1. Bydureon® (exenatide once weekly) clinical data slide deck
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.

2. Content guide
This deck comprises 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 notes to provide further information on:
Introduction to Bydureon, microsphere technology and the steady-state principle
Overview of the Bydureon clinical trial programme (DURATION studies)
Data from the Bydureon DURATION-1, -2 and -3 studies
Overview of study design (primary analysis and extension periods)
Detailed data from long-term extension studies
Cardiovascular data from Bydureon studies
Bydureon safety and tolerability profiles
Dosing, administration and tips for initiating patients on Bydureon

4. Introduction to Bydureon (exenatide once-weekly)

5. About Bydureon
Bydureon is a GLP-1 receptor agonist, and the first once-weekly treatment for Type 2 diabetes
EU marketing authorisation received in June 2006
Bydureon provides continuous glycaemic control in a single weekly injection
Bydureon is indicated for the treatment of Type 2 diabetes in combination with:
Metformin SU
TZD
Metformin + SU
Metformin + TZD
Main talking point: Bydureon is the first and only once-weekly treatment for Type 2 diabetes, approved in the EU in It is a GLP-1 receptor agonist indicated as add-on to one or more oral antidiabetic drugs.1
GLP-1, glucagon-like peptide-1.
Reference
Bydureon. Summary of product characteristics 2014.
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
GLP-1, glucagon-like peptide-1; SU, sulphonylurea; TZD, thiazolidinedione.
Bydureon. Summary of product characteristics, 2014.

6. Bydureon’s patented microsphere technology enables once-weekly dosing
Slide is animated
Bydureon’s patented microsphere technology enables once-weekly dosing
Proven microsphere technology provides a continuous level of exenatide1
Microspheres consist of a biodegradable polymer that dissipates into CO2 and water1
The technology is also used in other extended-release products such as risperidone and naltrexone2,3
Subcutaneous injection of microsphere suspension of exenatide1
Individual microspheres aggregate and initial release of exenatide1
Microsphere degradation and continued release of exenatide1
Further degradation and metabolism of microsphere polymer provide sustained level of exenatide1
Main talking point: Bydureon’s patented microsphere delivery system provides continuous therapeutic levels of exenatide that enables once-weekly dosing.
Notes:
Patented Medisorb® microspheres are a biodegradable polymer that dissipates into CO2 and water1
The microspheres deliver a constant presence of exenatide with a single weekly injection1
CO2, carbon dioxide.
Reference
DeYoung MB, et al. Diabetes Technol Ther 2011;13:1145–54.
CO2, carbon dioxide.
1. DeYoung MB, et al. Diabetes Technol Ther 2011;13:1145–54; 2. Risperdal Consta. Summary of product characteristics, 2013; 3. Vivitrol. Prescribing information. Alkermes, Inc, 2013.

7. Steady state is reached by 6–7 weeks1,2
Slide is animated
Steady-state exenatide concentrations provide continuous glycaemic control with a single weekly injection
With once-weekly injections of Bydureon, therapeutic concentrations of exenatide are reached in 2 weeks1,2
Steady state is reached by 6–7 weeks1,2
At steady state, there are minimal peak-to-trough fluctuations in exenatide levels
Steady state is maintained with subsequent weekly doses
Time (weeks)
450
400
350
300
250
200
150
100 50
Plasma exenatide (pg/mL) 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Weekly Bydureon injection
Steady state achieved for continuous glycaemic control
Main talking point: The microsphere delivery system provides continuous therapeutic levels of exenatide that reach therapeutic concentrations within 2 doses and steady-state after 6 or 7 doses.1,2
Notes:
[Click reveals first part of graph; second part animates automatically after a short pause]
After the initial dose of Bydureon, there is an increase in plasma exenatide concentration that declines over time2
Upon the second dose, diffusion of exenatide from the microsphere continues from the initial dose2
It takes about 2 weeks to achieve Bydureon concentrations in the therapeutic range (50 pg/mL)2
Steady-state exenatide concentration, which is in the therapeutic range, is reached at 6–7 weeks2
Since therapeutic concentrations of exenatide are achieved over time, individuals should expect glucose control to gradually improve over time2
Steady-state plasma concentrations of exenatide are maintained with subsequent weekly dosing2
References
Bydureon. Summary of product characteristics 2014.
Kim D, et al. Diabetes Care 2007;30:1487–93.
Figure adapted from Kim D, et al. 2007, showing mean ± standard deviation.2
1. Bydureon. Summary of product characteristics, 2014; 2. Kim D, et al. Diabetes Care 2007;30:1487–93.

8. Bydureon clinical trial programme
The following slides provide an overview of the core design of the DURATION clinical trials for Bydureon.

9. Core design of DURATION trials
DURATION: Diabetes Therapy Utilisation: Researching Changes in A1c, Weight, and Other Factors Through Intervention with Exenatide Once Weekly
Primary endpoint: Change in HbA1c from baseline1–6
Secondary endpoints included: Change in bodyweight, blood pressure and CV risk markers from baseline; safety and tolerability1–6
Patients with: Type 2 diabetes HbA1c 7.1–11.0% (54.1–96.7 mmol/mol)
Optional
Bydureon extension
Bydureon 2 mg
Active comparator agent(s)
24–30 weeks
Main talking point: This is the core design of the DURATION clinical trials.
Notes:
DURATION stands for Diabetes Therapy Utilisation: Researching Changes in A1c, Weight, and Other Factors Through Intervention with Exenatide Once Weekly
The purpose of the DURATION trials is to examine the effects of Bydureon on glucose control and safety in subjects with Type 2 diabetes managed with diet modification and exercise and/or oral antidiabetic drugs1–6
All of the DURATION trials were designed as either head-to-head comparator-controlled or multiple comparator-controlled studies, versus active comparators1–6
Type 2 diabetes patients with an HbA1c of 7.1–11.0% were treated with Bydureon or comparator agents for 24–30 weeks (primary endpoints)1–6
Patients were monitored to compare the effect on glucose control (change in HbA1c) to examine the safety and tolerability as well as the change in bodyweight from baseline to endpoint1–6
References
Drucker DJ, et al. Lancet 2008;372:1240–50.
Bergenstal RM, et al. Lancet 2010:376:431–9.
Diamant M, et al. Lancet 2010:375;2234–43.
Russell-Jones D, et al. Diabetes Care 2012;35:252–8.
Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10.
Buse JB, et al. Lancet 2013;381:117–24.
CV, cardiovascular.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Bergenstal RM, et al. Lancet 2010;376:431–9; 3. Diamant M, et al. Lancet 2010;375:2234–43; 4. Russell-Jones D, et al. Diabetes Care 2012;35:252–8; 5. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 6. Buse JB, et al. Lancet 2013;381:117–24. 9

10. Overview of DURATION trials
Slide is animated
Overview of DURATION trials
Trial
Comparator
Background
Subjects
In EU label
DURATION-11
Exenatide BID Open label
Drug naïve, MET, SU, TZD, or two of these agents
295 
DURATION-22
SITA (100 mg QD) or PIO (45 mg QD) Double-blind
MET
491
DURATION-33
Insulin glargine Open label
MET ± SU
456
DURATION-44
MET (2000 mg QD) or PIO (45 mg QD) or SITA (100 mg QD) Double-blind
Drug naïve
820 
DURATION-55
Drug naïve, MET, SU, TZD, or a combination of these agents
252
DURATION-66
Liraglutide (1.8 mg) Open label
MET, SU, TZD, or a combination of these agents
911
Main talking point: Six DURATION studies were conducted in total. [Click fades bottom half of table]. Data from DURATION-1, -2 and -3 only are presented in this deck, as these are the primary studies that are included in the summary of product characteristics and have also resulted in an indication for Bydureon.
References
Drucker DJ, et al. Lancet 2008;372:1240–50.
Bergenstal RM, et al. Lancet 2010:376:431–9.
Diamant M, et al. Lancet 2010:375;2234–43.
Russell-Jones D, et al. Diabetes Care 2012;35:252–8.
Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10.
Buse JB, et al. Lancet 2013;381:117–24.
Data from DURATION-1, -2 and -3 are shown here as the primary studies included in the Bydureon summary of product characteristics7
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia7
Bydureon is not indicated in Europe as monotherapy in patients uncontrolled on diet and exercise alone.7 BID, twice daily; MET, metformin; PIO, pioglitazone; QD, once daily; SITA, sitagliptin; SU, sulphoylurea; TZD, thiazolidinediones.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Bergenstal RM, et al. Lancet 2010;376:431–9; 3. Diamant M, et al. Lancet 2010;375:2234–43; 4. Russell-Jones D, et al. Diabetes Care 2012;35:252–8; 5. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 6. Buse JB, et al. Lancet 2013;381:117–24; 7. Bydureon. Summary of product characteristics, 2014.

11. DURATION-1
The following slides present detailed study information and results from the DURATION-1 clinical trial of Bydureon versus exenatide BID.
BID, twice daily.

12. DURATION-1: Study details
DURATION-1: Primary analysis
Study details
N=295 (ITT population)
Randomised, active-controlled, open-label, non-inferiority study
Study length
30 weeks
Background therapy
None (as initial therapy) or treatment with metformin, a SU, a TZD or any combination of these agents
Comparator to Bydureon
Exenatide BID
Primary endpoint
HbA1c change from baseline at Week 30
Secondary endpoints
Safety and tolerability; analysis of FPG, PPG, bodyweight, fasting glucagon, fasting lipids, blood pressure, exenatide pharmacokinetics, paracetamol absorption
Publication type
Peer-reviewed journal article
Main talking point: The DURATION-1 clinical trial examined efficacy and safety of Bydureon versus exenatide BID at the primary analysis of Week 30.
Notes:
Patients either received the study drugs as initial therapy, or were on a background of metformin, a SU, a TZD or a combination of these agents
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.
Reference
Drucker DJ, et al. Lancet 2008;372:1240–50.
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
BID, twice daily; FPG, fasting plasma glucose; ITT, intent-to-treat; PPG, postprandial glucose; SU, sulphonylurea; TZD, thiazolidinedione.
Drucker DJ, et al. Lancet 2008;372:1240–50.

13. DURATION-1: Study details (continued)
DURATION-1: 52-week extension study
Study details
N=258 (entering open-ended assessment period)
Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study
Study length
22 weeks after completion of the 30-week primary study
Background therapy
None (as initial therapy) or treatment with metformin, a SU, a TZD or any combination of these agents
Comparator to Bydureon
Exenatide BID  Bydureon at Week 30
Outcomes
Glucose control during the transition from exenatide BID to Bydureon; safety and tolerability; efficacy of Bydureon at Week 52
Publication type
Peer-reviewed journal article
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
Main talking point: The DURATION-1 clinical trial extension examined long-term efficacy and safety over 52 weeks of Bydureon, in patients treated with Bydureon for 52 weeks and in those treated with exenatide BID and switching to Bydureon after 30 weeks.
Notes:
In the initial 30 weeks of the study, patients either received the study drugs as initial therapy, or were on a background of metformin, a SU, a TZD or a combination of these agents
After the 30-week primary endpoint, patients receiving exenatide BID were switched to Bydureon for a 22-week extension period
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.
Reference
Buse JB, et al. Diabetes Care 2010;33:1255–61.
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.
Buse JB, et al. Diabetes Care 2010;33:1255–61.

14. DURATION-1: Study details (continued)
DURATION-1: 3-year extension study
Study details
N=258 (entering open-ended assessment period)
Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study
Study length
3-year extension (switch study)
Background therapy
None (as initial therapy) or treatment with metformin, a SU, a TZD or any combination of these agents
Comparator to Bydureon
No comparator; pooled population included patients initated on Bydureon and those initiated on exenatide BID and switching to Bydureon at Week 30
Study endpoints
Change in HbA1c, FPG, weight, lipid profile and SBP
Publication type
Peer-reviewed publication
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
Main talking point: The DURATION-1 clinical trial extension examined long-term efficacy and safety over 52 weeks of Bydureon, in patients treated with Bydureon for up to 5 years and in those treated with exenatide BID and switching to Bydureon after 30 weeks.
Notes:
In the initial 30 weeks of the study, patients either received the study drugs as initial therapy, or were on a background of metformin, a SU, a TZD or a combination of these agents
After the 30-week primary endpoint, patients receiving exenatide BID were switched to Bydureon for a 3-year extension period
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.
Reference
MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41
BID, twice daily; FPG, fasting plasma glucose; SBP, systolic blood pressure; SU, sulphonylurea; TZD, thiazolidinedione.
MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41.

15. DURATION-1: Study details (continued)
DURATION-1: 6-year extension study
Study details
N=258 (entering open-ended assessment period; completer population n=127)
Extension study after completing a 30-week randomised, active-controlled, open-label, non-inferiority study
Study length
6-year extension (switch study)
Background therapy
None (as initial therapy) or treatment with metformin, a SU, a TZD or any combination of these agents
Comparator to Bydureon
No comparator; pooled population included patients initiated on Bydureon and those initiated on exenatide BID and switching to Bydureon at Week 30
Study endpoints
Change in HbA1c, FPG, weight, lipid profile and SBP
Publication type
Congress abstract and poster presentation
Main talking point: The DURATION-1 clinical trial extension examined long-term efficacy and safety over 52 weeks of Bydureon, in patients treated with Bydureon for up to 6 years and in those treated with exenatide BID and switching to Bydureon after 30 weeks.
Notes:
In the initial 30 weeks of the study, patients either received the study drugs as initial therapy, or were on a background of metformin, a SU, a TZD or a combination of these agents
After the 30-week primary endpoint, patients receiving exenatide BID were switched to Bydureon for a 5-year extension period
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione.
Reference
Henry RH, et al. Poster presented at ADA P
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
BID, twice daily; FPG, fasting plasma glucose; SBP, systolic blood pressure; SU, sulphonylurea; TZD, thiazolidinedione.
Henry RH, et al. Poster presented at ADA P.

