1. Clinical aspects of managing the cardiovascular risk in diabetes Dr SH Song MD FRCP Consultant Diabetologist Northern General Hospital Sheffield

4. Increased CHD in type 1 diabetes Laing at al Diabetologia 2003; 46: 760-5

5. STENO-2 Evidence - Intensive multifactorial intervention are effective in reducing CVD events in type 2 DM Behaviour modification (weight, diet, smoking cessation) Pharmacological intervention aimed at diabetes, hypertension, lipids along with aspirin and ACE-I 50% reduction in CVD events, nephropathy, retinopathy and neuropathy Risk reduction 20% higher than single-factor intervention studies (glycaemia, BP, lipid lowering) Important to target all risk factors

6. JBS2 guidelines 2005 Treatment targets for patients with diabetes: –HbA 1c  6.5% –BP <130/80 mmHg (<125/75 in T1DM with micro-albuminuria) –TC <4.0 mmol/L –LDL-C <2.0 mmol/L Preferred values but not targets: –HDL-C <1.0 mmol/L in men (<1.2 mmol/L in women) are associated with an increased risk of cardiovascular disease –Non-HDL-C <3.0 mmol/L –TG <1.7 mmol/L “A statin should be recommended for all patients aged >40 years with either Type 1 or 2 diabetes” Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease in Clinical Practice 2005

7. Glycaemic control

8. Glycaemic control and CVD events

9. Effect of reducing HbA 1c : UKPDS 1% reduction in HbA 1c significantly reduced the risk of diabetes-related complications Stratton et al. BMJ 2000; 321: 405–412 Microvascular complications Any diabetes- related endpoint † Myocardial infarction Amputation or death from PVD Stroke * -37% * -21% * -14% * -43% ** -12% UKPDS, United Kingdom Prospective Diabetes Study PVD, peripheral vascular disease Median follow up = 10 years, n = 3642 for relative risk analysis † Primary endpoint; *p<0.0001; **p=0.035 Reduction in risk (%) Diabetes- related deaths * -21%

10. UKPDS found that metformin reduces risk of macrovascular complications death 0 5 10 15 20 25 30 35 40 45 P=0.0023 P=0.02 P=0.010 P=0.017 P=0.011 Diabetes 50 % risk reduction related outcome Any Macrovascular diabetes Myocardial infarction related All cause mortality UKPDS 34. Lancet 1998;352:854–865

11. Relative RR 16%, p=0.027 End-point: all-cause mortality, non-fatal MI, stroke ?Glitazone reduce CVD events

14. Post-hoc analysis

15. Effects of Pioglitazone in patients with or without a history of stroke — an analysis of PROactive Robert G. Wilcox; Marie-Germaine Bousser; John Betteridge; Guntram Schernthaner; Valdis Pirags; Stuart Kupfer ; John Dormandy

18. Summary: In T2DM with CVD, pioglitazone reduced risk of recurrent fatal/nonfatal MI by 28% and ACS by 37% In T2DM with previous stroke, pioglitazone reduced risk of recurrent fatal/nonfatal stroke by 47% In T2DM without previous stroke, pioglitazone has no effect on reducing the risk of first stroke

19. Blood pressure

20. Kannel WB, et al. Am Heart J. 1991;121:1268-1273. Blood Pressure and CVD: Framingham Heart Study No Glucose Intolerance Glucose Intolerance Age-adjusted CV Event Rate/1,000 Systolic BP (mmHg) 105135165195 Systolic BP (mmHg) 105135165195 Age-adjusted CV Event Rate/1,000 24 50 38 77 59 119 90 174 15 31 23 48 36 74 56 113 No Glucose Intolerance Glucose Intolerance MENWOMEN

21. Relative Risk of Stroke and of CHD Increases with Increasing DBP MacMahon S et al. Lancet 1990;335:765-774 Stroke and usual DBPCoronary Hearth Disease and usual DBP (in 5 categories defined by baseline DBP) 7 prospective observational studies: 843 events 4.00 2.00 1.00 0.50 768491 Approximate mean usual DBP 98105mm Hg 12345 768491 Approximate mean usual DBP 98105mm Hg 12345 Baseline DBP category Baseline DBP category 4.00 2.00 1.00 0.50 0.25 (in 5 categories defined by baseline DBP) 9 prospective observational studies: 4856 events Relative Risk of Stroke Relative Risk

