1. Prescribing information can be found at the end of this slide deck.
Bydureon® (exenatide once-weekly) Scientific slides: GLP-1 receptor agonists and the discovery of exenatide
Thank you for choosing to use these slides from the Bydureon® Educate By Expert toolkit to discuss GLP-1 receptor agonists and the discovery of exenatide. To ensure the high quality and relevance of the content, this toolkit has been developed with the guidance and approval of an independent international editorial committee:
Associate Professor Dr Javier Ampudia Blasco (Specialist in Endocrinology and Nutrition, Spain)
Paul Dromgoole (Diabetes Specialist Nurse and Clinical Lecturer, UK)
Gwen Hall (Diabetes Specialist Nurse, UK)
Professor Stephan Jacob (Specialist in Endocrinology and Diabetes, Germany)
Professor Kamlesh Khunti (Primary Care Diabetes and Vascular Medicine, UK)
Dr Orville Kolterman (Senior Vice President and Chief Medical Officer, Amylin Pharmaceuticals, US)
Date of approval: March | Date of expiry: March 2016
Approval code: 675,057.01
Developed with the guidance and approval of an independent international editorial committee
Prescribing information can be found at the end of this slide deck.
GLP-1, glucagon-like peptide-1.

2. Content guide
These decks comprise a number of slides, arranged in story order. You may find that some slides are not relevant to your audience. Please hide these as you feel necessary
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.

3. Executive summary
This slide deck covers the following topics and contains speaker notes to assist presentation:
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
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 to receive marketing authorisation

4. 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 state
Fed state
Reduces appetite and food intake4
Suppresses postprandial glucagon secretion  decreased hepatic glucose production2
Suppresses glucagon secretion  decreased hepatic glucose production2
Slows gastric emptying1
Main talking point: GLP-1 is an incretin hormone secreted by the gut, which acts on multiple systems in the body to regulate blood glucose levels.
GLP-1, glucagon-like peptide-1.
References:
Drucker DJ. Cell Metab 2006;3:153–65.
Larsson H, et al. Acta Physiol Scand 1997;160:413–22.
Quddusi S, et al. Diabetes Care 2003;26:719–98.
Flint A, et al. J Clin Invest 1998;101:515–20.
Improves first-phase insulin response3
Stimulates glucose-dependent insulin secretion1
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
GLP-1, glucagon-like peptide 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.

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 01 02 60
120
180 20 40 80
Time (min)
Insulin (mU/L) *
Oral glucose
IV glucose
Type 2 diabetes 01 02 60
120
180 20 40 80
Time (min)
Insulin (mU/L) *
Oral glucose
IV glucose
Main talking point: The incretin effect describes the way in which oral glucose elicits a greater plasma insulin response than IV glucose. The incretin effect is diminished in patients with Type 2 diabetes.1
Notes:
This slide shows the insulin response of metabolically healthy individuals (n=8) and subjects with Type 2 diabetes (n=14) in response to an oral glucose load (50 g/400 mL) versus isoglycaemic IV glucose infusion
The total quantity of IV glucose required to achieve isoglycaemia was considerably greater in patients with diabetes (44.6 ± 2.2 g) than in controls (23.6 ± 2.9 g; p=0.001)
The left-hand graph shows the incretin effect in subjects without diabetes, in whom a strong plasma insulin response is elicited within 60 minutes of oral glucose. A lesser response occurs with IV glucose
The right-hand graph shows the incretin effect in patients with Type 2 diabetes. Although oral glucose still elicits a stronger plasma insulin response compared with IV glucose, the overall insulin response is lower and levels plateau at around 50 minutes after glucose ingestion, rather than peaking as in controls
IV, intravenous.
Reference
Nauck M, et al. Diabetologia 1986;29:46–52.
*p≤0.05 to the respective value after the oral load.
IV, intravenous.
Nauck M, et al. Diabetologia 1986;29:46–52.

6. 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 20 15 10 5 60
120
180
240
Time (min)
Mean (SE) GLP-1 (pmol/L) *
Meal
Normal glucose tolerance subjects (n=33)
Impaired glucose tolerance subjects (n=15)
Type 2 diabetes patients (n=54)
Main talking point: Postprandial production of GLP-1 is reduced in patients with Type 2 diabetes or impaired glucose tolerance.
Notes:
After 3 days of discontinued antidiabetic medication and an overnight fast, 102 subjects consumed a standard mixed meal (41.8% fat, 40.7% carbohydrate and 17.5% protein; fibre content, 6.7 g), with plasma insulin response sampled over time
The meal was started at time zero and finished in the 10- to 15-minute period.
Fasting plasma GLP-1 concentrations were not significantly different between groups. Postprandial GLP-1 levels were significantly reduced in patients with Type 2 diabetes compared with both normal and impaired glucose tolerance subjects
GLP-1, glucagon-like peptide-1.
Reference
Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001;86:3717–23.
*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.

