1. Patient adherence in type 2 diabetes: What’s the issue and how to address it Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust, UK

2. Prescribed regimen for 12 months Fully compliant for 12 months Fully persistent for 12 months Partially compliant Non-persistent (stopped therapy before 12 months) Non-compliant and non-persistent Non-acceptance (does not start therapy) Definition of compliance and persistence Compliance: extent to which a patient acts in accordance with the prescribed interval and dose of dosing regimen Persistence: accumulation of time from initiation to discontinuation of therapy Adherence: encompasses both

3. US population 2002. J Int Med Res. 2002;30:71. So what really happens when you fill a prescription? PERSISTENCE Study periodStudy group a n Persistence (in days) b SD Persistence rate (%) c 1 yearMetformin (M)4,033183.8142.751.06 (360 days)Sulphonylurea (SU) 11,234183.1141.850.86 M+SU661111.1117.430.86 2 YEARSMetformin915296.7285.141.21 (720 days)Sulphonylurea2983274.3276.538.10 M+SU158121.9186.916.93 Persistent patients (%) Weeks of therapy

4. So what really happens when you fill a prescription? COMPLIANCE US population 2002. J Int Med Res. 2002;30:71. 65.06 64.64 44.42 63.07 60.54 35.76 0 20 40 60 80 100 Patients remaining compliant to therapy (%) 1 Year (360 days)2 Years (720 days) MetforminSulphonylureaMetformin + Sulphonylurea Study periodStudy group a n Compliance (in days) b SD Persistence rate (%) c 1 yearMetformin (M)4033234.2110.865.06 (360 days)Sulphonylurea (SU) 11,234232.7113.664.64 M+SU661159.9115.344.42 2 YEARSMetformin915454.1232.263.07 (720 days)Sulphonylurea2983435.9232.660.54 M+SU158257.5228.235.76

5. Diabetes Audit and Research in Tayside Study (DARTS) Study population –All people with Type 2 Diabetes living in Tayside, Scotland (~420,000) –First prescription for oral anti-diabetes drug from 1 January 1993 onward –Follow-up to 31 December 1995 with at least 12 months of prescriptions Donnan PT et al. Diabet Med. 2002;19:279-284. Total time drug prescribed Total time of follow-up = Adherence index

6. Adherence index by type of therapy MonotherapySulphonylurea31 Metformin34 PolytherapySulphonylurea19 Metformin13 Donnan PT et al. Diabet Med. 2002;19:279-284.

7. Retrospective, cohort study of community pharmacy records (N=2,325) Once the patient has ACCEPTED treatment, is everything fine? Van Wijk et al. J Hypertens. 2005;23:2101-2107. 012345678910 Years after first prescription Continuous hypertensive users (%) Men Women 0 10 20 30 40 50 60 70 80 90 100

8. Sokol et al. Med Care. 2005;43:521-530. Level of compliance (%) All-cause hospitalisation risk (%) 44 39 36 30 27 0 10 20 30 40 1-1920-3940-5960-7980-100 Does it matter? Lessons from hypertension: improved outcome

9. Odds ratio = 1.45. *P = 0.026 (controlling for age, gender, and co-morbidities). Does it matter? Lessons from hypertension: improved BP control Bramley et al. J Manag Care Pharm. 2006;12:239-245. 10 40 30 20 Medium (50%–79%) Low (< 50%) Compliance (measured using MPR) Patients with BP control* (%) 0 * 42% 33%32% High (≥ 80%)

10. BUT for type 2 diabetes it can be difficult Progressive disease Multi-system disease with co-morbidities—polypharmacy! Complex guidelines Unmet needs of pharmacotherapies

11. Progressively declining beta cell function in T2D ‘waiting for failure’ Adapted from: Heine RJ et al. BMJ. 2006;333:1200-1204. 100 0 0 HbA1c ß-cell function LifestyleMonotherapy Dual therapy Insulin ±oral drugs for lowering blood glucose Time (years) ß-cell function (%) HbA1c (%) 8 >15 5 6 7 9 0 10

12. The treatment complexity in type 2 diabetes drives non-adherence to management strategies Medication for Complex Diabetes A 42-year-old woman’s regimen for treating complex diabetes includes… At least 15 types of oral medication 2 over-the-counter products 7 to 10 injections 4 blood tests …per day, costing over $1,800 a month retail Source: Dr. John Buse, The New York Times

