ORIGINAL INVESTIGATION Non–High-Density Lipoprotein Cholesterol Level as a Predictor of Cardiovascular Disease Mortality Yadong Cui, MD, PhD; Roger S. Blumenthal, MD; Jodi A. Flaws, PhD; Maura K. Whiteman, BS; Patricia Langenberg, PhD; Paul S. Bachorik, PhD; Trudy L. Bush, PhD, MHS† Background: Non–high-density lipoprotein choles- Results: A total of 234 CVD deaths in men and 113 CVD terol (non–HDL-C) contains all known and potential ath- deaths in women occurred during follow-up. Levels of erogenic lipid particles. Therefore, non–HDL-C level may HDL-C and non–HDL-C at baseline were significant and be as good a potential predictor of risk for cardiovascu- strong predictors of CVD death in both sexes. In con- lar disease (CVD) as low-density lipoprotein choles- trast, LDL-C level was a somewhat weaker predictor of terol (LDL-C). CVD death in both. Differences of 0.78 mmol/L (30 mg/ dL) in non–HDL-C and LDL-C levels corresponded to Objectives: Todeterminewhethernon–HDL-Clevelcould increases in CVD risk of 19% and 15%, respectively, in be useful in predicting CVD mortality and to compare the men. In women, differences of 0.78 mmol/L (30 mg/dL) predictive value of non–HDL-C and LDL-C levels. in non–HDL-C and LDL-C levels corresponded to in- creases in CVD risk of 11% and 8%, respectively. Methods: Data are from the Lipid Research Clinics Pro- gram Follow-up Study, a mortality study with baseline Conclusions: Non–HDL-C level is a somewhat better data gathered from 1972 through 1976, and mortality as- predictor of CVD mortality than LDL-C level. Screening certained through 1995. A total of 2406 men and 2056 for non–HDL-C level may be useful for CVD risk assess- women aged 40 to 64 years at entry were observed for ment. an average of 19 years, with CVD death as the main out- come measure. Arch Intern Med. 2001;161:1413-1419 LEVATED LEVELS of low- nants; and estimation of LDL-C level us- density lipoprotein choles- ing the formula of Friedewald7 (Friede- terol (LDL-C) have been wald formula) can be inaccurate. consistently associated with an increased risk for devel- For editorial comment opment of and death due to cardiovascu- see page 1379 E 1-5 lar disease (CVD). The National Cho- lesterol Education Program (NCEP) Despite the potential usefulness of recommends that LDL-C values be used non–HDL-C level as a predictor of CVD to estimate the lipoprotein-related risks for mortality, only a few studies have dem- CVD in individuals.1 In addition, current onstrated that elevated non–HDL-C level treatment recommendations are based on is associated with an increased risk for de- discrete LDL-C level. Recently, however, velopment of CVD.8-13 However, to our From the Department of the use of non–high-density lipoprotein knowledge, no study has compared the Epidemiology and Preventive cholesterol (non–HDL-C) level has been relative values of LDL-C and non– Medicine, School of Medicine, suggested as a better tool for risk and treat- HDL-C levels in prediction of CVD. To ad- University of Maryland ment assessments than LDL-C level.6 dress this question directly, we used data (Drs Cui, Flaws, Langenberg, (Non–HDL-C level is defined as the dif- from the Lipid Research Clinics (LRC) Pro- and Bush and Ms Whiteman), ference between total cholesterol (TC) and gram Follow-up Study, a long-term ob- and the Division of Cardiology, HDL-C levels.) The rationale for this servational mortality study that includes Johns Hopkins Ciccarone recommendation is that non–HDL-C men and women with well-defined lipid Preventive Cardiology Center (Dr Blumenthal), and School of includes all cholesterol present in lipo- level measurements at baseline. Our goal Medicine (Dr Bachorik), protein particles considered to be athero- was to determine whether non–HDL-C The Johns Hopkins University, genic, including LDL, lipoprotein(a), in- level predicts CVD mortality in men and Baltimore, Md. termediate-density lipoprotein (IDL), and women, and whether it is as good as LDL-C †Dr Bush died March 14, 2001. very-low-density lipoprotein (VLDL) rem- level in predicting CVD death. (REPRINTED) ARCH INTERN MED/ VOL 161, JUNE 11, 2001 WWW.ARCHINTERNMED.COM 1413 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 SUBJECTS AND METHODS women. Age-adjusted CVD mortality rates were calculated based on person-years of follow-up using the distribution of STUDY POPULATION the random sample as the standard. Relative risk (RR) esti- mates and 95% confidence intervals (CIs) adjusted for base- All data were obtained from participants in the LRC Pro- line