1 glp-1 receptor agonists: emerging treatments in diabetes therapeutics shannon i. brow, rn, cde,...
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GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics GLP-1 Receptor Agonists: Emerging Treatments in Diabetes Therapeutics
Shannon I. Brow, RN, CDE, FNP-C
Medical Science Liaison
Amylin Pharmaceuticals, Inc
2
Faculty Disclosures:Faculty Disclosures:
• Shannon I. Brow, RN, CDE, FNP-C– Employee of Amylin Pharmaceuticals, Inc
– Stockholder: Amylin Pharmaceuticals, Inc
3
Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
4
Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
5
Microvascular changes
Macrovascular changesClinicalfeatures
Kendall DM, et al. Am J Med 2009;122:S37-S50.Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
Years
Rel
ativ
e A
mo
un
t
-10 -5 0 5 10 15 20 25 30
Insulin resistance
Insulin level
0
50
100
150
200
250
-15
Incretin effect
-cell function
β-cell failure
Onsetdiabetes
Glu
cose
(m
g/d
L)
Diabetesdiagnosis
50
100
150
200
250
300
350
Fasting glucose
Prediabetes (Obesity, IFG, IGT)
Postmeal Glucose
-10 -5 0 5 10 15 20 25 30-15Years
Progressive Nature of Type 2 DiabetesProgressive Nature of Type 2 Diabetes
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Postprandial Glucose Contribution to A1CPostprandial Glucose Contribution to A1C
% C
on
trib
uti
on
A1C Range (%)
0
20
40
60
80
100
FPG (Fasting Plasma Glucose)PPG (Postprandial Plasma Glucose)
>10.2
70%
30%
9.3-10.2
60%
40%
8.5-9.2
55%
45%
7.3-8.4
50%
50%
<7.3
30%
70%
Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.
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Pla
sm
a G
luc
os
e (
mg
/dL
)
Time of Day (h)
Plasma Glucose Is NormallyMaintained in a Narrow RangePlasma Glucose Is NormallyMaintained in a Narrow Range
Breakfast Lunch Dinner
400
300
200
100
0
06.00 10.00 14.00 18.00 22.00 02.00 08.00
N = 30; Mean (SE)Data from Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239
Healthy SubjectsType 2 Diabetes
8
A1C Goals Unmet in Majority of Patients With DiabetesA1C Goals Unmet in Majority of Patients With Diabetes
Upper limit of normal range (6%)
ACE recommended target (<6.5%)4
ADA recommended target (<7%)3
1. Data from Saydah SH, et al. JAMA 2004; 291:335-342.2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20. 3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50.4. Data from ACE. Endocrine Practice 2002.
8.0
9.5
A1C (%)
6.0
8.5
10.0
6.5
5.5
9.0
7.0
7.5
37.2% have A1C >8%
20.2% have A1C >9%
12.4% have A1C >10%1
64.2% of patients with type 2 diabetes have A1C 7%2
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Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
10
Criteria for the Diagnosis of DiabetesCriteria for the Diagnosis of Diabetes
1. A1c ≥ 6.5%. This test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*
OR
2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*
OR
3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. This test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l).
* In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing
American Diabetes Association. Diabetes Care 2010;33(suppl 1):S62-S69.