13. Mild to moderate hyperglycaemia (HbA1C <9.0%) Overweight (BMI ≥ 25 kg/m 2 ) Non-overweight (BMI < 25 kg/m 2 ) Biguanide alone or in combination with 1 of: insulin sensitizer insulin secretagogue insulin alpha-glucosidase inhibitor 1 or 2 anti-hyperglycaemic agents from different classes biguanide insulin sensitizer insulin secretagogue insulin alpha-glucosidase inhibitor Add a drug from a different class or use insulin alone or in combination with: biguanide insulin secretagogue insulin sensitizer alpha-glucosidase inhibitor Marked hyperglycaemia (HbA1C ≥9.0%) 2 anti-hyperglycaemic agents from different classes biguanide insulin sensitizer insulin secretagogue insulin alpha-glucosidase inhibitor Basal and/or pre-prandial insulin Add an oral anti-hyperglycaemic agent from a different class or insulin Intensify insulin regimen or add biguanide insulin secretagogue insulin sensitiser alpha-glucosidase inhibitor If not at target Timely adjustments to and/or additions of oral anti-hyperglycaemic agents and/or insulin should be made to attain target HbA1C within 6 to 12 months L I F E S T Y L E Current treatment paradigms for type 2 diabetes are not “user-friendly” If not at target

14. *Physicians were asked to indicate key areas. †Patients were asked to choose top three most important areas. Patients’ Need for Improvement † Percent Weight loss HbA1c Hypoglycaemia Ease of Use Reasons for choice † Percent Physicians’ Need for Improvement* Percent Reasons for choice* Percent HbA1c Preserves beta cell function Weight loss Cost GI side effect profile Unmet patient & physician needs in the treatment of type 2 diabetes in Europe

15. 1. Xingbao C. Chinese Health Economics. 2003. Ling T. China Diabetic Journal. 2003. 2. Harris SB et al. Diabetes Res Clin Pract. 2005;70:90-97. 3. Lopez Stewart G et al. Rev Panam Salud Publica. 2007;22:12-20. 4. Saydah SH et al. JAMA. 2004;291:335-342. 5. Liebl A et al. Diabetologia. 2002;45:S23-S28. US (NHANES) 4 HbA1c < 7% 37% 63% Europe (CODE-2) 5 HbA1c < 6.5% 31% 69% Canada (DICE) 2 HbA1c < 7% 51% 49% China (CODIC-2) 1 HbA1c < 7.5% 68% 32% Latin America (DEAL) 3 HbA1c <7% 43% 57% RESULT: Patients often fail to achieve glycaemic targets Achieving glycaemic target Failed to achieve glycaemic target

16. Grant RW et al. Diabetes Care. 2003;26:1408-1412. Side effects Difficulty in remembering doses Cost Others* Only 23% of patients who had side effects reported the problems to their primary care physician Most common factors related to non-adherence in patients with type 2 diabetes *Number of prescribed medications, patient characteristics N=128 patients with Type 2 Diabetes.

17. Adherence to oral anti-diabetes agents Literature search to determine extent of omitted oral anti-diabetes agents Cramer J. Diabetes Care. 2004;27:1218-1224. 79.1 65.6 38.1 0 10 20 30 40 50 60 70 80 90 100 Percentage of patients remaining compliant to therapy Once-daily regimens Twice-daily regimens Three times daily regimens

18. UKPDS 34. Lancet. 1998:352:854-865. n=at baseline; Kahn et al (ADOPT). N Engl J Med. 2006;355(23):2427-2443. Most current therapies promote weight gain Years from randomization Change in weight (kg) 0 1 5 8 7 6 4 3 2 UKPDS: up to 8 kg in 12 years Glibenclamide (n=277) Insulin (n=409) Metformin (n=342) 036912 Conventional treatment (n=411); diet initially then sulphonylureas, insulin, and/or metformin if FPG > 15 mmol/L ADOPT: up to 4.8 kg in 5 years Weight (kg) Annualized slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2) Glibenclamide, -0.2 (-0.3 to 0.0) Years 012345 96 92 88 0 100 Treatment difference (95% CI) Rosiglitazone vs metformin 6.9 (6.3 tp 7.4); P<0.001 Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1); P<0.001 Glibenclamide (n=1,441) Rosiglitazone (n=1,456) Metformin (n=1,454)

19. Hypoglycaemia The major limiting factor to achieving intensive glycaemic control for people with type 2 Diabetes Briscoe VJ et al. Clin Diab. 2006;24:115-121.