16. Change in HbA1c (mmol/mol)
DURATION-1: Reduced HbA1c with Bydureon versus exenatide BID over 1 year1
At the primary endpoint of 30 weeks, HbA1c reductions from baseline were –1.9% (–20.8 mmol/mol) with Bydureon and –1.5% (–16.4 mmol/mol) with exenatide BID (p=0.0023)2
At 1 year, patients receiving Bydureon maintained HbA1c reductions of –2.0% (–21.9 mmol/mol), regardless of whether they started on Bydureon or switched to Bydureon at 30 weeks1
71% of all patients achieved HbA1c <7% with Bydureon, irrespective of treatment at initiation
Bydureon
BL=8.3% (67.2 mmol/mol)
Exenatide BID  Bydureon
BL=8.2% (66.1 mmol/mol) 6 52 48 44 40 36 33 30 26 22 18 14 10
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
Time (weeks)
Change in HbA1c (%) *
All subjects received Bydureon
–2.0% (21.9 mmol/mol)
–2.0% (21.9 mmol/mol)
Change from BL:
–25
–20
–15
–10 –5
Change in HbA1c (mmol/mol)
Main talking point: This graph shows the primary endpoint of least-squares mean change in HbA1c for the intent-to-treat population for the DURATION-1 52-week, open-label extension.1
Notes:
At the primary endpoint of 30 weeks, HbA1c reductions from baseline were –1.9% with Bydureon and –1.5% with exenatide BID (p=0.0023)2
The 52-week endpoint demonstrated a reduction in HbA1c with Bydureon (–2.0%) similar to that in patients who were initially treated with exenatide BID and who switched to Bydureon at 30 weeks (–2.0%)1
BID, twice daily.
References
Buse JB, et al. Diabetes Care 2010;33:1255–61.
Drucker DJ, et al. Lancet 2008;372:1240–50.
Figure adapted from Buse JB, et al. 2010, showing least-squares mean ± standard error.1 *p<0.05 versus exenatide BID.
BID, twice daily; BL, baseline.
1. Buse JB, et al. Diabetes Care 2010;33:1255–61; 2. Drucker DJ, et al. Lancet 2008;372:1240–50.

17. DURATION-1: Reduced HbA1c with Bydureon sustained over 6 years
HbA1c reductions were sustained over 6 years with Bydureon (mean change in HbA1c from baseline –1.6% [95% CI, –1.9 to –1.4] [–17.5 mmol/mol])3
45% of all patients achieved HbA1c <7% with Bydureon, irrespective of treatment at initiation
6 years3
(n=127)
3 years2 (n=194)
30 weeks1 (n=148)
– 2.0
–1.5
–1.0
–0.5
0.0
Change in HbA1c (%)
–1.6% (17.5 mmol/mol)
–1.6% (–17.5 mmol/mol)
BL=8.2% (66.1 mmol/mol)
–1.9% (–20.8 mmol/mol)
BL=8.3% (67.2 mmol/mol)
–20
–15
–10 –5
Change in HbA1c (mmol/mol)
Randomised to Bydureon (evaluable population)
Pooled population (all Bydureon completers)
Main talking point: This graph shows the least-squares mean change in HbA1c for the completer population for the DURATION-1 6-year, open-label extension.
Notes:
In the DURATION-1 trial, all patients receiving exenatide BID switched to Bydureon at the 30-week primary endpoint and the data shown here are from the pooled populations. Final HbA1c reduction from baseline in the completer population at Year 6 was –1.6% (–17.5 mmol/mol)
BID, twice daily.
Reference
Henry RH, et al. Poster presented at ADA P.
Figure adapted from Drucker DJ, et al. 2008,1 MacConell L, et al. 2013,2 and Henry RH, et al
BID, twice daily; BL, baseline; CI, confidence interval.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41; 3. Henry RH, et al. Poster presented at ADA P.

18. Change in bodyweight (kg)
DURATION-1: Weight reductions with Bydureon versus exenatide BID over 1 year*
Powerful HbA1c reductions with Bydureon were accompanied by weight reductions of 4.1–4.5 kg at 1 year1 6 52 48 44 40 36 30 26 22 18 14 10 –5 –4 –3 –2 –1
Time (weeks)
Change in bodyweight (kg)
All subjects received Bydureon
–4.1 kg
–4.5 kg
Change from BL:
Bydureon
BL=103 kg
Exenatide BID  Bydureon
BL=102 kg
Main talking point: This graph shows a secondary endpoint of change in bodyweight for the intent-to-treat population for the DURATION-1 52-week, open-label extension.1
Notes:
The secondary endpoint demonstrated a reduction in bodyweight with Bydureon at 30 weeks (–3.7 kg) similar to that with maximum daily doses of exenatide BID (–3.6 kg)1
Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.2
BID, twice daily.
Reference
Buse JB, et al. Diabetes Care 2010;33:1255–61.
2. Bydureon. Summary of product characteristics 2014.
Figure adapted from Buse JB, et al. 2010, showing least squares mean ± standard error.1
*Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.3 BID, twice daily; BL, baseline. 1. Buse JB, et al. Diabetes Care 2010;33:1255–61; 2. MacConell L, et al. Presented at EASD Abstract 980; 3. Bydureon. Summary of product characteristics, 2014.

19. DURATION-1: Weight reductions with Bydureon sustained over 6 years*
Weight reductions with Bydureon were sustained over 6 years (mean reductions from baseline –4.3 kg [95% CI, –6.0 to –2.6])
6 years3
(n=127)
3 years2 (n=194)
30 weeks1 (n=148) –4 –3 –2 –1
Change in bodyweight (kg)
–1.6% (17.5 mmol/mol)
–2.3 kg
BL=101 kg
–4.3 kg
–4.0 kg
BL=102 kg
Randomised to Bydureon (evaluable population)
Pooled population (all Bydureon completers) –5
Main talking point: This graph shows the mean bodyweight reductions with Bydureon in the DURATION-1 6-year, open-label extension.
Notes:
In the DURATION-1 trial, all patients receiving exenatide BID switched to Bydureon at the 30-week primary endpoint and the data shown here are from the pooled populations. Final bodyweight reductions from baseline in the completer population at Year 6 were –4.3 kg1
Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials.2
BID, twice daily.
Reference
Henry RH, et al. Poster presented at ADA P.
Bydureon. Summary of product characteristics 2014.
Figures adapted from Drucker DJ, et al. 2008,1 MacConell L, et al. 2013,2 and Henry RH, et al
*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials.4 BID, twice daily; BL, baseline.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. MacConell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41; 3. Henry RH, et al. Poster presented at ADA P; 4. Bydureon. Summary of product characteristics, 2014.

20. DURATION-2
The following slides present detailed study information and results from the DURATION-2 clinical trial of Bydureon versus sitagliptin or pioglitazone.

21. DURATION-2: Study details
DURATION-2: Primary analysis
Study details
N=491 (ITT population)
Randomised, double-blind, double-dummy, active-controlled superiority trial
Study length
26 weeks
Background therapy
Metformin
Comparators to Bydureon
Sitagliptin 100 mg QD
Pioglitazone 45 mg QD
Primary endpoint
Change in HbA1c from baseline at Week 26
Secondary endpoints
Proportion of patients achieving HbA1c ≤6.5% (≤47.5 mmol/mol) or ≤7.0% (≤53.0 mmol/mol); FPG; six-point SMBG profile; bodyweight; fasting lipid profile; fasting insulin profile; blood pressure; CV risk markers; patient-reported HRQoL; safety and tolerability
Publication type
Peer-reviewed journal article
Main talking point: The DURATION-2 clinical trial examined efficacy and safety of Bydureon versus sitagliptin 100 mg QD or pioglitazone 45 mg QD at the primary analysis of Week 26.
Notes:
Patients were on a background therapy of metformin
QD, once daily.
Reference
Bergenstal RM, et al. Lancet 2010;376:431–39.
CV, cardiovascular; FPG, fasting plasma glucose; HRQoL, health-related quality of life; ITT, intent-to-treat; SMBG, self-monitored blood glucose; QD, once daily.
Bergenstal RM, et al. Lancet 2010;376:431–9.

