Bydureon® (exenatide once-weekly)Scientific slides: Introduction to Type 2 diabetes and the unmet need

Developed with the guidance and approval of an independent international editorial committee

Date of approval: March 2015 | Date of expiry: March 2016Approval code: 675,057.01

Prescribing information can be found at the end of this slide deck.

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.

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 to receive market

authorisation

Introduction to Type 2 diabetes: Unmet needs and barriers to treatment

<Insert speaker name>

The unmet needs in the management of Type 2 diabetes

Approximately 53 million adults suffer from diabetes in Europe

• 8.1% of the adult population in Europe suffer from diabetes

• By 2030, the prevalence of diabetes in Europe is forecast to rise to 9.5% of the adult population

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Prevalence* of diabetes (20–79 years) in Europe, 2011

Adapted from The International Diabetes Federation. Diabetes Atlas, 5th edition (2011). Available at: http://www.idf.org./diabetesatlas/5e/europe. Last accessed August 2013.

Despite advances in treatment, a significant proportion of patients with Type 2 diabetes still fail to reach target HbA1c levels

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PANORAMA study (2009)2

Percentage of patients not achieving target HbA1c level: <7.0% (<53 mmol/mol)

UK(n=501)

France(n=759)

Germany(n=808)

Italy(n=752)

Spain(n=752)

Nine EU countries(n=5817)

Belgium(n=659)

Netherlands(n=611)

Greece(n=375)

Turkey(n=600)

Adapted from De Pablos-Velasco P, et al. Clin Endocrinol (Oxf) 2012; Epub ahead of print.

Traditional approaches to Type 2 diabetes management often have limited success

• Traditionally, Type 2 diabetes has been managed by a stepwise, conservative approach where regimens are changed only when symptoms become apparent– In the majority of cases, this approach does not lead to sustained glycaemic control

Duration of diabetes

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Complex insulin regimen

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+ basal insulin

+ drug

Diagnosis +5 years +10 years +15 years

Diet

Adapted from Campbell IW. Br J Cardiol 2000;7:625–31.

Early, intensive interventions can support long-term glycaemic control

• Adoption of an intensive, goal-focused strategy from diagnosis can improve long-term glycaemic control in Type 2 diabetes– Any combination regimen should be well tolerated as well as efficacious, to promote adherence

Duration of diabetes

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Diagnosis +5 years +10 years +15 years

+ drug

Adapted from Campbell IW. Br J Cardiol 2000;7:625–31.

The barriers to effective treatment of Type 2 diabetes

• Many barriers to effective treatment of Type 2 diabetes have been identified. These include:1. Weight gain, either from lifestyle or antidiabetic medication1

2. Rates and fear of hypoglycaemia, due to use of certain classes of antidiabetic therapies2

3. Poor adherence to therapy3

4. Clinical inertia around the progressive nature of Type 2 diabetes and eventual requirement for insulin4,5

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65; 2. Amiel SA, et al. Diabet Med 2008;25:245–54; 3. Guisasola AF. Diabetes Obes Metab 2008;10(Suppl. 1):25–32; 4. Weyer C, et al. J Clin Invest 1999;104:787–94; 5. Khunti K, et al. Diabetes Care 2013;36:3411–7.

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0<23 <23–23.9 <24–24.9 <25–26.9 <27–28.9 <29–30.9 <31–32.9 <33–34.9 ≥35

Normal weight Overweight Obese

Women

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Diabetes and obesity are closely interlinked

Relationship between BMI and risk of Type 2 diabetes

*Results are from two different studies. The first study is from a cohort of 27,983 US male health professionals, 40–75 years of age in 1986 who completed biennial questionnaires sent out in 1986, 1988, 1990 and 1992 (follow-up: 1987–1992). The second study is from a cohort of 114,281 US female registered nurses, 30–55 years of age in 1976 who completed questionnaires (follow-up: 1976–1990). BMI, body mass index.Adapted from: 1. Chan J, et al. Diabetes Care 1994;17:961–9; 2. Colditz GA, et al. Ann Intern Med 1995;122:481–6.

Disease progression is associated with weight change

Baseline patient characteristics associated with diabetes progression* over the subsequent year (n=705)

Clinical characteristics Non-progressors(n=505)

Progressors(n=200) p value

Baseline weight (kg) 84.9 ± 19.5 88.3 ± 24.4 0.16

Baseline BMI (kg/m2) 32 ± 6.9 32.3 ± 9.3 0.78

Change in weight (kg) –0.9 ± 7.5 0.2 ± 7.2 0.17

Baseline SBP (mmHg) 129.3 ± 17.6 127.9 ± 16.5 0.36

Baseline DBP (mmHg) 74.7 ± 11.3 73.8 ± 10.9 0.36

*HbA1c levels ≥7% or initiation of antidiabetic agent in patients with HbA1c <7.0% (<53.0 mmol/mol) and not on glucose-lowering medications at baseline.BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.Pani LN, et al. Diabetes Care 2008;31:386–90.

In patients with Type 2 diabetes, weight loss provides multiple benefits: The Look AHEAD study

This study was an observational analysis of participants in the Look AHEAD study conducted at 16 US sites in 5,145 participants (40.5% male, 37% from ethnic/racial minorities).

Clinical criteria Odds ratio 95% CI

0.05% in HbA1c 3.52 2.81, 4.40

5 mmHg in SBP 1.56 1.27, 1.91

5 mmHg in DBP 1.48 1.20, 1.82

5 mg/dL in HDL cholesterol 1.69 1.37, 2.07

40 mg/dL in triglycerides 2.20 1.71, 2.83

Odds ratio for the percentage of the Look AHEAD patient cohort achieving clinically meaningful changes in CVD risk factors at 1 year after a weight loss of ≥5% to <10% (n=1000/5145)

AHEAD, Action for Health Diabetes; CI, confidence interval; CVD, cardiovascular disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein, SBP, systolic blood pressure.Wing RG, et al. Diabetes Care 2011;34:1481–6.

Many current therapies are associated with hypoglycaemia

• During the UKPDS, self-reported hypoglycaemic symptoms were graded using a four-point scale:1. Transitory symptoms not affecting normal activity

2. Temporarily incapacitated but patient able to control symptoms without help

3. Incapacitated and required assistance to control symptoms

4. Required medical attention or glucagon injection

Therapy n*Annual percentage of patients reporting at least

one hypoglycaemic episode, % (95% CI)

Grades 1–4 Grades 2–4

Diet 756 0.8 (0.6 to 1.0) 0.1 (0.1 to 0.2)

SU 1418 7.9 (5.1 to 11.9) 1.2 (0.4 to 3.4)

Metformin 290 1.7 (1.0 to 3.0) 0.3 (0.1 to 1.1)

Basal insulin 1036 21.2 (14.6 to 29.8) 3.8 (1.2 to 11.1)

Basal + prandial insulin 38 32.6 (21.8 to 45.6) 5.5 (2.0 to 14.0)

*Patients taking assigned therapy over 6 years’ follow-up.CI, confidence interval; SU, sulphonylurea; UKPDS, UK Prospective Diabetes Study.Wright AD, et al. J Diabetes Complications 2006;20:395–401.

No. of patients with events (%)

Events

Severe hypoglycaemia

(n=231)

No severe hypoglycaemia

(n=10,909) HR (95% CI)

Major macrovascular events Unadjusted model Adjusted model

33 (15.9) 1114 (10.2)4.05 (2.86 to 5.74)3.53 (2.41 to 5.17)

Major microvascular events Unadjusted model Adjusted model

24 (11.5) 1107 (10.1)2.39 (1.60 to 3.59)2.19 (1.40 to 3.45)

Death from any cause Unadjusted model Adjusted model

45 (19.5) 986 (9.0)4.86 (3.60 to 6.57)3.27 (2.29 to 4.65)

Death from CV cause Unadjusted model Adjusted model

22 (9.5) 520 (4.8)4.87 (3.17 to 7.49)3.79 (2.36 to 6.08)

Death from non-CV cause Unadjusted model Adjusted model

23 (10.0) 466 (4.3)4.82 (3.16 to 7.35)2.80 (1.64 to 4.79)

Severe hypoglycaemia is associated with poor CV outcomes and mortality

ADVANCE study

The HR represents the risk of an adverse clinical outcome or death among patients reporting severe hypoglycaemia compared with those not reporting severe hypoglycaemia.CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio. Zoungas S, et al. N Engl J Med 2010;363:1410–8.

The costs of severe hypoglycaemia

• The cost implications of severe hypoglycaemia, both direct hospital costs and indirect costs due to inability to work, are considerable1,2

• There is evidence to suggest that people with Type 2 diabetes lose, on average, 3 productive days following a severe hypoglycaemic attack1

• Inpatient costs are consistently higher than outpatient costs, due to increased medical care for diabetes-related complications3

Cost per severe hypoglycaemic event (year 2007)2

Country Average patient with Type 2 diabetes

Patient requiring hospitalisation

Germany €533 €3023

Spain €691 €1404

UK €537 €1314

1. Amiel SA, et al. Diabet Med 2008;25:245–54; 2. Hammer M, et al. J Med Econ 2009;12:281–90; 3. Kanavos P, et al. 2012. Available at: http://www.lse.ac.uk/lsehealthandsocialcare/research/lsehealth/mtrg/lsediabetesreport26jan2012.pdf. Last accessed June 2013.

