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Treatment of hyperlipidaemia

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Treatment of hyperlipidaemia

  1. 1. Lipid Lowering Drugs www.freelivedoctor.com
  2. 2. Pathways of Lipid Transport & Inherited Hyperlipidemias Familial HyperTriGlyceridemia – LPL deficiency etc. RARE Familial Combined Hypertriglyceridemia – Polygenic. VERY COMMON (ApoB) Remnant Removcal Disease – ApoE deficiency. UNCOMMON Familial Hypoalphalipoproteinemia (Tangier’s Disease) – HDL low. RARE Familial Hyper- cholesterolemia – LDL receptor deficiency. COMMON. Heterozygotes ~1:500. X X = HMG-coA Reductase step – blocked by Statins www.freelivedoctor.com
  3. 3. Endemic Hyperlipidemias <ul><li>66% UK population have a Total cholesterol >5.2 mmol/L </li></ul><ul><li>Reflects high dietary fat, obesity and genotype </li></ul><ul><li>Secondary causes should be excluded* but explains only a minority of cases </li></ul>* Liver or biliary disease, hypothyroidism, diabetes, nephrotic syndrome or drug-induced (etretinate, HAART, thiazides, OC, glucocorticoids,  -blockade and ciclosporin) www.freelivedoctor.com
  4. 4. Management Strategy <ul><li>Who to treat? </li></ul><ul><ul><li>Primary – 10 yr risk of event  30% </li></ul></ul><ul><ul><li>Secondary - Established IHD or CVD </li></ul></ul><ul><li>What degree of hyperlipidemia should trigger intervention? </li></ul><ul><ul><li>Total cholesterol > 5mmol/L (or LDL >3) </li></ul></ul><ul><li>What are the specific interventions </li></ul><ul><ul><li>Correct secondary causes – if possible </li></ul></ul><ul><ul><li>Dietary modification – in all subjects </li></ul></ul><ul><ul><li>Drug Rx – for vast majority a statin </li></ul></ul>www.freelivedoctor.com
  5. 5. Dietary Intervention <ul><li>Step II diet has <30% of calories as fat, <7% as saturated fat and <200mg cholesterol/day. </li></ul><ul><li>Can achieve a fall in LDL-C of 8-15% … but long-term compliance a problem. </li></ul><ul><li>Has useful 2ary benefits </li></ul><ul><ul><li>Weight reduction </li></ul></ul><ul><ul><li>BP reduction </li></ul></ul><ul><ul><li>Reduced insulin resistance </li></ul></ul><ul><ul><li>Improve intake vitamins & fresh fruit/vegetables (folate and antioxidants) </li></ul></ul>www.freelivedoctor.com
  6. 6. General points about Statins <ul><li>They competitively and potently inhibit HMG-CoA reductase (in nM range) leading to 2ary upregulation of surface LDL receptors </li></ul><ul><li>They have short half-lives (~2 hours except atorvastatin at 14h) but effective with once daily administration </li></ul><ul><li>All have slightly higher efficacy if given at night </li></ul><ul><li>All except pravastatin are metabolised through CYP enzymes in the liver (usually 3A4) which is the source of important interactions </li></ul><ul><li>Major side effects – hepatitis (stop if ALT rises > 3x ULN) and myositis </li></ul>www.freelivedoctor.com