20. Clinical consequences of hypoglycaemia Hospital admissions: –Prospective study 1 of well-controlled elderly T2D patients—25% of hospital admissions for diabetes for severe hypoglycaemia Increased mortality: –9% in a study 2 of severe SU-associated hypoglycaemia Road accidents caused by hypoglycaemia events 3 : –45 serious events per month 1. Diab Nutr Metab. 2004;17:23-26. 2. Horm Metab Res Suppl. 1985;15:105-111. 3. BMJ. 2006;332:812.

21. Multicentre study funded by Dept for Transport Determine the frequency of hypoglycaemia in type 2 Diabetes treated with SUs and insulin for differing duration Compare frequencies with type 1 Diabetes Prospective study over 9-12 months of patients with good glycaemic control Documented severe and mild hypoglycaemia prospectively, supplemented with CGM x 2 UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-1147.

22. Hypoglycaemia in type 2 diabetes: sulphonylureas vs insulin In patients treated for < 2 years, no difference in the proportion of patients experiencing: –severe hypoglycaemia (7% vs 7%) –mild symptomatic (39% vs 51%) –interstitial glucose < 2.2 mmol/L (22% vs 20%) UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-1147.

23. Hypoglycaemia in type 2 diabetes Hypoglycaemia symptoms common in type 2 diabetes, occurring in up to 38% of patients 1 Hypoglycaemia is associated with : –Reduced “quality of life” –Reduced treatment satisfaction –Reduced therapy adherence –More common at HbA1c <7% 1. Diab Obes and Metab. 2008;Suppl 1:25-32.

24. 1. Asian-Pacific Type 2 Diabetes Policy Group. 4th Edition. 2005:1-58. 2. Henderson JN et al. Diabet Med. 2003;20:1016-1021. 3. Matyka K et al. Diabetes Care. 1997;20(2):135-141. 4. Miller CD et al. Arch Intern Med. 2001;161:1653-1659. 5. Wright et al. J Diabet Complicat. 2006;20:395-401. 6. Chico A et al. Diabetes Care. 2003;26(4):1153-1157. 7. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabet. 2008;32(suppl 1):S62-S64. 8. California Healthcare Foundation. J Am Ger Soc. 2003;51(Suppl 5):S265-S280. 9. Amiel SA et al. Diabet Med. 2008;25(3):245-254. 10. Salti L. Diabetes Care. 2004. Type 2 diabetes: greatest risk of hypoglycaemia Use of insulin and sulphonylureas 1 Older people 2,3 Long-duration diabetes 2 Irregular eating habits 4 Exercise 4 Periods of fasting 4 (eg, Ramadan) Have lower HbA1c 5 Prior hypoglycaemia 6-8 Hypoglycaemia unawareness 9 Excessive alcohol use 10

25. Elderly Men Without Diabetes Matyka K et al. Diabetes Care. 1997;20(2):135-14. Hypoglycaemic clamp study of healthy men – symptom recognition is lower in older men Time, min Change in Total Symptom Score Plasma Glucose, mg/dL 200–40 36 54 72 90 108 04080120160 0 14 12 10 8 6 4 2 Glucose infusion maintained at 5 mmol/L Glucose infusion reduced stepwise from 5 to 2.4 mmol/L Glucose infusion restored to 5 mmol/L Young Men Without Diabetes

26. Wright et al. J Diabet Complicat. 2006;20:395-401. Rates of hypoglycaemia increase as HbA1c levels decrease in patients with type 2 diabetes on OADs 0 10 20 30 40 Annual rate, % 04567891011 Most recent HbA1c, %

27. Awareness of hypoglycaemia Recognition of warning symptoms fundamental for self-treatment and preventing progression to severe hypoglycaemia 1 Even mild hypoglycaemia induces defects in counter-regulatory responses and impaired awareness 2 Impaired awareness predisposes to 6-fold increase in the frequency of severe hypoglycaemia 3 Only 15% of type 2 diabetes patients who experienced a hypoglycaemic event reported the incident to their doctor 1,4 1. McAulay V et al. Diabet Med. 2001;18:690-705. 2. Amiel SA et al. Diabetic Med. 2008;25:245-254. 3. Gold AE et al. Diabetes Carem. 1994;17:697-703. 4. Leiter LA et al. Can J Diabetes. 2005;29(3):186-192.