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HyperglycemiaHyperglycemia
InsulinResistance
InsulinResistance
Insulin Deficiency
Insulin Deficiency
DiminishedBeta-Cell Response
(Insulin Deficiency)
DiminishedBeta-Cell Response
(Insulin Deficiency)
IncreasedBeta-Cell Workload
(Insulin Resistance)
The Pathogenesis of Type 2 DiabetesA New Perspective of the Core Defects ParadigmThe Pathogenesis of Type 2 DiabetesA New Perspective of the Core Defects Paradigm
Adapted from ©2005 International Diabetes Center, Minneapolis, MN All rights reserved
12
DecreasedDecreasedBeta-CellBeta-CellResponseResponse
DecreasedDecreasedBeta-CellBeta-CellResponseResponse
Insulin resistance
Obesity
Food intake
Gastric Emptying – Rate of nutrient absorption
Glucagon secretion
Hepatic glucose output
Insulin secretion in response to elevated glucose
First-phaseinsulin response
IncreasedIncreasedBeta-CellBeta-CellWorkloadWorkload
IncreasedIncreasedBeta-CellBeta-CellWorkloadWorkload
HyperglycemiaHyperglycemia
The Pathogenesis of Type 2 DiabetesAn Imbalance of Beta-Cell Workload and Beta-Cell ResponseThe Pathogenesis of Type 2 DiabetesAn Imbalance of Beta-Cell Workload and Beta-Cell Response
13
The Pathophysiology of Type 2 DiabetesThe Pathophysiology of Type 2 Diabetes
Insulin Resistance
Incretin“Defect”
Relative Insulin Deficiency
HyperglycemiaType 2 Diabetes
14
Clinical Challenges With Type 2 DiabetesClinical Challenges With Type 2 Diabetes
WeightA1C
Diet and ExerciseMETSFU
Insulin
6.2% A1C Upper limit of normal
0 2 4 6
Time From Randomization (y)
Med
ian
A1C
(%
)
8
9
7
6
Wei
gh
t (k
g)
0 2 4 6
Time From Randomization (y)
10
-5
5
0
n = 1704; A1C indicates glycosylated hemoglobin A1c; MET, metformin; SFU, sulfonylureaData from UKPDS Group (34). Lancet 1998;352:854-865.
Diet and ExerciseMETSFU
Insulin
15
Blood Glucose Concentrations Are Largely Determined by Beta-Cell FunctionBlood Glucose Concentrations Are Largely Determined by Beta-Cell Function
• Beta-Cell Function– Insulin synthesis
– Insulin secretion
• Beta-Cell Functional Capacity– Beta-cell mass (cell turnover and neogenesis)
– First-phase/second-phase insulin release
– Insulin processing (proinsulin to insulin)
– Glucose sensitivity
• Beta-Cell Functional Demand– Glucose absorption (diet, gastric emptying)
– Hepatic glucose production (glycolysis, gluconeogenesis)
– Peripheral glucose uptake (insulin sensitivity, exercise)
16
Multihormonal Regulation of Glucose Appearance and DisappearanceMultihormonal Regulation of Glucose Appearance and Disappearance
Time (min)
Mixed Meal (With ~85 g Dextrose)
0 120 240 360 480-0.6
-0.4
-0.2
0
0.2
0.4
0.6G
ram
s o
f G
luc
os
e (
flu
x/m
in)
-30
Insulin-mediatedglucose uptake
Balance of insulin suppression and
glucagon stimulation
Regulated by hormones: GLP-1, amylin, CCK, etc.
Meal-Derived Glucose
Hepatic Glucose Production
Total Glucose Uptake
N = 5; Mean (SE)Data from Pehling G, et al. J Clin Invest 1984;74:985-991.
17
Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
18
The Incretin Effect in Healthy Subjects The Incretin Effect in Healthy Subjects
C-P
ep
tid
e (
nm
ol/
L)
Time (min)
0.0
0.5
1.0
1.5
2.0
Incretin Effect*
*
**
* *
*
Oral Glucose Intravenous (IV) Glucose
Pla
sm
a G
luc
os
e (
mg
/dL
)
200
100
0
Time (min)
60 120 180060 120 1800
N = 6; Mean (SE); *P0.05Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492-498.
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IncretinsIncretins
• Gut-derived factors that potentiate insulin secretion following meal ingestion
• 2 principal incretins identified to date:
GIP 42-amino acid peptide
GLP-1 30-amino acid peptide
Adapted from Holst JJ, et al. Am J Physiol Endocrinol Metab 2004; 287:E199-E206. Drucker DJ. Diabetes Care 2003; 26:2929-2940.
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YesYesPromotes insulin biosynthesis
NoYesReduces food intake
NoYesDecreases secretion in T2DM
YesYesKnockout mice (result in IGT)
YesYesStimulates beta-cell mass/growth
NoYesSlows gastric emptying
NoYesInhibits glucagon secretion postprandially
Site of Production
Adapted from Mayo KE, et al. Pharmacol Rev 2003;55:167-194.Adapted from Drucker DJ. Diabetes Care 2003;26:2929-2940.Adapted from Nauck M, et al. Diabetologia 1986;29:46-52.