22. DURATION-2: Study details (continued)
DURATION-2: 52-week extension study
Study details
N=364 (entering extension study)
Extension study after completing a 26-week randomised, double-blind, double-dummy, superiority trial
Study length
26 weeks with a 26-week extension (switch study)
Background therapy
Metformin
Comparators to Bydureon
Patients initiated on sitagliptin 100 mg QD  Bydureon at Week 26
Patients initiated on pioglitazone 45 mg QD  Bydureon at Week 26
Outcomes
Change from baseline at Weeks 26 and 52 and from Week 26 to Week 52 in: HbA1c; patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); FPG; bodyweight; fasting lipids; fasting insulin; blood pressure; CV risk markers; safety and tolerability
Publication type
Peer-reviewed journal article
Main talking point: The DURATION-2 clinical trial extension examined long-term efficacy and safety over 52 weeks of Bydureon, in patients treated with Bydureon for 52 weeks and in those treated with sitagliptin or pioglitazone and switching to Bydureon after 26 weeks.
Notes:
Patients were on a background of metformin
After the 26-week primary endpoint, patients receiving sitagliptin or pioglitazone switched to Bydureon for a 26-week extension period
Reference:
Wysham C, et al. Diabet Med 2011;28:705–14.
CV, cardiovascular; FPG, fasting plasma glucose; QD, once daily.
Wysham C, et al. Diabet Med 2011;28:705–14.

23. Change in HbA1c from baseline (mmol/mol)
DURATION-2: Reduced HbA1c with Bydureon versus sitagliptin and pioglitazone
At the primary endpoint of 26 weeks, HbA1c changes from baseline were –1.5% (–16.4 mmol/mol) with Bydureon, –0.9% (–9.8 mmol/mol) with sitagliptin and –1.2% (–13.1 mmol/mol) with pioglitazone (p<0.05 for Bydureon vs both comparators)1
Significant HbA1c reductions with Bydureon were achieved at 1 year, regardless of initial therapy2
Bydureon, BL=8.6% (70.5 mmol/mol)
Sitagliptin  Bydureon, BL=8.5% (69.4 mmol/mol)
Pioglitazone  Bydureon, BL=8.5% (69.4 mmol/mol)
–0.31% (95 % CI, –0.50 to –0.13)* (–3.4 mmol/mol)
Change from Week 26 to Week 52:
0.06% (95 % CI, –0.13 to 0.25) (0.7 mmol/mol)
–0.10% (95 % CI, –0.29 to 0.09) (–1.1 mmol/mol) 6 52 46 40 34 30 26 22 18 14 10
–2.0
–0.5
0.0
Time (weeks)
Change in HbA1c (%) 4
–1.5
–1.0
–20
–15
–10 –5
Change in HbA1c from baseline (mmol/mol)
Main talking point: This graph shows the change in HbA1c for the evaluable population for the DURATION-2 52-week, open-label extension trial.
Notes:
At the primary endpoint of 26 weeks, HbA1c changes from baseline were –1.5% (–16.4 mmol/mol) with Bydureon, –0.9% (–9.8 mmol/mol) with sitagliptin and –1.2% (–13.1 mmol/mol) with pioglitazone (p<0.05 for Bydureon vs both comparators)1
After the 26-week blinded period, subjects could enter an open-ended study period2
The study demonstrated an overall reduction in HbA1c from baseline with Bydureon (–1.5% [–16.4 mmol/mol]) similar to that in patients treated with sitagliptin  Bydureon (–1.21% [–13.2 mmol/mol]) or pioglitazone  Bydureon (–1.30% [–14.2 mmol/mol])2
Patients in the sitagliptin group experienced significant reductions in HbA1c after switching to Bydureon at Week 26 (–0.31% [–3.4 mmol/mol])2
References
1. Bergenstal RM, et al. Lancet 2010;376:431–9.
2. Wysham C, et al. Diabet Med 2011;28:705–14.
Graph adapted from Wysham C, et al. 2011, showing data for the evaluable population as least squares mean ± standard error.2 *p<0.05 versus Week 26.
BL, baseline; CI, confidence interval.
1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Wysham C, et al. Diabet Med 2011;28:705–14.

24. Change in bodyweight (kg)
DURATION-2: Weight change* with Bydureon versus sitagliptin and pioglitazone
Patients treated with Bydureon achieved significant weight reductions at 26 weeks*1
Individuals who switched to Bydureon from sitagliptin or pioglitazone at the end of the blinded period experienced further weight reductions2
Blinded period
–1.1 kg (95% CI, –1.8 to –0.5)†
Change from Week 26:
0.7 kg (95 % CI, 0.1 to 1.4)†
–3.0 kg (95 % CI, –3.7 to –2.3)† 6 52 46 40 34 30 26 22 18 14 10 –3 –2 2 3 5
Time (weeks)
Change in bodyweight (kg) 4 –1 1
Open-label period
Bydureon, BL=90 kg
Sitagliptin  Bydureon, BL=86 kg
Pioglitazone  Bydureon, BL=86 kg
Main talking point: This graph shows a secondary analysis of change in bodyweight for the evaluable population for the DURATION-2 52-week, open-label extension trial.1
Notes:
Patients treated with Bydureon achieved significant weight reductions at 26 weeks2
The study demonstrated an overall reduction in bodyweight from baseline at Week 52 in patients receiving Bydureon (–1.6 kg) or sitagliptin  Bydureon (–1.9 kg)1
Patients receiving pioglitazone achieved weight reductions of –3.0 kg after switching to Bydureon at Week 26;1 the overall weight change from baseline at Week 52 was similar to original baseline1
Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.3
References
Wysham C, et al. Diabet Med 2011;28:705–14.
Bergenstal RM, et al. Lancet 2010;376:431–9.
Bydureon. Summary of product characteristics 2014.
Graph adapted from Wysham C, et al. 2011, showing data for the evaluable population (least squares mean ± standard error).2 †p<0.05 versus Week 26.
*Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.3
BL, baseline; CI, confidence interval.
1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Wysham C, et al. Diabet Med 2011;28:705–14; 3. Bydureon. Summary of product characteristics, 2014.

25. DURATION-3
The following slides present detailed study information and results from the DURATION-3 clinical trial of Bydureon versus insulin glargine.

26. DURATION-3: Study details
DURATION-3: Primary analysis
Study details
N=456 (ITT population)
Open-label, randomised, parallel-group study
Study length
26 weeks
Background therapy
Metformin ± SU
Comparator to Bydureon
Insulin glargine (starting dose: 10 IU/day)
Primary endpoint
Change in HbA1c from baseline at Week 26
Secondary endpoints
Patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); FPG; SMBG; bodyweight; fasting plasma lipids; urinary ACR; CRP; HOMA β-cell function and insulin sensitivity; AAT; HRQoL; 1,5-anhydroglucitol; safety and tolerability
Publication type
Peer-reviewed journal article
Main talking point: The DURATION-3 clinical trial examined efficacy and safety of Bydureon versus insulin glargine at the primary analysis of Week 26.
Notes:
Patients were on a background therapy of metformin ± SU
SU, sulphonylurea.
Reference
Diamant M, et al. Lancet 2010;375:2234–43.
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
AAT, alanine aminotransferase; ACR, albumin-to-creatinine ratio; CRP, C-reactive protein; FPG, fasting plasma glucose; HOMA, homeostasis model assessment; HRQoL, health-related quality of life; SMBG, self-monitored blood glucose; SU, sulphonylurea.
Diamant M, et al. Lancet 2010;375:2234–43.

