Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis | Cardiology | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.204.227.34. Please contact the publisher to request reinstatement.
1.
Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;344:1383-13897968073Google Scholar
2.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med. 1998;339:1349-13579841303Google ScholarCrossref
3.
MRC/BHF Heart Protection Study Investigators.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;360:7-2212114036Google ScholarCrossref
4.
Downs JR, Clearfield M, Weis S.  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. AirForce/Texas Coronary Atherosclerosis Prevention Study.  JAMA. 1998;279:1615-16229613910Google ScholarCrossref
5.
Sacks FM, Pfeffer MA, Moye LA.  et al. Cholesterol and Recurrent Events Trial Investigators.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med. 1996;335:1001-10098801446Google ScholarCrossref
6.
Shepherd J, Cobbe SM, Ford I.  et al. West of Scotland Coronary Prevention Study Group.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med. 1995;333:1301-13077566020Google ScholarCrossref
7.
Grundy SM, Cleeman JI, Merz CN.  et al.  Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.  Circulation. 2004;110:227-23915249516Google ScholarCrossref
8.
Cannon CP, Braunwald E, McCabe CH.  et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350:1495-150415007110Google ScholarCrossref
9.
LaRosa JC, Grundy SM, Waters DD.  et al.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  N Engl J Med. 2005;352:1425-143515755765Google ScholarCrossref
10.
Pedersen TR, Faergeman O, Kastelein JJ.  et al.  High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.  JAMA. 2005;294:2437-244516287954Google ScholarCrossref
11.
Nissen SE, Tuzcu EM, Schoenhagen P.  et al.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA. 2004;291:1071-108014996776Google ScholarCrossref
12.
Nissen SE, Tuzcu EM, Schoenhagen P.  et al.  Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.  N Engl J Med. 2005;352:29-3815635110Google ScholarCrossref
13.
Ridker PM, Cannon CP, Morrow D.  et al.  C-reactive protein levels and outcomes after statin therapy.  N Engl J Med. 2005;352:20-2815635109Google ScholarCrossref
14.
Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes.  J Am Coll Cardiol. 2005;46:1425-143316226165Google ScholarCrossref
15.
Jensen LO, Thayssen P, Pedersen KE, Stender S, Haghfelt T. Regression of coronary atherosclerosis by simvastatin: a serial intravascular ultrasound study.  Circulation. 2004;110:265-27015238460Google ScholarCrossref
16.
Okazaki S, Yokoyama T, Miyauchi K.  et al.  Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study.  Circulation. 2004;110:1061-106815326073Google ScholarCrossref
17.
Nissen SE, Nicholls SJ, Sipahi I.  et al.  Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.  JAMA. 2006;295:1556-156516533939Google ScholarCrossref
18.
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.  Circulation. 2004;110:3512-351715537681Google ScholarCrossref
19.
Brown BG, Zhao XQ, Chait A.  et al.  Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.  N Engl J Med. 2001;345:1583-159211757504Google ScholarCrossref
20.
Rubins HB, Robins SJ, Collins D.  et al. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;341:410-41810438259Google ScholarCrossref
21.
Frick MH, Elo O, Haapa K.  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 1987;317:1237-12453313041Google ScholarCrossref
22.
Canner PL, Berge KG, Wenger NK.  et al.  Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.  J Am Coll Cardiol. 1986;8:1245-12553782631Google ScholarCrossref
23.
Nissen SE, Tuzcu EM, Libby P.  et al.  Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.  JAMA. 2004;292:2217-222515536108Google ScholarCrossref
24.
Nissen SE, Tuzcu EM, Brewer HB.  et al.  Effect of ACAT inhibition on the progression of coronary atherosclerosis.  N Engl J Med. 2006;354:1253-126316554527Google ScholarCrossref
25.
Mintz GS, Nissen SE, Anderson WD.  et al.  American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS): a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.  J Am Coll Cardiol. 2001;37:1478-149211300468Google ScholarCrossref
26.
Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).  JAMA. 1986;256:2823-28283773199Google ScholarCrossref
27.
Brousseau ME, Schaefer EJ, Wolfe ML.  et al.  Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.  N Engl J Med. 2004;350:1505-151515071125Google ScholarCrossref
28.
Keech A, Simes RJ, Barter P.  et al.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.  Lancet. 2005;366:1849-186116310551Google ScholarCrossref
29.
Bezafibrate Infarction Prevention (BIP) Study Group.  Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.  Circulation. 2000;102:21-2710880410Google ScholarCrossref
30.
Diabetes Atherosclerosis Intervention Study Group.  Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study.  Lancet. 2001;357:905-91011289345Google ScholarCrossref
31.
Otvos JD, Collins D, Freedman DS.  et al.  Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.  Circulation. 2006;113:1556-156316534013Google ScholarCrossref
32.
Luc G, Bard JM, Ferrieres J.  et al.  Value of HDL cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I/A-II in prediction of coronary heart disease: the PRIME Study: Prospective Epidemiological Study of Myocardial Infarction.  Arterioscler Thromb Vasc Biol. 2002;22:1155-116112117731Google ScholarCrossref
33.
Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse.  Proc Natl Acad Sci U S A. 1994;91:9607-96117937814Google ScholarCrossref
34.
Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.  J Clin Invest. 1990;85:1234-12412318976Google ScholarCrossref
35.
Nissen SE, Tsunoda T, Tuzcu EM.  et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.  JAMA. 2003;290:2292-230014600188Google ScholarCrossref
36.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.  Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;106:3143-342112485966Google Scholar
37.
Martin G, Duez H, Blanquart C.  et al.  Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.  J Clin Invest. 2001;107:1423-143211390424Google ScholarCrossref
38.
Bays H, Stein EA. Pharmacotherapy for dyslipidaemia–current therapies and future agents.  Expert Opin Pharmacother. 2003;4:1901-193814596646Google ScholarCrossref
39.
Guerin M, Lassel TS, Le Goff W, Farnier M, Chapman MJ. Action of atorvastatin in combined hyperlipidemia: preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles.  Arterioscler Thromb Vasc Biol. 2000;20:189-19710634817Google ScholarCrossref
40.
Ross R. Atherosclerosis—an inflammatory disease.  N Engl J Med. 1999;340:115-1269887164Google ScholarCrossref
41.
Arnaud C, Burger F, Steffens S.  et al.  Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes: new evidence for direct antiinflammatory effects of statins.  Arterioscler Thromb Vasc Biol. 2005;25:1231-123615790934Google ScholarCrossref
42.
Aikawa M, Rabkin E, Sugiyama S.  et al.  An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro.  Circulation. 2001;103:276-28311208689Google ScholarCrossref
43.
Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL.  Circ Res. 2004;95:764-77215486323Google ScholarCrossref
Preliminary Communication
February 7, 2007

Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis

Author Affiliations
 

Author Affiliations: Departments of Cardiovascular Medicine (Drs Nicholls, Tuzcu, Sipahi, Grasso, Schoenhagen, Desai, Hazen, Kapadia, and Nissen, Messrs Hu and Crowe, and Ms Wolski), Cell Biology (Drs Nicholls and Hazen), and Diagnostic Radiology (Dr Schoenhagen), and Center for Cardiovascular Diagnostics and Prevention (Drs Nicholls and Hazen), Cleveland Clinic, Cleveland, Ohio.

JAMA. 2007;297(5):499-508. doi:10.1001/jama.297.5.499
Abstract

Context Statins reduce low-density lipoprotein cholesterol (LDL-C) levels and slow progression of coronary atherosclerosis. However, no data exist describing the relationship between statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and disease progression.

Objective To investigate the relationship between changes in LDL-C and HDL-C levels and atheroma burden.

Design, Setting, and Patients Post-hoc analysis combining raw data from 4 prospective randomized trials (performed in the United States, North America, Europe, and Australia between 1999 and 2005), in which 1455 patients with angiographic coronary disease underwent serial intravascular ultrasonography while receiving statin treatment for 18 months or for 24 months. Ultrasound analysis was performed in the same core laboratory for all of the studies.

Main Outcome Measure Relationship between changes in lipoprotein levels and coronary artery atheroma volume.

Results During statin therapy, mean (SD) LDL-C levels were reduced from 124.0 (38.3) mg/dL (3.2 [0.99] mmol/L) to 87.5 (28.8) mg/dL (2.3 [0.75] mmol/L) (a 23.5% decrease; P<.001), and HDL-C levels increased from 42.5 (11.0) mg/dL (1.1 [0.28] mmol/L) to 45.1 (11.4) mg/dL (1.2 [0.29] mmol/L) (a 7.5% increase; P<.001). The ratio of LDL-C to HDL-C was reduced from a mean (SD) of 3.0 (1.1) to 2.1 (0.9) (a 26.7% decrease; P<.001). These changes were accompanied by a mean (SD) increase in percent atheroma volume from 39.7% (9.8%) to 40.1% (9.7%) (a 0.5% [3.9%] increase; P = .001) and a mean (SD) decrease in total atheroma volume of 2.4 (23.6) mm3 (P<.001). In univariate analysis, mean levels and treatment-mediated changes in LDL-C, total cholesterol, non-HDL cholesterol, apolipoprotein B, and ratio of apolipoprotein B to apolipoprotein A-I were significantly correlated with the rate of atherosclerotic progression, whereas treatment-mediated changes in HDL-C were inversely correlated with atheroma progression. In multivariate analysis, mean levels of LDL-C (β coefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (β coefficient, −0.26 [95% confidence interval, −0.41 to −0.10]) remained independent predictors of atheroma regression. Substantial atheroma regression (≥5% reduction in atheroma volume) was observed in patients with levels of LDL-C less than the mean (87.5 mg/dL) during treatment and percentage increases of HDL-C greater than the mean (7.5%; P<.001). No significant differences were found with regard to clinical events.

Conclusions Statin therapy is associated with regression of coronary atherosclerosis when LDL-C is substantially reduced and HDL-C is increased by more than 7.5%. These findings suggest that statin benefits are derived from both reductions in atherogenic lipoprotein levels and increases in HDL-C, although it remains to be determined whether the atherosclerotic regression associated with these changes in lipid levels will translate to meaningful reductions in clinical events and improved clinical outcomes.

×