CHOLESTEROL LOWERING

Lipids in T1D and T2D T1D T2D TC N LDL-C HDL-C N or TG Qualitative changes ? Small dense LDL particles

“ The fact that LDL-cholesterol is not raised does not exclude it as a risk factor. ”

CHD mortality rises in line with total cholesterol 100 Annual age-standardised CHD mortality (%) 10 The data on this slide are taken from over 356,000 men aged 35-57 years screened for inclusion in the MRFIT trial2, although the majority of these patients did not go on to take part in the study itself, their baseline cholesterol was recorded and long-term outcomes monitored. There is a clear relationship between serum total cholesterol and six-year, age-adjusted CHD mortality. The use of a logarithmic scale on the y-axis demonstrates the linearity of this relationship. An association between treated total cholesterol and cardiovascular risk is clearly of great importance, however one cannot comment on any possible benefits of treatment from this sort of prospective cohort study. 1 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Total cholesterol (mmol/l) Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):2823-2828.

CHD mortality rises in line with total cholesterol 100 Annual age-standardised CHD mortality (%) 10 The data on this slide are taken from over 356,000 men aged 35-57 years screened for inclusion in the MRFIT trial2, although the majority of these patients did not go on to take part in the study itself, their baseline cholesterol was recorded and long-term outcomes monitored. There is a clear relationship between serum total cholesterol and six-year, age-adjusted CHD mortality. The use of a logarithmic scale on the y-axis demonstrates the linearity of this relationship. An association between treated total cholesterol and cardiovascular risk is clearly of great importance, however one cannot comment on any possible benefits of treatment from this sort of prospective cohort study. 1 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Total cholesterol (mmol/l) Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):2823-2828.

Reducing cholesterol reduces CHD mortality 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% 4 4.5 5 5.5 6 6.5 7 7.5 Total cholesterol (mmol/l) Annual CHD mortality rate 4S LIPID HPS High risk study groups CARE POSCH Low risk study groups The data on this slide demonstrate that in studies of lipid lowering, the reduction in CHD mortality is consistently proportional to the degree of total cholesterol reduction3-11. This effect is observed both in high-risk populations (the five studies in the upper half of the graph)3-7 and those at lower risk (the lower half of the graph)8-11. Also worthy of note is the fact that the degree of reduction in mortality is consistent across all the studies of lipid lowering shown, not simply those using statins. WOSCOPS LRC Helsinki AFCAPS/TexCAPS Start of study End of study

MRC/BHF Heart Protection Study 20,000 subjects with Increased CHD risk due to prior disease : Myocardial infarction or other CHD ; Occlusive disease of non-coronary arteries ; or Diabetes mellitus or treated hypertension. Age 40-80 years Total cholesterol >3.5 mmol/l ( >135mg/dl) Randomised to simvastatin 40 mg or placebo

CARDS Collaborative Atorvastatin Diabetes Study Helen Colhoun, John Betteridge, Paul Durrington, Graham Hitman, Andrew Neil, Shona Livingstone, Margaret Thomason, Michael Mackness, Valentine Menys, John Fuller on behalf of the CARDS Investigators

CARDS Design Placebo Atorvastatin 10mg 2838 Placebo patients Primary prevention diabetes patients with one other risk factor (hypertension, smoker, micro-albuminuria, retinopathy)

Treatment effect on the primary endpoint 21 (1.5%) 24 (1.7%) 51 (3.6%) 83 (5.8%) Atorva* 48% (11- 69) 39 (2.8%) Stroke 31% (16- 59) 34 (2.4%) Coronary revascularisation 36% (9- 55) 77 (5.5%) Acute coronary events 37% (17- 52) p=0.001 127 (9.0%) Primary endpoint** Hazard Ratio Risk Reduction (CI) Placebo* Event .2 .4 .6 .8 1 1.2 ** Fatal MI, other acute CHD death, non fatal MI, unstable angina, CABG, fatal stroke, non fatal stroke

Treatment effect on the primary endpoint by lipid levels Subgroup* Placebo** Atorva** Hazard Ratio Risk Reduction (CI) LDL-C ≥ 3.06 66 (9.5) 44 (6.1) 38% (9-58) LDL-C < 3.06 61 (8.5) 39 (5.6) 37% (6-58) p=0.96 HDL-C ≥ 1.35 62 (8.4) 36 (5.2) 41% (11-61) HDL-C < 1.35 65 (9.6) 47 (6.4) 35% (5-55) p=0.71 Trig. ≥ 1.7 67 (9.6) 40 (5.5) 44% (18-62) Trig. < 1.7 60 (8.4) 43 (6.1) 29% (-5-52) p=0.40 .2 .4 .6 .8 1 1.2

JBS 2 : indications for statin therapy in type 1 or type 2 diabetes Age > 40 years Retinopathy of greater than background severity Nephropathy, including microalbuminuria Poor glycaemic control (HbA1c > 9%) Hypertension requiring treatment Elevated total cholesterol ( > 6.0 mmol/l) Metabolic syndrome Family history of premature CHD in a first degree relative

Total cholesterol still > 4 ? Use a more potent statin ? Add cholesterol absorption inhibitor : ezetimibe ? Role of fibrate or nicotinic acid ? There are two main sources of cholesterol: absorption from the intestine and biosynthesis in the liver20. Biliary cholesterol from the liver accounts for 50% of daily intestinal cholesterol, 30% is from dietary sources and 20% from sloughing of epithelial cells21.

