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John Betteridge University College London, London UK.

Association of British Clinical Diabetologists Autumn Meeting 2004 Lipid Lowering Therapy in Diabetes Post CARDS: What More Do We Need to Do?. John Betteridge University College London, London UK. Diabetes and Cardiovascular Disease: Time To Act!.

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John Betteridge University College London, London UK.

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  1. Association of British Clinical DiabetologistsAutumn Meeting 2004Lipid Lowering Therapy in Diabetes Post CARDS: What More Do We Need to Do? John Betteridge University College London, London UK.

  2. Diabetes and Cardiovascular Disease: Time To Act! “With the rising tide of diabetes around the globe, the double jeopardy of diabetes and cardiovascular disease is set to result in an explosion of these and other complications- unless preventive action is taken.” Prof Sir George Alberti, IDF President. International Diabetes Federation, 2001.

  3. United Kingdom Prospective Diabetes StudyRisk Factors for MI. • LDL cholesterol • HDL cholesterol • HbA1c • Systolic blood pressure • Smoking Baseline Epidemiology Data Turner et al BMJ 1998

  4. Statins:The Evidence Base. Continuum of risk High-risk CHD patients (high cholesterol) 4S (simvastatin) Secondaryprevention 22.6 Majority of CHD patients (broad range of cholesterol levels) CARE (pravastatin) LIPID(pravastatin) HPS 12.9 Placebo MI rate per 100 subjects per 5 years 8.44 Patients at high risk of CHD (high cholesterol) 7.9 WOSCOPS (pravastatin) Primaryprevention Patients at low risk of CHD (low HDL-C) 2.8 AFCAPS/TexCAPS (lovastatin)

  5. Major Coronary Events in 4S: with and Without Diabetes 1.0 0.9 0.8 0.7 0.6 0.5 0 No diabetes (n=4142) Diabetes (n=202) Proportion without major CHD event No diabetes,* simvastatinNo diabetes,* placebo p=0.0001 Diabetes,* simvastatinDiabetes,* placebo p=0.002 1 2 3 4 5 6 Years since randomization Pyörälä K et al Diabetes Care 1997;20:614.

  6. CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses. CHD % Risk Reduction Secondary prevention CARE Pravastatin 586 23 25 (p=0.05) 4S Simvastatin 202 32 55 (p=0.002) LIPID Pravastatin 782 24 19 (NS) 4S reanalysis Simvastatin 483 32 42 (p=0.001) HPS Simvastatin 3050 24 18.4(p<0.0001) Diabetes Overall 51 Atorvastatin 1600 GREACE 58 (p<0.0001)

  7. HPSMajor Vascular Events in Cohort of Diabetic Patients 30 Population: 5963 patients (1816 women), mean age 62.1yrs. Simvastatin (40mg/day) vs placebo.Absolute LDL reduction 0.9mmol/l Major Vascular Events: Coronary death Non-fatal MI, Stroke and Revascularisation Risk reduction: 22% (95% CI 13-30) p<0.0001 25 Placebo 20 Simvastatin 15 Major Vascular Events (%) 10 5 p< 0.0001 0 0 1 2 3 6 5 4 Years of follow-up HPS Collaborative Group Lancet 2003

  8. Absolute Benefits of Simvastatin in Diabetic Patients With and Without Vascular Disease Absolute benefits of simvastatin (40mg/day) 5-year rates of first major vascular event: non-fatal MI, coronary death, stroke and revascularization P 40 36% S 30 P 31% s 20 20% P % with first vascular event 25% S 10 9% 13% 0 Diabetes alone Arterial disease Diabetes and Arterial Propn32.9% 24.5% 18.4% Lancet 2003; 361: 2005 Absolute 44 62 66/1000

  9. Greek Atorvastatin and Coronary Heart Disease Evaluation Study(GREACE) Population: 1600 CHD patients (344 women) Design: Randomised, open, 3yr. study, Atorvastatin (10-80mg) vs usual care. Atorvastatin titrated to achieve NCEP goal of LDL< 100mg/dl. Mean dose 24mg/day. Baseline LDL-C 4.66mmol/l Usual care group 14% lipid-lowering drugs. Lipid changes: LDL-C 46%; (2.15mmol/l) non-HDL-C 44%; Trig.31% HDL-C 7%. Primary endpoints: Death, non-fatal MI, unstable angina, CHF, stoke, and revascularisation Athyros et al 2002

  10. GREACE:Diabetic Cohort Risk reduction in composite primary endpoint: Diabetes 0.42 N = 313 (20%) P <0.0001 All Patients 0.49 P <0.0001 0 Atorvastatin Usual Care Athyros et al Current Medical Research and Opinions 2002 18 220

  11. PROVE-IT TrialIntensive and Moderate Lipid-Lowering after Acute Coronary Syndromes Population: 4162 patients hospitalised for acute coronary syndrome within 10 days. 734 diabetic patients Treatment: Standard Pravastatin 40mg/day mean LDL 2.46mmol/l Intensive Atorvastatin 80mg/day mean LDL 1.6mmol/l Primary endpoint: Death from any cause, MI, unstable angina requiring hospitalisation, revascularisation and stroke Follow-up: 18-36 months (mean 24 months) Pravastatin 40mg 26.3% Atorvastatin 80mg 22.4% CVD Endpoints 16% reduction p=0.005 6 12 18 24 30 Months Cannon et al N Engl J Med April 8th 2004