age were obtained from Cox proportional hazards mod- gram Prevalence Study.14 Details of the prevalence study de- els. To assess the linearity of the association between lipid lev- sign and data collection have been described elsewhere.14-16 els and CVD mortality, and for ease of interpretation and Briefly, from 1972 through 1976, a preliminary screening (visit presentation, lipids were grouped into categories on the ba- 1) was conducted at 10 centers throughout North America. sis of clinical recommendations.1,21 Level of LDL-C was cat- A 15% random sample of persons attending visit 1 was asked egorized as follows: less than 3.36 mmol/L (,130 mg/dL), to return for a second visit (visit 2). In addition, all persons 3.36 to less than 4.14 mmol/L (130 to ,160 mg/dL), 4.14 to who had elevated lipid levels and/or who were taking medi- less than 4.91 mmol/L (160 to ,190 mg/dL), and at least 4.91 cations to lower lipid levels were asked to return for visit 2. mmol/L ($190 mg/dL). Cut points for LDL-C level were in- During visit 2, each participant completed a detailed ques- creased by 0.78 mmol/L (30 mg/dL) to create analogous cut tionnaire and provided a fasting blood sample. Triglyceride, points for non–HDL-C levels.1,21 Total cholesterol level was TC, LDL-C, and HDL-C levels were measured using the stan- separatedintothefollowing4categories:lessthan5.17mmol/L dardized LRC protocol previously described.17 Briefly, plasma (,200 mg/dL), 5.17 to less than 6.21 mmol/L (200 to ,240 triglyceride level was estimated fluorometrically. Level of mg/dL), 6.21 to less than 7.24 mmol/L (240 to ,280 mg/dL), HDL-C was estimated in plasma after precipitation of the apo- and at least 7.24 mmol/L ($280 mg/dL). Because of differ- liprotein B–containing lipoprotein using heparin and man- ent distributions of HDL-C levels in men and women, HDL-C ganese chloride. Lipoproteins then were separated by cen- level categories were different by sex. In men, these were less trifugation in a saline density gradient to yield a fraction than 0.91 mmol/L (,35 mg/dL), 0.91 to less than 1.16 mmol/L containing VLDL and a fraction containing LDL and HDL. (35 to ,45 mg/dL), 1.16 to less than 1.42 mmol/L (45 to ,55 Level of LDL-C was calculated by subtracting HDL-C from mg/dL), and at least 1.42 mmol/L ($55 mg/dL); in women, the total infranatant cholesterol. Non–HDL-C level was cal- less than 1.16 mmol/L (,45 mg/dL), 1.16 to less than 1.42 culated by subtracting HDL-C from TC levels. mmol/L (45 to ,55 mg/dL), 1.42 to less than 1.68 mmol/L From January 1, 1977, through November 14, 1987, (55 to ,65 mg/dL), and at least 1.68 mmol/L ($65 mg/dL). each participant was contacted annually to determine vital Cox proportional hazards models were used to assess status using a mailed questionnaire.18 Nonrespondents were the value of non–HDL-C, LDL-C, TC, and HDL-C levels contacted by telephone or home visit or were traced, when in predicting CVD mortality. The age-only model, which necessary, using other sources. Confirmation of any deaths served as the model with which all others were compared, was obtained from death certificates, hospital and physi- included age alone as a predictor of CVD death. Subse- cian records, and next of kin. The cause of death for those quently, separate models with non–HDL-C, LDL-C, TC, identified before November 14, 1987, was determined by a and HDL-C levels added as continuous variables were fit. mortality-classification panel after review of relevant docu- The differences in the −2 logarithm likelihood (−2ln[L]) ments.19 The cause of death for those identified after No- of each of these 4 lipid models with the −2ln(L) of the vember 14, 1987, was determined by trained nosologists from age-only model were calculated. These differences follow death certificates obtained using the National Death Index. an approximate x2 distribution with 1 df, and provide a Individuals aged 40 to 64 years at visit 2 were eligible for statistical test for the predictive value of a given lipid this analysis (n=4968). Participants not fasting between 12 level. When compared between lipid models, these x2 val- and 16 hours were excluded (n=72). In addition, those with ues assess which lipid level measure added the most pre- clinicallyevidentCVDatbaseline(n=434)wereexcluded.Clini- dictive value to the age-only model; higher x2 values indi- cally evident CVD was defined as a finding of any of the fol- cated better prediction of CVD mortality by that lipid lowing: angina defined by a positive response on the Rose ques- level.