28. Brain damage Sweating, tremor 4 3 2 1 Blood glucose (mmol/L) Start of brain dysfunction Confusion/loss of concentration Adrenaline release Coma/seizure Normal physiological response to hypoglycaemia

29. 4 3 2 1 Confusion/loss of concentration Sweating, tremor Start of brain dysfunction Coma/seizure Impaired physiological response and unawareness Adrenaline release Blood glucose (mmol/L) Brain damage

30. Potential mechanisms of hypoglycaemia-induced mortality Cardiac arrhythmias due to abnormal cardiac repolarization in high-risk patients (IHD, cardiac autonomic neuropathy) Increased thrombotic tendency/decreased thrombolysis Cardiovascular changes induced by catecholamines –Increased heart rate –Silent myocardial ischaemia –Angina and myocardial infarction

31. Effect of experimental hypoglycaemia on QT interval 5.0 mM QTc = 456 ms HR = 66 bpm A 2.5 mM QTc = 610 ms HR = 61 bpm B

32. What can we do? Progressive disease: need for therapies that influence natural history of the disease Polypharmacy: education, multi-disciplinary support, FDCs Simplify guidelines Better tolerated drugs: low risk of hypoglycaemia/ weight neutral or weight loss

33. The ‘ideal’ drug for type 2 diabetes Safe Efficacious Durable control Well tolerated Low risk of hypoglycaemia Weight neutral or weight loss Incretin based therapies come close to this but long-term safety and outcome data are awaited

34. Fixed-dose combination therapy meta-analysis of cardiovascular drugs and adherence Amer J Med. 2007;120:713-719..1110 Risk ratio Publication Bias (Egger’s) P=0.43 Favours Fixed Dose Combinations Favours Free Drug Combinations Heterogeneity chi 2 =14.49 (P=0.07) Overall 0.74 (0.69, 0.80) 0.74 (0.67, 0.81) 0.89 (0.51, 1.57) 0.81 (0.77, 0.86) 0.47 (0.22, 1.01) 0.50 (0.35, 0.71) 0.88 (0.55, 1.42) 0.78 (0.55, 1.11) 0.71 (0.62, 0.80) 0.74 (0.65, 0.84) Risk ratio (95% Cl) 100.0Overall 22.1Taylor AA et al, 2003 1.8Taylor AA et al, 2003 29.0NDC Dataset, 2003 1.0Melikian C et al, 2002 4.2Melikian C et al, 2002 2.5Geiter LJ et al, 1987 4.3Eron JJ et al, 2000 17.6Dezii CM et al, 2000 17.5Dezii CM et al, 2000 % Weight Study

35. Compliance = days supplied/total days. Modified from Melikian C et al. Clin Ther. 2002;24:460-467. Compliance decreases when switching to non-FDC therapy Monotherapy (n=33,567) Switched to FDC (Glyburide/ Metformin) Switched to Non-FDC (Glyburide + Metformin) Compliance rate (%) 82 77 54 0 20 40 60 80 100 (n = 105) (n = 1,815) (n = 33,567)

36. Fixed-dose combination therapy and diabetes: compliance with >6,000 US patients over 6 months Clin Ther. 2002;24:3. Adherence rate (%) Comparison of adjusted adherence rates in patients receiving metformin and glyburide combination therapy and those receiving fixed-dose glyburide/metformin combination therapy. *P = 0.001. *

37. FDA on fixed-dose combination therapy (2005) – advantages Advantages of fixed-dose combination drug therapy: –Better adherence to a therapeutic regimen –Patient convenience –Economy (cost savings) –Generation of information regarding drug compatability and drug interactions Federal Register. 1971;36(33):3126-3127. Am J Cardiol. 2005;96:28K-33K.

38. Fixed-dose combination therapy – conclusions In many conditions, including diabetes, combination therapy is inevitable Poor adherence is common and significantly affects outcome FDC reduce non-adherence by ~25% FDC may improve long-term outcomes and makes life easier for the adherent

39. Improving adherence We have or will have: –Better tolerated drugs with low risk of hypoglycaemia and weight gain, even weight loss! –Fixed-dose combinations for some –Possibility of once-weekly injectables coming through The missing link: good rapport between patient, family, and healthcare professionals, including multi-professional support

40. Diagnosis of Type 2 Diabetes = loss of patient’s accustomed state of health Patient’s willpower and ability to improve outcomes depend on degree of acceptance of the serious nature of their condition Relationship between patient and healthcare professionals critical in this process Lacroix A et al. Schweiz Rundsch Med Prax. 1993;82:1370-1372. Helping patients to accept their condition and adhere to a management plan