Substitute rosuvastatin Cost Effectiveness Intervention Substitute rosuvastatin Add ezetimibe Cost 10 mg £18.03 20 mg £26.02 £1.31 + £26.31 = £27.62 Expected TC reduction 10% 25% British National Formulary 2008

Patients not on target on simvastatin 40 mg Total cholesterol Target < 5.0 < 4.0 Action > 5.5 Add ezetimibe 5.5 – 5.0 Rosuvastatin 5.0 – 4.5 On target 4.5 – 4.0

Fibrates : FIELD Study 9795 subjects with T2D : 7664 no CVD Fenofibrate 200 mg versus placebo Average 5 year follow up 36% of placebo group and 19% of fenofibrate group given statins Fenofibrate : TC  11%, LDL  12%, HDL  5% , TG  29% Primary endpoint  11% (NS) Reduction in laser therapy / progression of albuminuria in fenofibrate group Myositis / rhabdomyolysis < 1% FIELD Study Investigators, Lancet 2005; 366; 1849-1861

The Alphabet Strategy Advice Smoking , diet , exercise Blood pressure < 140/80 Cholesterol TC < 4.0 mmol/l , LDL ≤ 2.0 mmol/l HDL > 1.0 mmol/l, TGs < 1.7 mmol/l Diabetes control HbA1c ≤ 7% Eye examination Annual examination Feet examination Annual examination Guardian drugs Aspirin, ACEI, ARB, statins

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Cholesterol metabolism Two main sources of cholesterol : Absorption of cholesterol from the intestine Biosynthesis of cholesterol in the liver There are two main sources of cholesterol: absorption from the intestine and biosynthesis in the liver20. Biliary cholesterol from the liver accounts for 50% of daily intestinal cholesterol, 30% is from dietary sources and 20% from sloughing of epithelial cells21.

Cholesterol balance: absorption and synthesis Circulation Dietary intake ~300-700 mg/day Small bowel absorption ~700 mg/day Biliary excretion ~1,000 mg/day Faecal loss 650-850 mg/day Liver synthesis ~800 mg/day As we have seen, dietary cholesterol accounts for a relatively small proportion of circulating cholesterol21. From a typical dietary intake of 300-700 mg/day21 about half is absorbed in the small bowel and transported to the liver. In the liver it joins the pool of cholesterol which has been synthesised de novo within the liver. Approximately one-third of this is released into the circulation as part of a lipoprotein molecule, while the remainder, approximately 1,000 mg/day is excreted back into the bowel via the bile21. Overall, 50% of cholesterol in the intestine is absorbed and metabolised, and 50% is excreted in the faeces21. Shepherd J. Eur Heart J Supplements 2001;3:E2-E5. Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

x x Dual inhibition Dietary intake STATINS Liver synthesis Biliary Circulation Dietary intake ~300-700 mg/day Small bowel absorption ~700 mg/day Biliary excretion ~1,000 mg/day Faecal loss 650-850 mg/day Liver synthesis ~800 mg/day STATINS x x As we have seen, dietary cholesterol accounts for a relatively small proportion of circulating cholesterol21. From a typical dietary intake of 300-700 mg/day21 about half is absorbed in the small bowel and transported to the liver. In the liver it joins the pool of cholesterol which has been synthesised de novo within the liver. Approximately one-third of this is released into the circulation as part of a lipoprotein molecule, while the remainder, approximately 1,000 mg/day is excreted back into the bowel via the bile21. Overall, 50% of cholesterol in the intestine is absorbed and metabolised, and 50% is excreted in the faeces21. EZETIMIBE Shepherd J. Eur Heart J Supplements 2001;3:E2-E5. Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

Co-administration therapy with ezetimibe + statin 6% 6% 6% 20 mg 40 mg 80 mg Three-step titration Statin 10 mg 25% The co-administration studies demonstrate that the effect of ezetimibe when added to a 10 mg dose of statin is equivalent to the 80 mg dose of the statin alone (or a three-fold dose titration)27-29. However, when using statins to lower cholesterol, the majority of the reduction in LDL-C is achieved at the starting dose33, and doubling the dose yields a relatively small additional reduction in LDL-C of approximately 6%. Therefore, a three-step doubling of the dose – i.e. increasing the dose from 10 mg to 80 mg, is required to produce an approximate 18% reduction in LDL-C. One-step co-administration + Ezetimibe 10 mg Statin 10 mg Statin 10 mg 10 20 30 40 50 % reduction in LDL-C Stein E. Eur Heart J Supplements 2001:3(Suppl E):E11-E16.

Ezetimibe Consider in statin-intolerant patients Well tolerated Rational approach to reducing TC / LDL Consider in patients not achieving TC / LDL targets on statin alone Consider in statin-intolerant patients Well tolerated Dose = 10 mg daily

Fibrates : VA - HIT Study 2500 patients with established CHD : 600 with diabetes Gemfibrozil versus placebo In diabetics HDL-C  5% , TG  20%, cardiovascular events  33% ? Mechanism :  HDL-C ? ,  TG ? , both ? What are the targets for HDL-C and TG ? Is this a class effect ? Cannot extrapolate to primary prevention subjects Rubins H et al. N Engl J Med 1999: 341: 410