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Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors

Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors. Cholesterol Biosynthetic Pathway. HMG-CoA reductase. Squalene synthase. Dolichol. Acetyl CoA. HMG- CoA. Farnesyl pyrophosphate. Mevalonate. Squalene. Cholesterol. Ras protein. Farnesyl- transferase.

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Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors

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  1. Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors

  2. Cholesterol Biosynthetic Pathway HMG-CoA reductase Squalene synthase Dolichol Acetyl CoA HMG- CoA Farnesyl pyrophosphate Mevalonate Squalene Cholesterol Ras protein Farnesyl- transferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones

  3. Metabolic Effects of Lipid-Lowering Agents on Lipoproteins • Agents LDL-C HDL-C VLDL-C • Bile acid sequestrants Ç clearance (modest Ç) Ç secretion • Niacin È synthesis Ç clearance È synthesis • Fibric acid derivatives (modest È) Ç synthesis Ç clearance • HMG-CoA reductase Ç clearance (modest Ç) Ç clearanceinhibitors (statins) È synthesis* * with atorvastatin Adapted from Levy et al. Circulation. 1993;87:III45-III53.

  4. HO O HO COONa O O OH O Lovastatin 1987 O O Pravastatin 1991 H3C HO F HO O O O OH OH O Simvastatin 1991 O O-Na+ Fluvastatin 1993 N H3C H3C Chemical Structures of Older Statins

  5. H3C CH3 OH OH CH O O CH2 CH CH N NHC O-Ca+ CH2 CH2 CH2 2 F F OH OH O ONa CH3O N Chemical Structures of Newer Statins Atorvastatin Cerivastatin

  6. Comparative Efficacy of Available Statins Dose (mg) of agent % Reduction • Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin Cerivastatin TC LDL-C • — 10 20 20 40 0.2* 22 27 • 10 20 40 40 80 0.4 27 34 • 20 40 80 32 41 • 40 80 37 48 • 80 160* 42 55 * Not FDA approved. Roberts WC. Am J Cardiol. 1997;80:106-107. Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

  7. Cerivastatin 0.1 mg bid Cerivastatin 0.2 mg qpm 10 * 5.3 Placebo * 5 2.3 0 -0.01 -0.4 -1.2 -1.4 -5 -3.1 -10 -11.6 -11.6 -15 -20 * -18.9 * *† -21.4 * -21.9 -25 -23.0 * -25.7 -30 *† -29.4 Lipid Lowering With Cerivastatin in Primary Hypercholesterolemia Mean % + after 4 wk TC LDL-C HDL-C TG ApoB * Significantly different from placebo (P<0.05). † Significantly different from 0.1 mg bid (P<0.05). Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

  8. Cerivastatin: TC and LDL-C Lowering in Patients With Primary Hypercholesterolemia 20 LDL-C TC LDL-C Lova TC Lova 10 0 -10 %+ -20 -30 -40 0 0.05 0.1 0.15 0.2 0.25 0.3 40 Dose (mg) Insull W et al. JACC. 1997;29(suppl A):46A.

  9. Atorvastatin Dose-Response Relationship in Primary Hypercholesterolemia 0 -10 -20 Mean % +in LDL-C at 6 wk -30 10 mg 20 mg -40 40 mg -50 80 mg -60 -70 Baseline Week 2 Week 4 Last DB visit P<0.05. DB=double blind. Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.

  10. Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin The CURVES Trial: A Comparison of LDL-C Lowering Among Statins 0 -10 * * -20 * * * * * Mean % LDL-C reduction -30 † † ‡ † -40 ‡ ‡ -50 -60 0 10 20 30 40 50 60 70 80 90 Dose range (mg) * Significantly less than atorvastatin 10 mg (P<0.02). † Significantly less than atorvastatin 20 mg (P<0.01). ‡ Significantly greater than mg-equivalent dose of comparative agents (P0.01). Jones P et al. Am J Cardiol. 1998;81:582-587.