22. UK Prospective Diabetes Study Group. BMJ 1998; 317: 703–713. Preventing cardiovascular complications UKPDS: benefits of reducing blood pressure -47 -44 -56 -34 -37 -32 -24 -75 -50 -25 0 % Risk reduction associated with tighter blood pressure control* p = 0.019 p = 0.0046 p = 0.0092 p = 0.0038 p = 0.0036 p = 0.013 p = 0.0043 Any diabetes- related endpoint Diabetes- related and all-cause mortality Retinopathy progression Micro -vascular disease Vision deterioration Stroke Heart failure *Tight control vs less tight control = 144/82 mmHg vs 154/87 mmHg

23. Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup Hansson L, et al. Lancet. 1998;351: 1755-1762. Major CV Events MI Events/1000 Pt-Years CV Mortality 90 mmHg (N=501) 85 mmHg (N=501) 80 mmHg (N=499) Diastolic Target p<0.045 p<0.016 p<0.005

24. BP Treatment Threshold JNC 7ESH-ESCWHO-ISHBHS IV 2004 140/90 All risk strata140/90160/100 -Inc? low risk 130/85 v high and high risk Consider resources 140/90 10 year CV risk  20%

25. BP Targets JNC7ESH-ESCWHO-ISHBHS IV 2004 <140/90 SBP <140<140/85 DM renal <130/80 Lower if Tolerated DM <130/80 DM renal CVD <130/80 DM renal CVD <130/80

26. Updated UK NICE Guidelines for the Treatment of Newly Diagnosed Hypertension http://www.nice.org.uk/download.aspx?o=CG034fullguideline. Accessed June 2006 *If ACE inhibitor (ACEI) not tolerated ACEI (or ARB*) + CCB or ACEI (or ARB*) + thiazide diuretic <55 years ACEI (or ARB*) + CCB + diuretic CCB or thiazide- type diuretic ACEI (or ARB*)  55 years or black at any age Add further diuretic therapy, α-blocker, or β-blocker. Consider seeking specialist advice Step 1 Step 2 Step 3 Step 4

27. Principles behind latest BP guideline in the UK Monotherapy inadequate Underscores the need for at least 2 drugs Provides rational for drug selection based on ethnicity and age Not restrictive or prescriptive & offers therapeutic choice

29. Lipid

30. Spectrum of CHD Risk – to guide lipid-lowering strategy Expert Panel. JAMA 2001;285:2486-2497. MetabolicSyndrome LDL-C  HDL-C TG + Glucose intolerance Abdominal obesity  BP Should we treat low HDL? Achieving low LDL/total cholesterol target evidence how to achieve it? Lipid-lowering guidelines (JBS-2, NICE type 1 DM) and young diabetics ?role of metabolic syndrome

31. Diabetic dyslipidaemialow HDL (<1.03 mmol/l male) (<1.29 mmol/l female) raised triglyceride (>1.7 mmol/l) Emphasis on treating total cholesterol HDL and triglyceride – no evidence

32. Statin potent agent in lowering total/LDL cholesterol consistently demonstrated importance of lowering LDL/total cholesterol to reduce CVD events agent of choice for lipid-lowering Rx I guidelines important component of multi-factorial diabetes management ‘easier’ component to achieve target tot chol 70-75% BP 50%, HbA1c 15% (STENO-2) recent trials showed ‘lower the better’ (HPS, TNT, PROVE-IT)

33. Reduction in 1 mmol/l LDL leads to 20-25% reduction in CVD events (major coronary events, coronary revascularisation and ischaemic stroke) Target total/LDL cholesterol - ‘the lower the better’ Statin meta-analysis Lancet 2005

34. Lower cholesterol target – strategies to achieve it (1) Use more potent statin

35. ‘Rule of 6’

36. Most guidelines – simvastatin (1 st ) and atorvastatin (2 nd ) Statin choice if these statins fail to achieve cholesterol target MERCURY II Initital Rx:Switched to:% reduction in LDL Atorvastatin 10Rosuvastatin 1017 Atorvastatin 20Rosuvastatin 2016 Simvastatin 20Rosuvastatin 1018 Simvastatin 40Rosuvastatin 2027 Ballantyne CM et al. Am Heart J 2006: 151; 975 Lower cholesterol target – strategies to achieve it (2) Switching to more potent statin

37. Lower cholesterol target – strategies to achieve it (3) Adding fibrate, nicotinic acid and ezetimibe to statin Adding fibrate, nicotinic acid and ezetimibe to statin LDLTGHDL Statin + fibrate-28%-41%+22% Statin + niaspan (1g)-8%-24%+24 Statin + niaspan (2g)-23%-30%+27% Statin + ezetimibe-20%-11%+1.7% Fibrate and nicotinic acid – LDL, TG, HDL Ezetimibe - LDL