Quality of life issues: Patient fear regarding hypoglycaemia

• Fear of hypoglycaemia:1

– Is an additional psychological burden on patients– May limit the aggressiveness of drug therapy– Can decrease adherence to treatment recommendations– May reduce compliance with therapy

• Fear of hypoglycaemia can influence:– Patient health outcomes (prevention or delay of diabetes-related complications)2 – Post-episode lifestyle changes2

• A severe hypoglycaemic event can increase fear of hypoglycaemia in the future3

1. Leiter LA, et al. Can J Diab 2005;29:186–92; 2. Davis S, et al. J Diab Comp 2004;18:60–8; 3. Currie CJ, et al. Curr Med Res Opin 2006;22:1523–34.

Hypoglycaemia is a cause of lifestyle modifications in patients with Type 2 diabetes

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Severe hypoglycaemia

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Graph shows patients (n=202) who ‘sometimes’ or ‘always’ made lifestyle changes within 24 hours of a hypoglycaemic episode, in a self-administered questionnaire. Mild/moderate hypoglycaemia, plasma glucose ≤4.0 mol/L; severe hypoglycaemia, plasma glucose <2.8 mmol/L and requiring assistance.Adapted from Leiter LA, et al. Can J Diab 2005;29:186–92.

Many patients with diabetes do not adhere to their treatment

• Poor patient adherence to treatment is an important barrier to glycaemic control1

• Retrospective studies in people with Type 2 diabetes reported adherence rates of 36–93% for oral agents and 62–64% for insulin1

• Therapy persistence has been shown to decrease with time, and with polytherapy compared with monotherapy2

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00 8 16 24 32 40 48 56 64 72 80 88 96

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Metformin monotherapySU monotherapyMetformin + SU polytherapy

Figure from Dailey et al.2

SU, sulphonylurea.1. Cramer JA. Diabetes Care 2004;27:1218–24; 2. Dailey G, et al. J Int Med Res 2002;30:71–9.

Clinical inertia can lead to poor glycaemic control in patients with Type 2 diabetes

• Clinical inertia is the failure to intensify treatment in a timely manner

• There is a delay in intensifying treatment in people with Type 2 diabetes with poor glycaemic control, which leads to prolonged periods of hyperglycaemia

– Patients may remain in poor glycaemic control for over 7 years before intensification of treatment with insulin

– In patients taking 1 or 2 OADs, median time from initiation of treatment to intensification with an additional OAD exceeded the study’s maximum follow-up time of 7.3–7.3 years

Treatment intensification was defined as either addition of further OAD prescription without changes in current OAD prescription, or initiation of insulin irrespective of changes in OAD regimen.OAD, oral antidiabetic drug.Khunti K, et al. Diabetes Care 2013;36:3411–7.

The Type 2 diabetes treatment pathway and individualised care

ADA/EASD 2012 position statement on the management of Type 2 diabetes

• Key points:– Glycaemic targets and glucose-lowering therapies must be individualised

• HbA1c <7% (<53 mmol/mol) for most patients

• More stringent (e.g. 6.0–6.5% [42.1–47.5 mmol/mol]) and less stringent HbA1c targets might be considered in selected patients

– Diet, exercise, and education remain key

– All treatment decisions should be made in conjunction with the patient, focusing on his/her preferences, needs and values

– Comprehensive CV risk reduction must be a major focus of therapy

– Additional considerations include: Age, weight, sex/racial/ethnic/genetic differences and comorbidities

“An approach to providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.” – ADA/EASD position statement 2012

ADA, American Diabetes Association; CV, cardiovascular; EASD, European Association for the Study of Diabetes.Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

Individualisation of treatment goals is key

Approach to management of hyperglycaemia

The figure depicts elements to consider when making decisions about HbA1c targets for specific patients.

The scale is not designed to be applied rigidly but to serve as a broad framework to assist in determining glycaemic targets.

