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Assessment of Reaching Goal in Patients with Combined Hyperlipidemia: Low-Density Lipoprotein Cholesterol, Non–High-Density Lipoprotein Cholesterol, or Apolipoprotein B
Assessment of Reaching Goal in Patients with Combined Hyperlipidemia: Low-Density Lipoprotein Cholesterol, Non–High-Density Lipoprotein Cholesterol, or Apolipoprotein B Evan A. Stein, MD, PhD,a,b,* Allan Sniderman, MD,c and Peter Laskarzewski, MDb It is well established that patients with combined hyperlipidemia, defined as elevated triglyceride levels between 200 and 500 mg/dL and elevated low-density lipoprotein cholesterol >130 mg/dL, are at increased risk for coronary artery disease. The optimal assessment of reaching lipid goals in patients with combined hyperlipidemia is still far from settled and has been an area of revision and modification in recent guidelines. Although controversy remains as to the best single measurement to be used in treatment goals, current focus is on the use of low-density lipoprotein cholesterol, non– high-density lipoprotein cholesterol, and apolipoprotein B. This article reviews the use of these 3 biomarkers in assessing cardiovascular risk, and the strategies for managing combined hyperlipidemia. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96[suppl]:36K– 43K)
Combined hyperlipidemia (CHL) is perhaps the most common lipid disorder, characterized by moderately elevated triglyceride (TG) levels (200 to 500 mg/dL) and elevated low-density lipoprotein (LDL) cholesterol (⬎130 mg/dL). It is also often associated with reduced high-density lipoprotein (HDL) cholesterol (⬍45 mg/dL) and other established increased risk factors for coronary artery disease (CAD), such as hypertension, obesity, and diabetes. Guidelines for the management of CAD emphasize the importance of riskfactor modification and aggressive treatment to achieve cholesterol and lipoprotein goals.1 However, optimal assessment of reaching goal for patients with CHL continues to be an area of revision, and it was recently modified further in recent guidelines.2 Lipid and lipoprotein indexes used in identifying cardiovascular risk, in implementing treatment, and in judging the adequacy of therapy for CHL include LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB). To assess which of these 3 biomarkers would be most appropriate for determining cardiovascular risk, we begin with a brief overview of the pathophysiology of atherogenic lipoproteins, followed by the relation of these lipid parameters to each other based on current treatment guidelines using a large database incorporating patients with CHL. Figure 1 shows that most atherogenic lipoproteins contain apoB100 and originate in the liver. Additional apoB containing-lipoproteins, apoB48, enter the circulation from a Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio, USA; bMedical Research Laboratories, Highland Heights, Kentucky, USA; and cMcGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada. *Address for reprints: Evan A. Stein, MD, PhD, Metabolic and Atherosclerosis Research Center, Suite 201, 3131 Harvey Avenue, Cincinnati, Ohio, 41075. E-mail address: [email protected].
0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.006
the gut as chylomicrons, and are rapidly catabolized to remnant lipoproteins via a mechanism very similar to that of very-low-density lipoprotein (VLDL) cholesterol to intermediate-density lipoprotein cholesterol. As the apoB-containing lipoprotein particles travel through the circulation, there is constant remodeling and lipid transfer between them, other lipoprotein species such as HDL and cells. These interchanges are mediated by a variety of enzymes and cellular receptors. Through this cascade, the amount and type of lipid on the apoB particles is thus constantly changing. Even within the various subclasses of LDL (LDL1, LDL2, LDL3), which are not discrete but arbitrary cuts based on selected densities or other separation techniques, there is a constant differential in the lipid content, because they continue to be remodeled before eventual uptake and degradation by the LDL or apoB receptor. The major focus for diagnosis and treatment over the past 30 years has been on LDL, because when patients have relatively normal TGs, LDL cholesterol accounts for approximately 90% of all plasma cholesterol and most of the atherogenic or apoB-containing lipoproteins. However, as soon as there is a larger proportion of TG-rich lipoproteins, the use of LDL cholesterol becomes less reliable. To capture all of the atherogenic lipoproteins with a relatively easy, inexpensive, and simple test, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines in 2001 introduced the concept of non-HDL cholesterol.2 However, even this non-HDL cholesterol will vary in lipid content per particle (Figure 1), and the only constant component in all of these atherogenic lipoproteins is apoB, because there is always just 1 apoB per lipoprotein particle. It has been postulated that 1 LDL particle is slightly more or less atherogenic than another based on the lipid content3; however, it is well accepted that all apoB particles www.AJConline.org
Stein et al/Assessment of Reaching Goals in Patients with Combined Hyperlipidemia
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N on - H D L -C h o l e s t e ro l III C-
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II C- HL
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LPL
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LPL
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V L DL
LDL LDL 3
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Oxidation C D 36
TG
SR-BI
B B
A- I
Nascent HDL
A -I
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SR-A Ch olesterol P ool
ABCA1
Arterial Wall
Figure 1. Non– high-density lipoprotein (HDL) cholesterol (Chol). ABCA1 ⫽ adensosine triphosphate-binding cassette A1; CETP ⫽ cholesterol ester transfer protein; HL ⫽ hyperlipidemia; IDL ⫽ intermediate-density lipoprotein; LCAT ⫽ lecithin:cholesterol acyltransferase; LDL ⫽ low-density lipoprotein; LDLr ⫽ low-density lipoprotein receptor; LPL ⫽ lipoprotein lipase; SR-A ⫽ scavenger receptor A; SR-B1 ⫽ scavenger receptor B1; TG ⫽ triglycerides; VLDL ⫽ very-low-density lipoprotein. (Adapted with permission from Dr. Bryan Brewer).
