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Patient adherence in type 2 diabetes: What’s the issue and how to address it

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. Prescribed regimen for 12 months Fully compliant for 12 months Fully persistent for 12 months Partially compliant

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Patient adherence in type 2 diabetes: What’s the issue and how to address it

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  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. So what really happens when you fill a prescription? PERSISTENCE Persistent patients (%) Weeks of therapy US population 2002. J Int Med Res. 2002;30:71.

  4. So what really happens when you fill a prescription? COMPLIANCE 100 80 Patients remaining compliant to therapy (%) 60 64.64 65.06 63.07 60.54 40 44.42 35.76 20 0 1 Year (360 days) 2 Years (720 days) Metformin Sulphonylurea Metformin + Sulphonylurea US population 2002. J Int Med Res. 2002;30:71.

  5. Total time drug prescribed Total time of follow-up = Adherence index 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.

  6. Adherence index by type of therapy Monotherapy Sulphonylurea 31 Metformin 34 Polytherapy Sulphonylurea 19 Metformin 13 Donnan PT et al. Diabet Med. 2002;19:279-284.

  7. Once the patient has ACCEPTED treatment, is everything fine? Retrospective, cohort study of community pharmacy records (N=2,325) 100 90 80 70 60 Continuous hypertensive users (%) 50 Men Women 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Years after first prescription Van Wijk et al. J Hypertens. 2005;23:2101-2107.

  8. 40 44 39 36 30 30 27 20 All-cause hospitalisation risk (%) 10 0 1-19 20-39 40-59 60-79 80-100 Level of compliance (%) Does it matter?Lessons from hypertension: improved outcome Sokol et al. Med Care. 2005;43:521-530.

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

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

  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. 2 anti-hyperglycaemic agents from different classes • biguanide • insulin sensitizer • insulin secretagogue • insulin • alpha-glucosidase inhibitor Current treatment paradigms for type 2 diabetes are not “user-friendly” Marked hyperglycaemia (HbA1C ≥9.0%) Mild to moderate hyperglycaemia (HbA1C <9.0%) Non-overweight (BMI < 25 kg/m2) Overweight (BMI ≥ 25 kg/m2) Biguanide alone or in combination with 1 of: 1 or 2anti-hyperglycaemic agents from different classes Basal and/or pre-prandial insulin • insulin sensitizer • insulin secretagogue • insulin • alpha-glucosidase inhibitor • biguanide • insulin sensitizer • insulin secretagogue • insulin • alpha-glucosidase inhibitor L I F E S T Y L E If not at target If not at target If not at target If not at target Add an oral anti-hyperglycaemic agent from a different class or insulin Intensify insulin regimen or add Add a drug from a different class or use insulin alone or in combination with: • biguanide • insulin secretagogue • insulin sensitizer • alpha-glucosidase inhibitor • biguanide • insulin secretagogue • insulin sensitiser • alpha-glucosidase inhibitor 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

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

  15. RESULT: Patients often fail to achieve glycaemic targets Europe (CODE-2)5 China (CODIC-2)1 Latin America (DEAL)3 HbA1c< 6.5% HbA1c< 7.5% HbA1c<7% 31% 68% 43% 32% 57% 69% US (NHANES)4 Canada (DICE)2 HbA1c< 7% HbA1c< 7% 37% 51% 49% 63% Achieving glycaemic target Failed to achieve glycaemic target 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.

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

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

  18. UKPDS: up to 8 kg in 12 years 8 Insulin (n=409) 7 6 5 Glibenclamide (n=277) 4 3 2 1 Metformin (n=342) 0 0 3 6 9 12 Conventional treatment (n=411); diet initially then sulphonylureas, insulin, and/or metformin if FPG > 15 mmol/L Most current therapies promote weight gain ADOPT: up to 4.8 kg in 5 years 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<0.001 100 Rosiglitazone (n=1,456) 96 Weight (kg) Change in weight (kg) 92 Glibenclamide (n=1,441) 88 Metformin (n=1,454) 0 0 1 2 3 4 5 Years from randomization Years 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) UKPDS 34. Lancet. 1998:352:854-865. n=at baseline; Kahn et al (ADOPT). N Engl J Med. 2006;355(23):2427-2443.

  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 study1 of well-controlled elderly T2D patients—25% of hospital admissions for diabetes for severe hypoglycaemia • Increased mortality: • 9% in a study2 of severe SU-associated hypoglycaemia • Road accidents caused by hypoglycaemia events3: • 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 patients1 • 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. Type 2 diabetes: greatest risk of hypoglycaemia • Use of insulin and sulphonylureas1 • Older people2,3 • Long-duration diabetes2 • Irregular eating habits4 • Exercise4 • Periods of fasting4 (eg, Ramadan) • Have lower HbA1c5 • Prior hypoglycaemia6-8 • Hypoglycaemia unawareness9 • Excessive alcohol use10 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.