  11. 0 -10 Atorvastatin (10 mg)* Simvastatin (10 mg)* -17† -20 Pravastatin (20 mg)* -24† Lovastatin (20 mg)* -30 -28† Fluvastatin (20 mg)* -29† -40 -38† The CURVES Trial: Comparative LDL-C Reductions Mean % LDL-C reduction *Most commonly prescribed doses. Source: IMS NPA Plus™, December 1996. †Significantly less than atorvastatin 10 mg (P<0.01). Jones PH et al. Am J Cardiol. 1998;81:582-587.

  12. + Mean % in LDL-C Placebo Atorvastatin 10 mg Lovastatin 20 mg Reaching NCEP Goals for LDL-C:Atorvastatin vs Lovastatin % Patients reaching NCEP LDL-C target† 100 10 1* 74 80 0 55 60 -10 -20 40 -30 20 -27* 7 -40 0 -36 *P<0.05 vs atorvastatin. †<160 mg/dL (<2RFs) 95% vs 86% <130 mg/dL (>2RFs) 67% vs 42% <100 mg/dL (CHD) 18% vs 3% Davidson M et al. Am J Cardiol. 1997;79:1475-1481.

  13. + Mean % in LDL-C 10 100 0 80 65 -10 60 -20 40 19* -23* -30 20 -35 0 -40 Reaching NCEP Goals for LDL-C:Atorvastatin vs Pravastatin % Patients reaching LDL-C target (<130 mg/dL) Atorvastatin 10 mg Pravastatin 20 mg *P<0.05 vs atorvastatin. Bertolini S et al. Atherosclerosis. 1997;130:191-197.

  14. + Mean % in LDL-C 10 100 0 80 -10 60 46 -20 40 27 -30 20 -30* -40 0 -37 Atorvastatin 10 mg Simvastatin 10 mg Reaching NCEP Goals for LDL-C:Atorvastatin vs Simvastatin % Patients reaching LDL-C target (<130 mg/dL) *P<0.05 vs atorvastatin. Dart A et al. Am J Cardiol. 1997;80:39-44.

  15. Placebo Atorvastatin 5 mg Atorvastatin 20 mg Atorvastatin 80 mg Impact of Atorvastatin on Lipids in Patients With Hypertriglyceridemia % Lipid levels at 4 wk 20 * 13 12 Baseline LDL-C=119 mg/dL Baseline TG=603 mg/dL 9 10 6 0 Baseline HDL-C=32 mg/dL -1 Mean %+in lipids at 4 wk -10 -9 * -20 -17 -30 -26 * *† -32 -33 -40 *† -41 * -50 -46 TG LDL-C HDL-C *P<0.05 vs placebo. †P<0.05 vs 5-mg dose. Bakker-Arkema RG et al. JAMA. 1996;275:128-133.

  16. Impact of Statin Therapy on LDL-C in Patients With Homozygous FH Receptor negative (N=2) Baseline LDL-C: 498 mg/dL (12.9 mmol/L) Receptor defective (N=6) Baseline LDL-C: 521 mg/dL (13.5 mmol/L) 0 -5 -3 -10 % Reduction in LDL-C -15 -17 -20 -22 -25 -30 -35 -35 Atorvastatin Simvastatin Marais AD et al. 12th DALM Symposium; November 7-10, 1995.

  17. 40 25* 20 0 -20 -40 -34 † -45* -60 -57* TC LDL-C TG HDL-C Impact of Statin Therapy on LDL-C in Patients With Heterozygous FH % Change in lipids at 6 wk %+ *P<0.001. †P<0.01. Marais AD et al. Arterioscler Thromb Vasc Biol. 1997;17:1527-1531.

  18. 14 0 12 -2 10 -4 8 %+in HDL-C %+in LDL-C -6 6 -8 4 -10 2 -12 0 -14 -2 -4 -16 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Time (yr) Time (yr) Impact of Estrogen and Progestin on Cholesterol Concentrations Placebo CEE only CEE + MP (cyc) CEE + MPA (cyc) CEE + MPA (con) PEPI Writing Group. JAMA. 1995;273:199-208.