carry atherogenic potential and that there is only 1 apoB molecule per lipoprotein irrespective of its size or lipid content. LDL has served as an excellent first step for us to get from an era in which 30 years ago a minority of physicians believed that lowering cholesterol would have benefit on cardiovascular disease, to what is probably now the most solid evidence-based therapy in medicine, that is, that reducing LDL is critical in treating and preventing CAD. Recent guidelines have made an attempt to incorporate non-HDL as a secondary target in order to improve risk determination, especially when there are more TG-rich lipoproteins present. Although it is an easy test to calculate, by subtracting HDL from total cholesterol, it is not well accepted and not understood by clinicians. Even in the United States, only about one third of doctors accept and use non-HDL. It is even less well accepted in the rest of the world. There is also confusion as to when it should be applied; is it when TGs are elevated at baseline before treatment or after treatment? In the light of a number of recent studies, apoB has demonstrated, from prospective epidemiologic studies such as Apolipoprotein-Related Mortality Risk (AMORIS4 and Inter-Heart),5 and randomized treatment studies such as Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)6 to be superior to LDL or non–HDL cholesterol for prospectively determining cardiovascular risk. From the recent Inter-Heart5 and AFCAPS/TexCAPS6 studies, the single most powerful predictor of all of the routine risk factors for CAD, and 1 with a very good linear risk relation, is the apoB/apo A1 ratio, which takes into account all atherogenic and nonatherogenic lipoprotein spe-
cies. This was best demonstrated in AFCAPS/TexCAPS, where the on-treatment LDL cholesterol values at 1 year showed a “gap” in cardiovascular disease risk between those taking a statin and those taking a placebo. This gap diminishes substantially if apoB is substituted and is totally eliminated if the apoB/apoA1 ratio is used. In fact, it made no difference what treatment group a patient was assigned to in AFCAPS/TexCAPS, because only the apoB/apoA1 ratio determined future risk. Therefore, the apoB/apo A1 ratio is not only very predictive in epidemiologic studies, it is also predictive in prospective randomized trials. With regard to treatment guidelines, the NCEP ATP III1 introduced the concept of non-HDL cholesterol in patients who had elevated TG levels defined as 200 to 500 mg/dL. This lower cut point is similar to what was also incorporated in the definition of the metabolic syndrome. Non-HDL targets were set 30 mg/dL higher than those for LDL cholesterol at each risk strata. Some of the reasons for selecting non-HDL cholesterol was because it was simple, inexpensive, reliably measured, easily calculated, and also could be measured in patients who were not fasting, because neither total nor HDL cholesterol is significantly affected by food intake. It was also an attempt to provide a surrogate for all apoB lipoproteins that contribute to atherosclerosis (ie, a measurement of atherogenic cholesterol). The initial ATP III goal for LDL cholesterol in high-risk subjects was ⬍100 mg/dL, but that has recently been modified2 to an optional goal of ⬍70 mg/dL in very-high-risk patients; the non-HDL, which in the ATP III was ⬍130 mg/dL, has also been modified in very-high-risk patients to ⬍100 mg/dL. The apoB goal is now suggested at ⬍90
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Table 1 Adult Treatment Panel III (ATP III): low-density lipoprotein cholesterol (LDL-C), non– high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (apoB) goals and treatment cutpoints Risk Category
Non–HDL-C Goal (only if TG 200–500 mg/dL)
LDL-C Goal
High risk: CAD or CAD risk equivalents (10-yr risk ⬎20%) Moderately high risk: ⬎2 risk factors (10-yr risk 10%–20%) Moderate risk: ⱖ2 risk factors (10-yr risk ⬍10%) Lower risk: 0–1 risk factor
†
ApoB Goal
⬍100 mg/dL (optional: ⬍70 mg/dL)
⬍130 mg/dL (optional: ⬍100 mg/dL)†
⬍130 mg/dL (optional: ⬍100 mg/dL)
⬍160 mg/dL (optional: ⬍130 mg/dL)
⬍130 mg/dL
⬍160 mg/dL
⬍90 mg/dL* (? new optional: ⬍80 mg/dL) ⬍105 mg/dL (⬍110 mg/dL)* (optional: ⬍90 mg/dL) ⬍105 mg/dL (⬍110 mg/dL)*
⬍160 mg/dL
⬍190 mg/dL
⬍120 mg/dL (⬍130 mg/dL)*
* Adapted from Circulation3 and Can Med Assoc J.7 Adapted from Circulation.2 CAD ⫽ coronary artery disease; TG ⫽ triglycerides. †
Table 2 Correlation of low-density lipoprotein cholesterol (LDL-C), non– high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (apoB) 22,070 samples from a large clinical database where cholesterol, triglyceride (TG), HDL-C, LDLC, and apoB were available on the same samples Samples taken during treatment periods; multiple samples per patient; Rx could vary both in terms of drug (mainly statin monotherapy) and dose All analysis by same laboratory, methods, and standardization 14,425 samples with TGs ⬍200 mg/dL analyzed separately as a subset 7,611 samples with TGs 200–500 mg/dL analyzed separately as a subset Rx ⫽ treatment.
