Atherosclerosis Timeline Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Plaque Rupture Cholesterol Accumulation - Inflammation Decades Modified from Stary HC et al, Circulation 92:1355, 1995 Thrombosis Seconds Normal Asymptomatic Atherosclerosis Symptomatic Atherosclerosis: Angina Myocardial Infarction Stroke
Cholesterol Transport and Atherosclerosis Atherogenic Transport Liver VLDL, LDL Cholesterol Core Arterial Wall HDL Bile Franceschini, 1999 Antiatherogenic Transport
CHD Prevention through Plaque Stabilization Atherogenic Transport Liver VLDL, LDL Today Cholesterol Core Arterial Wall Franceschini, 1999 Antiatherogenic Transport
The Statins First generation O H 3 C CH 3 O HO H O O CH 3 HO O O O H 3 C O H 3 C CH 3 H CH 3 H 3 C CH 3 HO O H COOH OH CH 3 HMG-CoA H 3 C H 3 C HO Lovastatin Simvastatin Pravastatin Second generation Third generation HO COOH OH HO COOH OH HO COOH OH F Fluvastatin CH 3 N CH 3 F N HN CH 3 O CH 3 F N H 3 C N CH 3 CH 3 N SO 2 CH 3 Atorvastatin Rosuvastatin
Statins and Cardiovascular Disease A Meta-analysis Relative Risk Reduction (%) 0-5 -10-15 -20-25 -30-35 4S, WOSCOPS, CARE, AFCAPS/TexCAPS, LIPID, HPS, LIPS, PROSPER, ASCOT-LLA n=79494-27 Major Coronary Events -18-15 Stroke All-cause Mortality Cheung et al, BJCP 57:640,2004
Proportion with event (%) 30 20 10 0 Statins and CHD Heart Protection Study 20536 high-risk subjects 0 1 2 3 4 5 6 HPS Collaborative Group, Lancet 360:7,2002 Years of follow-up Placebo -27% Simvastatin 898 unavoided coronary events (vs 1212 on placebo)
Liver CHD Prevention through Plaque Stabilization Atherogenic Transport VLDL, LDL Today Cholesterol Core Arterial Wall Bile Franceschini, 1999 HDL Tomorrow? Antiatherogenic Transport
HDL Metabolism and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PL CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney
HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002
HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002
Fibrates and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney
Fibrates in Secondary Prevention The VA-HIT Study CHD Events (%) 25 20 15 10 2531 coronary patients < 74 y HDL-C <40 mg/dl; TG <300 mg/dl; LDL-C <140 mg/dl Gemfibrozil (1200 mg/d) for 5.1 years HDL-C: +6%; LDL-C: = Placebo -22% Gemfibrozil 5 0 0 1 2 3 4 5 6 Years Rubins et al, NEJM 341:410,1999
HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002
CETP Inhibitors and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney
CETP Inhibitors and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney
Torcetrapib in Volunteers 100 CETP Inhibition (%) 80 60 40 20 0 Clark et al, ATVB 24:490,2004 120 mg/day 240 mg/day 0 4 8 12 16 20 24 Time after dose (hrs)
Torcetrapib in Low-HDL Patients 80 160 HDL Cholesterol (mg/dl) 70 60 50 40 30 20 10 Placebo Treatment LDL Cholesterol (mg/dl) 140 120 100 80 60 40 20 0 0 120 mg/day 240 mg/day 120 mg/day 240 mg/day Brousseau et al, NEJM 350:1505,2004 Torcetrapib
HDL-therapy target Small Molecules PPARα, CETP, ABCA1, others Synthetic HDL plaque mode of action administration use plasma HDL raising oral chronic plaque stabilization parental acute/subacute Franceschini et al, 2002
Plasma vs. Synthetic HDL Unesterified Cholesterol Phospholipids (PCs, SM, etc.) Phosphatidylcholine (DPPC) CE,TG ApoA-I Plasma HDL Franceschini et al, 2003 ApoA-II Apolipoprotein (ApoA-I, ra-i M /A-I M ) Synthetic HDL
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS Nissen et al, JAMA 290:2292, 2003
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 47 patients, 5 weekly injections of ra-i M /A-I M shdl (15 or 45 mg/kg) Vessel Area Lumen Area Atheroma Area Primary end-point: change in total atheroma volume Nissen et al, JAMA 290:2292, 2003
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 0.5 Atheroma Volume (% change) 0.0-0.5-1.0-1.5 Placebo Nissen et al, JAMA 290:2292, 2003 n=21 n=15 n=36 shdl (15 mg/kg) shdl (45 mg/kg) n=11 n=36 shdl all
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 47 patients, 5 weekly injections of ra-i M /A-I M shdl (15 or 45 mg/kg) Vessel Area Lumen Area Atheroma Area Secondary end-point: change in the most severely diseased 10-mm segment Nissen et al, JAMA 290:2292, 2003
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS Atheroma Volume (% change) 0-2 -4-6 -8-10 Most Severely Diseased 10-mm Segment Nissen et al, JAMA 290:2292, 2003 Placebo shdl
Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS -34% Nissen et al, JAMA 290:2292, 2003
Soft Plaque Regression by ra-i M /A-I M shdl in Rabbits shdl (1.0 g ra-i M /A-I M ) infusion over 90 min through IVUS catheter Chiesa et al, Circ Res 90:974, 2002 Saline (3 days) shdl (3 days) Oil Red O Stain
Liver CHD Prevention through Plaque Stabilization Atherogenic Transport VLDL, LDL Today Cholesterol Core Arterial Wall Bile Franceschini, 1999 HDL Tomorrow Antiatherogenic Transport
Regression of Coronary Atherosclerosis LDL-lowering or shdl-therapy? Atheroma Volume (change, %) 3.0 2.5 2.0 1.5 1.0 0.5 0.0-0.5-1.0-1.5 Pravastatin (LDL-C 150 110 mg/dl) 18 months Atorvastatin (LDL-C 150 79 mg/dl) 5 weeks ra-i M /A-I M shdl Nissen et al, JAMA 290:2292, 2003 Nissen et al, JAMA 291:1071, 2004