Translating Clinical Trials Into Clinical Practice Cliff Bailey

Translating Clinical Trials Into Clinical Practice Cliff Bailey on behalf of the Global Partnership for Effective Diabetes Management This slideset was developed in 2009 with support from Glaxo. Smith. Kline

Translating clinical trials into clinical practice • Importance of good glycemic control – More trials, more evidence • Type 1: DCCT/EDIC • Type 2: UKPDS, Steno-2, ADVANCE, VADT, ACCORD, meta-analyses • Guidelines and targets • The 10 steps: treading carefully • Recommendations for managing type 2 diabetes

9 8 P < 0. 001 7 Intensive treatment (n = 711) 6 0 0 1 2 3 4 5 6 7 8 9 10 Reduction (%) Hb. A 1 c (%) ia ur in M ic al robu m op at y hr th pa ro 0 Conventional treatment (n = 730) 10 Ne p 11 Ne u Re t in op at h y* Conventional versus intensive insulin therapy (n = 1, 441) hy DCCT: intensive control reduces complications in type 1 diabetes 20 39% 40 54% 60% 60 76% 80 Year of study *Subdivided to primary and secondary prevention of retinopathy. Age 27 years, Hb. A 1 c 8. 8%. DCCT Research Group. N Engl J Med 1993; 329: 977– 986. Insulin dose (U/kg/d) 0. 62 (primary), 0. 71 (secondary).

DCCT/EDIC: long-term follow-up and legacy effect Glucose similar BUT CV events still higher Hb. A 1 C (%) 9 Conventional treatment 8 Intensive treatment 7 0 Cumulative incidence of non-fatal MI, stroke or death from CVD 1 0. 06 Years 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 DCCT (intervention period) EDIC (observational follow-up) 57% risk reduction in non-fatal MI, stroke or CVD death* 0. 04 0. 02 Conventional treatment Intensive treatment 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 DCCT (intervention period) EDIC (observational follow-up) *Intensive vs conventional treatment. Years DCCT Research Group. N Engl J Med 1993; 329: 977– 986. Nathan DM, et al. N Engl J Med 2005; 353: 2643– 2653. Copyright Massachusetts Medical Society.

Translating clinical trials into clinical practice • Importance of good glycemic control – More trials, more evidence • Type 1: DCCT/EDIC • Type 2: UKPDS, Steno-2, ADVANCE, VADT, ACCORD, meta-analyses • Guidelines and targets • The 10 steps: treading carefully • Recommendations for managing type 2 diabetes

Median Hb. A 1 C (%) Conventional 8 Intensive 7 6. 2% = upper limit of normal range 6 0 0 5 10 15 An re y d la te iab d et en es d po M i c in di ro t se va as sc e ul ar M in yoc fa ar rc di tio al n Al m l-ca or u ta se lit y 9 Relative risk reduction (%) UKPDS: intensive control reduces complications in type 2 diabetes 0 6% – 5 – 10 12% – 15 P = 0. 029 P = 0. 44 16% P = 0. 052 – 20 – 25 – 30 25% P = 0. 0099 UKPDS randomized years Reproduced from UKPDS Study Group. Lancet 1998; 352: 837– 853. Copyright 1998 with permission from Elsevier.

An re y d la te iab d et M end esp di icro se va oin as sc t e ul ar M y in oc fa ar rc di tio al n Al m l-ca or u ta se lit y UKPDS: long-term follow-up and legacy effect Median Hb. A 1 c (%) 10 9 Conventional Biochemical data no longer collected 8 Intensive 7 6 0 1977 5 10 15 5 1997 10 2007 Relative risk reduction (%) Intervention ends 0 – 5 9% – 10 P = 0. 040 13% 15% P = 0. 007 P = 0. 014 – 15 – 20 24% – 25 P = 0. 001 – 30 Years from randomization Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8: 242– 247. Holman RR, et al. N Engl J Med 2008; 359: 1577– 1589. Copyright © 2008. Reprinted by permission of SAGE.

Predictions from VADT: impact of bad glycemic legacy Before entering VADT intensive treatment arm 9. 5 After entering VADT intensive treatment arm Drives risk of complications Generation of a ‘bad glycemic legacy’ 9. 0 Hb. A 1 c (%) T i m e s i n c e d i a g n o s i s ( y e a 8. 5 8. 0 7. 5 7. 0 6. 5 6. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Del Prato S. Diabetologia 2009; 52: 1219– 1226. Reproduced with kind permission of Springer Science and Business Media.

Meta-analysis: impact of intensive glucose control on coronary heart disease* events Intensive treatment/standard treatment Odds ratio (95% CI) Participants Events UKPDS 3, 071/1549 426/259 0. 75 (0. 54– 1. 04) PROactive 2, 605/2633 164/202 0. 81 (0. 65– 1. 00) ADVANCE 5, 571/5, 569 310/337 0. 92 (0. 78– 1. 07) 892/899 77/90 0. 85 (0. 62– 1. 17) 5, 128/5123 205/248 0. 82 (0. 68– 0. 99) 17, 267/15, 773 1, 182/1, 136 0. 85 (0. 77– 0. 93) VADT ACCORD Overall 0. 4 0. 6 0. 8 Intensive treatment better 1. 0 1. 2 1. 4 1. 6 1. 8 2. 0 Standard treatment better *Included non-fatal myocardial infarction and death from all cardiac mortality. Reproduced from Ray KK, et al. Lancet 2009; 373: 1765– 1772. Copyright 1998 with permission from Elsevier.

? ACCORD Translating Into Clinical Practice Trials ADVANCE DCCT/EDIC ? STENO-2 VADT ? UKPDS ?