More stringent Less stringent

Risks potentially associated withhypoglycaemia and other adverse events

Disease duration

Life expectancy

Important comorbidities

Established vascular complications

Resources, support system

HighLow

Newly diagnosed Long-standing

Long Short

Absent Severe

SevereAbsent

Readily available Limited

Few/mild

Few/mild

Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

Antihyperglycaemic therapy in Type 2 diabetes

• Metformin is the most commonly used first-line drug for treating Type 2 diabetes1

• After metformin, there are a number of treatment options available1

– Combination therapy is reasonable, aiming to minimise side effects where possible

• Recent guidelines position GLP-1 receptor agonists as add-on to metformin or multiple OADs in the treatment pathway1

• Ultimately, many patients will require insulin therapy1

MET DPP4-i GLP-1 RA SGLT2-i SU TZD

Hypoglycaemia risk

Neutral Neutral Neutral Neutral Moderate / severe

Neutral

Weight Slight loss Neutral Loss Loss Gain Gain

Renal impairment

Contra-indicated Stage 3B–5

Dose adjustment required†

Exenatide contraindicated CrCl <30

Infections More hypo risk May worsen fluid retention

GI Sx Moderate Neutral Moderate Neutral Neutral Neutral

Considerations when prescribing commonly-used non-insulin antidiabetic agents2

Table adapted from Garber AJ, et al. 2013.2

*In patients intolerant to metformin or for whom metformin is contraindicated. †Except linagliptin.CrCl, creatinine clearance; DPP4-i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; MET, metformin; OAD, oral antidiabetic drug; SGLT2-i, sodium-glucose co-transporter 2 inhibitor; SU, sulphonylurea; Sx, side effects; TZD, thiazolidinedione.Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79; 2. Garber AJ, et al. Endocr Pract 2013;19:327–36.

Complexity of insulin regimens increases as Type 2 diabetes progresses

Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

Non-insulin regimens

Basal insulin only (usually with oral agents)

Pre-mixed insulin twice daily

Basal insulin +1 (mealtime) rapid-acting

insulin injection

Basal insulin + ≥2 (mealtime)

rapid-acting insulin injections

Regimen complexity

Low

High

Number of injections

1

2

3+

FlexibilityMore flexibleLess flexible

Treatment convenience

More convenient

Lessconvenient

Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

Comparison of GLP-1 receptor agonists with insulin

• GLP-1 receptor agonists offer a different suite of advantages and disadvantages for consideration when individualising care

GLP-1 receptor agonist Insulin

Hypoglycaemia risk Low High

Weight change Loss Gain

Major side effect(s) Gastrointestinal Hypoglycaemia

Daily titration required?

Additional blood glucose monitoring required?

Costs High Variable

GLP-1, glucagon-like peptide-1.Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

The 4-T study: Increasing the basal insulin dose does not always result in further HbA1c reductions

Mean changes in basal insulin dose

Years since randomisation

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Mean changes in HbA1c

Years since randomisation

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4-T, Treating to Target in Type 2 diabetes.Adapted from Holman R, et al. N Engl J Med 2009;361:1736–47.

Basal insulin is sometimes not sufficient to achieve glycaemic control, even when titrated properly

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Insulin determir

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Percentage of patients achieving HbA1c ≤7% (≤53 mmol/mol) at 1 year2

Insulin glargine NPH0

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Percentage of patients who did not reach HbA1c ≤7.0% (≤53 mmol/mol) after 6 months of basal insulin therapy with forced titration to

target FPG ≤5.5 mmol/L (100 mg/dL)1

Percentage of patients who did not reach HbA1c ≤7% (≤53 mmol/mol) after 6 months1

FPG, fasting plasma glucose; NPH, neutral protamine Hagedorn.1. Riddle MC, et al. Diabetes Care 2003;26:3080–6; 2. Holman R, et al. N Engl J Med 2007;357:1716–30.

Reasons why patients may be unwilling to begin insulin therapy

Unwilling to begin insulin (%)

Willing to begin insulin* (%)

Significantly different?

Low self-efficacy 58.1 39.7

Restrictiveness 56.1 41.6

Personal failure 55.0 33.6

Permanence 53.1 42.6

Anticipated pain 50.8 30.2

Problematic hypoglycaemia 49.3 37.9

Severity of illness 46.7 35.4

Lack of fairness 41.5 21.9

Expected harm 16.7 8.0

Data from n=3833 attendees at nine public sessions on ‘Taking control of your diabetes’. 1267 questionnaires were returned; 708 individuals had Type 2 diabetes and were not receiving insulin.*Percentages of patients responding that they would be slightly willing, 24.8%; moderately willing, 23.3%; very willing, 24.4%.Polonsky WH, et al. Diabetes Care 2005 28:2543–5.

Summary: Type 2 diabetes and individualised care

• There are a number of unmet needs in Type 2 diabetes, which are in part fuelled by barriers to treatment such as:

– Weight gain

– Hypoglycaemia and patient fear of hypoglycaemia

– The progressive nature of the disease and patients’ unwillingness to start insulin

– Poor adherence to medication

• An individualised approach to diabetes care may help to overcome some barriers to treatment

Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.

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

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