7. Continuous GLP-1 infusion
Replacement of GLP-1 can restore glucose homeostasis in patients with Type 2 diabetes 2 4 6 8 10 12 14 16
00:00
04:00
08:00
12:00
16:00
Snack
Lunch
Breakfast
Glucose (mmol/L)
Time of day
Type 2 diabetes: Saline (n=8)
Type 2 diabetes: Exogenous GLP-1 (n=7)
Healthy subjects (n=6)
20:00
Continuous GLP-1 infusion
Main talking point: Administration of GLP-1 to patients with Type 2 diabetes can restore fasting and PPG concentrations to that of healthy controls.
Notes:
Subjects with Type 2 diabetes received an IV infusion of GLP-1 or saline for 19 hours, starting at 22:00 and finishing at 17:30. Subjects received three standard meals during the daytime, at 08:00, 12:00 and 15:00, with blood samples withdrawn intermittently. Healthy control subjects underwent the same procedure without administration of GLP-1
On the saline infusion, the overnight glucose concentrations were higher in subjects with Type 2 diabetes (median [range] 7.8 mmol/L [6.1–13.8]) than healthy controls (5.6 mmol/L [5.0–5.8]; p<0.001). Continuous GLP-1 infusion reduced the overnight glucose in subjects with Type 2 diabetes to 5.1 mmol/L (4.0–9.2), which was not significantly different from healthy controls
GLP-1, glucagon-like peptide-1; IV, intravenous; PPG, postprandial glucose.
Reference
Rachman J, et al. Diabetologia 1997;40:205–11.
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.

8. GLP-1 delays gastric emptying and regulates insulin levels
100
200
300
400
500
–60 60
120
180
240
Insulin (pmol/L)
Time (min) *
Liquid meal
GLP-1
GLP-1 + erythromycin
Placebo
Main talking point: Administration of GLP-1 delays gastric emptying and reduces the rapid postprandial rise in glycaemia, thus slowing insulin secretion after a meal.
Notes:
When subjects were treated with placebo therapy and then given a liquid meal, a rapid increase in insulin concentration followed that meal in response to glucose emptying from the stomach
Subjects receiving an infusion of GLP-1 did not experience this rapid increase in glucose concentration
When erythromycin was used to mask the delayed gastric emptying associated with GLP-1 therapy, the insulin profile was similar to placebo, revealing that delayed gastric emptying is responsible for slowing the secretion of insulin
These results indicate that the rate of gastric emptying is directly associated with postprandial insulin concentrations
GLP-1, glucagon-like peptide-1.
Reference:
Meier JJ, et al. Diabetes 2005;54:2212–8.
*p<0.05.
GLP-1, glucagon-like peptide-1.
Meier JJ, et al. Diabetes 2005;54:2212–8.

9. Exenatide: The first GLP-1 receptor agonist to receive marketing authorisation
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
Main talking point: Exenatide is a GLP-1 receptor agonist with prolonged duration of action.
Discussion:
Exenatide is an incretin mimetic developed from a natural product found in the Gila monster that shares >50% amino acid identity with human GLP-11
The amino acid at position 2, the site of DPP4 inactivation on the GLP-1 molecule, is different in exenatide, making exenatide resistant to DPP4 enzymatic degradation2
DPP4, dipepetidyl peptidase-4; GLP-1, glucagon-like peptide-1.
References:
Nielsen LL, et al. Regul Pept. 2004;117:77–88.
Baggio LL, et al. Gastroenterology. 2007;132:2131–57.
BID, twice daily; DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; QW, once weekly.
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.