41. “I don’t really monitor my blood glucose levels. It doesn’t seem that important. The physician never asks me my numbers or measurements, so why am I doing it?” “My healthcare professional has helped me understand my blood glucose results and the importance of regular testing. I feel more in control of my diabetes.” The need for good patient-healthcare professional rapport is essential to driving treatment adherence

42. Motivating patients to achieve and maintain glycaemic control will drive treatment adherence Heisler M et al. Diabetes Care. 2005;28:816-822. “This is great news. Continue with the good work and keep your blood sugar under control – you’ll feel better for it!” “I’ve reached my glucose target by eating properly, exercising more, and taking my medicine.”

43. Establish a partnership between the patient and the healthcare professional Discuss importance of implementing change Build confidence that change is possible Establish rapport Agree on mutual agenda Work together to: Reduce resistance to change Exchange information

44. Challenges in improving patient understanding 35% recalled receiving advice about their medication 15% knew the mechanism of action of their therapy 10% taking sulphonylureas knew that they could cause hypoglycaemia 20% taking metformin knew it could cause GI side effects Patient knowledge of oral anti-diabetes agents Browne DL et al. Diabet Med. 2000;17:528-531. Expectations regarding side effects should be appropriately managed

45. OutcomeWeight (lbs)% Reduction Initial consultation N = 60 Obese Women 2180 Dream13538 Happy15031 Acceptable16325 Disappointed18017 Foster et al. J Consult Clin Psychol. 1997;65:79. Treatment adherence can only be achieved by ensuring appropriate treatment goals Unrealistic weight loss goals in obese patients seeking treatment

46. A multi-disciplinary team has a significant impact on glycaemic control and hospital admissions HbA1c -1.4 -1.2 -0.8 -0.6 -0.4 -0.2 0 Multi-disciplinary team Control Change in HbA1c from baseline (%) Sadur CN et al. Diabetes Care. 1999;22:2011-2017. Multi-disciplinary team Control 30 25 20 15 10 5 0 Hospitalizations/1,000 person-months Hospitalizations

47. Variable Period of time after attending education courses 0 months12 months FPG (mmol/L) 10.28.7* HbA1c (%)8.97.8* Body weight (kg)83.081.0* Systolic BP (mmHg)154.0143.0* Diastolic BP (mmHg)95.087.0* Cholesterol (mmol/L)6.25.4* Triglycerides (mmol/L)2.82.1* Impact of implementing an educational program via a multi-disciplinary team *Significant improvement versus 0 months. Gagliardino JJ et al. Diabetes Care. 2001;24:1001-1007.

48. Clear benefits of a multi-disciplinary team approach in type 2 diabetes care 1. Codispoti C et al. J Okla State Med Assoc. 2004;97:201-204. 2. Gagliardino JJ et al. Diabetes Care. 2001;24:1001-1007. Improved glycaemic control 1,2 Improved quality of life 1 Improved patient follow-up 1 Higher patient satisfaction 1 Decreased healthcare costs 2 Lower risk of complications 2 Improved treatment adherence 1,2 Decreased CV risk 2

49. Personalized care is paramount When dealing with a complex chronic disease such as type 2 diabetes: “... the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, and informed by the summary of product characteristics of any drug they are considering.” NICE Clinical Guidelines for the Management of Type 2 Diabetes. May 2009.

50. Need for personalized care: the benefits versus risks of diabetes therapy must be assessed for each patient Tolerability/Side Effects Improved Outcomes β-cell deterioration CV risk Glycaemic Control Hypo Poor management/ inertia Weight gain

51. Personalised care in type 2 diabetes The healthcare professional must agree with the individual patient on their glycaemic target, how this can be achieved, and measures of success Guidelines are guidelines, not absolutes

52. Summary and conclusions Patient adherence to agreed management plans is the major challenge in type 2 diabetes Poor adherence is due to many factors, including: –tolerability issues, complexity of the disease and its co-morbidities, lack of knowledge and support Therapeutic advances can help with the problem of adherence: –modern drugs may be better tolerated with lower risk of hypoglycaemia and weight gain –increasing availability of fixed-dose combination therapies Multi-disciplinary care and a good relationship between the patient and healthcare professionals can improve long-term outcomes Personalized care should be the cornerstone of good diabetes management

53. Patient adherence in type 2 diabetes: What’s the issue and how to address Anthony Barnett University of Birmingham and Heart of England NHS Foundation Trust, UK