27. DURATION-3: Study details (continued)
DURATION-3: Planned interim analysis at 84 weeks of open-ended extension study
Study details
N=390 (entering extension study)
Open-label, randomised, parallel-group study
Study length
26 weeks with open-ended extension study; interim analysis at 84 weeks
Background therapy
Metformin ± SU
Comparator to Bydureon
Insulin glargine (starting dose 10 IU/day; target glucose range, 4.0–5.5 mmol/L)
Key efficacy measure
Change in HbA1c from baseline to study treatment endpoint
Secondary efficacy measures
Time to failure to maintain glycaemic control; patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5% (≤47.5 mmol/mol); bodyweight; FPG; SMBG, fasting serum lipids
Exploratory measures
Urinary ACR; HOMA β-cell function; WHR; anti-exenatide antibody titre; safety and tolerability
Publication type
Peer-reviewed journal article
Main talking point: This DURATION-3 clinical trial interim analysis at 84 weeks compared the efficacy and safety of Bydureon with insulin glargine.
Notes:
Patients were on a background of metformin ± SU
SU, sulphonylurea.
Reference
Diamant M, et al. Diabetes Care 2012;35:683–9.
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
ACR, albumin-to-creatinine ratio; FPG, fasting plasma glucose; HOMA, homeostasis model assessment; SMBG, self-monitored blood glucose; SU, sulphonylurea; WHR, waist-to-hip ratio.
Diamant M, et al. Diabetes Care 2012;35:683–9.

28. DURATION-3: Study details (continued)
DURATION-3: 3-year extension study
Study details
N=390 (entering extension study; completer population n=287)
Open-label, randomised, parallel study
Study length
26 weeks with 3-year extension
Background therapy
Metformin ± SU
Comparator to Bydureon
Insulin glargine (starting dose 10 IU/day; target glucose range, 4.0–5.5 mmol/L)
Key efficacy measure
Change in HbA1c from baseline to study treatment endpoint
Secondary measures
Patients achieving HbA1c <7.0% (<53.0 mmol/mol) and ≤6.5%
(≤47.5 mmol/mol); bodyweight; FPG; SMBG, fasting serum lipids; patient-reported outcomes; safety and tolerability
Exploratory measures
Blood CRP concentrations; urinary ACR; WHR
Publication type
Peer-reviewed publication
Main talking point: This DURATION-3 clinical trial 3-year extension compared the efficacy and safety of Bydureon with insulin glargine.
Notes:
Patients were on a background of metformin ± SU
SU, sulphonylurea.
Reference
Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73;
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
ACR, albumin-to-creatinine ratio; CRP, C-reactive protein; FPG, fasting plasma glucose; SMBG, self-monitored blood glucose; SU, sulphonylurea; WHR, waist-to-hip ratio.
Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.

29. DURATION-3: Reduced HbA1c with Bydureon versus basal insulin over 3 years
At the primary endpoint of 26 weeks, HbA1c reductions from baseline were –1.5% (–16.4 mmol/mol) with Bydureon and –1.3% (–14.2 mmol/mol) with insulin glargine (p=0.017)1
Bydureon-treated patients experienced significantly greater HbA1c reductions at 3 years than those treated with insulin glargine2
156
144
108 84 72 48 60 36 26 18 3 5
HbA1c (%)
Time (weeks) 10
HbA1c (mmol/mol) 50 20 8 96
120
132 70 4 1 2 6 7 9 40 30
Bydureon, BL=8.3% (67.2 mmol/mol; n=228)
Insulin glargine, BL=8.3% (67.2 mmol/mol; n=220)
–1.01 ± 0.7% (–11.0 mmol/mol)*
–0.81 ± 0.07% (–8.9 mmol/mol)
Change from BL:
Main talking point: This graph shows the change in HbA1c for the intent-to-treat population for the DURATION-3 clinical trial 3-year extension.
Notes:
At the primary endpoint of 26 weeks, HbA1c reductions from baseline were –1.5% (–16.4 mmol/mol) with Bydureon and –1.3% (–14.2 mmol/mol) with insulin glargine (p=0.017)1
The study demonstrated an overall reduction in HbA1c from baseline with Bydureon (–1.01% [–11.0 mmol/mol]) that was significantly greater than insulin glargine (–0.81% [–8.9 mmol/mol])2
References
1. Diamant M, et al. Lancet 2010;375:2234–43.
2. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.
Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ± standard error.2 *p=0.03.
BL, baseline Diamant M, et al. Lancet 2010;375:2234–43; 2. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.

30. Change in bodyweight (kg)
DURATION-3: Weight change with Bydureon versus basal insulin over 3 years
Treatment with Bydureon resulted in significant weight reduction instead of weight gain with insulin glargine over 3 years1
Time (weeks)
+2.01 ± 0.28 kg
–2.49 ± 0.28 kg*
156
132 84 72 48 36 60 26 8 –4 –2 2 4
Change in bodyweight (kg)
Bydureon, BL=91.2 kg (n=233)
Insulin glargine, BL=90.6 kg (n=222)
Change from BL: 18 96
108
120
144
Main talking point: This graph shows a secondary endpoint of change in bodyweight for the intent-to-treat population for the DURATION-3 clinical trial 3-year extension period.1
Notes:
The study demonstrated an overall reduction in bodyweight from baseline with Bydureon (–2.49 kg), compared with weight gain with insulin glargine (+2.01 kg)1
Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.2
References
Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73.
Bydureon. Summary of product characteristics 2014.
Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ± standard error.1 *p<0.001.
BL, baseline.
Bydureon is not indicated for the treatment of obesity and weight change was a secondary endpoint in clinical trials.2 1. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73; 2. Bydureon. Summary of product characteristics, 2014.

31. Weight change from baseline (kg) HbA1c (%) change from baseline
DURATION-3: Individual associations between HbA1c and body weight with Bydureon versus insulin glargine at 26 weeks*1
Insulin glargine
Bydureon
79%
31% 4% 1%
16%
63%
Modified ITT population, N=448.
Weight change from baseline (kg)
HbA1c (%) change from baseline 16 12 8 4 –4 –8
–12
–16 –6 –2 2 6 0% 5%
Main talking point: At the 26-week primary endpoint of the DURATION-3 trial, more patients taking Bydureon lost weight and experienced a reduction in HbA1c than patients taking insulin glargine.1
Notes:
Analysis of the composite endpoint of HbA1c reduction with weight reduction demonstrated that 79% of Bydureon patients achieved HbA1c reduction with weight reduction versus 31% of insulin glargine patients1
Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials.2
References
Diamant M, et al. Lancet 2010;375:2234–43.
Bydureon. Summary of product characteristics 2014.
*Figure adapted from Diamant M, et al. Lancet
*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials.2
1. Diamant M, et al. Lancet 2010;375:2234–43; Bydureon. Summary of product characteristics, 2014. 31

