Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.
BACKGROUND
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.


METHODS
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.


METHODS
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 (beta coefficient, 0.11 [95% confidence interval, 0.07-0.15]) and increases in HDL-C (beta coefficient, -0.26 [95% confidence interval, -0.41 to -0.10]) remained independent predictors of atheroma regression. Substantial atheroma regression (> or =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.
Nicholls
Stephen J
SJ
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA. nichols1@ccf.org
Tuzcu
E Murat
EM
Sipahi
Ilke
I
Grasso
Adam W
AW
Schoenhagen
Paul
P
Hu
Tingfei
T
Wolski
Kathy
K
Crowe
Tim
T
Desai
Milind Y
MY
Hazen
Stanley L
SL
Kapadia
Samir R
SR
Nissen
Steven E
SE
D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D018084:Ultrasonography, Interventional
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins