LDL and HDL Particle Subclasses Predict Coronary Events
LDL and HDL Particle Subclasses Predict Coronary Events and are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT) Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, Mc. Namara J, Bloomfield HE, Robins SJ Circulation 2006; 113: 1556 -63
VA-HIT Background Purpose: Randomized, double-blind trial to determine if increasing low HDL-C will decrease CHD events Subjects: 2531 men with CHD, low HDL-C (31. 5 mg/d. L), and low LDL-C (111 mg/d. L) Therapy: The fibric acid, gemfibrozil (1. 2 g/d) vs. placebo
VA-HIT Background Principal Results: Gemfibrozil treatment resulted in a 22% decrease in nonfatal MI + CHD death 31% decrease in stroke No increase in adverse events N Engl J Med 1999; 341: 410 -418 Circulation 2001; 103: 2828 -2833
VA-HIT Background Principal Results: Gemfibrozil induced a 6% increase in HDL-C, 31% decrease in triglycerides, and no change in LDL-C Only HDL-C was a significant independent predictor of CHD events among on-trial lipid/apolipoprotein variables However, changes in levels of HDL-C and other lipids could account for <25% of the drug benefit JAMA 2001; 285: 1585 -91
VA-HIT Background Unresolved: Is some of the benefit of gemfibrozil due to favorable changes in lipoprotein particle subclass levels or size distributions that are not reflected by conventional lipid or apolipoprotein measurements?
Study Design Ê Nested case-control design - 364 men with nonfatal MI or CHD death during 5 -year follow-up - 697 age-matched controls Ë Lipids / lipoproteins measured at baseline and on-trial - Lipids / apolipoproteins by standard chemical methods - LDL and HDL particle subclass concentrations by NMR Ì All data analysis performed at VA Medical Center Cooperative Studies Program Coordinating Center
NMR Lipo. Profile V 6 V 5 Large VLDL V 4 V 3 V 2 V 1 Medium VLDL Small VLDL IDL L 3 L 2 L 1 IDL Large Small LDL H 5 H 4 H 3 H 2 H 1 Large Med Small HDL HDL Subclass Particle Concentrations (nmol/L, mol/L) Weighted Ave VLDL, HDL Particle Sizes (nm)
Gemfibrozil Treatment Effects Circulation 2006; 113: 1556 -63
Lipids/Apolipoproteins as Predictors of CHD Events * ** Adjusted for treatment, age, diabetes, hypertension, smoking, and BMI *p<0. 05 **p<0. 01 ***p<0. 001 Circulation 2006; 113: 1556 -63
NMR Lipoprotein Particle Measures as Predictors of CHD Events ** *** ** * Adjusted for treatment, age, diabetes, hypertension, smoking, and BMI *p<0. 05 **p<0. 01 ***p<0. 001 Circulation 2006; 113: 1556 -63
Lipoprotein Particles as Multivariable Predictors of CHD Events *** *** *** **p<0. 01; ***p<0. 001 All NMR parameters were included in the same regression model, adjusted for treatment, age, diabetes, hypertension, smoking, and BMI Circulation 2006; 113: 1556 -63
Residual Risk of CHD Events in Gemfibrozil Group by Achieved Levels of LDL and HDL Particle Number in VA-HIT Adjusted for age, diabetes, hypertension, smoking, and BMI 2002 AHA Scientific Sessions
Relative Risk of CHD Events According to Quartile of Lipid/Lipoprotein Ratios P values for trend p=0. 009 p=0. 27 p=0. 37 Circulation 2006; 113: 1556 -63
Conclusion In this nested case-control sub-study of VA-HIT, NMR-measured HDL and LDL particle numbers were significant independent predictors of incident CHD events, whereas levels of HDL and LDL cholesterol (or apolipoproteins A-1 and B) were not. Circulation 2006; 113: 1556 -63
Gemfibrozil Treatment Effects in VA-HIT Large LDL-P Mean Percent Change 36* Small HDL-P 21* HDL-C LDL-C 10* 6* 3 -5* LDL-P -15 -20* Small LDL-P * p<0. 001 HDL-P Large HDL-P Circulation 2006; 113: 1556 -63
Alternative Measures of LDL as Predictors of CHD Events in VA-HIT Odds Ratio per 1 -SD Increment of on-trial value p<0. 001 p=0. 25 LDL-C p=0. 17 p=0. 31 Non. HDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Apo. B LDL-P Circulation 2006; 113: 1556 -63
Odds Ratio per 1 -SD Decrement of on-trial value Alternative Measures of HDL as Predictors of CHD Events in VA-HIT p<0. 001 p=0. 18 p=0. 42 HDL-C Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Apo. A-1 HDL-P Circulation 2006; 113: 1556 -63
Alternative Measures of LDL and HDL as Predictors of CHD Events in VA-HIT LDL Odds Ratio per 1 -SD Increment p<0. 001 LDL-C Non. HDL-C Apo. B Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes LDL-P Odds Ratio per 1 -SD Decrement HDL p<0. 001 HDL-C Apo. A-1 HDL-P Circulation 2006; 113: 1556 -63
Odds Ratio per 1 -SD Increment of on-trial values LDL Subclasses as Predictors of CHD Events in VA-HIT p<0. 001 p=0. 02 p=0. 03 p=0. 35 LDL-P IDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Large LDL-P Small LDL-P Circulation 2006; 113: 1556 -63
Odds Ratio per 1 -SD Decrement of on-trial value HDL Subclasses as Predictors of CHD Events in VA-HIT p<0. 001 p=0. 37 p=0. 52 HDL-P Large HDL-P Adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Medium HDL-P Small HDL-P Circulation 2006; 113: 1556 -63
Odds Ratio per 1 -SD Increment On-Trial LDL and HDL Subclasses as Multivariate Predictors of CHD Events in VA-HIT p=0. 001 p=0. 002 p=0. 11 p=0. 30 p=0. 02 p<0. 001 IDL-P Large LDL-P Small LDL-P Large Medium HDL-P All subclasses in 1 model, adjusted for treatment, age, hypertension, smoking, BMI, and diabetes Small HDL-P Circulation 2006; 113: 1556 -63
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