  7. 7. Clinical Trials in Primary and Secondary Prevention of IHD LRC-CPPT = Lipid Research Clinics-Coronary Primary Prevention Trial; BAS = bile acid sequestrant; NR = not reported; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS = West of Scotland Coronary Prevention Study; HHS = Helsinki Heart Study; CDP = Coronary Drug Project; NA = not applicable; 4S = Scandinavian Simvastatin Survival Study; CARE = Cholesterol and Recurrent Events; LIPID = Long-Term Intervention with Pravastatin in Ischaemic Disease; PostCABG = Post Coronary Artery Bypass Graft Trial; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; BIP = Bezafibrate Infarction Prevention Study; POSCH = Program on the Surgical Control of Hyperlipidemias. www.freelivedoctor.com Study No. of Patients Follow-up (yrs) Drug LDL/HDL Change (%) Total Mortality (%) CHD Death, Nonfatal MI (%) PTCA, Bypass (%) Primary prevention     LRC-CPPT [4] 3806 7.4 BAS -13/2 -7 -19 NR     AFCAPS/TexCAPS [14] 6605 4.8 Lovastatin -25/6 NR -40 -33     WOSCOPS [13] 6595 4.9 Pravastatin -26/5 -22 -31 -37     HHS [8] 4081 5 Gemfibrozil -10/10 0 -34 NR Secondary prevention     CDP [7] 1119 15 Niacin -10/NA -11 NR NR     4S [12] 4444 5.4 Simvastatin -35/8 -30 -34 -34     CARE [11] 4159 5 Pravastatin -28/2 -9 -24 -27     LIPID [10] 9014 6 Pravastatin -25/6 -22 -24 -20     PostCABG [16] 1351 4.3 + 3a Lovastatin -40/4 -35 -31 -30     VA-HIT [9] 2531 5.1 Gemfibrozil 0/6 -11 -22 -9     BIP [5] 3090 6.2 Bezafibrate -7/18 +6 -11 -4     POSCH [6] 838 14.7 Surgery -38/4 -25 -40 -69
  8. 8. ELIGIBILITY: MRC/BHF Heart Protection Study (HPS)* <ul><li>Increased risk of CHD death due to prior disease: </li></ul><ul><li>Myocardial infarction or other coronary heart disease; </li></ul><ul><li>Occlusive disease of non-coronary arteries; or </li></ul><ul><li>Diabetes mellitus or treated hypertension </li></ul><ul><li>Age 40-80 years </li></ul><ul><li>Total cholesterol  3.5 mmol/l (  135mg/dl) </li></ul><ul><li>Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors </li></ul><ul><li>* Lancet 2002;360:7-22 </li></ul>www.freelivedoctor.com
  9. 9. PRIOR DISEASE at BASELINE www.freelivedoctor.com
  10. 10. TOTAL & LDL CHOLESTEROL terciles at BASELINE www.freelivedoctor.com
  11. 11. SIMVASTATIN 40mg daily: Muscle symptoms www.freelivedoctor.com
  12. 12. SIMVASTATIN 40mg daily: Safety monitoring www.freelivedoctor.com
  13. 13. Fatal Rhabdomyolysis with Statins <ul><li>Rare – probably a class effect </li></ul><ul><li>Appears to be dose-dependent </li></ul><ul><ul><li>implications for superstatins </li></ul></ul><ul><li>Risk increased by combination with fibrate </li></ul><ul><ul><li>Fibrates especially for gemfibrozil/cerivastatin </li></ul></ul><ul><ul><li>Nicotinic acid </li></ul></ul><ul><ul><li>Protease Inhibitors (HAART therapy) </li></ul></ul><ul><ul><li>Interacting drugs affecting metabolism through CYP pathway </li></ul></ul>www.freelivedoctor.com FDA 2001 Data Lova- Prava- Simva- Fluva- Atorva- Ceriva- All Cases 19 3 14 0 6 31 73 Total Scripts 99.2 81.4 116 37.4 140 9.8 484 Rate/million scripts 0.19 0.04 0.12 0 0.04 3.16 0.15
  14. 14. SIMVASTATIN: CORONARY EVENTS & REVASCULARISATION (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Major coronary event 357 574 Non-fatal MI 587 707 Coronary death (8.7%) (11.8%) 27% SE 4 reduction 898 1212 (2P<0.00001) CORONARY EVENTS Revascularisation 513 725 Coronary 450 532 Non-coronary (9.1%) (11.7%) 24% SE 4 reduction 939 1205 (2P<0.00001) REVASCULARISATIONS 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
  15. 15. SIMVASTATIN: MAJOR VASCULAR EVENTS (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Vascular event 898 1212 Major coronary 444 585 Any stroke 939 1205 Revascularisation (19.8%) (25.2%) 24% SE 3 reduction 2033 2585 (2P<0.00001) ANY OF ABOVE 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