  19. Impact of Atorvastatin on Lipids in Postmenopausal Women % Lipid levels at 12 wk 20 16 11 9 10 7 4* 2 1 0 -3 -5 Mean %+ at 12 wk -10 -7* -9 Placebo -20 Atorvastatin 10 mg -30 Placebo + estradiol 1 mg -30 -31* Atorvastatin 10 mg + -40 estradiol 1 mg -43* -50 -46 TC TG LDL-C HDL-C *P<0.05 vs placebo. Heinonen TM et al. 66th Congress, European Atherosclerosis Society. July 13-17, 1996.

  20. TG 40 29 30 HDL-C 20 TC LDL-C Lp(a) 7 7 10 0 0 -10 -14 -14 -20 -24 -30 -26* -27 -40 -36* Effects of HRT and Simvastatin Compared in Hypercholesterolemic Postmenopausal Women %+ E+P Simvastatin *P < 0.001. HRT=hormone replacement therapy; E=estrogen; P=medroxyprogesterone. Darling GM et al. N Engl J Med. 1997;337:595-601.

  21. HERS: Combined HRT Does Not Decrease All-Cause Mortality 15 Estrogen-Progestin* Placebo 10 Incidence (%) 5 0 0(2,763) 1(2,720) 2(2,666) 3(2,595) 4(1,590) 5(130) Follow-up, yr (No. at risk) Log rank P=0.56 *0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate. Hulley S et al. JAMA. 1998;280:605-613.

  22. HERS: Primary CHD Events 60 Placebo HRT 50 40 ­52% ¯25% Events/1,000women-years 30 20 10 0 1 2 3 (4-5) (2,763) (2,720) (2,666) (1,590®130) Follow-up, yr (No. at risk) Data from Blumenthal RS, Post WS. Mediguide to Heart Diseases. 1999;2:1-7.

  23. HERS: HDL-C Distribution in a Cohort With CHD 80 72 70 60 50 Postmenopausalwomen*(%) 40 30 20 20 8 10 0 Low Normal High <35 35–59 60 *Mean age 67 years. HDL-C (mg/dL) Bittner V et al. Am Heart J. 2000;139:288-296.

  24. HERS: Combined HRT Does Not Reduce Primary CHD End Points* 15 Estrogen-Progestin* Placebo 10 Incidence (%) 5 0 0(2,763) 1(2,631) 2(2,506) 3(2,392) 4(1,435) 5(113) Follow-up, yr (No. at risk) Log rank P=0.91. * Combined incidence of nonfatal MI and CHD death. † 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate. Hulley S et al. JAMA. 1998;280:605-613.

  25. HERS: Primary CHD Events 60 Placebo HRT 50 40 Events/1,000women-years 30 20 10 P for time trend=0.009 0 1 2 3 (4-5) Yr Data from Hulley S et al. JAMA. 1998;280:605-613.

  26. HRT Effects on C-Reactive Protein Levels 1.2 1.0 0.8 0.6 0.4 0.2 0.0 P=0.001 P=0.003 P=0.03 CRP(mg/dL) Men Women Women Women Women (n=291) no HRT any HRT estrogen estrogen plus (n=311) (n=182) alone progestin (n=99) (n=83) Box plots show 10th, 25th, 50th, 75th, and 90th percentile cutpoints of CRP distribution for each study group. CRP=C-reactive protein. Ridker PM et al. Circulation. 1999;100:713-716.

  27. HRT Effects on C-Reactive Protein Levels: PEPI Trial Subgroup 3 2.5 2 CRP(mg/L) 1.5 1 P=0.0001 0 Time (mo) CRP = C-reactive protein Cushman M et al. Circulation. 1999;100:717-722.

  28. Raloxifene: Effects on Lipids in Postmenopausal Women %+ Delmas PD et al. N Engl J Med. 1997;337:1641-1647.

  29. AVERT: Study Design and Inclusion Criteria Patients recommended for angioplasty CAD ³1 lesion 50% stenosisLDL-C ³115 mg/dL (3.0 mmol/L) TG £500 mg/dL (£5.6 mmol/L); LVEF ³40%Bruce protocol treadmill test or 20-W/minbicycle exercise test 4 min Atorvastatin 80 mg/d+usual medical therapy (n=164) Angioplasty+usual care, including lipid lowering (n=177) 18 months • Occurrence of ischemic events (death from cardiac causes, nonfatal MI, CVA, CABG, angioplasty, worsening angina verified by objective evidence resulting in hospitalization, resuscitation after cardiac arrest) • Time to first ischemic event • Change in lipid parameters • Safety Pitt B et al. N Engl J Med. 1999;341:70-76.