Comparison of the IncretinsComparison of the Incretins
GIPK-cells
(Duodenumand Jejunum)
GLP-1L-cells
(Ileum and Colon)
21
Ins
uli
n (
mU
/L)
The Incretin Effect Is Reduced in Type 2 DiabetesThe Incretin Effect Is Reduced in Type 2 Diabetes
Time (min)
Healthy Subjects
Ins
uli
n (
mU
/L)
Time (min)
Type 2 Diabetes
N = 22; Mean (SE); *P0.05 Data from Nauck M, et al. Diabetologia 1986;29:46-52.
0
20
40
60
80
0 60 120 1800
20
40
60
80
0 60 120 180
Intravenous (IV) GlucoseOral Glucose
Incretin EffectIncretin Effect
*
*
*
*
*
**
***
22
Glucagon-Like Peptide-1 (GLP-1) is an Important Incretin HormoneGlucagon-Like Peptide-1 (GLP-1) is an Important Incretin Hormone
• The “incretin effect” started the search
• Incretins– Gut hormones that enhance insulin secretion in response to food
– Glucose-dependent insulin secretion
• GLP-1– Secreted from L cells of the intestines
– Most well-characterized incretin
– Diminished in type 2 diabetes
• Glucagon– Secreted from pancreatic alpha cells
– Counterregulatory hormone to insulin
– Elevated in type 2 diabetes
Adapted from Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190.
23
600 120 180 240
Postprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 DiabetesPostprandial GLP-1 Concentrations Are Lower in Subjects With IGT and Type 2 Diabetes
N = 102; Mean (SE); *P<0.05 between type 2 diabetes and healthy subjectsData from Toft-Nielsen MB, et al. J Clin Endocrinol Metab 2001;86:3717-3723.
20
15
10
5
0
Time (min)
GL
P-1
(p
mo
l/L
)
* * * * **
*
*
Meal
Healthy SubjectsImpaired Glucose ToleranceType 2 Diabetes
24
80
0
-60 120 180 240
Time (min)
120
60
100
120
140
140
360
300
240
Insulin and Glucagon Responses Are Altered in Type 2 DiabetesInsulin and Glucagon Responses Are Altered in Type 2 Diabetes
Healthy SubjectsType 2 Diabetes
600
N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med 1970;283:109-115.
Insulin(µU/mL)
Glucagon(pg/mL)
Glucose(mg/dL)
Carbohydrate MealCarbohydrate Meal
Me
al
25
GLP-1 Modulates Numerous Functions in HumansGLP-1 Modulates Numerous Functions in Humans
Stomach:Stomach: Helps regulate Helps regulate
gastric emptyinggastric emptying
Promotes satiety and Promotes satiety and reduces appetitereduces appetite
Liver:Liver: Glucagon Glucagon reduces reduces
hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:EnhancesEnhances glucose- glucose-
dependent dependent insulin secretioninsulin secretion
Alpha cells:Alpha cells: Glucose-dependent Glucose-dependent
postprandialpostprandialglucagon secretionglucagon secretion
GLP-1: Secreted upon the ingestion of food
Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.
26
GLP-1 Effects Are Glucose Dependentin Type 2 DiabetesGLP-1 Effects Are Glucose Dependentin Type 2 Diabetes
Placebo
Glu
ca
go
n (
pm
ol/
L)
GLP-1
300
200
100
0
Ins
uli
n (
pm
ol/
L)
Time (min)
-30 0 60 120 180 240
PBOPBOGLP-1GLP-1
*** **
* *
*
Glu
co
se
(m
g/d
L)
270
180
90
0-30 0 60 120 180 240
*
*
*
*
* * *
PBOPBOGLP-1GLP-1
Time (min)
-30 0 60 120 180 240
20
10
0
** * *
PBOPBOGLP-1GLP-1
Time (min)
N = 10; Mean (SE); *P<0.05Data from Nauck MA, et al. Diabetologia 1993;36:741-744.
27
GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV)GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV)
His Ala Glu Gly Thr Phe Thr Ser Asp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
Lys
DPP-IV
7
37
9
Adapted from Mentlein R. Eur. J. Biochem 1993;214:829-835.