  25. Hypoglycaemic clamp study of healthy men– symptom recognition is lower in older men 14 Young Men Without Diabetes 108 Elderly Men Without Diabetes 12 90 10 8 Change in Total Symptom Score Plasma Glucose, mg/dL 72 6 4 54 2 0 36 –40 0 40 80 120 160 200 Glucose infusion reduced stepwise from 5 to 2.4 mmol/L Glucose infusion maintained at 5 mmol/L Glucose infusion restored to 5 mmol/L Time, min Matyka K et al. Diabetes Care. 1997;20(2):135-14.

  26. 40 30 Annual rate, % 20 10 0 0 4 5 6 7 8 9 10 11 Most recent HbA1c, % Rates of hypoglycaemia increase as HbA1c levels decrease in patients with type 2 diabetes on OADs Wright et al. J Diabet Complicat. 2006;20:395-401.

  27. Awareness of hypoglycaemia • Recognition of warning symptoms fundamental for self-treatment and preventing progression to severe hypoglycaemia1 • Even mild hypoglycaemia induces defects in counter-regulatory responses and impaired awareness2 • Impaired awareness predisposes to 6-fold increase in the frequency of severe hypoglycaemia3 • Only 15% of type 2 diabetes patients who experienced a hypoglycaemic event reported the incident to their doctor1,4 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. Adrenaline release Sweating, tremor Start of brain dysfunction Confusion/loss of concentration Coma/seizure Normal physiological response to hypoglycaemia 4 3 2 1 Brain damage Blood glucose (mmol/L)

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

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

  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 .1 1 10 Overall Study Risk ratio(95% Cl) % Weight Dezii CM et al, 2000 0.74 (0.65, 0.84) 17.5 Dezii CM et al, 2000 0.71 (0.62, 0.80) 17.6 Eron JJ et al, 2000 0.78 (0.55, 1.11) 4.3 Geiter LJ et al, 1987 0.88 (0.55, 1.42) 2.5 Melikian C et al, 2002 0.50 (0.35, 0.71) 4.2 Melikian C et al, 2002 0.47 (0.22, 1.01) 1.0 NDC Dataset, 2003 0.81 (0.77, 0.86) 29.0 Taylor AA et al, 2003 0.89 (0.51, 1.57) 1.8 Taylor AA et al, 2003 0.74 (0.67, 0.81) 22.1 Overall 0.74 (0.69, 0.80) 100.0 Risk ratio Favours Fixed Dose Combinations Favours Free Drug Combinations Heterogeneity chi2=14.49 (P=0.07) Publication Bias (Egger’s) P=0.43 Amer J Med. 2007;120:713-719.

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

  36. * Fixed-dose combination therapy and diabetes:compliance with >6,000 US patients over 6 months 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. Clin Ther. 2002;24:3.

  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. Helping patients to accept their condition andadhere to a management plan 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 healthcareprofessionals critical in this process Lacroix A et al. Schweiz Rundsch Med Prax. 1993;82:1370-1372.

  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?” The need for good patient-healthcare professional rapport is essential to driving treatment adherence “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.”

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

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

  44. 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 Challenges in improving patient understanding Expectations regarding side effects should be appropriately managed Browne DL et al. Diabet Med. 2000;17:528-531.

  45. Treatment adherence can only be achieved by ensuring appropriate treatment goals Unrealistic weight loss goals in obese patients seeking treatment Foster et al. J Consult Clin Psychol. 1997;65:79.

  46. HbA1c 0 -0.2 -0.4 -0.6 Change in HbA1c from baseline (%) -0.8 -1.0 -1.2 -1.4 Control Multi-disciplinary team A multi-disciplinary team has a significant impact on glycaemic control and hospital admissions Hospitalizations 30 25 20 15 Hospitalizations/1,000 person-months 10 5 0 Control Multi-disciplinary team Sadur CN et al. Diabetes Care. 1999;22:2011-2017.

  47. HbA1c (%) Impact of implementing an educational program via a multi-disciplinary team Variable Period of time after attending education courses 0 months 12 months FPG (mmol/L) 10.2 8.7* 8.9 7.8* Body weight (kg) 83.0 81.0* Systolic BP (mmHg) 154.0 143.0* Diastolic BP (mmHg) 95.0 87.0* Cholesterol (mmol/L) 6.2 5.4* Triglycerides (mmol/L) 2.8 2.1* *Significant improvement versus 0 months. Gagliardino JJ et al. Diabetes Care. 2001;24:1001-1007.

  48. Improved glycaemic control1,2 Improved quality of life1 Improved treatment adherence1,2 Decreased CV risk2 Improved patient follow-up1 Higher patient satisfaction1 Lower risk of complications2 Decreased healthcare costs2 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.

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

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