  16. 16. 60(18) Benefit/1000 (SE): People suffering events (%) www.freelivedoctor.com SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR 0 1 2 3 4 5 6 0 5 10 15 20 25 30 Years of follow-up 5(3) 20(4) 35(5) SIMVASTATIN PLACEBO 46(5) 54(7)
  17. 17. SIMVASTATIN: MAJOR VASCULAR EVENT by LDL & TOTAL CHOLESTEROL (10269) (10267) SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Lipid levels at entry LDL cholesterol (mmol/l) 598 756 (17.6%) (22.2%) < 3.0 (116 mg/dl) 484 646 (19.0%) (25.7%)  3.0 < 3.5 951 1183 (22.0%) (27.2%)  3.5 (135 mg/dl) Total cholesterol (mmol/l) 360 472 (17.7%) (23.1%) < 5.0 (193 mg/dl) 744 964 (18.9%) (24.5%)  5.0 < 6.0 929 1149 (21.6%) (26.8%) > 6.0 (323 mg/dl) 24% SE 3 reduction (2P<0.00001) 2033 2585 (19.8%) (25.2%) ALL PATIENTS 0.4 0.6 0.8 1.0 1.2 1.4 www.freelivedoctor.com
  18. 18. SIMVASTATIN: Main conclusions <ul><li>After allowance for non-compliance, 40mg daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularisation by about one-third </li></ul><ul><li>5 years of statin treatment typically prevents these “major vascular events” in about: </li></ul><ul><li>100 of every 1000 people with previous MI </li></ul><ul><li> 80 &quot; &quot; &quot; other CHD </li></ul><ul><li> 70 &quot; &quot; &quot; cerebrovascular disease </li></ul><ul><li> 70 &quot; &quot; &quot; other arterial disease </li></ul><ul><li> 70 &quot; &quot; &quot; diabetes (age 40+) </li></ul><ul><li>irrespective of cholesterol level (or age, or sex, or other treatments) </li></ul>www.freelivedoctor.com
  19. 19. Prospective Pravastatin Pooling Project: Coronary Event Rates in CARE and LIPID Patients with Baseline LDL-C <3.3mmol/L Coronary Event Rate (%) Sacks FM et al. Circulation 2002;105:1424-1428. <60 F M + — + — + — > 27 <27 <40 > 40 > 150 <150 Age Sex HTN Smoking DM BMI HDL-C TG ** * Pravastatin Placebo *p=.004 **p (interaction) =.005 > 60
  20. 20. Cumulative Coronary Event Rates in Diabetic and Nondiabetic Patients with Baseline LDL-C <3.3mmol/L Cumulative Risk of Coronary Event or Procedure (%) Years Follow-up Sacks FM et al. Circulation 2002;105:1424-1428. Placebo Diabetic Pravastatin Nondiabetic Pravastatin Diabetic Placebo Nondiabetic 0 1 2 3 4 6 7 5
  21. 21. Are the effects of Statins solely explained by reduction in cholesterol ? <ul><li>Atherosclerosis can be viewed as an inflammatory process </li></ul><ul><li>Statins could affect inflammatory process by </li></ul><ul><ul><li>2ary effect on LDL uptake by macrophages (as source of CRP) </li></ul></ul><ul><ul><li>1ary effect on the acute phase-response </li></ul></ul><ul><li>Both scenarios suggest an exclusive focus on cholesterol reduction may be misplaced </li></ul>
  22. 22. Cardiovascular Risk Prediction: the role of hs-CRP (1) <ul><li>Women’s Health Survey – long term effects of ASA & vit E </li></ul><ul><li>Baseline samples from 27,939 patients </li></ul><ul><li>Mean age 55. 25% had HT, 12% smoked, 45% on HRT & 2.5% had DM </li></ul><ul><li>Followed for mean of 8 years </li></ul><ul><li>Endpoint of MI, stroke, revascularization of CV death </li></ul>Ridker et al , NEJM 2002;347:1557
