Coronary heart disease (CHD) is the most commoncause of death among men and women in the
United States, accounting for approximately 500,000deaths per year.1 Atherosclerosis is a complex processinvolving multiple interactions among immune, coagulation, hormonal, and vascular systems. Dys-lipidemia is a major risk factor for CHD; thus, itsdiagnosis and management are key factors in the pre-vention of atherosclerotic plaque and development ofcardiovascular disease (CVD) events. Decreases incholesterol levels lead to diminished macrophageactivity and improvement in endothelial function, andthus lead to increased levels of the antiatheroscleroticmolecule, nitric oxide.2,3 Improvements in endothelial
function are associated with plaque stabilization andprevention of acute CHD events. Obtaining a stan-dard lipid profile in a clinical setting involves meas-urement of the total cholesterol (TC), high-densitylipoprotein cholesterol (HDL-C), and triglyceride(TG) levels, while the low-density lipoprotein choles-terol (LDL-C) level is a calculated value.
Lipoproteins are particles containing cholesterolesters and TGs in their core, with their surface layerscomposed of apolipoproteins, phospholipids, andfree cholesterol. The classification of apolipoproteinsis based on density. The most dense, chylomicrons,contain the most TGs, followed by very low-densitylipoproteins (VLDLs), LDLs that are cholesterol-rich,and HDLs, whose composition is almost one halfapolipoproteins.4
The role of LDL-C in the pathogenesis of CHDhas been established.5–9 Nevertheless, there are somepatients with CHD with plasma LDL-C levels with-in the normal range. The variation in size, density,and composition of the LDL-C particle governs itsproperties. The use of gradient gel electrophoresishas demonstrated the existence of two distinct LDL-C phenotypes.10 The larger, less dense particles areknown as pattern A and the smaller, denser particlesare known as pattern B. These small, dense LDL-Cparticles are more prevalent in patients with theatherogenic metabolic syndrome (low HDL-C andhigh TG levels) and those with CHD.11–14
Among the different risk factors for CHD,increased LDL-C levels are a major contributoryfactor in atherogenic processes. Drug therapy aimedat reducing LDL-C levels significantly reduces therisk of coronary events. The 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductaseinhibitors, statins, are the mainstay of treatment toachieve target LDL-C levels15; in addition, theylower TG levels.
The expert panel on the Detection, Evaluation,and Treatment of Increased Blood Cholesterol—theAdult Treatment Panel (ATP) III of the NationalCholesterol Education Program (NCEP)—has con-sistently targeted high LDL-C levels as a method ofprimary prevention of CHD. The latest report, pub-lished in May, 2001,16 emphasized the need for
The Significance of Measuring Non-HDL-CholesterolGlenn A. Hirsch, MD; Nidhi Vaid, MBBS; Roger S. Blumenthal, MD
From Johns Hopkins Ciccarone Center, Baltimore, MDAddress for correspondence:Roger S. Blumenthal, MD, Johns Hopkins CiccaroneCenter, Division of Cardiology, Johns Hopkins Hospital,Carnegie 538, Baltimore, MD 21287E-mail: [email protected] received October 1, 2001;accepted October 3, 2001
more intensive LDL-C-lowering therapy in both theprimary and secondary prevention of CHD. It alsoemphasized the need for primary prevention inpatients with multiple risk factors.
The indications for therapy are based on thepatient’s risk status, including the measurement ofLDL-C. Adults who are ≥20 years of age are recom-mended to obtain a fasting lipid profile once every 5years. Lipid-lowering therapy consists of both thera-peutic lifestyle changes and drug therapy. The typeof lipid-lowering therapy initiated is dependent onthe calculation of the Framingham 10-year risk of acoronary event. The Framingham risk score takesinto account age, TC, cigarette smoking, HDL, andsystolic blood pressure. In patients in the highest riskcategory—that is, those with a 10-year risk of a coro-nary event >20%, the optimal LDL goal would be avalue <100 mg/dL, with therapeutic lifestylechanges being initiated at LDL levels >100 mg/dLand drug therapy at >130 mg/dL.16
The NCEP emphasizes the need for optimizationof LDL levels, but it has recently been suggested thatnon-HDL-C may be a better predictor of cardiovas-cular risk.17,18 Non-HDL-C encompasses all choles-terol present in potentially atherogenic lipoproteinparticles (VLDL, intermediate-density lipoprotein[IDL], LDL, and lipoprotein[a]). At present, the con-centration of LDL-C is estimated using theFriedewald equation: LDL-C=TC−HDL-C−TG/5mg/dL.17 This equation requires measurement ofTC, TG, and HDL-C. Although the LDL-C concen-tration estimated by this method provides a reason-able estimate of the amount of LDL-C, it alsoencompasses IDL-C and lipoprotein(a). As plasmaTG concentration increases, as in patients with dia-betes mellitus, the VLDL composition is altered andthe estimation of LDL-C concentration becomesprogressively less accurate. The Friedewald equationis generally considered to be less accurate withincreasing TG levels and inapplicable at TG concen-trations >400 mg/dL.19 The advantages of usingnon-HDL-C as a screening tool include the fact that
it requires measurement of only TC and HDL-C,both of which can be measured reasonably accurate-ly in a nonfasting sample, as opposed to LDL-Cmeasurement, which requires a fasting sample.19–21
Non-HDL-C targets are calculated by adding 30 tothe standard ATP III target LDL-C level, as demon-strated in the Table.
Although LDL-C has always been regarded as themost atherogenic of the lipoproteins, it has nowbecome clearer that TG-rich lipoproteins, especiallyVLDLs, are also associated with the development ofvascular disease.20 Particles known as VLDL remnantscontain more cholesterol and less TG than VLDLs, andit has been suggested that these particles may be par-ticularly atherogenic.17,21 IDL-C also has many of thesame properties as VLDL remnants and therefore isthought to confer similar atherogenic potential. Inaddition, raised VLDL concentrations are associatedwith procoagulant and prothrombotic factors in plas-ma, which also contribute to the development of arte-rial disease.18 Using the Friedewald equation for LDL-C ignores these important atherogenic VLDL rem-nants as targets for therapy. Meanwhile, these VLDLremnants, as well as the atherogenic IDL-C, LDL-C,and TGs, are accounted for using the simple non-HDL-C calculation.
Data are currently limited, although a few studieshave demonstrated a correlation between elevatednon-HDL-C and increased atherogenic risk. Onerecent study compared the efficacy of LDL-C and non-HDL-C as predictive factors in deaths from cardiovas-cular events.22 Data from the Lipid Research Clinicprogram cohort study22 were used to compare the pre-dictive value of non-HDL-C as a risk factor for CVDmortality with the current “gold standard,” LDL-C.
In this study, a total of 2406 men and 2056 womenwithout pre-existing CVD at study onset, with agesranging from 40–64 years at entry, were included.After a follow-up period averaging 19 years, therewere a total of 234 male deaths and 113 female deathsattributable to CVD. In men, an increase in non-HDL-C level was shown to be associated with an increase in
SUMMER 2002 PREVENTIVE CARDIOLOGY 157
Table. Risk Categories and Their Respective LDL-C and Non-HDL-C Goals
This table presents an adaptation of the Adult Treatment Panel (ATP) III guidelines for LDL-C and non-HDL-Ctreatment targets. Treatment refers to therapeutic lifestyle changes and, if necessary, drug therapy. ATP IIIrecommends use of non-HDL-C for patients with triglyceride levels >200 mg/dL.LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CHD=coronary heartdisease; risk factors=Framingham risk factors, and the risk score is the 10-year calculated Framingham risk forCHD.16
CVD mortality.22 When men with non-HDL-C valuesof <160 mg/dL were compared to those with valuesbetween 190 and 220 mg/dL, the latter group wasfound to have a 43% increased risk of death fromCVD.22 This risk was further increased as the non-HDL-C level increased, and in men with non-HDL-Cmeasurements of >220 mg/dL, the relative risk ofCVD mortality was found to be 2.14 (95% confidenceinterval, 1.50–3.04).
As expected, an association was also found betweenthe level of LDL-C and CVD mortality in males, withLDL-C measurements ≥190 mg/dL associated with a77% increase in CVD deaths, as compared to menwith LDL-C levels <130 mg/dL. An interesting obser-vation in this group was that men with LDL-C levels<100 mg/dL had a higher risk of CVD mortality thanthose with values in the 100–130 mg/dL range. Thisincreased risk, however, was confined to patients withTG levels >200 mg/dL. An inverse association was alsonoted between HDL-C levels and the risk of CVDmortality. A comparison of non-HDL-C vs. LDL-C aspredictive risk factors revealed that both HDL-C andnon-HDL-C levels were better predictors of CVDmortality than LDL-C levels, in both men and women(relative risk for non-HDL-C levels in men, 1.19; inwomen, 1.15; relative risk for LDL-C levels in men,1.11; in women, 1.08).22
Analysis of the female subjects in the study alsodemonstrated an increased risk of CVD mortalityassociated with an increase in non-HDL-C levels. Acomparison between women with non-HDL-C levels<160 mg/dL and those with levels between 190 and220 mg/dL demonstrated 61% increased CVD mor-tality, with a relative risk of 1.61 in the latter group.This risk was increased to 2.43 in women with non-HDL-C levels >220 mg/dL. Of significant interestwas the finding that only non-HDL-C and HDL-Clevels significantly predicted CVD death in females,since, surprisingly, there was found to be no signifi-cant correlation between LDL-C levels and CVDdeaths. In women, as in men, LDL-C levels werefound to be the least reliable predictor of CVD mor-tality, with the best being HDL-C and non-HDL-C.22
Based on the results of this study, the acceptance ofnon-HDL-C level as a principal CVD risk factor mayresult in a more effective approach to cardiovascularrisk reduction.
Supporting evidence for the above suggestioncomes in the form of a recent study using data fromthe Atorvastatin Comparative Cholesterol Efficacyand Safety Study (ACCESS).23 This study looked atthe effect of statins on lipid and apolipoprotein lev-els, including non-HDL-C. Specifically, it comparedthe relationships of baseline apolipoprotein (apo) Blevels with LDL-C and non-HDL-C levels, as wellas those relationships after treatment with statintherapy. Apolipoproteins are the chief structuralcomponents of lipoproteins, and apo B, in particu-lar, is integral to the production of chylomicronsand VLDLs. Since total plasma apo B concentration
reflects the number of LDL-C- and TG-rich parti-cles, it is an approximate guide to the amount ofatherogenic particles in plasma.24 Therefore, whileall of the lipoproteins discussed above have athero-genic potential, measurement of apo B may bemore useful than calculation of LDL-C in terms ofidentifying modifiable risk factors. This is support-ed by the Quebec Cardiovascular Study,25 whichestablished apo B as a more powerful predictor ofCHD than LDL-C. Because LDL-C was calculatedusing the Friedewald equation, patients with a TGlevel >400 mg/dL were excluded to avoid inaccu-rate LDL-C levels, although this would not haveaffected the accuracy of non-HDL-C measure-ments. Patients were then randomized to one offive statins over a period of 54 weeks, with lipidlevels assessed regularly at 6-week intervals. Apo Bwas also measured at weeks 0, 6, and 54.23
Measurements at weeks 6 and 54 showed that ator-vastatin was the most effective drug in the lowering ofLDL-C; however, HDL-C change did not differ signif-icantly among the different statins. Non-HDL-C wasstrongly correlated with apo B across CHD risk cate-gories (week 0, r=0.914; week 54, r=0.938). This cor-relation was found to be much stronger than thatbetween LDL-C and apo B, although the latter associ-ation was still statistically significant. The correlationbetween LDL-C and apo B was especially weak inpatients with CHD. Although the correlation betweennon-HDL-C and apo B remained consistently strongwith variations in TG levels, the correlation betweenLDL-C and apo B became weaker as TG levels orCHD risk increased.23
Although atorvastatin was the most effectivestatin at lowering both LDL-C and non-HDL-C,fewer patients reached non-HDL-C targets thanLDL-C targets for all the statins studied. Comparisonof baseline non-HDL-C with LDL-C levels showedthat in patients with CHD, both non-HDL-C andapo B were significantly elevated relative to LDL-C,suggesting that greater reduction in non-HDL-Cthan LDL-C would be required for optimal risk fac-tor management.
The difficulty with measurement of apo B,although recently improved, lies in the lack of stan-dardization across centers. Within the realms of thestandard lipid profile, non-HDL appears to be theparameter correlating best with apo B.22,23 It there-fore appears prudent to establish non-HDL-C as atarget for modification of CVD death risk.
The studies described above provide evidence sup-porting the rationale of using non-HDL-C as a targetfor lipid-lowering therapy. In both males and females,non-HDL-C predicted CVD death better than LDL-C,with increasing levels of non-HDL-C correspondingto an increased risk of CVD mortality. In addition, forfemale patients, only HDL-C and non-HDL-C signif-icantly predicted CVD death, while the currently tar-geted lipoprotein, LDL-C, did not correlate with out-comes. In fact, LDL-C levels were the least reliable
PREVENTIVE CARDIOLOGY SUMMER 2002158
predictor of CVD deaths in women, when comparedwith non-HDL-C and HDL-C.
SUMMARY Non-HDL-C incorporates all cholesterol in poten-tially atherogenic lipoprotein particles, VLDL-C,IDL-C, LDL-C, and lipoprotein(a). Although it waspreviously believed that LDL-C was the mostatherogenic lipoprotein and thus became the targetfor therapy surveillance, it is now realized that all ofthese lipoproteins confer some atherogenic poten-tial. The total apo B level indicates the total numberof lipoprotein particles in LDL, IDL-C, and VLDL-C. Since most apo B-containing particles are athero-genic, it was hypothesized that the total apo B con-centration should be a better predictor of CHD riskthan LDL-C. The Quebec Cardiovascular Study25
established that apo B is a more powerful predictorof CHD than LDL-C. The cost and difficulties instandardization of measurement of apo B across cen-ters, combined with its strong correlation with non-HDL-C, suggests that measurement of non-HDL-C(rather than LDL-C) would be a better target fortherapy, especially in persons with a TG level >200mg/dL.
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