/kg/min for 240 minutes.
Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741–744.
0
–30
0
30 60 90 120 150 180 210 240
Time (Min)
Time (Min)
GLP-1†
Placebo
95
Synergy between Vildagliptin and Metformin
on Prandial GLP-1


Vildagliptin increases active GLP-1
levels by 2–4x through inhibition of
the DPP-4 enzyme1-4
Metformin raises GLP-1 levels,
presumably through increasing
GLP-1 synthesis and not through
DPP-4 inhibition5-7
Vildagliptin and metformin are
known to have synergy to
maximise levels of intact GLP-18,9
30
Active GLP-1 AUC0-2hr
(pmol/L)

Effect of vildagliptin on
prandial active GLP-1 levels
in drug-naïve versus
metformin-treated patients
*
25
20
15
10
5
0
Vildagliptin
in drug-naïve
patients
(n=5)
Vildagliptin in
patients on
metformin
(n=12)
*P <0.05.
1Ahrén B, et al. J Clin Endocrinol Metab. 2004; 89: 2078–2084; 2Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255;
3Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057; 4Rosenstock J, et al. Diabetes Care. 2008; 31: 30–35;
5Yasuda N, et al. Biochem Biophys Ref Commun. 2002; 298: 779–784; 6Hinke S, et al. Biochem Biophys Ref Commun. 2002; 291: 1302–1308;
7Migoya E, et al. Presented at EASD 2007; abstract 0111; 8Dunning B, et al. Presented at EASD 2006; abstract 0174; 9D’Alessio DA, et al.
J Clin Endocrinol Metab. 2008; Epub ahead of print.
96
Synergy between Vildagliptin and Metformin
on Fasting GLP-1
Fasting levels of intact GLP-1 in
vildagliptin subgroups at 3 months
Fasting levels of intact GLP-1 at
baseline and at 3 months
Vilda group
20
20
19
Vilda only
19
7
14
14
12
12
10
Intact GLP-1 (pM)
Intact GLP-1 (pM)
n=
Placebo
*
8
6
4
6
4
0
0
BL
**
8
2
3 months
13
10
2
BL
Vilda + met
3 months
*P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline.
BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin
D’Alessio DA, et al. J Clin Endocrinol Metab. 2008; Epub ahead of print.
97
Vildagliptin Monotherapy: Reductions in HbA1c
over 24 Weeks
Mean HbA1c (%)
9.0
Vilda 50 mg once daily (n=84)
Vilda 50 mg twice daily (n=79)
Vilda 100 mg once daily (n=89)
PBO (n=88)
8.6
8.2
7.8
*
**
**
7.4
7.0
-4
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (weeks)
HbA1c=hemoglobin A1c; PBO=placebo; vilda=vildagliptin
Primary intention-to-treat population. *P=0.01; **P <0.001 vs placebo.
Pi-Sunyer F, et al. Diabetes Res Clin Pract 2007; 76: 132-138.
98
Vildagliptin: Effective FPG Reduction
Duration: 24 weeks
Change in FPG from
BL vs placebo
Mean BL ~10.5 mmol/L
0.4
Change in FPG
0.0
-0.4
-0.8
-0.6
-1.2
-1.3
-1.6
BL=baseline; FPG=fasting plasma glucose; vilda=vildagliptin
Primary intention-to-treat population.
*P <0.001 vs placebo.
Pi-Sunyer F, et al. Diabetes Res Clin Pract 2007; 76: 132-138.
*
-1.3
*
Vilda 50 mg once daily (n=84)
Vilda 50 mg twice daily (n=79)
Vilda 100 mg once daily (n=89)
99
Vildagliptin: No Weight Gain Overall
Duration: 52 weeks
Vilda vs met
100
Mean body weight (kg)
Vilda 50 mg twice daily (n=511)
Met 1000 mg twice daily (n=249)
95
90
85
80
−4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Time (weeks)
Met=metformin; vilda=vildagliptin. Intention-to-treat population.
Schweizer A, et al. Diabet Med 2007; 24: 955-961.
100
Vildagliptin Clinical Highlights (1)
By inhibiting the enzyme DPP-4, Vildagliptin has been shown to enhance the
physiological effects of incretin hormones such as GLP-1 and GIP, thereby increasing
alpha and beta cell responsiveness to glucose
By enhancing the effects of GLP-1 and GIP, Vildagliptin has shown
 Equivalent efficacy as a TZD in head-to-head trial in monotherapy following 24
weeks of treatment, with up to 1.9% HbA1c reductions in high baseline patients
(efficacy was inferior to rosiglitazone following 104 weeks treatment)
 Powerful additional HbA1c reductions of 1.1% vs metformin alone when given
to patients inadequately treated with full-dose metformin (mean dose 2.1g)
 No weight gain as monotherapy; up to 2.8kg relative weight difference vs TZDs
in obese patients (following 24 weeks of treatment)
 Neutral to favorable lipid profile
 Modest, but consistent blood pressure lowering effect
 Effective up to 2 years in controlled monotherapy studies
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide;
GIP = glucose-dependent insulinotropic peptide
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Vildagliptin Clinical Highlights (2)
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
Vildagliptin has shown good tolerability profile
•
Very low incidence of hypoglycaemia and edema in
monotherapy studies, comparable to placebo
•
Superior GI tolerability vs. metformin
Vildagliptin is convenient to use
•
No dose titration
•
No dose adjustment in mild renal impairment (BPI)
•
No dose adjustment required by age, gender, body mass
index, or ethnicity
•
Should not be used in patients with hepatic impairment or
elevated liver enzymes (>2.5 times upper limit of normal)
(BPI)
BPI= Basic Prescribing Information (Novartis Core Data Sheet)
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Exenatide (Byetta®)
Lilly/Amylin
•
Liraglutide (Victoza®)
Novo Nordisk
•
Exen LAR (Byetta® LAR)
Lilly/Amylin
•
Taspoglutide®
Roche/Ipsen
•
Lixisenatide
sanofi aventis
•
Syncria® (albiglutide)
GSK/HGS
•
Other (GLP-1 intranasal & oral)
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What do we know, don’t know
and need to know?
• What we don’t know
─ What is the optimal drug after metformin?
─ What is the optimal combination of insulin and/or oral
drugs on glycemic durability and clinical outcomes?
─ What are the confounding effects of risk factors and
comorbidites on the impact of these treatments on
clinical outcomes?
• What do we need to know
─ Better phenotyping and more evidence to support
various treatment guidelines
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What do we know, don’t know
and need to know?
What do we know •
Beta cell insufficiency and progressive beta cell failure
are hallmarks of T2D
Insulin and oral blood glucose lowering drugs are
efficacious
Improving glycemic control early improves clinical
outcomes in the long term
Restoring euglycemia and providing ‘beta cell rest’ may
improve beta cell function in patients with short duration
of disease
Short term study suggests superior effect of insulin over
SU in preserving beta cell function
Benefits of blood glucose lowering with insulin need to
be balanced against risk of hypoglycemia and weight
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