28
Leveraging the Therapeutic Potential of GLP-1Leveraging the Therapeutic Potential of GLP-1
• GLP-1– Short half-life (2 minutes)
Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)
• DPP-IV inhibition– Extends endogenous GLP-1 half-life
Approved in US:
– Sitagliptin (Merck)
– Saxaglitpin (BMS and AZ) In development, e.g.,
– Alogliptin (Takeda)
– Denagliptin (Glaxo)
– Melogliptin (Glenmark)
– Vildagliptin – LAF 237 (Novartis)
29
Leveraging the Therapeutic Potential of GLP-1Leveraging the Therapeutic Potential of GLP-1
• GLP-1 receptor agonists– Mimic many of the glucoregulatory effects of GLP-1
– Resistant to DPP-IV Approved in US:
– Exenatide (Amylin and Lilly)
– Liraglutide (Novo Nordisk) In development, e.g.,
– Albiglutide (Glaxo Smith Kline)
– CJC 11134 (ConjuChem)
– Exenatide once weekly (Amylin, Lilly, Alkermes)
– Lixisenatide (Sanofi- Aventis)
– Taspoglutide (Roche)
30
Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
31
DPP-4 Inhibitor and GLP-1 Receptor Agonist DiscussionDPP-4 Inhibitor and GLP-1 Receptor Agonist Discussion
• The slides that follow include data from the first FDA approved agent in each class
• Concepts are broad, yet representative of drugs that are FDA approved in each class
• There is no intent to claim superiority of the drug discussed compared to the other same class agent
32
Continuously Infused GLP-1 Improved the Defects of T2DContinuously Infused GLP-1 Improved the Defects of T2D
T2D Defects1Continuously Infused
GLP-11,2
Insulin production
First-phase insulin response
Glucagon; glucose output
Gastric emptying
Food intake
1. Aronoff SL, et al. Diabetes Spectrum 2004;17:183-190. 2. Nielsen LL, et al. Regul Pep. 2004;117:77-88.
33
Effects of GLP-1 on the cell in Healthy SubjectsEffects of GLP-1 on the cell in Healthy Subjects
34
GLP-1 in T2DGLP-1 in T2D
35
GLP-1 Is Cleaved and Inactivated by DPP-4GLP-1 Is Cleaved and Inactivated by DPP-4
36
Mechanism of Action: DPP-4 InhibitorsMechanism of Action: DPP-4 Inhibitors
• Sitagliptin example
www.januvia.com/januvia/hcp/januvia/documents/MOAcard_JANUVIA.pdf
37
Sitagliptin Decreased A1C From Baseline Over 24 wksSitagliptin Decreased A1C From Baseline Over 24 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
38
Sitagliptin Decreased A1C Over 52 wksSitagliptin Decreased A1C Over 52 wks
Januvia [package insert]. Whitehouse Station, New Jersey, Merck; 2009
39
DPP-4 Inhibitors Prevent the Inactivation of GLP-1 DPP-4 Inhibitors Prevent the Inactivation of GLP-1
40
The BeginningThe Beginning
• Exenatide– Synthetic version of salivary protein found in
the Gila monster
– More than 50% amino acid sequence identity with human GLP-1 Binds to known human GLP-1 receptors on beta cells (in vitro) Resistant to DPP-IV inactivation
Adapted from Nielsen LL, et al. Regul Pept 2004;117:77-88.Adapted from Kolterman OG, et al. Am J Health-Syst Pharm 2005;62:173-181.
• Following injection, exenatide is measurable in plasma for up to 10 hours
Site of DPP-IV Inactivation
41
Exenatide Restored First-Phase Insulin ResponseExenatide Restored First-Phase Insulin Response
Time (min)
Evaluable; N = 25; Mean (SE)Fehse F, et al. J Clin Endocrinol Metab 2005;90(11):5991-5997.
Healthy Controls
IV Glucose IV Glucose
-180 -90 0 30 60 90 1200
10
20
30
-180 -90 0 30 60 90 120
Type 2 Diabetes
Exenatide
Exenatide
Placebo
Placebo0
10
20
30
Ins
uli
n (
pM
/kg
/min
)
Ins
uli
n (
pM
/kg
/min
)
Time (min)
42
Exenatide Suppressed Postprandial Glucose and Glucagon in Type 2 DiabetesExenatide Suppressed Postprandial Glucose and Glucagon in Type 2 Diabetes
N = 20; Mean (SE)Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.