mg/dL as a tertiary goal.2 Other goals for apoB have been suggested for moderate-risk subjects, varying from 105 to 110 mg/dL to the goals for low-risk subjects (120 to 130 mg/dL).2,7 These goals are summarized in Table 1. ApoB was not incorporated originally in NCEP 2001 guidelines, apparently because the committee believed that these measurements were not reliable or readily available. However, apoB is now readily and reliably analyzed in most clinical laboratories. Standardization for apoB is available and achievable8; it has been available since the mid-1990s, and is better standardized than HDL cholesterol measurement, which has tended to have deteriorated over the past few years as cheaper on-line or “direct” methods have been introduced. ApoB eliminates the need for, and expense of, more complicated analyses of minor VLDL or LDL subfractions, which are poorly understood and are confusing to physicians. ApoB provides a concept that is easy to understand and has simple cut points that are based on equivalent LDL population distributions or relations to non-HDL; it has already been used in some countries such as Canada, and it has been proposed as an alternative secondary target in the United States. However, there are few data to compare the efficacy of the new lipid-lowering therapies with treatment guidelines to achieve apoB versus non-HDL cholesterol and LDL cholesterol targets. We have assessed these relationships by using a very large database from our laboratory, with ⬎22,000 samples from various clinical trials in which TGs, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and ApoB were available on the same sample (Table 2). Samples were
obtained during various treatment periods, and may reflect multiple samples per patient on different treatments. The treatment could vary in terms of the drug and dose, but it was mainly statin monotherapy and included all the statins and all of the doses that are currently available. All of the analyses were consistent, because they were measured by the same laboratory and by the same method and used the same standardization. Data were analyzed so as to look at those samples with baseline TGs ⬍200 mg/dL (Table 3), and those with baseline TGs 200 to 500 (Table 4). This allowed assessment according to the NCEP guidelines for non-HDL. If assessment is first obtained with the distribution of patients with TGs ⬍200 mg/dL (Table 3), it can be seen that in those with normal TGs, the LDL goal was harder to achieve than the non-HDL goal; this is anticipated because TGs were low and there was less cholesterol in the VLDL fraction. In this database, approximately 60% of patients achieved LDL and non-HDL goals. However, only about 30% (half of those patients) achieved an apoB goal of ⬍90 mg/dL. At very high cut points for LDL cholesterol of ⬎160 mg/dL or non–HDL cholesterol of ⬎190 mg/dL, only 5% of these patients were above these goals. However, 22% had apoB levels that were significantly elevated above the goal of ⬎120 mg/dL. With regard to subjects with baseline TG between 200 and 500 mg/dL (Table 4), although the number of patients at an LDL cholesterol goal of ⬍100 mg/dL still remains around 60%, there is a decrease in subjects reaching a non-HDL cholesterol goal of ⬍130 mg/dL. Again, this is
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Table 3 Lipid distribution: 14,425 samples with baseline triglycerides ⬍200 mg/dL Parameter (mg/dL) LDL-C Non–HDL-C
Goal
Goal
Goal
Goal
⬍70 14% ⬍100 25%
⬍100 58% ⬍130 66% ⬍90 30%
100–⬍130 27% 130–⬍160 21% 90–⬍105 29%
130–⬍160 10% 160–⬍190 8% 105–⬍120 26%
ApoB
Cut Point ⬎160 5% ⬎190 5% ⬎120 22%
ApoB ⫽ apolipoprotein B; LDL-C ⫽ low-density lipoprotein cholesterol; HDL-C ⫽ high-density lipoprotein cholesterol. Table 4 Lipid distribution: 7,611 samples with baseline triglycerides 200 –500 mg/dL Parameter (mg/dL)
Goal
Goal
Goal
Goal
LDL-C
⬍70 15% ⬍100 14%
⬍100 60% ⬍130 51% ⬍90 17% ⬍150 35%
100–⬍130 25% 130–⬍160 29% 90–⬍105 27% 150–⬍200 33%
130–⬍160 14% 160–⬍190 13% 105–⬍120 20% 200–500 32%
Non–HDL-C ApoB Triglyceride during treatment
Cut Point ⬎160 1% ⬎190 7% ⬎120 36%
ApoB ⫽ apolipoprotein B; LDL-C ⫽ low-density lipoprotein cholesterol; HDL-C ⫽ high-density lipoprotein cholesterol.
entirely consistent with what the guidelines were designed to do in order to indicate the need for more aggressive treatment, because these subjects have more small, dense LDL or they have more VLDL. However, in these subjects the number of subjects achieving apoB goals has decreased from 30% of patients to only 17%, and it has increased to nearly 50% of patients who have an apoB of ⬎120 mg/dL. This clearly reflects that there are more atherogenic particles and most likely more small dense LDL. Thus, for baseline TG levels ⬎200 mg/dL, non-HDL targets are harder to reach than LDL cholesterol targets the higher the baseline TGs, thus achieving the objectives of including them in the guidelines. However, apoB goals are the most difficult to achieve and get more difficult, the higher the baseline TGs; this is consistent with more small, dense LDL and a greater burden of atherogenic particles. In patients with high TG levels, while 51% achieve non-HDL goals, only 17% achieve apoB targets. What about correlations between these parameters within these hypertriglyceridemic patient populations? Figure 2 shows data from approximately 4,500 patients who were at their primary goal of an LDL level of ⬍100 mg/dL. When these subjects were at the LDL goal of ⬍100 mg/dL, 84% of the time they were also at the non-HDL goal of ⬍130 mg/dL; the remaining 16% of patients were fairly close to this goal (between 130 and 160 mg/dL). However, when apoB is evaluated, only 30% of the time was it at the equivalent goal of ⬍90 mg/dL. In fact, the same percentage of patients had apoBs 2 cut points away (ie, ⬎120 mg/dL) from what is considered the optimal goal. Most of these
patients had apoB levels in the intermediate cut point (between 90 and 105 mg/dL). In Figure 3, the focus is the non-HDL goal, which is the recommended target for patients with moderate hypertriglyceridemia. Using a non-HDL goal of ⬍130 mg/dL, in the approximately 4,000 samples in this subset, it can be seen that almost all (97%) are also at the LDL cholesterol goal of ⬍100 mg/dL. Although there is an improvement in the number of patients who are at apoB goal from 30% to 34%, and a reduction of those ⬎2 cut points are away from optimal goal from 30% to 22%, more than two thirds of patients are not at apoB goal. What if patients are at their apoB goal of ⬍90 mg/dL? Whereas considerably fewer patients achieve this goal in this study, it is still very robust data (nearly 1,300 patients; Figure 4). These data clearly demonstrate that if an apoB goal of ⬍90 mg/dL is achieved, there is virtual assurance that 100% of the time the patient is going to be both at LDL and non-HDL goals of ⬍100 and ⬍130 mg/dL, respectively. What about the new, more aggressive, cut points promulgated in the recent update of the NCEP ATP III guidelines?2 The assessment is based on an LDL level of ⬍70 mg/dL as the primary cut point in very-high-risk patients (Figure 5). Although it is not easy to reduce LDL cholesterol to ⬍70 mg/dL, it was achieved in ⬎1,100 samples in our database; however, even in these subjects, the goals for non-HDL cholesterol of ⬍100 mg/dL and an apoB of ⬍90 mg/dL were achieved in just 70% of patients. Although most of those not achieving the goals were in the next cut-point range, 5% were 2 cut points higher.
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Figure 2. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein goal of ⬍100 mg/dL (n ⫽ 4,454): distribution of non– high-density lipoprotein cholesterol (non–HDL-C) and apolipoprotein B (apoB) relative to their goals.
Figure 3. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal of ⬍130 mg/dL (n ⫽ 3,884): distribution of LDL-C and apolipoprotein B (apoB) relative to their goals.
LDL-C
Patients (%)
100
non–HDL-C
99% 98%
80 60 40 20
1%
2%
0 LDL-C 100 to <130 mg/dL LDL-C <100 mg/dL non–HDL-C <130 mg/dL non–HDL-C 130 to <160 mg/dL Figure 4. Patients with triglyceride levels of 200 to 500 mg/dL at the apolipoprotein B (apoB) goal of ⬍90 mg/dL (n ⫽ 1,279): distribution of low-density lipoprotein cholesterol (LDL-C) and non– high-density lipoprotein cholesterol (non–HDL-C) relative to their Adult Treatment Panel III goals.