  30. Left main disease or 3-vessel disease Unstable angina MI within previous 14 days Known ejection fraction <40% or NYHA Class III or IV heart failure Previous CABG, unless grafts were patent and patient did not have 3-vessel disease CABG recommended based on current angiogram Percutaneous revascularization in previous 6 months Known hypersensitivity to HMG-CoA reductaseinhibitors AST/ALT >2 x ULN CPK >3 x ULN or unexplained elevations AVERT: Major Exclusion Criteria Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  31. AVERT: Overview of Study Procedures Treatment phase • Patients randomized to atorvastatin • discontinued other lipid-lowering medication and immediately began atorvastatin 80 mg/d • Patients randomized to angioplasty/usual care (UC) • underwent angioplasty followed by “usual care” • usual care may or may not have included lipid-lowering therapy (eg, diet, behavior modification, or medication) • angioplasty may or may not have included stenting • usual care was determined by investigator or patient’s primary physician Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  32. AVERT: Primary Efficacy Assessment • Incidence of an ischemic event in each treatment group • Ischemic event was defined as occurrence of one of the following: • cardiac death • resuscitation aftercardiac arrest • nonfatal MI • CVA • CABG • angioplasty (other than the original procedure in angioplasty/usual care group) • worsening angina verified by objective evidence resulting in hospitalization CVA=cerebrovascular accident. Pitt B et al. N Engl J Med. 1999;341:70-76.

  33. AVERT: Secondary Efficacy Assessments • Time from randomization to ischemic event • Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a) • All-cause mortality • Change from baseline in angina class • Worsening angina with objective evidence • Change in quality of life • Economic assessment Pitt B et al. N Engl J Med. 1999;341:70-76. McCormick LS et al. Am J Cardiol. 1997;80:1130-1133.

  34. AVERT: Baseline Patient Characteristics • Atorvastatin (n=164) Angioplasty/UC (n=177) • Age (yr), mean 59 58 • Gender • Male 130 (79%) 157 (89%) • Female 34 (21%) 20 (11%) • Mean ejection fraction 61% 61% • Nature of CHD • Single vessel 94 (57%) 99 (56%) • Double vessel 70 (43%) 78 (44%) • Mean % stenosis 80% 81% • Mean no. of risk factors 2.5 2.5 • Prior MI 73 (45%) 70 (40%) • Patients with target lesion • LAD 70 (43%) 53 (30%) • LCX 59 (36%) 63 (36%) • RCA 59 (36%) 64 (36%) • CCS Angina Class • Asymptomatic 29 (18%) 27 (15%) • Class I 74 (45%) 70 (40%) • Class II 60 (37%) 77 (44%) • Class III 1 (1%) 2 (1%) • Class IV 0 (0%) 1 (1%) Pitt B et al. N Engl J Med. 1999;341:70-76.

  35. AVERT: Ischemic Events Number (%) of patients experiencing an ischemic event Atorvastatin Angioplasty/UC n=164 n=177 % Any Ischemic event 22 (13) 37 (21) -36* Death 1 (0.6) 1 (0.6) Resuscitated cardiac arrest 0 (0.0) 0 (0.0) Nonfatal MI 4 (2.4) 5 (2.8) CVA 0 (0.0) 0 (0.0) CABG 2 (1.2) 9 (5.1) Revascularization 18 (11.0) 21 (11.9) Worsening angina with objectiveevidence & hospitalization 11 (6.7) 25 (14.1) *P=0.048 vs an adjusted significance level of 0.045. Pitt B et al. N Engl J Med. 1999;341:70-76.