Pla
sm
a G
luc
ag
on
(p
g/m
L)
Pla
sm
a G
luc
os
e (
mg
/dL
)
0 120 1806050
100
150
200
Exenatide or PlaceboStandardized Breakfast
90
180
270
360
Exenatide or PlaceboStandardized Breakfast
0 60 120 180 240 300
Time (min)
Placebo0.10 µg/kg Exenatide
Time (min)
43
Exenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin SecretionExenatide Acutely Reduced Glucose Through Enhanced Glucose-Dependent Insulin Secretion
Type 2 Diabetes; N = 34; Mean (SE)Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003;88:3082-3089.
Time (h)
Pla
sm
a G
luc
os
e (
mg
/dL
)
0 2 4 6 890
135
180
225
SC Injection SC Injection
0 2 4 6 8
Placebo 0.05 µg/kg Exenatide 0.10 µg/kg Exenatide
Time (h)
Se
rum
In
su
lin
(p
mo
l/L
)
100
150
200
250
50
44
Exenatide Is Not Inactivated by DPP-4Exenatide Is Not Inactivated by DPP-4
45
Exenatide vs Sitagliptin MOA Study: Study DesignExenatide vs Sitagliptin MOA Study: Study Design
• Primary endpoint: comparison of the effects of exenatide and sitagliptin on 2-hour PPG concentrations in patients with T2D
MET background; MOA indicates mechanism of action; QAM, once per day in the morningDeFronzo RA, et al. Curr Med Res Opin 2008;24;2943-2952.
Study TerminationCrossover
Treatment Period 1 Treatment Period 2
Randomization
Placebo Lead-in
Exenatide 5 µg BID Exenatide 10 µg BID Exenatide 5 µg BID Exenatide 10 µg BID
StandardMeal Test
StandardMeal Test
StandardMeal Test
1 week 2 weeks 2 weeks
Sitagliptin 100 mg QAM Sitagliptin 100 mg QAM
Sequence A
Sequence B
46
Plasma GLP-1 Plasma Exenatide
Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1Postprandial Plasma Levels of Exenatide Exceeded Physiologic Levels of GLP-1
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE2-wk posttreatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
BaselineExenatideSitagliptin
2-h
Po
stp
ran
dia
l Pla
sma
GL
P-1
(p
M)
2-h P
lasma E
xenatid
e (pM
)
0
25
50
75
0
25
50
75
7.2 7.9
15.1
63.8
47
-30 0 30 60 90 120 150 180 210 240120
160
200
240
280
PP
G (
mg
/dL
)
Time (min)Standard Meal
Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin Exenatide Reduced PPG Concentrations To a Greater Extent Than Sitagliptin
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P<0.0001DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
BaselineExenatideSitagliptin
Primary Endpoint
48
2-h
r P
PG
(m
g/d
L)
110
130
150
170
190
210
230
250
270
Baseline End of Period 1
End of Period 2
Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32Mean ± SE; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
Reductions in 2-Hour PPG Were Greater With Exenatide Than With SitagliptinReductions in 2-Hour PPG Were Greater With Exenatide Than With Sitagliptin
ExenatideSitagliptin
• After Period 1, patients were switched to the other therapy
49
Improvement in Insulinogenic Index Was Greater With Exenatide Than With SitagliptinImprovement in Insulinogenic Index Was Greater With Exenatide Than With Sitagliptin
Insu
lino
gen
ic In
dex
1
0.55
P = 0.02
0.82
Exenatide Sitagliptin
Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean ± SE Standard meals administered at t = 0 min; 1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. 2. Data on file, Amylin Pharmaceuticals, Inc.
Geometric Mean Baseline Insulinogenic Index2: 0.4
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.55
0.82
50
Exenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than SitagliptinExenatide Reduced Postprandial Glucagon Levels to a Greater Extent Than Sitagliptin
-30 0 30 60 90 120 150 180 210 24070
80
90
100
110
120
Pla
sma
Glu
cag
on
(p
g/m
L)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SEDeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
Time (min)Standard Meal
BaselineExenatideSitagliptin
51
-30 0 30 60 90 120 150 180 210 240
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately before the standard meal; DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952.