Stein et al/Assessment of Reaching Goals in Patients with Combined Hyperlipidemia
non– HDL- C
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Apo B
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100 80
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60 40
30%
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0 non– HDL- C <100 mg/dL non– HDL- C 100 to <130 mg/dL non– HDL-C >130 mg/dL Apo B >105 mg/dL Apo B 90 to < 105 mg/dL Apo B <90 mg/dL Figure 5. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein cholesterol goal of ⬍70 mg/dL (n ⫽ 1,158): distribution of non– high-density lipoprotein cholesterol (non–HDL-C) and apolipoprotein B (apoB). (Adapted from Circulation.3)
Figure 6. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III non– high-density lipoprotein cholesterol goal of ⬍100 mg/dL (n ⫽ 1,034): distribution of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). (Adapted from Circulation.3)
If one looks at the new non-HDL cholesterol goal (Figure 6), it is, as expected, a little better than the LDL cholesterol in these patients with mild to moderate TG elevation. The LDL cholesterol goal was achieved in approximately 80% of samples, and the remaining 20% achieved levels only slightly above goal. Eighty-five percent of the patients will be at the apoB goal, and the remaining 15% will be just 1 cut point higher, with no one very far from the optimal range. If the new guidelines are viewed in terms of an apoB level ⬍90 mg/dL—a goal unchanged from the original ATP III guidelines—it can be seen from Figure 7 that 64% of patients will be within the LDL cholesterol goal of ⬍70 mg/dL, and 70% will have non-HDL cholesterol ⬍100 mg/dL. There are very few discrepant patients in the ⬎100-mg/dL range. Finally, an alternative way to evaluate the same data is by taking the ATP III guidelines1 and then the newer modifications.2 To begin, we looked at when LDL cholesterol was ⬍100 mg/dL and determined the non-HDL cholesterol and apoB levels. In these samples, mean LDL was 78
mg/dL, mean non-HDL was 113 mg/dL, and mean apoB was 98 mg/dL. Thus, even the average apoB level was above the target of ⬍90 mg/dL. For the non-HDL cholesterol goal of ⬍130 mg/dL, approximately the same mean LDL cholesterol was found, a slightly lower mean non-HDL cholesterol, and a slightly lower mean apoB. However, when an apoB of ⬍90 mg/dL is taken, the mean LDL cholesterol is 66 mg/dL in these patients, the mean nonHDL cholesterol is 94 mg/dL, and the mean apoB is 80 mg/dL. When looking at the recently revised guidelines and the LDL cholesterol of ⬍70 mg/dL, the results are a mean LDL cholesterol ⬍60 mg/dL, a mean non-HDL cholesterol of 94 mg/dL, and a mean apoB of 84 mg/dL. For non-HDL cholesterol goals of ⬍100 mg/dL, the mean LDL cholesterol is 62 mg/dL, mean non-HDL cholesterol is 89 mg/dL, and, because non-HDL cholesterol is a harder target to reach when TGs are elevated, the mean apoB is 81 mg/dL. Similarly, an apoB target of ⬍90 mg/dL is very similar in terms of the levels of LDL and non-HDL cholesterol relative to what the new ATP III guidelines recommend (Figure 7).
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Figure 7. Patients with triglyceride levels of 200 to 500 mg/dL at the apolipoprotein B goal of ⬍90 mg/dL (n ⫽ 1,279): distribiution of non– high-density lipoprotein cholesterol (non–HDL-C) and low-density lipoprotein cholesterol (LDL-C) relative to their Adult Treatment Panel III goals. (Adapted from Circulation.3) Table 5 Superiority of apolipoprotein B (apoB) as guide for both risk and treatment adequacy measurement ● ApoB is a better guide to both risk and adequacy of treatment than either lipid indexes ● ApoB is superior, especially in patients with lipid-poor (“small dense”) lipoproteins where lipid indexes underestimate risk ● The data shown indicate that at an LDL-C target of ⬍100 mg/dL and even ⬍70 mg/dL, a significant number of patients have elevated apoB (⬎90 mg/dL and even ⬎105 mg/dL) ● In patients with elevated triglyceride (TGs), although non–HDL-C is better than LDL-C, it still significantly underestimates atherogenic lipoprotein burden as judged by apoB ● When apoB is ⬍90 mg/dL, values for both LDL-C and non–HDL-C are both almost always below ATP III targets, and approximately half are less than the new cut points ● Current guidelines for LDL-C and non–HDL-C still leaves many patients with elevated apoB levels, especially those with elevated TG levels such as those found in the metabolic syndrome ● In patients with combined HLP and triglyerides 200–500 mg/dL, non–HDL-C, LDL-C, and apoB are not equivalent targets, and thus may not yield the same anticipated reduction in cardiovascular risk with therapy ● ApoB measurements should be incorporated into all end point trials, or measured on stored samples from completed trials to increase information as to possible new lower cut points ● ApoB should be incorporated into guidelines sooner rather than later because they provide a simpler, more reliable objective for clinicians ● ApoB can be more universally applied irrespective of TG levels ATP III ⫽ Adult Treatment Panel III; HDL-C ⫽ high-density lipoprotein cholesterol; HLP ⫽ hyperlipoproteinemia; LDL-C ⫽ low-density lipoprotein cholesterol.