Translating clinical trials into clinical practice • Importance of good glycemic control – More trials, more evidence • Type 1: DCCT/EDIC • Type 2: UKPDS, Steno-2, ADVANCE, VADT, ACCORD, meta-analyses • Guidelines and targets • The 10 steps: treading carefully • Recommendations for managing type 2 diabetes

Hb. A 1 c targets generally 6. 5– 7% when safe and appropriate CDA (Canada) Hb. A 1 c 7% ADA (US) Hb. A 1 c < 7% AACE (US) Hb. A 1 c 6. 5% NICE (UK) Hb. A 1 c 6. 5%/7. 5% Joint British Societies (JBS 2) Hb. A 1 c < 6. 5% APPG (Asia-Pacific) Hb. A 1 c 6. 5% IDF (Europe) Hb. A 1 c 6. 5% Australia Hb. A 1 c 7% ALAD (Latin America) Hb. A 1 c < 6– 7% ADA. Diabetes Care 2009; 32(Suppl 1): S 13–S 61; American Association of Clinical Endocrinologists. Endocr Pract 2007; 13(Suppl. 1): 1– 68. IDF. Global guideline for type 2 diabetes, IDF 2005. Available at: http: //www. idf. org/Global_guideline. JBS 2. Heart 2005; 91(Suppl. V): 1– 52. European Diabetes Policy Group. Diabet Med 1999; 16: 716– 730. CDA. Can J Diabetes 2008; 32(Suppl. 1): S 1–S 201. NICE. 2009. Available at: http: //www. nice. org. uk/nicemedia/pdf/CG 87 Short. Guideline. pdf; ALAD. Rev Assoc Lat Diab 2000; Suppl. 1. Asian-Pacific Policy Group. Practical Targets and Treatments (3 rd Edn). Available at: http: //www. idf. org/webdata/docs/T 2 D_practical_tt. pdf. NSW Health Department. The Principles of Diabetes Care and Guidelines for the Clinical Management of Diabetes Mellitus in Adults. NSW Health Department 1996.

Current management often fails to achieve glycemic targets China Latin America (CODIC-2)1 Hb. A 1 c < 7. 5% (DEAL)3 Hb. A 1 c <7% 32% 68% 57% Canada (DICE)2 Hb. A 1 c 7% 49% Europe (CODE-2)5 Hb. A 1 c < 6. 5% 31% 43% (NHANES)4 Hb. A 1 c < 7% 37% 51% 69% US 63% 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: S 23–S 28.

Translating clinical trials into clinical practice • Importance of good glycemic control – More trials, more evidence • Type 1: DCCT/EDIC • Type 2: UKPDS, Steno-2, ADVANCE, VADT, ACCORD, meta-analyses • Guidelines and targets • The 10 steps: treading carefully • Recommendations for managing type 2 diabetes

Evolution of the ten steps to good glucose control www. effectivediabetesmanagement. com Del Prato S, et al. Int J Clin Pract 2005; 59: 1345– 1355. Bailey CJ, et al. Diab Vasc Dis Res 2009; 6: 283– 287.

Ten steps: reconsidering targets Aim for good glycemic control, e. g. Hb. A 1 c 6. 5– 7%* when safe and appropriate 6. 5– 7% Treat to achieve appropriate target Hb. A 1 c within 6 months of diagnosis After 3 months, if patients are not at target Hb. A 1 c, consider combination therapy Consider initiating combination therapy or insulin for patients with Hb. A 1 c > 9% *Or fasting/pre-prandial plasma glucose 110– 130 mg/dl (6. 0– 7. 2 mmol/l) where assessment of Hb. A 1 c is not possible. Bailey CJ, et al. Diab Vasc Dis Res 2009; 6: 283– 287.

Ten steps: taking a multifactorial approach FPG TC TGs P SB Appropriately manage all cardiovascular risk M LD HDL factors ABP L Hb. A 1 c DBP Implement a multidisciplinary team approach that encourages patient self-management, education and self-care, with shared responsibilities to achieve goals Bailey CJ, et al. Diab Vasc Dis Res 2009; 6: 283– 287.

Ten steps: targeting the underlying pathophysiology of type 2 diabetes Address the underlying pathophysiology of diabetes, including the treatment of β-cell dysfunction and insulin resistance IR Use combinations of antihyperglycemic agents with complementary mechanisms of action Bailey CJ, et al. Diab Vasc Dis Res 2009; 6: 283– 287.

Ten steps: monitoring regularly Monitor Hb. A 1 c every 3 months in addition to appropriate glucose self-monitoring Refer all newly diagnosed patients to a unit specializing in diabetes care where possible Bailey CJ, et al. Diab Vasc Dis Res 2009; 6: 283– 287.

Translating clinical trials into clinical practice • Importance of good glycemic control – More trials, more evidence • Type 1: DCCT/EDIC • Type 2: UKPDS, Steno-2, ADVANCE, VADT, ACCORD, meta-analyses • Guidelines and targets • The 10 steps: treading carefully • Recommendations for managing type 2 diabetes

Glycemic control: how intensive? • Aim for: – Hb. A 1 c < 7% for younger, healthier, newly diagnosed patients with compatible lifestyle, no contraindications and no signs of hypoglycemia • Consider lower (< 6. 5%) if easy and safe • Individualize – – Existing guidelines are appropriate if applied flexibly to fit individual circumstances Type 2 diabetes is heterogeneous and progressive, with multivariable pathogenic routes (treating a moving target)

Glycemic control: how intensive? • Early and durable – To avoid a vascular legacy of ‘hyperglycemic memory’ • Intensive enough, but safely – – To minimize complications without causing hypoglycemic events And to be practicable without undue imposition • Integrated – Within a comprehensive program to reduce cardiovascular risk