Transcript GLP-1 - Bydureon

Bydureon® Educate By Expert toolkit
Scientific slides: GLP-1 receptor agonists and the discovery of
exenatide
Date of preparation: Apri l 2014 150515
Developed with the guidance and approval of an
independent international editorial committee
GLP-1, glucagon-like peptide-1.
Content guide
• These decks comprise a number of slides, arranged in story order. You may find
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necessary
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i
Expert sound bite
• All graphs have been created in PowerPoint to enable easy amends and translation
• HbA1c values and appropriate graphs include both
DCCT (%) and IFFC (mmol/mol) units. Please delete where not appropriate for your
market
DCCT, Diabetes Control and Complications Trial; IFFC, International Federation of Clinical Chemistry and Laboratory Medicine.
Executive summary
• This slide deck covers the following topics and contains speaker
notes to assist presentation:
1. Introduction to Type 2 diabetes
• Unmet needs and barriers to treatment
– Epidemiology of Type 2 diabetes
– Barriers to treatment (weight gain, hypoglycaemia, adherence to treatment)
• The Type 2 diabetes treatment pathway and individualised care
– The place of GLP-1 receptor agonists and insulin in the treatment pathway
2. GLP-1 receptor agonists and the discovery of exenatide
• GLP-1 mechanism of action and the incretin effect
• The discovery of exenatide, the first GLP-1 receptor agonist
Slide is animated
What is GLP-1?
• GLP-1 is an incretin hormone that is secreted by the L-cells in the gut1
– Secreted in a nutrient-dependent manner1
– Exerts multiple glucoregulatory properties1
Fasting
Fed state
state
Suppresses postprandial
glucagon
secretion

Suppresses
glucagon
secretion
decreased
decreasedhepatic
hepaticglucose
glucose
2
production
Stimulates glucose-dependent
insulin secretion1
Reduces appetite and food intake4
Slows gastric emptying1
Improves first-phase insulin
response3
Figure adapted from Drucker DJ, et al. 2006,1 Larsson H, et al. 1997,2 Quddusi S, et al. 2003,3 and Flint A, et al. 1998.4
GLP-1, glucagon-like peptide-1.
1. Drucker DJ. Cell Metab 2006;3:153–65; 2. Larsson H, et al. Acta Physiol Scand 1997;160:413–22; 3. Quddusi S, et al. Diabetes Care 2003;26:791–8;
4. Flint A, et al. J Clin Invest 1998;101:515–20.
Pathophysiology of Type 2 diabetes and the incretin pathway
i
Expert sound bite
• Placeholder for video 1Bi. Professor Stephan Jacob: Pathophysiology of
Type 2 diabetes and the incretin pathway
5
The incretin effect is diminished in Type 2 diabetes
• The way in which oral glucose elicits a greater plasma insulin response than
IV glucose is referred to as the ‘incretin effect’, which is reduced in patients
with Type 2 diabetes1
Control
Type 2 diabetes
80
Oral glucose
IV glucose
60
40
* * *
* *
*
*
20
Insulin (mU/L)
Insulin (mU/L)
80
Oral glucose
IV glucose
60
40
* *
20
0
*
0
01 02
60
120
Time (min)
*p≤0.05 to the respective value after the oral load.
IV, intravenous.
Nauck M, et al. Diabetologia 1986;29:46–52.
180
01 02
60
120
Time (min)
180
The production of GLP-1 is diminished in people with
Type 2 diabetes
• Postprandial GLP-1 levels are also reduced in subjects with impaired
glucose tolerance and Type 2 diabetes
Meal
Mean (SE) GLP-1 (pmol/L)
20
* *
*
Normal glucose tolerance subjects (n=33)
Impaired glucose tolerance subjects (n=15)
Type 2 diabetes patients (n=54)
* *
*
15
*
10
*
5
0
0
60
120
Time (min)
*p<0.05 between the Type 2 diabetes and the normal glucose tolerance groups.
GLP-1, glucagon-like peptide-1; SE, standard error.
Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001;86:3717–23.
180
240
The effect of GLP-1 deficits on metabolic regulation
i
Expert sound bite
• Placeholder for video 1Bii. Professor Stephan Jacob: The effect of GLP-1
deficits on metabolic regulation
8
Replacement of GLP-1 can restore glucose homeostasis in
patients with Type 2 diabetes
Type 2 diabetes: Saline (n=8)
16
Type 2 diabetes: Exogenous GLP-1 (n=7)
Healthy subjects (n=6)
14
Glucose (mmol/L)
12
10
8
6
4
Breakfast
Lunch
Snack
2
Continuous GLP-1 infusion
0
00:00
04:00
08:00
Time of day
Healthy subjects, n=6; patients with Type 2 diabetes, n=7.
GLP-1, glucagon-like peptide-1.
Rachman J, et al. Diabetologia 1997;40:205–11.
12:00
16:00
20:00
GLP-1 delays gastric emptying and regulates insulin levels
500
GLP-1
GLP-1 + erythromycin
Placebo
400
Insulin (pmol/L)
*
300
*
*
*
200
Liquid meal
100
0
–60
*p<0.05.
GLP-1, glucagon-like peptide-1.
Meier JJ, et al. Diabetes 2005;54:2212–8.