  12. Plasma Lipoprotein Species and Subspecies Chylo- micron VLDL 0.95 IDL 1.006 Remnant Chylomicrons 1.02 LDL HDL1 Density 1.06 HDL2 Lp(a) 1.10 HDL3 1.14 HDL4 1.18 60 100 140 200 240 280 400 600 800 1000 Diameter(A)

  13. Diabetic Dyslipidaemia Triglycerides Insulin resistance Small, dense LDL Remnants HDL2

  14. Veterans Administration HDL Intervention Trial: VAHIT Patient population: 2531 men,established CHD with low HDL-C and relatively normal LDL-C. (25% with diabetes) Design: Randomised,double-blind allocation to gemfibrozil (1200mg/day) or matching placebo. Primary endpoint: Combined incidence of non-fatal MI or CHD death. Baseline lipids: TC 175mg/dl,(4.5mmol/l) HDL-C 32mg/dl,(0.8) LDL 111mg/dl,(2.8) Tg 161mg/dl.(1.8) No difference between treatment groups. Rubins et al N Engl J Med 1999;341:410

  15. VAHITLipid Changes * * * % change * P<0.001

  16. VAHITResults Median follow-up 5.1 years. Primary endpoint: 22% risk reduction, p=0.006. Secondary endpoints: 31% reduction in stoke, 59% reduction in TIAs, 9% reduction in coronary revascularization surgery and 22% reduction in hospitalisation for CHF. Rubins et al N Engl J Med 1999,341;410

  17. VA-HIT StudyFibrate Therapy and CVD in Diabetes Sub-Group -3% -10% -18% -32% RR reduction (%) P=0.07 -41% -40% P=0.004 P=0.02 P=0.046 CVD Events CHD Death Stroke Rubins et al Arch Intern Med 2002;162;2597

  18. CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses. CHD % Risk Diabetes Overall Primary prevention AFCAPS/TexCAPS Lovastatin 155 37 43 (NS) HPS Simvastatin 2912 24 33 (p<0.0003) ASCOT-LLA Atorvastatin 2532 36 16 (NS) Secondary prevention CARE Pravastatin 586 23 25 (p=0.05) 4S Simvastatin 202 32 55 (p=0.002) LIPID Pravastatin 782 24 19 (NS) 4S reanalysis Simvastatin 483 32 42 (p=0.001) HPS Simvastatin 3050 24 18.4(<0.0001) Primary/Secondary ALLHAT Pravastatin 3648 9 11 (p=NS)

  19. CARDSThe Rationale CARDS determines the degree of benefit for primary prevention of coronary heart disease and stroke from lipid lowering with atorvastatin 10 mg in people with type 2 diabetes who do not have markedly elevated LDL-C levels. CARDS provides important information for the formulation of health policy in diabetes and will help improve cardiovascular health for individual patients.

  20. CARDS:Collaborative AtoRvastatin Diabetes Study Patient Population • Type 2 diabetes (40-75y) • No prior MI or CVD • Other risk factors + • Lipid profile: • LDL-C <159 mg/dL (4.14 mmol/L) • TG <600 mg/dL (6.78 mmol/L) • Collaboration in the UK with Diabetes UK, NHS R&D and Pfizer d/b PBO 2,838Patients Atorvastatin 10 mg 304 events Expected completion 2005 Actual termination June 2003 after 2nd interim analysis 210 events • Primary Endpoint • Time to first major CVD event Colhoun et al. Diabetic Med 2002; 32: 259-264.

  21. CARDSSome Baseline Characteristics PLACEBO ATORVASTATIN Mean Age 61.8 yrs 61.5 yrs Women 453 (32%) 456 (32%) BMI (kg/m2 ) 28.8 28.7 Obese (>30) 537 (38%) 515 (36%) Diabetes Duration 7.8 yrs 7.9 yrs Plasma Glucose mmol/l 9.84 (177mg/dl) 10.01 (180mg/dl) 7.8 7.9 HbA1c (%)

  22. CARDSOther Risk Factors PLACEBO ATORVASTATIN Retinopathy 427 (30%) 426 (30%) Microalbuminuria ACR2.5mg/mmol 153 (15%) 148 (15%) Macroalbuminuria ACR25mg/mmol 17 (2%) 24 (2%) Hypertension 1184 (84%) 1193 (84%) On BP drug 940 (67%) 1193 (67%) Systolic BP mmHg 144 144 Diastolic BP mmHg 83 83 Current smoker 323 (23%) 308 (22%)

  23. Lipid Levels by Treatment Total cholesterol LDL cholesterol Average difference 26% 1.4 mmol/l (54mg/dl) p<0.0001 Average difference 40% 1.2 mmol/l (46mg/dl) p<0.0001 6 4 3 4 2 2 1 0 0 0 1 2 3 4.5 0 1 2 3 4 4.5 4 Years of Study Years of Study Placebo Atorvastatin Baseline 5.35mmol/l (214mg/dl) Baseline 3.02mmol/l (117mg/dl)