10. Exendin-4 (exenatide) is a GLP-1 receptor agonist with a prolonged half-life
100,000
10,000
1000
100 10 1 –1 2 3 4 5 6 7
Hours after injection
Plasma GLP-1 (pM)
50 nmol
5 nmol
0.5 nmol
0.05 nmol
GLP-1
100,000
10,000
1000
100 10 1 –1 2 3 4 5 6 7
Hours after injection
Plasma exendin-4 (pM)
50 nmol
5 nmol
0.5 nmol
0.05 nmol
Exendin-4
Main talking point: Exendin-4, of which exenatide is a synthetic version, has a longer half-life than GLP-1.
Notes:
The study compared the pharmacokinetics of exendin-4 and GLP-1 in rats (n=4–7) after IV, SC or IP administration
Estimated half-lives were as follows:
IV bolus: GLP-1, 0.8–4.7 min; exendin-4, 18–41 min
SC: GLP-1, 4.6–7.1 min; exendin-4, 90–216 min
IP: GLP-1, 0.6–13.5; exendin-4, 125–174 min
Bioavailability from SC injection was 44–71% for GLP-1 and 65–75% for exendin-4
GLP-1, glucagon-like peptide-1; IP, intraperitoneal; IV, intravenous; SC, subcutaneous.
References:
Parkes D, et al. Drug Devel Res 2001;53:260–7.
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.

11. Exenatide restores the first-phase insulin response10 20 30
–180 60
120
Time (min)
Insulin secretion (pmol/kg/min) 90
p=0.0029
p=0.0002
Type 2 diabetes + exenatide vs Type 2 diabetes + saline
Type 2 diabetes + exenatide vs healthy controls + saline
Type 2 diabetes + exenatide 10 µg BID (n=13)
Type 2 diabetes + saline (n=13)
Healthy controls + saline (n=12)
Main talking point: Administration of exenatide 10 µg BID restores the first-phase insulin response in patients with Type 2 diabetes in response to acute rises in plasma glucose.
Notes:
13 fasted subjects with Type 2 diabetes received IV insulin infusion to reach plasma glucose concentrations of 4.4–5.6 mmol/L, followed first by IV exenatide (10 µg BID) or saline and then an IV glucose challenge. 12 healthy controls underwent the same protocol and received saline only
In subjects with Type 2 diabetes receiving saline, the first-phase insulin response was significantly blunted compared to healthy controls; treatment with exenatide significantly increased plasma insulin (p<0.005) during the first (0–10 min) and second (10–120 min) phases of glucose-stimulated insulin secretion by 180–310%
BID, twice daily; IV, intravenous.
References:
Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991–7.
BID, twice daily.
Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991–7.

12. Plasma glucagon (pg/mL) Plasma glucose (mg/dL)
Exenatide suppresses inappropriately elevated postprandial glucagon concentrations
Meal
Baseline
Exenatide BID (n=61)
120
110
100 90 80 70
Plasma glucagon (pg/mL)
–30 30 60
150
180
210
240
Time (min)
275
250
200
175
125
Plasma glucose (mg/dL)
225
Main talking point: Administration of exenatide to patients with Type 2 diabetes reduces PPG and postprandial glucagon concentrations.
Notes:
This was a Phase IV, double-blind, randomised, double-dummy, cross-over, multi-centre study of a 1-week placebo lead-in period followed by two 2-week treatment periods. Subjects had Type 2 diabetes and were on a stable regimen of metformin. The aim was to directly compare the pharmacological actions and acute effects of exenatide (1 week at 5 µg BID and 1 week at 10 µg BID) and sitagliptin (100 mg QAM) in patients with Type 2 diabetes. The trial was designed as a crossover study; however, only exenatide and baseline data are presented on this slide
Analyses were performed on the evaluable population (n=61), who completed standard meal procedures in both treatment periods, who received treatment per assigned sequence, and had at least one quantifiable post-dose plasma exenatide and sitagliptin measurement within the first 2 hours following the standard meal
Exenatide treatment reduced PPG from baseline; the majority of PPG values with exenatide were lower than FPG values
Exenatide treatment also reduced mean postprandial glucagon concentration from baseline
BID, twice daily; FPG, fasting plasma glucose; PPG, postprandial glucose; QAM, every morning.
References:
DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943–52.
BID, twice daily.
DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943–52.

13. 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
Exenatide 2 mg once weekly
Main talking point: Research into the physiological actions of GLP-1 and its deficits in Type 2 diabetes have led to the discovery and development of exenatide, the first synthetic GLP-1 receptor agonist approved for the treatment of Type 2 diabetes. Exenatide is now available in two formulations: Byetta® (5 or 10 µg twice daily) and Bydureon® (2 mg once weekly).
GLP-1, glucagon-like peptide-1.
BID, twice daily; GLP-1, glucagon-like peptide-1; QW, once-weekly.
Byetta. Summary of Product Characteristics; 2 Bydureon. Summary of Product Characteristics.

14. This information is consistent with the UK marketing authorisation
This information is consistent with the UK marketing authorisation. Please refer to your local prescribing information for full details.

15. This information is consistent with the UK marketing authorisation
This information is consistent with the UK marketing authorisation. Please refer to your local prescribing information for full details.