Conclusion In summary, apoB is a better guide to determine both risk and adequacy of treatment than both currently recommended lipid indexes (LDL cholesterol and non-HDL cholesterol) (Table 5). It is superior in patients with mild to moderate hypertriglyceridemia where smaller and less lipidrich (dense) lipoproteins result in the 2 cholesterol indexes grossly underestimating risk. The data presented indicate that at an LDL cholesterol target of ⬍100 mg/dL, and even ⬍70 mg/dL, a number of high-risk patients will still have elevated apoB levels (even ⬎105 mg/dL) 2 cut points away from optimal. In patients with elevated TGs, although nonHDL cholesterol is certainly better than LDL cholesterol as a target, it still significantly underestimates the risk of lipoprotein burden as judged by apoB. When apoB is selected as the target with a goal of ⬍90 mg/dL, values for both LDL
and non-HDL cholesterol are almost always below the original ATP III targets, and more than half of them are below the revised 2004 cut points. ApoB can be more universally applied than either LDL or non-HDL cholesterol, because if apoB goal is reached, then so were goals for non-HDL and LDL cholesterol, irrespective of the baseline TGs. Thus apoB, which is now reliably measured and widely available, is easier for physicians to understand and implement than both LDL and non-HDL cholesterol; it should be incorporated into guidelines sooner, rather than later, because it provides a simple, more reliable objective for clinicians. To confirm the apoB/ apoB A1 ratio as the most reliable and predictive parameters for prospective risk assessment, we would strongly advocate that apoB and apoA1 measurements be incorporated into all end point trials or measured on stored samples from completed trials. This would also increase the information as to more possible optimal cut points.
Stein et al/Assessment of Reaching Goals in Patients with Combined Hyperlipidemia 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486 –2497. 2. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239. [erratum in: Circulation 2004;110:763]. 3. Grundy SM. Low density lipoprotein, non-high density lipoprotein and apolipoprotein B as targets of lipid lowering therapy. Circulation 2002; 106:2526 –2529. 4. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026 –2033.
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5. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budai A, Pais P, Varigos J, Lisheng L, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study). Lancet 2004;364:937–952. 6. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. 7. Genest J, Frohlich J, Fodor G, McPherson R, for the Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. Can Med Assoc J 2003;169;921–924. 8. Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of international reference material. Clin Chem 1994;40:586 –592.
Combined hyperlipidemia (CHL) is perhaps the most common lipid disorder, characterized by moderately elevated triglyceride (TG) levels (200 to 500 mg/dL) and elevated low-density lipoprotein (LDL) cholesterol (⬎130 mg/dL). It is also often associated with reduced high-density lipoprotein (HDL) cholesterol (⬍45 mg/dL) and other established increased risk factors for coronary artery disease (CAD), such as hypertension, obesity, and diabetes. Guidelines for the management of CAD emphasize the importance of riskfactor modification and aggressive treatment to achieve cholesterol and lipoprotein goals.1 However, optimal assessment of reaching goal for patients with CHL continues to be an area of revision, and it was recently modified further in recent guidelines.2 Lipid and lipoprotein indexes used in identifying cardiovascular risk, in implementing treatment, and in judging the adequacy of therapy for CHL include LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB). To assess which of these 3 biomarkers would be most appropriate for determining cardiovascular risk, we begin with a brief overview of the pathophysiology of atherogenic lipoproteins, followed by the relation of these lipid parameters to each other based on current treatment guidelines using a large database incorporating patients with CHL. Figure 1 shows that most atherogenic lipoproteins contain apoB100 and originate in the liver. Additional apoB containing-lipoproteins, apoB48, enter the circulation from a Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio, USA; bMedical Research Laboratories, Highland Heights, Kentucky, USA; and cMcGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada. *Address for reprints: Evan A. Stein, MD, PhD, Metabolic and Atherosclerosis Research Center, Suite 201, 3131 Harvey Avenue, Cincinnati, Ohio, 41075. E-mail address: [email protected].
0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.08.006
the gut as chylomicrons, and are rapidly catabolized to remnant lipoproteins via a mechanism very similar to that of very-low-density lipoprotein (VLDL) cholesterol to intermediate-density lipoprotein cholesterol. As the apoB-containing lipoprotein particles travel through the circulation, there is constant remodeling and lipid transfer between them, other lipoprotein species such as HDL and cells. These interchanges are mediated by a variety of enzymes and cellular receptors. Through this cascade, the amount and type of lipid on the apoB particles is thus constantly changing. Even within the various subclasses of LDL (LDL1, LDL2, LDL3), which are not discrete but arbitrary cuts based on selected densities or other separation techniques, there is a constant differential in the lipid content, because they continue to be remodeled before eventual uptake and degradation by the LDL or apoB receptor. The major focus for diagnosis and treatment over the past 30 years has been on LDL, because when patients have relatively normal TGs, LDL cholesterol accounts for approximately 90% of all plasma cholesterol and most of the atherogenic or apoB-containing lipoproteins. However, as soon as there is a larger proportion of TG-rich lipoproteins, the use of LDL cholesterol becomes less reliable. To capture all of the atherogenic lipoproteins with a relatively easy, inexpensive, and simple test, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines in 2001 introduced the concept of non-HDL cholesterol.2 However, even this non-HDL cholesterol will vary in lipid content per particle (Figure 1), and the only constant component in all of these atherogenic lipoproteins is apoB, because there is always just 1 apoB per lipoprotein particle. It has been postulated that 1 LDL particle is slightly more or less atherogenic than another based on the lipid content3; however, it is well accepted that all apoB particles www.AJConline.org
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N on - H D L -C h o l e s t e ro l III C-
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II C- HL
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V L DL
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Oxidation C D 36
TG
SR-BI
B B
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Nascent HDL
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SR-A Ch olesterol P ool
ABCA1
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Figure 1. Non– high-density lipoprotein (HDL) cholesterol (Chol). ABCA1 ⫽ adensosine triphosphate-binding cassette A1; CETP ⫽ cholesterol ester transfer protein; HL ⫽ hyperlipidemia; IDL ⫽ intermediate-density lipoprotein; LCAT ⫽ lecithin:cholesterol acyltransferase; LDL ⫽ low-density lipoprotein; LDLr ⫽ low-density lipoprotein receptor; LPL ⫽ lipoprotein lipase; SR-A ⫽ scavenger receptor A; SR-B1 ⫽ scavenger receptor B1; TG ⫽ triglycerides; VLDL ⫽ very-low-density lipoprotein. (Adapted with permission from Dr. Bryan Brewer).