32. DURATION-3: Incidence of minor hypoglycaemia versus insulin glargine
Bydureon was associated with a lower rate of minor hypoglycaemia than insulin glargine at 84 weeks1
The exposure-adjusted rate of overall hypoglycaemia at 3 years was three times higher with insulin glargine (0.9 events/patient/year) than with Bydureon (0.3 events/patient/year)2
SUs are associated with a higher risk of hypoglycaemia; when Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia3
Metformin background
Patients reporting minor hypoglycaemia (%)
32% n=51
Bydureon (n= 233)
Insulin glargine (n=223)
54% n=36
Metformin + SU background
8% n=13 *
24% n=17 50 70 20 30 60 40 10 80
100 90
Graph adapted from Diamant et al. Diabetes Care *p< Minor hypoglycaemia was defined any time a paitent felt that he or she had a sign or symptom of hypoglycaemia that was associated with concurrent blood glucose <3.0 mmol/L and that was either self-treated by the patient or resolved independently.1 Three patients (one Bydureon + metformin, one insulin glargine + metformin and insulin glargine + metformin and SU) had an episode of hypoglycaemia requiring the assistance of another person, but not involving loss or severe impairment of consciousness, during the first 26 weeks.1
Main talking point: This slide represents the incidence of treatment-emergent hypoglycaemia by background therapy in the DURATION-3 trial at the 84-week planned interim analysis.1
Notes:
The risk of hypoglycaemia with Bydureon was less than with insulin glargine1,2
Incidence of minor hypoglycaemia with Bydureon was low versus insulin glargine and was related to the concomitant use of an SU agent1
When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.2
SU, sulphonylurea.
References
Diamant M, et al. Lancet 2010;375:2234–43.
Bydureon. Summary of product characteristics 2014.
SU, sulphonylurea.
1. Diamant M, et al. Diabetes Care 2012;35:683–9; 2. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73; 3. Bydureon. Summary of product characteristics, 2014.

33. Change in CV risk markers with Bydureon
Evidence from DURATION-1
Bydureon is not indicated for the management of blood pressure or cholesterol.1
CV, cardiovascular.
1. Bydureon. Summary of product characteristics, 2014.

34. DURATION-1: Changes in blood pressure over 1 year with Bydureon
Over 1 year in the DURATION-1 study, improvements from baseline in blood pressure were seen with Bydureon treatment1,2
At 1 year, 50% of patients with a high baseline SBP (≥130 mmHg) achieved a normal SBP2 –1 –2 –3 –4 –5 –6
Change in BP (mmHg)
SBP
Week 301
n=148
–4.7 mmHg
–6.2 mmHg
–1.7 mmHg
–2.8 mmHg
Year 12 n=148
DBP
Baseline
128
129 78 –7
Main talking point: Blood pressure improvements were observed in patients treated with Bydureon over 1 year.1,2
DBP, diastolic blood pressure; SBP, systolic blood pressure.
References
Drucker DJ, et al. Lancet 2008;372:1240–50.
Buse JB, et al. Diabetes Care 2010;33:1255–61.
Figure adapted from Drucker DJ, et al and Buse JB, et al. 2010,2 showing ITT population of patients randomised to Bydureon (n=148).
Bydureon is not indicated for the management of blood pressure or cholesterol.3
DBP, diastolic blood pressure; SBP, systolic blood pressure.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Buse JB, et al. Diabetes Care 2010;33:1255–61; 3. Bydureon. Summary of product characteristics, 2014.

35. DURATION-1: Changes in lipid profile at 1 year with Bydureon
Over 1 year in the DURATION-1 study, improvements from baseline in plasma lipids were observed with Bydureon treatment1,2
Improvements were maintained for up to 6 years3
0.0
–0.1
–0.2
–0.3
–0.4
Change from BL (mmol/L)
Total cholesterol
Week 301
–0.31 mmol/L
–0.25 mmol/L
Year 12
BL=4.49
BL=4.40
0.1
0.0
–0.1
–0.2
–0.3
Change from BL (mmol/L)
LDL-C
Week 301
–0.13 mmol/L
–0.09 mmol/L
Year 12
BL=2.37
BL=2.30
0.1
0.0
–0.1
Change from BL (mmol/L)
HDL-C
Week 301
–0.02 mmol/L
+0.02 mmol/L
Year 12
BL=1.14 –5
–10
–15
Change from BL (%)
Triglycerides
Week 301
–15%
Year 12
BL=1.88
BL=1.82
Main talking point: Plasma lipid improvements (total cholesterol, LDL-C, HDL-C and triglycerides) were observed in patients treated with Bydureon over 1 year,1,2 and maintained up to Year 6.3
Notes:
Triglyceride data are reported as a percent change from baseline due to a non-normal distribution of the data. These changes were clinically significant, but a statistical comparison and p values are not available
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
References
Drucker DJ, et al. Lancet 2008;372:1240–50.
Buse JB, et al. Diabetes Care 2010;33:1255–61.
Henry RH, et al. Poster presented at ADA P.
Figures adapted from Drucker DJ, et al and Buse JB, et al. 2010,2 showing ITT population of patients randomised to Bydureon (n=148).
Bydureon is not indicated for the management of blood pressure or cholesterol.4
BL, baseline; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NR, not reported; TG, triglycerides.
1. Drucker DJ, et al. Lancet 2008;372:1240–50; 2. Buse JB, et al. Diabetes Care 2010;33:1255–61; 3. Henry RH, et al. Poster presented at ADA P; 4. Bydureon. Summary of product characteristics, 2014.

36. Bydureon safety and tolerability profile
Main talking point: The following slides detail the safety and tolerability profile of Bydureon.

37. Bydureon: Summary of safety and tolerability profile
As with other GLP-1 receptor agonists,1–4 the most frequent adverse drug reactions (≥5% of patients treated with Bydureon) were mainly gastrointestinal-related (nausea, vomiting, diarrhoea and constipation)
In addition, injection-site reactions (pruritus, nodules, erythema), hypoglycaemia (with a SU) and headache occurred1
Most adverse reactions associated with Bydureon were mild to moderate in intensity1
There have been rare, spontaneously reported events of acute pancreatitis and renal failure. If pancreatitis is suspected, Bydureon should be discontinued1
Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents. BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione. 1. Bydureon. Summary of product characteristics, 2014; 2. Byetta. Summary of product characteristics, 2014; Victoza. Summary of product characteristics, 2014; 4. Lyxumia. Summary of product characteristics, 2014.

38. System organ class/adverse reaction terms Frequency of occurrence†
Very common and common adverse reactions reported with Bydureon in clinical trials
Most adverse reactions associated with BYDUREON were mild to moderate in intensity and only infrequently* led to discontinuation
There have been rare, spontaneously reported events of acute pancreatitis and renal failure. If pancreatitis is suspected, Bydureon should be discontinued
System organ class/adverse reaction terms
Frequency of occurrence†
Very common (≥1/10)
Common (≥1/100 to <1/10)
Metabolism and nutrition disorders
Hypoglycaemia (with a SU)‡
Decreased appetite‡
Nervous system disorders
Headache‡
Dizziness‡
Gastrointestinal disorders
Nausea‡
Vomiting‡
Diarrhoea‡
Constipation
Dyspepsia‡
Abdominal pain‡
Gastroesophageal reflux disease‡
Abdominal distension‡
Eructation
Flatulence‡
Skin and subcutaneous tissue disorders
Hyperhidrosis‡
General disorders and administration site conditions
Injection-site pruritus
Fatigue‡
Injection-site erythema
Injection-site rash
Somnolence
Main talking point: This slide shows the very common and common adverse reactions reported with Bydureon in clinical trials.
Notes:
The majority of adverse reactions observed with Bydureon in clinical trials and from post-marketing experience were gastrointestinal in nature (nausea, vomiting, diarrhoea and constipation); were mild to moderate; and rarely led to discontinuation
Reference
Bydureon. Summary of product characteristics 2014.
*The incidence of withdrawal due to adverse events in Bydureon-treated patients during the 30-week controlled trial was 6%. †Rate based on Bydureon clinical trial data (N=592 total; n=135 patients on SU) When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia. ‡Reactions were in the same frequency grouping in the exenatide BID group. Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents.
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione. Bydureon. Summary of product characteristics, 2014.