  23. 23. Cardiovascular Risk Prediction: the role of hs-CRP (2) <ul><li>CRP provides additional risk prediction to that provided by Framingham risk assessor across all LDL-C groups. </li></ul>
  24. 24. Statins have an Effect on Inflammatory Markers such as CRP <ul><li>CHEST study (Heart 2003;5:2-7) – in 80 dyslipidaemic patients statins (atorva, simva and pravastatin) reduced CRP at 1 week with further falls up to 12 weeks. Fall in CRP correlated closely with the fall in LDL-cholesterol </li></ul><ul><li>PRINCE study (JAMA 2001;286:9) – primary prevention study of 1702 subjects randomised to placebo or 40mg prava and CRP followed to 24 weeks. Prava reduced CRP by 17% </li></ul><ul><li>Atheroscleosis 2003;166:129 – 186 Type2 DM patients randomised to placebo or 10/80mg atorvastatin. Atorva reduced CRP by 15 & 47% without significant effect on plasma IL-6 </li></ul>
  25. 25. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM): Statin Therapy Reduced Event Rate Event Rates [Mortality, MI] (%) 30-day Follow-up Period 0 1 2 3 4 7 5 Heeschen C et al. Circulation 2002;105:1446-1452. Statins discontinued No statins Statin continued
  26. 26. Current Unresolved Issues on the Use of Statins <ul><li>For secondary prevention we should treat all patients with established IHD but … </li></ul><ul><ul><li>How soon after an event should they be started? </li></ul></ul><ul><ul><li>Is dose-titration versus LDL-chol still appropriate? </li></ul></ul><ul><ul><li>Should we simply put all patients on a high dose of a statin without titration in keeping with HPS? </li></ul></ul><ul><li>For primary prevention is the current threshold of 30% risk over 10 years too stringent? </li></ul>
  27. 27. Fibrates <ul><li> FA oxidation in muscle and liver and lipogenesis in the liver </li></ul><ul><li>Most effective at reducing VLDL (TG); smaller  in LDL-chol but useful  in HDL-chol </li></ul><ul><li>Act as PPAR  ligands (cf glitazones) - reduced expression of Apo C11 is key to  VLDL catabolism </li></ul><ul><li>Main side effects </li></ul><ul><ul><li>GI intolerance </li></ul></ul><ul><ul><li>1-2% increase in the incidence of gallstones </li></ul></ul><ul><li>Important interactions </li></ul><ul><ul><li>increased risk of myositis on a statin </li></ul></ul><ul><ul><li>reduction in dose requirements (~30%) for patients on warfarin </li></ul></ul>
  28. 28. Nicotinic Acid <ul><li>1ary effect is reduced FA mobilization from the periphery   hepatic VLDL synthesis </li></ul><ul><li>Is the agent with largest impact on HDL, and the only agent that lowers Lp(a) (by ~ 30%) </li></ul><ul><li>Usually employed in combination with fibrate, resin or statin – this avoids side effects of higher doses </li></ul><ul><li>Major side effects </li></ul><ul><ul><li>Flushing – prostaglandin mediated </li></ul></ul><ul><ul><li>Skin drying & GI intolerance </li></ul></ul>
  29. 29. Anion-Exchange Resins <ul><li>Sequester bile acids (BA) in the gut hence blocking enterohepatic cycling of BA e.g. cholestyramine and colestipol </li></ul><ul><li>2ary effect on cholesterol synthesis actually  VLDL and hyperTG may limit use </li></ul><ul><li>Usually used in combination with a statin </li></ul><ul><li>Major side effect – not palatable and constipate </li></ul><ul><li>Important interactions – bind polar drugs such as warfarin, digoxin, thyroxine and statins  give 1 hr before resin </li></ul>