Pla
sma
Ace
tam
ino
ph
en (
µg
/mL
)Exenatide Slowed Gastric Emptying Compared to SitagliptinExenatide Slowed Gastric Emptying Compared to Sitagliptin
Time (min)Standard Meal
BaselineExenatideSitagliptin
52
ActionGLP-1 Receptor
Agonists1,2DPP-4
Inhibitors1,2
Insulin production +++ ++
First-phase insulin response
+++ ++
Glucagon; glucose output
+++ +
Gastric emptying Delayed No effect
Food intake Decreased No effect
Actions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 InhibitorsActions of Incretin-Based Therapies for T2D: GLP-1 Receptor Agonists and DPP-4 Inhibitors
1. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943-2952. 2. Drucker DJ and Nauck MA. Lancet 2006;368:1696-1705.
53
Learning ObjectivesLearning Objectives
• Discuss the progressive nature of diabetes
• Discuss the new ADA diagnostic criteria for diabetes published Jan 2010
• Review incretin physiology in healthy individuals and in patients with type 2 diabetes
• Discuss mechanism of action of incretin mimetics: DPP-4 inhibitors and GLP-1 receptor agonists
• Identify where incretin therapies can be used in the treatment of type 2 diabetes
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Diagnosis:
Lifestyle+
Metformin
Lifestyle + Metformin+
Basal insulin
Lifestyle + Metformin+
Sulfonylurea
Lifestyle + Metformin+
Intensive insulin
Step 1 Step 2 Step 3
Lifestyle + Metformin+
Pioglitazone (no hypoglycemia /edema (CHF)/ bone loss)
Tier 1: well-validated core therapies
Tier 2: less well-validated core therapies
Lifestyle + Metformin+
GLP-1 agonist (no hypoglycemia/weight loss /nausea/vomiting )
Lifestyle + Metformin+
Pioglitazone +
Sulfonylurea
Lifestyle + Metformin+
Basal insulin
Algorithm for Type 2 Diabetes
Validation based on clinical trials & clinical judgmentNathan DM, et al. Diabetes Care 2008;31(12):1-11.
55
AACE/ACE Glycemic Control Algorithm: T2 DiabetesAACE/ACE Glycemic Control Algorithm: T2 Diabetes
6.5%
7.5%7.6%
9.0%>9.0
Lifestyle Modification
(to be considered throughout treatment)
MonotherapyCan include:• MET• DPP4• GLP-1• TZD• AGI
Dual Therapy• MET+GLP-
1, DPP4,or TZD
• TZD+GLP-1 or DPP4
• MET+Colsevelam or AGI
Dual Therapy• MET+GLP-
1, DPP4, or TZD
• MET+SFU or Glinide
Triple Therapy• MET+GLP-1
or DPP4 with TZD or SFU
Triple Therapy• MET+GLP-1
or DPP4 + TZD or SFU
• MET + TZD + SFU
After Orals• Insulin ±
other agents
Symptoms• Insulin ±
other agents
No Symptoms• MET+GLP-1 or
DPP4 + TZD or SFU
• MET + TZD + SFU• Insulin ± other
agents
A1CA1C
Adapted from AACE Glycemic Control Algorithm, Rodbard HW, et al. Endocr Pract 2009. Reproductions can be found at www.aace.com/pub
Increase therapy every 2-3 months if glycemic goal is not achieved
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AACE/ACE Algorithm SummaryAACE/ACE Algorithm Summary
• The algorithm is intended for use in conjunction with more detailed and comprehensive information (e.g., prescribing information, ACE/AACE Road Maps, etc)
• The algorithm is intended to provide guidance
• A1C goal of ≤ 6.5% or less– Needs to be individualized to minimize risks of hypoglycemia
• Therapeutic pathways stratified based on current A1C values
• 8 major classes of medications– Prioritized by safety, efficacy, risk of hypo, simplicity, patient
adherence and cost of medication
– Combination medications that have complimentary mechanisms of action
Rodbard HW, et al. Endocr Pract 2009;15(6):541-559.