carry atherogenic potential and that there is only 1 apoB molecule per lipoprotein irrespective of its size or lipid content. LDL has served as an excellent first step for us to get from an era in which 30 years ago a minority of physicians believed that lowering cholesterol would have benefit on cardiovascular disease, to what is probably now the most solid evidence-based therapy in medicine, that is, that reducing LDL is critical in treating and preventing CAD. Recent guidelines have made an attempt to incorporate non-HDL as a secondary target in order to improve risk determination, especially when there are more TG-rich lipoproteins present. Although it is an easy test to calculate, by subtracting HDL from total cholesterol, it is not well accepted and not understood by clinicians. Even in the United States, only about one third of doctors accept and use non-HDL. It is even less well accepted in the rest of the world. There is also confusion as to when it should be applied; is it when TGs are elevated at baseline before treatment or after treatment? In the light of a number of recent studies, apoB has demonstrated, from prospective epidemiologic studies such as Apolipoprotein-Related Mortality Risk (AMORIS4 and Inter-Heart),5 and randomized treatment studies such as Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)6 to be superior to LDL or non–HDL cholesterol for prospectively determining cardiovascular risk. From the recent Inter-Heart5 and AFCAPS/TexCAPS6 studies, the single most powerful predictor of all of the routine risk factors for CAD, and 1 with a very good linear risk relation, is the apoB/apo A1 ratio, which takes into account all atherogenic and nonatherogenic lipoprotein spe-
cies. This was best demonstrated in AFCAPS/TexCAPS, where the on-treatment LDL cholesterol values at 1 year showed a “gap” in cardiovascular disease risk between those taking a statin and those taking a placebo. This gap diminishes substantially if apoB is substituted and is totally eliminated if the apoB/apoA1 ratio is used. In fact, it made no difference what treatment group a patient was assigned to in AFCAPS/TexCAPS, because only the apoB/apoA1 ratio determined future risk. Therefore, the apoB/apo A1 ratio is not only very predictive in epidemiologic studies, it is also predictive in prospective randomized trials. With regard to treatment guidelines, the NCEP ATP III1 introduced the concept of non-HDL cholesterol in patients who had elevated TG levels defined as 200 to 500 mg/dL. This lower cut point is similar to what was also incorporated in the definition of the metabolic syndrome. Non-HDL targets were set 30 mg/dL higher than those for LDL cholesterol at each risk strata. Some of the reasons for selecting non-HDL cholesterol was because it was simple, inexpensive, reliably measured, easily calculated, and also could be measured in patients who were not fasting, because neither total nor HDL cholesterol is significantly affected by food intake. It was also an attempt to provide a surrogate for all apoB lipoproteins that contribute to atherosclerosis (ie, a measurement of atherogenic cholesterol). The initial ATP III goal for LDL cholesterol in high-risk subjects was ⬍100 mg/dL, but that has recently been modified2 to an optional goal of ⬍70 mg/dL in very-high-risk patients; the non-HDL, which in the ATP III was ⬍130 mg/dL, has also been modified in very-high-risk patients to ⬍100 mg/dL. The apoB goal is now suggested at ⬍90
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Table 1 Adult Treatment Panel III (ATP III): low-density lipoprotein cholesterol (LDL-C), non– high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (apoB) goals and treatment cutpoints Risk Category
Non–HDL-C Goal (only if TG 200–500 mg/dL)
LDL-C Goal
High risk: CAD or CAD risk equivalents (10-yr risk ⬎20%) Moderately high risk: ⬎2 risk factors (10-yr risk 10%–20%) Moderate risk: ⱖ2 risk factors (10-yr risk ⬍10%) Lower risk: 0–1 risk factor
†
ApoB Goal
⬍100 mg/dL (optional: ⬍70 mg/dL)
⬍130 mg/dL (optional: ⬍100 mg/dL)†
⬍130 mg/dL (optional: ⬍100 mg/dL)
⬍160 mg/dL (optional: ⬍130 mg/dL)
⬍130 mg/dL
⬍160 mg/dL
⬍90 mg/dL* (? new optional: ⬍80 mg/dL) ⬍105 mg/dL (⬍110 mg/dL)* (optional: ⬍90 mg/dL) ⬍105 mg/dL (⬍110 mg/dL)*
⬍160 mg/dL
⬍190 mg/dL
⬍120 mg/dL (⬍130 mg/dL)*
* Adapted from Circulation3 and Can Med Assoc J.7 Adapted from Circulation.2 CAD ⫽ coronary artery disease; TG ⫽ triglycerides. †
Table 2 Correlation of low-density lipoprotein cholesterol (LDL-C), non– high-density lipoprotein cholesterol (non–HDL-C), and apolipoprotein B (apoB) 22,070 samples from a large clinical database where cholesterol, triglyceride (TG), HDL-C, LDLC, and apoB were available on the same samples Samples taken during treatment periods; multiple samples per patient; Rx could vary both in terms of drug (mainly statin monotherapy) and dose All analysis by same laboratory, methods, and standardization 14,425 samples with TGs ⬍200 mg/dL analyzed separately as a subset 7,611 samples with TGs 200–500 mg/dL analyzed separately as a subset Rx ⫽ treatment.
