1. 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 GlaxoSmithKline

2. 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

3. 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

4. DCCT: intensive control reduces complications in type 1 diabetes *Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA 1c 8.8%. Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary). Conventional versus intensive insulin therapy (n = 1,441) Micro- albuminuria Nephropathy Retinopathy* 0 20 40 60 80 Reduction (%) Neuropathy 76% 60% 54% 39% 54% 0 0 1 2 3 4 5 6 7 8 9 10 Year of study HbA 1c (%) Conventional treatment (n = 730) Intensive treatment (n = 711) P < 0.001 6 7 8 9 10 11 DCCT Research Group. N Engl J Med 1993; 329:977–986.

5. 57% risk reduction in non-fatal MI, stroke or CVD death* Intensive treatment Cumulative incidence of non-fatal MI, stroke or death from CVD Conventional treatment 01234567891011121314151617 18 19 20 21 Years 0.06 0.04 0.02 0 DCCT (intervention period) EDIC (observational follow-up) *Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986. Nathan DM, et al. N Engl J Med 2005; 353:2643–2653. 0 7 16 HbA 1C (%) 9 8 2345789 Conventional treatment Intensive treatment 1112131415161710 DCCT (intervention period) Years EDIC (observational follow-up) DCCT/EDIC: long-term follow-up and legacy effect Glucose similar BUT CV events still higher Copyright Massachusetts Medical Society.

6. 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

7. Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853. UKPDS randomized years 0 6 7 8 9 051015 Conventional Intensive 6.2% = upper limit of normal range Median HbA 1C (%) UKPDS: intensive control reduces complications in type 2 diabetes All-cause mortality Any diabetes- related end point Microvascular disease Myocardial infarction –30 –25 –20 –15 –10 –5 0 Relative risk reduction (%) 12% 25% 16% 6% P = 0.029 P = 0.0099 P = 0.052 P = 0.44 Copyright 1998 with permission from Elsevier.

8. –30 –25 –20 –15 –10 –5–5 0 Relative risk reduction (%) All-cause mortality Any diabetes- related end point Myocardial infarction Microvascular disease 9% 24% 15% 13% P = 0.040 P = 0.001 P = 0.014 P = 0.007 UKPDS: long-term follow-up and legacy effect 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. 10 9 8 7 6 0 5 10 15 5 10 1977 1997 2007 Years from randomization UKPDS Active Conventional Intensive Intervention ends UKPDS Follow-up Median HbA 1c (%) Biochemical data no longer collected Copyright © 2008. Reprinted by permission of SAGE.

9. Predictions from VADT: impact of bad glycemic legacy Del Prato S. Diabetologia 2009; 52:1219–1226. Time since diagnosis (years) HbA 1c (%) 1 2 3 8 9 12 13 64 5 10 11 14 15 716 17 9.0 8.5 8.0 7.5 7.0 6.5 6.0 9.5 Drives risk of complications Before entering VADT intensive treatment arm After entering VADT intensive treatment arm Generation of a ‘bad glycemic legacy’ Reproduced with kind permission of Springer Science and Business Media.

10. Meta-analysis: impact of intensive glucose control on coronary heart disease* events Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772. Intensive treatment/standard treatment Odds ratio (95% CI) ParticipantsEvents UKPDS3,071/1549426/2590.75 (0.54–1.04) PROactive2,605/2633164/2020.81 (0.65–1.00) ADVANCE5,571/5,569310/3370.92 (0.78–1.07) VADT892/89977/900.85 (0.62–1.17) ACCORD5,128/5123205/2480.82 (0.68–0.99) Overall17,267/15,7731,182/1,1360.85 (0.77–0.93) 0.40.60.81.01.21.41.61.82.0 Intensive treatment betterStandard treatment better *Included non-fatal myocardial infarction and death from all cardiac mortality. Copyright 1998 with permission from Elsevier.

11. Clinical Trials Translating Clinical Practice Into ACCORD ADVANCE VADTUKPDS STENO-2 DCCT/EDIC ? ? ? ?

12. 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

13. HbA 1c targets generally 6.5 – 7% when safe and appropriate ADA (US) HbA 1c < 7% IDF (Europe) HbA 1c  6.5% CDA (Canada) HbA 1c  7% NICE (UK) HbA 1c 6.5%/7.5% AACE (US) HbA 1c  6.5% ALAD (Latin America) HbA 1c < 6 – 7% APPG (Asia-Pacific) HbA 1c  6.5% Australia HbA 1c  7% ADA. Diabetes Care 2009; 32(Suppl 1):S13–S61; 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. JBS2. 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):S1–S201. NICE. 2009. Available at: http://www.nice.org.uk/nicemedia/pdf/CG87ShortGuideline.pdf; ALAD. Rev Assoc Lat Diab 2000; Suppl. 1. Asian-Pacific Policy Group. Practical Targets and Treatments (3rd Edn). Available at: http://www.idf.org/webdata/docs/T2D_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.http://www.idf.org/Global_guideline http://www.nice.org.uk/nicemedia/pdf/CG87ShortGuideline.pdf Joint British Societies (JBS 2) HbA 1c < 6.5%

14. Current management often fails to achieve glycemic targets 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 HbA 1c < 7% 37% 63% Europe (CODE-2) 5 HbA 1c < 6.5% 31% 69% Canada (DICE) 2 HbA 1c  7% 51% 49% China (CODIC-2) 1 HbA 1c < 7.5% 68% 32% Latin America (DEAL) 3 HbA 1c <7% 43% 57%

15. 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

16. Evolution of the ten steps to good glucose control 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. www.effectivediabetesmanagement.com

17. Ten steps: reconsidering targets Aim for good glycemic control, e.g. HbA 1c 6.5–7%* when safe and appropriate *Or fasting/pre-prandial plasma glucose 110–130 mg/dl (6.0–7.2 mmol/l) where assessment of HbA 1c is not possible. 6.5–7% Treat to achieve appropriate target HbA 1c within 6 months of diagnosis After 3 months, if patients are not at target HbA 1c, consider combination therapy Consider initiating combination therapy or insulin for patients with HbA 1c > 9% Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.

18. Ten steps: taking a multifactorial approach Appropriately manage all cardiovascular risk factors HbA 1c FPG TC LDL HDL TGs SBP DBP ABPM 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.

19. 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.

20. Ten steps: monitoring regularly Monitor HbA 1c 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.

21. 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

22. Glycemic control: how intensive? Aim for: –HbA 1c < 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)

23. 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