39. System organ class/adverse reaction terms Frequency of occurrence*
Very common and common adverse reactions observed from clinical trial experience that were not observed with Bydureon at an incidence of ≥1%
System organ class/adverse reaction terms
Frequency of occurrence*
Very common (≥1/10)
Common (≥1/100 to <1/10)
Skin and subcutaneous tissue disorders
Hyperhidrosis
General disorders and administration site conditions
Asthenia
Feeling jittery
*Rate based on Bydureon clinical trial data (N=592 total; n=135 patients on SU).
Data source comprises two placebo-controlled studies (10 and 15 weeks) and three studies of Bydureon versus exenatide BID (30-week study), sitagliptin and pioglitazone (26-week study) or insulin glargine (26-week study). Background therapies included diet and exercise, metformin, a SU, a TZD or a combination of oral antidiabetic agents. When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.
Main talking point: This slide shows the very common and common adverse reactions that were not observed with Bydureon at an incidence of ≥1%.
Notes:
The majority of adverse reactions observed with Bydureon in clinical trials and from post-marketing experience were gastrointestinal in nature (nausea, vomiting, diarrhoea and constipation); were mild to moderate; and rarely led to discontinuation
Reference
Bydureon. Summary of product characteristics 2014.
BID, twice daily; SU, sulphonylurea; TZD, thiazolidinedione. Bydureon. Summary of product characteristics, 2014.

40. Handling nausea that may occur with Bydureon treatment
Nausea is a frequent side effect with all GLP-1 receptor agonists1–4
<1% of patients discontinued Bydureon due to nausea1
Most episodes of nausea were mild to moderate and decreased over time1,5
In a 52-week trial, even when patients experienced nausea, it did not affect their reported level of treatment satisfaction with Bydureon6
Incidence of nausea (%)
100 40 60 80 20
0–30
30–60
60–90
90–120
120–150
150–180
180–212
Weeks
Main talking point: As with other GLP-1 receptor agonists, Bydureon is frequently associated with nausea.1–4
Notes:
Patients will usually find that nausea is mild to moderate and lessens over time1
If nausea is intolerable, patients should be encouraged to speak to their healthcare professional who will be able to help them manage their symptoms
GLP-1, glucagon-like peptide-1.
References
Bydureon. Summary of product characteristics 2014.
Byetta. Summary of product characteristics 2014.
Victoza. Summary of product characteristics, 2014.
Lyxumia. Summary of product characteristics, 2014.
Figure adapted from Maggs D, et al
GLP-1, glucagon-like peptide-1.
1. Bydureon. Summary of product characteristics, 2014; 2. Byetta. Summary of product characteristics Victoza. Summary of product characteristics, 2014; 4. Lyxumia. Summary of product characteristics, 2014; 5. Maggs D, et al. Presented at EASD Presentation #4; 6. Best JH, et al. Diabet Med 2009;26:722–8.

41. Handling injection-site reactions that may occur with Bydureon treatment
Injection-site reactions versus bumps
Injection-site bumps
Injection-site reactions associated with symptoms were categorised as adverse events (erythema, pruritus, rash)
Occurred in 16% of patients in Phase III studies
Mostly mild to moderate
Usually did not lead to withdrawal from studies
Small, raised nodules that very frequently occur at the injection site
These are consistent with known properties of poly (D,L-lactide co-glycolide) polymer microsphere technology
Bumps are normally harmless and resolve over 4–8 weeks
Size of bump
Main talking point: Small injection-site nodules are known properties of the microsphere technology.1,2
Notes:
Small subcutaneous injection-site nodules were observed frequently and are an expected property of the microsphere delivery system1,2
These individual small bumps were mostly asymptomatic, did not interfere with study participation, and resolved over 4–8 weeks1
References
Bydureon. Summary of product characteristics 2014.
DeYoung MB, et al. Diabetes Technol Ther 2011;13:1145–54.
Bydureon. Summary of product characteristics, 2014.

42. Contraindications and special warnings and precautions
Hypersensitivity to the active substance or to any of the excipients.
Warnings and precautions
Not to be used in patients with Type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Bydureon must not be administered by intravenous or intramuscular injection.
Renal impairment Rare, spontaneously reported events of altered renal function with exenatide, including increase serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some occurred in patients experiencing events that may affect hydration and/or receiving medicinal products known to affect renal function/hydration status, including angiotensin converting enzyme inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide. No dose adjustment required for patients with mild renal impairment (CrCl 50–80 mL/min). Very limited experience in moderate renal impairment (CrCl 30–50 mL/min). Not recommended in patients with moderate renal impairment, severe renal impairment (CrCl <30 mL/min) or end-stage renal disease.
Severe gastrointestinal disease Not recommended.
Please see the Bydureon summary of product characteristics for full safety information.
Main talking point: This slide lists the contraindications and warnings and precautions for Bydureon, as stated in the prescribing information.
CrCl, creatinine clearance. Bydureon. Summary of product characteristics, 2014. 42

43. Contraindications and special warnings and precautions (continued)
Acute pancreatitis Rare, spontaneously reported events of acute pancreatitis. Inform patients of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis suspected, discontinue use of Bydureon and other potentially suspect medicinal products. Do not resume Bydureon after pancreatitis has been diagnosed.
Concomitant medicinal products Concurrent use of Bydureon with insulin, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of Bydureon and exenatide BID has not been studied and is not recommended.
Weight loss Rapid weight loss at a rate of >1.5 kg per week has been reported with exenatide, which may have harmful consequences.
Discontinuation of treatment The effect of Bydureon may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly until exenatide levels decline.
Please see the Bydureon summary of product characteristics for full safety information.
Main talking point: This slide continues to list the warnings and precautions for Bydureon, as stated in the prescribing information.
BID, twice daily; GLP-1, glucagon-like peptide-1. Bydureon. Summary of product characteristics, 2014. 43

44. Drug interactions
No dose adjustment required for medicinal products sensitive to delayed gastric emptying.
Warfarin and cumarol derivatives Increased INR reported during concomitant use of warfarin and exenatide. INR should be monitored during initiation of Bydureon.
HMG CoA reductase inhibitors Concomitant use with exenatide was not associated with consistent changes in lipid profiles. Lipid profiles should be monitored as appropriate.
Please see the Bydureon summary of product characteristics for full safety information.
Main talking point: This slide lists the drug interactions for Bydureon, as stated in the prescribing information.
AUC, area under curve; BID, twice daily; HMG, hydroxy methyl glutaryl coenzyme A; INR, international normalised ratio. Bydureon. Summary of product characteristics, 2014. 44

45. Anti-exenatide antibodies
Patients may develop antibodies to exenatide following treatment with Bydureon
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals1
In clinical studies of Bydureon, approximately 45% of patients had low-titre antibodies at the study endpoint1
Antibody titres usually diminish over time1
Four clinical trials showing clinically relevant HbA1c reduction regardless of antibody status2
A small proportion of patients (2.6%) had higher titres and showed no glycaemic improvement1
–2.0
–0.5
0.0
Change in HbA1c (%)
–1.5
–1.0
–1.6% (–15.5 mmol/mol)
–1.3%
(–14.2 mmol/mol)
Antibody-negative patients
Antibody-positive patients
Reduction in mean HbA1c by antibody status2
–20
–15
–10 –5
Change in HbA1c (mmol/mol)
n=280
n=371
Main talking point: Some patients may develop antibodies to exenatide following treatment with Bydureon. The presence of antibodies is not predicative of glycaemic control for an individual patient.1
Notes:
The development of antibodies is an expected response to the potentially immunogenic properties of protein and peptide pharmaceuticals1
In most patients who develop anti-exenatide antibodies, titres diminish over time1
Patients who developed anti-exenatide antibodies tend to have more injection-site reactions (e.g. redness of skin and itching), but otherwise have similar rates and types of adverse events as those without anti-exenatide antibodies1
The presence of antibodies caused a slightly lesser HbA1c decrease with Bydureon2
References
Bydureon. Summary of product characteristics 2014.
Fineman MS, et al. Diabetes Obes Metab 2012;14:546–54.
1. Bydureon. Summary of product characteristics, 2014; 2. Fineman MS, et al. Diabetes Obes Metab 2012;14:546–54.

46. Bydureon dosing, administration and initiation

47. Bydureon dosing
Bydureon comes in a convenient single-dose kit that contains everything patients need to prepare and deliver their once-weekly injection
Injection can be administered at any time of the day, independently of meals
Fixed dose with no titration required
Patients can change their day of weekly dosing as long as doses are 1 day apart*
CONNECT
Connect the parts securely before mixing
SHAKE
Shake vigorously to mix the medicine with the liquid
INJECT
Attach the needle, line up the plunger with the dose line, and inject
Main talking point: Bydureon is prescribed in a single-dose kit that contains everything patients need to administer a once-weekly injection of Bydureon. Administration is straightforward: Patients need to connect the parts, shake to mix the medicine and inject for for continuous glycaemic control.
Reference
Bydureon. Summary of product characteristics 2014.
*If a dose is missed, it should be administered as soon as practical. Thereafter, patients can resume their once-weekly dosing schedule. The use of Bydureon does not require additional self-monitoring of blood glucose.
Bydureon. Summary of product characteristics, 2014.

48. Bydureon device: Overview of the Connect, Shake, Inject process
Contains an overview of the injection device
Straightforward dosing: Connect, Shake, Inject
Remember: Patients should follow all of the steps in the instructions for the user that comes with the single-dose kit
Bydureon. Summary of product characteristics, 2014.

49. The Bydureon usability study
A usability study of 102 individuals with Type 2 diabetes found that 88% of patients were able to prepare and deliver a dummy dose of Bydureon
Subjects who succeeded in preparing and delivering a dose of Bydureon
72.6%
(n=74)
Without assistance
With use of customer support helpline
15.7%
(n=16)
11.8%
(n=12)
Did not complete
Questionnaire responses to ‘If I only had the instructions for use, I could use the single-dose kit at home’
69%
(n=70)
22%
(n=22) 7%
(n=7) 2%
(n=2)
Strongly agree
Agree
Neutral
Disagree/ strongly disagree
Main talking point: A usability study of the Bydureon device found that most people were able to prepare and deliver a dummy injection of Bydureon using just the instructions for use provided with the kit.
Notes:
The usability study consisted of 102 subjects with Type 2 diabetes. Its purpose was to evaluate the effectiveness of the ‘Instructions for user’ in training patients to prepare and deliver a dose of Bydureon in the absence of any other educational support
The study population was aged between 21–75 years, with 78% injection naïve, 22% current exenatide BID users, 12% left-handed, 79% required visual assistance (glasses or contact lenses) and 21% reported physical limitations (5% neuropathy, 8% hand weakness and 8% arthritis)
Subjects were given a single-dose kit and asked by a facilitator to use the instructions for use and prepare a dummy dose for injection into an injection ball. The facilitator could not answer any questions or give further support, but participants were permitted to contact a simulated customer support centre for specific questions
Participants’ ability to complete the steps was assessed by the facilitator, which was supplemented by feedback from participants in a standardised questionnaire
More than 90% of participants reported confidence in their ability to prepare and deliver the injection at home with access to only the ‘Instructions for user’
Around 85% of participants found the ‘Instructions for user’ easy to use
Completion success was slightly affected by physical and visual limitations or requirement for visual correction. Age did not influence participants’ ability to successfully compete the task
BID, twice daily.
Reference
Lorenzi G, et al. Clin Diabetes 2010;28:157–62.
Adapted from Lorenzi G, et al. Clin Diabetes 2010;28:157–62.

50. Expectation setting: Benefits
To maximise adherence, a care plan should be agreed with the individual patient, including setting of expectations by the HCP, upon initiation of treatment
Explain to patients that, due to its unique once-weekly formulation, they need to give Bydureon time to work
When you may see an effect
Changes patients may notice
After four doses1,2
FPG improvements
PPG improvements
After six or seven doses1,3
HbA1c reductions
Over time1
Feeling less hungry and eating less
Most patients will experience weight reduction*
*Bydureon is not indicated for the management of obesity and weight change was a secondary endpoint in clinical trials.1
FPG, fasting plasma glucose; HCP, healthcare professional; PPG, postprandial glucose.
1. Bydureon. Summary of product characteristics, 2014; 2. Blevins T, et al. J Clin Endocrinol Metab 2011;96:1301–10; 3. Drucker DJ, et al. Lancet 2008; 372:1240–50.

51. Once-weekly Bydureon: Continuous glycaemic control for your patients
Bydureon provides powerful efficacy with HbA1c reductions, sustained for up to 6 years1
Potential for sustained weight reduction over 6 years* and low risk of hypoglycaemia†1,2
Withdrawal rate of <1% due to nausea and vomiting2
The most frequent adverse reactions (≥5% of Bydureon patients) were mainly gastrointestinal related (nausea, vomiting, diarrhoea and constipation)2
In addition, injection-site reactions (pruritus, nodules, erythema) were observed
Straightforward administration that patients can manage in a once-weekly injection2,3
Main talking point: Bydureon provides powerful efficacy with the added benefit of weight reduction, in a single weekly injection that can easily fit into a patient’s life.
*Bydureon is not indicated for obesity and weight change was a secondary endpoint in clinical trials.2
†SUs are associated with an increased risk of hypoglycaemia. When Bydureon is added to SU therapy, a reduction in the dose of SU should be considered to reduce the risk of hypoglycaemia.2
1. Henry RH, et al. Poster presented at ADA P; 2. Bydureon. Summary of product characteristics, 2014; 3. Lorenzi G, et al. Clin Diabetes 2010;28:157–62.

52. 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.

53. 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.