Bydureon® Educate By Expert toolkit Scientific slides: Introduction to Type 2 diabetes and the unmet need Date of preparation: Apri l 2014 150515 Developed with the guidance and approval of an independent international editorial committee 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 • Some slides are accompanied by a short sound bite video of an expert that you may wish to embed from the toolkit. These are marked with the ‘expert sound bite’ symbol i Expert sound bite • All graphs have been created in PowerPoint to enable easy amends and translation • HbA1c values and appropriate graphs include both DCCT (%) and IFFC (mmol/mol) units. Please delete where not appropriate for your market DCCT, Diabetes Control and Complications Trial; IFFC, International Federation of Clinical Chemistry and Laboratory Medicine. Executive summary • This slide deck covers the following topics and contains speaker notes to assist presentation: 1. Introduction to Type 2 diabetes • Unmet needs and barriers to treatment – Epidemiology of Type 2 diabetes – Barriers to treatment (weight gain, hypoglycaemia, adherence to treatment) • The Type 2 diabetes treatment pathway and individualised care – The place of GLP-1 receptor agonists and insulin in the treatment pathway 2. GLP-1 receptor agonists and the discovery of exenatide • GLP-1 mechanism of action and the incretin effect • The discovery of exenatide, the first GLP-1 receptor agonist 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 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. 6 The growing burden of Type 2 diabetes i Expert sound bite • Placeholder for video 1Ai. Dr Javier Francisco Ampudia Blasco: The growing burden of Type 2 diabetes 7 Despite advances in treatment, a significant proportion of patients with Type 2 diabetes still fail to reach target HbA1c levels PANORAMA study (2009)2 Percentage of patients not achieving target HbA1c level: <7.0% (<53 mmol/mol) Patients not controlled (%) 100 90 80 70 60 50 40 30 20 10 0 Nine EU countries (n=5817) UK (n=501) France (n=759) Germany (n=808) Italy (n=752) Adapted from De Pablos-Velasco P, et al. Clin Endocrinol (Oxf) 2012; Epub ahead of print. Spain (n=752) Belgium Netherlands Greece (n=611) (n=659) (n=375) Turkey (n=600) Type 2 diabetes as a progressive disease and its increasing unmet need i Expert sound bite • Placeholder for video 1Aii. Professor Stephan Jacob: Type 2 diabetes as a progressive disease and its increasing unmet need 9 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 Diet + drug + drug + basal insulin Complex insulin regimen 10 HbA1c levels (%) 9 70 8 60 7 6 50 Diagnosis +5 years Duration of diabetes Adapted from Campbell IW. Br J Cardiol 2000;7:625–31. +10 years +15 years HbA1c levels (mmol/mol) 80 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 Diet + drug + drug + basal insulin Complex insulin regimen 10 HbA1c levels (%) 9 70 8 60 7 6 50 Diagnosis +5 years Duration of diabetes Adapted from Campbell IW. Br J Cardiol 2000;7:625–31. +10 years +15 years HbA1c levels (mmol/mol) 80 Managing Type 2 diabetes through early interventions i Expert sound bite • Placeholder for video 1Aiii. Professor Kamlesh Khunti: Managing Type 2 diabetes through early interventions 12 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. Raising awareness of diabetes and its associated risk factors i Expert sound bite • Placeholder for video 1Aiv. Paul Dromgoole: Raising awareness of diabetes and its associated risk factors 14 Diabetes and obesity are closely interlinked Relationship between BMI and risk of Type 2 diabetes Age-adjusted relative risk for Type 2 diabetes 100 Normal weight Overweight Obese 75 Women 50 Men 25 0 <23 <23–23.9 <24–24.9 <25–26.9 <27–28.9 <29–30.9 <31–32.9 <33–34.9 ≥35 BMI (kg/m2) *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) 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 Clinical characteristics *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 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) Clinical criteria 0.05% in HbA1c Odds ratio 95% CI 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 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). 40 mg/dL in triglycerides 2.20 1.71, 2.83 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. 2. 3. 4. Transitory symptoms not affecting normal activity Temporarily incapacitated but patient able to control symptoms without help Incapacitated and required assistance to control symptoms 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) 38 32.6 (21.8 to 45.6) 5.5 (2.0 to 14.0) Basal + prandial insulin *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. Severe hypoglycaemia is associated with poor CV outcomes and mortality ADVANCE study Events No. of patients with events (%) Severe No severe hypoglycaemia hypoglycaemia (n=231) (n=10,909) Major macrovascular events Unadjusted model Adjusted model 33 (15.9) Major microvascular events Unadjusted model Adjusted model 24 (11.5) Death from any cause Unadjusted model Adjusted model 45 (19.5) Death from CV cause Unadjusted model Adjusted model 22 (9.5) Death from non-CV cause Unadjusted model Adjusted model 23 (10.0) HR (95% CI) 1114 (10.2) 4.05 (2.86 to 5.74) 3.53 (2.41 to 5.17) 1107 (10.1) 2.39 (1.60 to 3.59) 2.19 (1.40 to 3.45) 986 (9.0) 4.86 (3.60 to 6.57) 3.27 (2.29 to 4.65) 520 (4.8) 4.87 (3.17 to 7.49) 3.79 (2.36 to 6.08) 466 (4.3) 4.82 (3.16 to 7.35) 2.80 (1.64 to 4.79) 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 Cost per severe hypoglycaemic event (year 2007)2 Average patient with Type 2 diabetes Patient requiring hospitalisation Germany €533 €3023 Spain €691 €1404 UK €537 €1314 Country • 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 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. Patients making lifestyle changes following a