  36. -36% difference* (P=0.048) 25 21% 20 % of patients with an ischemic event 13% 15 10 5 0 Atorvastatin Angioplasty/UC n=22 of 164 n=37 of 177 AVERT: Ischemic Events * P=0.048 vs an adjusted significance level of 0.045 atorvastatin vs angioplasty/UC. Data from Pitt B et al. N Engl J Med. 1999;341:70-76.

  37. AVERT: Time to First Ischemic Event Angioplasty/UC (n=177) Atorvastatin (n=164) P=0.03 Cumulative incidence (%) Time since randomization (months) Pitt B et al. N Engl J Med. 1999;341:70-76.

  38. AVERT: Summary of Lipid Parameters Atorvastatin baseline† 250 31% * (6.5) 10%  Atorvastatin end of study Angioplasty/UC baseline† Angioplasty/UC end of study 200 11% * (5.2) 46% * 10%  18%  mg/dL (mmol/L) 150 (3.9) 100 (2.6) 8%  11%  50 (1.3) 0 LDL-C TC TG HDL-C *Significantly different from angioplasty/UC (P<0.05). † Baseline values represented patients at randomization without a washout period from existing lipid-lowering therapy. Note: 73% of angioplasty/UC-treated patients were on lipid-lowering medication. Pitt B et al. N Engl J Med. 1999;341:70-76.

  39. AVERT: Incidence of First Ischemic Event by Time Atorvastatin 20 Angioplasty/UC 46% difference 24% difference 15 11% % of patients with an ischemic event 10% 10 7% 6% 5 0 0-6 months >6-18 months Pitt B et al. N Engl J Med. 1999;341:70-76.

  40. AVERT: Safety Evaluation • Elevations in AST or ALT (consecutive elevations >3 x ULN) • 4 (2.4%) atorvastatin-treated patients • none in angioplasty/UC-treated patients • Elevations in CPK (>10 x ULN) • none in either treatment group • There were no clinically significant differences in adverse event rates between the two treatment groups • in this study, eight patients discontinued atorvastatin treatment due to an adverse event, seven of which remained in the study Pitt B et al. N Engl J Med. 1999;341:70-76.

  41. AVERT: Conclusions Aggressive lipid lowering with atorvastatin in stable CAD patients: • Reduces ischemic events by 36% • Delays the time to first event • Is safe • Can delay or prevent the need for percutaneous revascularization Pitt B et al. N Engl J Med. 1999;341:70-76.

  42. Safety Summary for HMG-CoA Reductase Inhibitors • Excellent patient acceptance • Few drug-drug interactions • Few side effects • most common are gastrointestinal: mild to moderate • at high doses, elevated ALT/AST in 1% to 2% • myopathy reported in 0.1% (CK >10 x ULN) • Only rare cases of toxicity • No increases in total or non-CHD mortality Lovastatin Study Groups I through IV. Arch Intern Med. 1993;153:1079-1087. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP II). September 1993; NIH Publication 93-3095.

  43. 25 20 Post-CABG-M 4S-C 5-yr CVevents (%) 4S-T 15 Post-CABG-A CARE-T 10 CARE-C 5 155 174 193 212 232 251 271 Post-treatment TC (mg/dL) Risk of CHD Events and Level of Cholesterol C=control; T=treatment; A=aggressive; M=moderate. Yusuf S, Anand S. Circulation. 1996;93:1774-1776.

  44. Relation Between CHD Events and LDL-C in Recent Statin Trials 4S-PI 30 2° Prevention 25 4S-Rx 20 % with LIPID-Rx 15 LIPID-PI 1° Prevention CHD event CARE-Rx CARE-PI WOSCOPS-PI 10 AFCAPS/TexCAPS-PI 5 WOSCOPS-Rx AFCAPS/TexCAPS-Rx 0 90 110 130 150 170 190 210 Mean LDL-C level at follow-up (mg/dL) PI=placebo; Rx=treatment Shepherd J et al. N Engl J Med. 1995;333:1301-1307. 4S Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:1001-1009. Downs JR et al. JAMA. 1998;279:1615-1622. Tonkin A. Presented at AHA Scientific Sessions, 1997.

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