  30. 30. ‘ Super’ Statins <ul><li>New ‘Superstatins’ </li></ul><ul><ul><li>Rosuvastatin launched 2003, Pitavastatin expected 2005 </li></ul></ul><ul><li>‘ Super’ is an exaggeration </li></ul><ul><li>Do we really need them? </li></ul><ul><ul><li>No doubt that reduction in ischaemic end-points is a class-effect </li></ul></ul><ul><ul><li>Proven safety should probably be the major concern following cerivastatin withdrawal </li></ul></ul><ul><ul><li>Older statins going generic i.e. costs likely to fall </li></ul></ul>
  31. 31. Does the intensity of Lipid reduction matter? <ul><li>PROVE IT-TIMI 22 Trial (NEJM 2004; 350:1495) </li></ul><ul><li>designed as a non-inferiority study of the two agents </li></ul><ul><li>4162 patients within 10 days of an ACS were randomized to pravastatin 40mg/d or atorvastatin 80mg/d </li></ul><ul><li>followed up for mean of 24 months </li></ul><ul><li>Atorvastatin limb produced a 16% reduction in primary end point events </li></ul><ul><li>LDL-cholesterol was 1.6 mmol/l vs 2.46 in pravastatin limb </li></ul>Note early separation of event curves vs. 12-18 m delay in 2ary prevention trials – does this still reflect differences in the pleiotropic actions of the 2 statins?
  32. 32. The Z phase of the A to Z Trial: intense vs leisurely simvastatin, SS <ul><li>Patients with ACS randomised to either SS 40mg/d for 1/12 then 80mg/d OR placebo for 4/12 then SS 20mg/d </li></ul><ul><li>No difference in 1ary end point (composite CV death, non-fatal MI, ACS or need for revasc) in first 4/12 </li></ul><ul><li>Differences only obvious after 6-8/12 </li></ul><ul><li>Only 10 episodes of myopathy (9 in intense limb) </li></ul>
  33. 33. Newer Therapies - Ezetimibe <ul><li>Novel inhibitor of intestinal cholesterol transporter (? SR-B1) </li></ul><ul><li>Rapidly metabolised to glucuronide (EZEG) – which has 400x the potency of EZE and prolongs action by enterohepatic cycling </li></ul><ul><li>No important adverse effects OR significant drug interactions </li></ul><ul><li>Effective in mild/moderate HC as monotherapy or in combination with statins for moderate/severe HC where it acts synergistically </li></ul><ul><li>Unlike resins does not raise TG - actually falls and again synergism with a statin </li></ul>www.freelivedoctor.com
  34. 34. Emerging Therapy - Torcetrapib <ul><li>Novel inhibitor of cholesteryl ester transfer protein, (CETP), that is normally responsible for transfer of these esters from HDL to Apo-B1 => fall in HDL-cholesterol content and particle size. </li></ul>NEJM 2004;350:1505 <ul><li>small rise in HDL with atorvastatin 20mg/d </li></ul><ul><li>much larger and dose-dependent rise with Torcetrapib </li></ul>www.freelivedoctor.com
  35. 35. Important points <ul><li>Hyperlipidemia is common and a major risk factor for IHD and stroke </li></ul><ul><li>Intervention with a statin is highly effective and can reduce risk by ~ 1/3 rd </li></ul><ul><li>Statins are safe but still under prescribed even to high risk groups (e.g. diabetics) </li></ul><ul><li>HPS has still to impact on guidelines and clarification needed on the dogma of dose-titration </li></ul><ul><li>Prescription of statins is likely to expand substantially driven by appearance of generics and OTC sales? </li></ul>www.freelivedoctor.com

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