hypoglycaemic episode (%) Hypoglycaemia is a cause of lifestyle modifications in patients with Type 2 diabetes 100 Mild/moderate hypoglycaemia 90 Severe hypoglycaemia 84.2 80 70 62.9 63.2 57.9 60 50 57.9 43.3 40 30 32 29.9 26.3 15.8 20 10 9.4 14.4 10.3 9.3 0 Modified insulin Ate extra food Increased fear Additional Asked Went home dose of future hypo concerns about someone to from driving check on them work/activities Stayed home the next day 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. The requirement for more intelligent compounds such as the incretin-based agents i Expert sound bite • Placeholder for video 1Av. Professor Stephan Jacob: The requirement for more intelligent compounds such as the incretin-based agents 23 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 Persistent patients (%) • 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 100 Metformin monotherapy SU monotherapy Metformin + SU polytherapy 80 60 40 20 0 0 8 16 24 32 40 48 Week 56 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. 64 72 80 88 96 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. Requirements for aggressive antidiabetic treatment beyond diet and exercise i Expert sound bite • Placeholder for video 1Avi. Professor Kamlesh Khunti: Requirements for aggressive antidiabetic treatment beyond diet and exercise 26 The Type 2 diabetes treatment pathway and individualised care ADA/EASD 2012 position statement on the management of Type 2 diabetes “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 • 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 ADA, American Diabetes Association; CV, cardiovascular; EASD, European Association for the Study of Diabetes. Inzucchi SE, et al. Diabetes Care 2012;35:1364–79. Avoiding side effects of treatment with antidiabetic agents i Expert sound bite • Placeholder for video 1Avii. Paul Dromgoole: Avoiding side effects of treatment with antidiabetic agents 29 Individualisation of treatment goals is key Approach to management of hyperglycaemia More stringent Less stringent Risks potentially associated with hypoglycaemia and other adverse events Low High Disease duration Newly diagnosed Long-standing Life expectancy Long Short Important comorbidities Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Resources, support system Readily available Limited Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79. 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. 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 Considerations when prescribing commonly-used non-insulin antidiabetic agents2 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 Contraindicated 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 • 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 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 Non-insulin regimens Treatment convenience Number of Regimen injections complexity Basal insulin only (usually with oral agents) Low 1 Pre-mixed insulin twice daily 2 3+ High Basal insulin +1 (mealtime) rapid-acting insulin injection Basal insulin + ≥2 (mealtime) rapid-acting insulin injections Less flexible Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79. Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79. More convenient Less convenient More flexible Flexibility Use of GLP-1 receptor agonists early in the treatment pathway i Expert sound bite • Placeholder for video 1Aviii. Paul Dromgoole: Use of GLP-1 receptor agonists early in the treatment pathway 33 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. Advantages of new antidiabetic treatments i Expert sound bite • Placeholder for video 1Aix. Paul Dromgoole: Advantages of new antidiabetic treatments 35 The 4-T study: Increasing the basal insulin dose does not always result in further HbA1c reductions Mean changes in basal insulin dose Mean changes in HbA1c Basal insulin Biphasic insulin Prandial insulin 75 1.5 70 HbA1c (%) 65 60 55 7 50 45 6 0 0 0 0.5 1 1.5 2 2.5 3 Years since randomisation 4-T, Treating to Target in Type 2 diabetes. Adapted from Holman R, et al. N Engl J Med 2009;361:1736–47. HbA1c (mmol/mol) 8 Daily insulin dose (IU/kg) 9 Basal insulin Biphasic insulin Prandial insulin 1.0 0.5 0.0 0 0.5 1 1.5 2 2.5 Years since randomisation 3 Basal insulin is sometimes not sufficient to achieve glycaemic control, even when titrated properly Percentage of patients who did not reach HbA1c ≤7% (≤53 mmol/mol) after 6 months1 Percentage of patients achieving HbA1c ≤7% (≤53 mmol/mol) at 1 year2 100 80 60 42.0% 42.7% 40 20 Percentage of patients at target HbA1c (%) Percentage of patients at target HbA1c(%) 100 0 80 60 40 27.8% 20 0 Insulin glargine Insulin determir NPH 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 at or below target HbA1c after 1 year of basal insulin therapy2 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. Discussing potential use of injectable agents with patients for treatment of Type 2 diabetes i Expert sound bite • Placeholder for video 1Ax. Paul Dromgoole: Discussing potential use of injectable agents with patients for treatment of Type 2 diabetes 38 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. Patient beliefs and ability to engage with treatment i Expert sound bite • Placeholder for video 1Axi. Paul Dromgoole: Patient beliefs and ability to engage with treatment 40 Changing patient and healthcare professional perceptions of injectable agents i Expert sound bite • Placeholder for video 1Axii. Paul Dromgoole: Changing patient and healthcare professional perceptions of injectable agents 41 Halting Type 2 diabetes disease progression by physiological mechanisms i Expert sound bite • Placeholder for video 1Axiii. Professor Stephan Jacob: Halting Type 2 diabetes disease progression by physiological mechanisms 42 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.