translating clinical trials into clinical practice cliff bailey on behalf of the global partnership...

Translating Clinical Trials Into Clinical Practice

Cliff Baileyon behalf of the

Global Partnership for Effective Diabetes Management

This slideset was developed in 2009 with support from GlaxoSmithKline

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

DCCT: intensive control reduces complications in type 1 diabetes

*Subdivided to primary and secondary prevention of retinopathy. Age 27 years, HbA1c 8.8%.Insulin dose (U/kg/d) 0.62 (primary), 0.71 (secondary).

Conventional versus intensive insulin therapy (n = 1,441)

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DCCT Research Group. N Engl J Med 1993; 329:977–986.

57% risk reduction in non-fatal MI, stroke or CVD death*

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*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.

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DCCT/EDIC: long-term follow-up and legacy effect

Glucose similar BUT CV events

still higher

Copyright Massachusetts Medical Society.

Reproduced from UKPDS Study Group. Lancet 1998; 352:837–853.

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UKPDS: intensive control reduces complications in type 2 diabetes

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Copyright 1998 with permission from Elsevier.

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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.

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Copyright © 2008. Reprinted by permission of SAGE.

Predictions from VADT: impact of bad glycemic legacy

Del Prato S. Diabetologia 2009; 52:1219–1226.

Time since diagnosis (years)

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1 2 3 8 9 12 1364 5 10 11 14 157 16 17

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Before entering VADT intensive treatment arm After entering VADT intensivetreatment arm

Generation of a‘bad glycemic

legacy’

Reproduced with kind permission of Springer Science and Business Media.

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)

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)

VADT 892/899 77/90 0.85 (0.62–1.17)

ACCORD 5,128/5123 205/248 0.82 (0.68–0.99)

Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93)

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Intensive treatment better Standard treatment better

*Included non-fatal myocardial infarction and death from all cardiac mortality.

Copyright 1998 with permission from Elsevier.

Clinical Trials

Translating

Clinical Practice

Into

ACCORD

ADVANCE

VADT UKPDS

STENO-2

DCCT/EDIC

?

?

?

?

HbA1c targets generally 6.5–7% when safe and appropriate

ADA (US)

HbA1c < 7%

IDF (Europe)

HbA1c 6.5%

CDA (Canada)

HbA1c 7%

NICE (UK)

HbA1c 6.5%/7.5%

AACE (US)

HbA1c 6.5% ALAD (Latin America)

HbA1c < 6–7%

APPG (Asia-Pacific)

HbA1c 6.5%

Australia

HbA1c 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.

Joint British Societies (JBS 2)

HbA1c < 6.5%

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

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%

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

Ten steps: reconsidering targets

Aim for good glycemic control, e.g. HbA1c 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%6.5–7%

Treat to achieve appropriate target HbA1c within 6 months of diagnosis

After 3 months, if patients are not at target HbA1c, consider combination therapy

Consider initiating combination therapy or insulin for patients with HbA1c > 9%

Bailey CJ, et al. Diab Vasc Dis Res 2009; 6:283–287.

Ten steps: taking a multifactorial approach

Appropriately manage all cardiovascular risk factors HbA1c

FPG TC

LDLHDL

TGsSBP

DBPABPM

Implement a multidisciplinary team approach that encourages patient self-management, education and self-care, with shared responsibilities to achieve goals


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

IRIR

Use combinations of antihyperglycemic agents with complementary mechanisms of action


Ten steps: monitoring regularly

Monitor HbA1c every 3 months in addition to appropriate glucose self-monitoring

Refer all newly diagnosed patients to a unit specializing in diabetes care where possible


Glycemic control: how intensive?

• Aim for:– HbA1c < 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

translating clinical trials into clinical practice cliff bailey on behalf of the global partnership...

Documents

intensive control

n engl j med

intensive insulin therapy

ukpds study group

bad glycemic legacyreproduced

metaanalyses guidelines

permission of sage

br j diabetes vasc