38. No role for CVD risk calculation table To guide initiation of lipid-lowering treatment in primary prevention Calculates absolute risk of developing CHD (over 10 yrs) introduced when statin cost was expensive (predominantly financial reason) prior to statin trials in diabetes (HPS, CARDS) not evidence-based Purpose: to target high risk individuals to maximise cost-effectiveness to reduce unnecessary treatment in some individuals JBS (1998) and NICE (2002) recommends risk tables statin Rx when >15% (NICE) or >30% (JBS) Available risk calculators:Framingham & UKPDS risk engine

39. Framingham equation under-estimate CHD risk in diabetes up to 50% PredictedObserved UKPDSCHD event (%/yr)1.62.7 (Diabetes) WOSCOPSCHD event (%/yr)1.91.8 (Non-diabetes) (Yeo et al Diabet Med 2001; 18: 341-44) CardiffCHD eventMale8.319 (Diabetes)(% / 4 yrs) Female7.517 Stevens et al Diabet Med 2005; 22: 228

40. UKPDS risk engine is not a better alternative Comparison between UKPDS risk engine and Framingham equation SH Song et al Diabetic Med 2004; 21: 238-45 Mean CHD risk (over 10 yrs) in type 2 diabetes malefemale JBS1917.3 UKPDS24.916.5 Conclusion: Overall, UKPDS risk engine estimated higher CHD risk score. At high risk (>30%), UKPDS risk engine consistently estimated higher risk score than Framingham equation. At lower risk levels (~15%) where clinical decision to start statin occurs (as per NICE), UKPDS risk engine and Framingham equation equivalent. 15% threshold UKPDS risk engine better Framingham calculator better

41. Why under-estimate risk in diabetes? Model based on largely non-DM population (Framingham calculator) Traditional risk factors do not account for excess CHD death in diabetes. Other important factors not included in risk calculation. (ie small dense LDL, microalbuminuria, hypercoagulable state, impaired fibrinolysis, endothelial dysfunction, inflammatory states, insulin resistance etc) Other limitations: No risk calculation method for type 1 diabetes. Young type 2 diabetes increasing and risk can’t be calculated by current methods.

42. Forms the basis for degree of aggressiveness with lipid Rx

43. Young T2DM patients

44. Facts: high CVD risk (especially with CVD risk factors) no trial data in this age group (compared to >40yrs – HPS/CARDS) increasing number of young T2DM patients

46. SH Song, CA Hardisty. Practical Diabetes International 2007;24: 20-24 Sheffield experience Young type 2 diabetes patients: Similar CVD risk profile as older type 2 diabetes patients High prevalence of obesity, hypertension and dyslipidaemia Less likely to be treated with statin and anti-hypertensive agents

47. Sheffield experience Tendency to multiple CVD risk factor clustering in young type 2 diabetes patients of similar proportion to older T2DM SH Song, CA Hardisty. Practical Diabetes International 2007;24: 20-24

48. High prevalence of metabolic syndrome in T2DM regardless of age ~70% 40 yrs 70 IDF ATP Average WC ~113 cm or 44 inches (male and female) 70 SH Song. Presented at EASD Copenhagen 2006 Sheffield experience (2)

49. Recommendation for statin in diabetes: Joint British Societies–2 guideline (Dec 2005)

50. Effect of intensive lifestyle intervention on CVD risk factors in T2DM Diabetes Care 2007; 30: 1374-83 T2DM 45-74 yrs Intensive lifestyle intervention with diet, physical activity, behaviour modification Aim: to determine effect of intensive lifestyle intervention on CVD outcome

51. Diabetes Care 2007; 30: 1374-83 At 1 yr, Intensive life style intervention results improvement in: Glycaemic control BP Lipid profile (HDL, Trig)

52. Intensive life style management focusing on dietary and physical activity with community dietitian and Sheffield Active group To achieve coordinated and integrated intervention with diet and exercise T2DM inadequately controlled on oral hypoglycaemic agents Started May 2007 for 2 years

53. Conclusions: Intensive management focusing on glycaemic control, BP, lipid, lifestyle Oral hypoglycaemic agents with CVD outcome data – metformin, pioglitazone Lowering BP require multiple agents including ACE-I Statin remains first choice for lipid lowering. Additional agents may be needed to further lower cholesterol in some patients Young T2DM have multiple CVD risk factors as older patients Some evidence of lifestyle intervention beneficial effect on CVD risk factors