  24. Cumulative Hazard for Primary Endpoint 15 HR = 0.63 (95% C.I. 0.48, 0.83)p=0.001 Relative risk reduction 37% Placebo 127 events 10 (9.0%) Cumulative Hazard (%) Atorvastatin 5 83events (5.8%) 0 Years 1 2 3 4 4.75 Placebo 1410 1351 1306 1023 651 305 1428 1392 1361 1074 694 328 Atorvastatin

  25. Consistency of Effect P value No evidence of heterogeneity by: Age Sex Baseline lipids Baseline systolic blood pressure Retinopathy Albuminuria Smoking HbA1c 0.58 0.59 ≥ 0.4 for all 0.2 0.7 0.34 0.70 0.70

  26. Treatment Effect on Primaryand Secondary Endpoints Event Placebo* Atorvastatin* Risk Reduction (CI) HR Primary endpoint 127 (9.0%) 83 (5.8%) 37% (17-52) p=0.001 Acute coronary events 36% (9-55) 77 (5.5%) 51 (3.6%) Coronary revascularisation 31% (-16-59) 34 (2.4%) 24 (1.7%) Stroke 48% (11-69) 39 (2.8%) 21 (1.5%) .2 .4 .6 .8 1 1.2 * N (% randomised) Favours Atorvastatin Favours Placebo

  27. Cumulative Hazard for Death Placebo 8 HR = 0.73 (95% C.I.) 0.52, 1.01 Relative Risk Reduction 27%p=0.059 82 deaths 6 Atorvastatin Cumulative Hazard (%) 4 61 deaths 2 0 Years 1 2 3 4 4.75 Placebo 1410 1395 1370 1094 709 332 Atorva 1428 1418 1401 1110 730 351

  28. Absolute Effects of Treatment Primary end-point incidence rate / 100 person years at risk Placebo 2.46 Atorvastatin 1.54 Expected events per 1000 patients over 4 yrs Placebo 98.3 Atorvastatin 61.7 Events saved per 1000 treated for 4 yrs 36.7 Absolute risk reduction in four years 3.7% NNT for four years 27

  29. LIPID-LOWERING TARGETS IN DIABETES ATP III NCEP: Diabetes is a CHD risk Equivalent. LDL goal 100mg/dl (2.6mmol/l) JOINT EUROPEAN: (2003) Diabetes type 2 or type 1 with albuminuria should receive maximal attention. No risk calculation necessary Total chol<4.5mmol/l, LDL<2.5mmol/l

  30. Implications of Recent Trials Adult Treatment Panel III GuidelinesDiabetes Diabetes plus CVD: Initiate statin therapy regardless of baseline LDL-C; LDL goal <70mg/dL (1.8mmol/L) Diabetes without CVD: Most patients at high risk. Recent trials support LDL goal <100mg/dL (2.6mmol/l) Whether to treat when LDL-C <100mg/dL is matter of clinical judgement In lower risk patients (10-20%) statin therapy might not be started if LDL-C <130mg/dL Circulation 2004;110 227

  31. CARDSImplications for Guidelines Much of the efficacy and safety profile in CARDS relates to starting and achieved LDL-Cholesterol levels below ADA and European guidelines.

  32. CARDSImplications for Further Guideline Change? At baseline: Two-thirds had LDL-C <3.4mmol/dL (130mg/dL); unequivocal ADA treatment threshold. A quarter of patients had LDL-C <2.6mmol/L (100mg/dL); current ADA and Joint European target level.

  33. CARDSImplications for Further Guideline Change? On treatment: 75% of treated patients achieved LDL-C at or below European target of 2.5mmolL The median LDL-C on atorvastatin was 2mmol/L (77mg/dL) A quarter of patients had LDL-C <1.7mmoL (64mg/dL) Risk reduction in patients with LDL-C<3mmol/L (116mg/dL) was significant p=0.025 Risk reduction in patients (n=743) with LDL-C<2.6mmol/l (100mg/dL), was 27%.

  34. Conclusions In patients with type 2 diabetes and cholesterol levels at the lower end of the distribution, atorvastatin 10mg daily is safe and highly efficacious in reducing the risk of first CVD events, including stroke CARDS suggests that there is no justification for having a threshold level of LDL-C as the sole arbiter of which patients with type 2 diabetes should receive statin treatment. The overall cardiovascular risk should be the principle determinant The debate about whether all patients with type 2 diabetes warrant statin therapy should now focus on whether there are any patients at sufficiently low risk for this safe and efficacious treatment to be withheld

  35. CARDS Future Analyses Health economics Nephropathy outcomes Retinopathy outcomes Risk prediction Inflammatory markers

  36. What of the Future? • Whither guidelines? • How low to lower LDL-cholesterol? eg high dose statins, statin/cholesterol absorption inhibitor. • Combination therapy? better effects on HDL, triglycerides, dense LDL etc: eg statin/fibrate, statin/nicotinic acid, statin/PPAR,, statin/CETP inhibitor. Additional benefits of lipid-lowering.

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