0
60
Time (min)
120
180
240
Benefits of targeting the GLP-1 pathway in Type 2 diabetes
i
Expert sound bite
• Placeholder for video 1Biii. Professor Stephan Jacob: Benefits of targeting
the GLP-1 pathway in Type 2 diabetes
11
Exenatide: The first GLP-1 receptor agonist
• Exenatide is a synthetic version of exendin-4 that shares
over 50% similarity with human GLP-11
– Isolated from the Gila monster lizard saliva
• Exenatide and GLP-1 bind to the GLP-1 receptor with
equal affinity, which is where their effects are exerted2,3
– The effects of exenatide when it binds to the GLP-1 receptor
are equivalent to native GLP-14
• Unlike native GLP-1, exenatide is not inactivated by the
DPP4 enzyme, which means it remains active for longer5
• Exenatide is now available in BID (Byetta®) and QW
(Bydureon®) formulations
BID, twice daily; DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; QW, once weekly.
1. Nielsen LL, et al. Regul Pept 2004;117:77–88; 2. Raufman JP. Regul Pept 1996;61:1–18; 3. Fehmann HC, et al. Peptides 1994;15:453–6; 4. Göke R, et al. J Biol Chem
1993;268:19650–5; 5. Baggio LL, et al. Gastroenterology 2007;132:2131–57.
Discovery and licensing of exenatide
i
Expert sound bite
• Placeholder for video 1Biv. Dr Orville Kolterman: Discovery and licensing of
exenatide
13
Exendin-4 (exenatide) is a GLP-1 receptor agonist with a prolonged
half-life
Exendin-4
GLP-1
100,000
10,000
10,000
Plasma GLP-1 (pM)
Plasma exendin-4 (pM)
100,000
100
0
10
0
50 nmol
5 nmol
0.5 nmol
0.05 nmol
1
0
50 nmol
5 nmol
0.5 nmol
0.05 nmol
100
0
10
0
1
0
1
1
–1
0
1
5
3
4
2
Hours after injection
6
7
–1
Graphs show plasma concentrations of exending-4 or GLP-1 after administration by subcutaneous bolus.
GLP-1, glucagon-like peptide-1.
Parkes D, et al. Drug Devel Res 2001;53:260–7.
0
1
5
3
4
2
Hours after injection
6
7
Persistent pharmacological effects of exenatide
i
Expert sound bite
• Placeholder for video 1Bv. Dr Orville Kolterman: Persistent pharmacological
effects of exenatide
15
Exenatide significantly reduces PPG when given before meals
Exenatide 10 mg
Placebo
14
Serum glucose (mmol/L)
12
10
8
** * * *
6
** * * *
* * ** **** * *
4
2
Meal
Meal
Meal
0
16:00
00:00
06:00
Time of day
Graph shows the 24-hour glucose profiles comparing exenatide and placebo after 2 weeks. *p<0.05 versus placebo.
FPG, fasting plasma glucose; PPG, postprandial glucose.
Schwartz SL, et al. Clin Ther 2008;30:858–67.
12:00
16:00
Postprandial effects of exenatide
i
Expert sound bite
• Placeholder for video 1Bvi. Dr Orville Kolterman: Postprandial effects of
exenatide
17
Exenatide restores the first-phase insulin response
p=0.0002
Insulin secretion (pmol/kg/min)
30
p=0.0002
Type 2 diabetes + exenatide
vs Type 2 diabetes + saline
Type 2 diabetes + exenatide
vs healthy controls + saline
p=0.0029
20
Type 2 diabetes + exenatide 10 µg BID (n=13)
Type 2 diabetes + saline (n=13)
Healthy controls + saline (n=12)
10
0
–180
0
10
20
Time (min)
BID, twice daily.
Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991–7.
30
60
90
120
Plasma glucagon (pg/mL)
Plasma glucose (mg/dL)
Exenatide suppresses inappropriately elevated postprandial
glucagon concentrations
Meal
275
Baseline
250
Exenatide BID (n=61)
225
200
175
150
125
120
110
100
90
80
70
–30
0
30
60
BID, twice daily.
DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943–52.
90
150
120
Time (min)
180
210
240
Discovering the secondary benefits of exenatide
i
Expert sound bite
• Placeholder for video 1Bvii. Dr Orville Kolterman: Discovering the secondary
benefits of exenatide
20
Physiological differences between replacement of GLP-1 and
DPP4 inhibitors in the treatment of Type 2 diabetes
i
Expert sound bite
• Placeholder for video 1Bviii. Professor Stephan Jacob: Physiological
differences between replacement of GLP-1 and DPP4 inhibitors in the
treatment of Type 2 diabetes
21
Summary: GLP-1 and exenatide
• GLP-1 is a gut-derived incretin hormone that regulates glucose homeostasis
– GLP-1 production and the incretin effect are suppressed in Type 2 diabetes
– Replacement of GLP-1 restored the insulin response and glucose homeostasis in patients with
Type 2 diabetes
• Exenatide was the first GLP-1 receptor agonist to be developed for the treatment of
Type 2 diabetes and is now available in two formulations:
Exenatide 5 or 10 µg
twice daily
BID, twice daily; GLP-1, glucagon-like peptide-1; QW, once-weekly.
Byetta. Summary of Product Characteristics; 2 Bydureon. Summary of Product Characteristics.
Exenatide 2 mg
once weekly