mg/dL as a tertiary goal.2 Other goals for apoB have been suggested for moderate-risk subjects, varying from 105 to 110 mg/dL to the goals for low-risk subjects (120 to 130 mg/dL).2,7 These goals are summarized in Table 1. ApoB was not incorporated originally in NCEP 2001 guidelines, apparently because the committee believed that these measurements were not reliable or readily available. However, apoB is now readily and reliably analyzed in most clinical laboratories. Standardization for apoB is available and achievable8; it has been available since the mid-1990s, and is better standardized than HDL cholesterol measurement, which has tended to have deteriorated over the past few years as cheaper on-line or “direct” methods have been introduced. ApoB eliminates the need for, and expense of, more complicated analyses of minor VLDL or LDL subfractions, which are poorly understood and are confusing to physicians. ApoB provides a concept that is easy to understand and has simple cut points that are based on equivalent LDL population distributions or relations to non-HDL; it has already been used in some countries such as Canada, and it has been proposed as an alternative secondary target in the United States. However, there are few data to compare the efficacy of the new lipid-lowering therapies with treatment guidelines to achieve apoB versus non-HDL cholesterol and LDL cholesterol targets. We have assessed these relationships by using a very large database from our laboratory, with ⬎22,000 samples from various clinical trials in which TGs, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and ApoB were available on the same sample (Table 2). Samples were
obtained during various treatment periods, and may reflect multiple samples per patient on different treatments. The treatment could vary in terms of the drug and dose, but it was mainly statin monotherapy and included all the statins and all of the doses that are currently available. All of the analyses were consistent, because they were measured by the same laboratory and by the same method and used the same standardization. Data were analyzed so as to look at those samples with baseline TGs ⬍200 mg/dL (Table 3), and those with baseline TGs 200 to 500 (Table 4). This allowed assessment according to the NCEP guidelines for non-HDL. If assessment is first obtained with the distribution of patients with TGs ⬍200 mg/dL (Table 3), it can be seen that in those with normal TGs, the LDL goal was harder to achieve than the non-HDL goal; this is anticipated because TGs were low and there was less cholesterol in the VLDL fraction. In this database, approximately 60% of patients achieved LDL and non-HDL goals. However, only about 30% (half of those patients) achieved an apoB goal of ⬍90 mg/dL. At very high cut points for LDL cholesterol of ⬎160 mg/dL or non–HDL cholesterol of ⬎190 mg/dL, only 5% of these patients were above these goals. However, 22% had apoB levels that were significantly elevated above the goal of ⬎120 mg/dL. With regard to subjects with baseline TG between 200 and 500 mg/dL (Table 4), although the number of patients at an LDL cholesterol goal of ⬍100 mg/dL still remains around 60%, there is a decrease in subjects reaching a non-HDL cholesterol goal of ⬍130 mg/dL. Again, this is
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Table 3 Lipid distribution: 14,425 samples with baseline triglycerides ⬍200 mg/dL Parameter (mg/dL) LDL-C Non–HDL-C
Goal
Goal
Goal
Goal
⬍70 14% ⬍100 25%
⬍100 58% ⬍130 66% ⬍90 30%
100–⬍130 27% 130–⬍160 21% 90–⬍105 29%
130–⬍160 10% 160–⬍190 8% 105–⬍120 26%
ApoB
Cut Point ⬎160 5% ⬎190 5% ⬎120 22%
ApoB ⫽ apolipoprotein B; LDL-C ⫽ low-density lipoprotein cholesterol; HDL-C ⫽ high-density lipoprotein cholesterol. Table 4 Lipid distribution: 7,611 samples with baseline triglycerides 200 –500 mg/dL Parameter (mg/dL)
Goal
Goal
Goal
Goal
LDL-C
⬍70 15% ⬍100 14%
⬍100 60% ⬍130 51% ⬍90 17% ⬍150 35%
100–⬍130 25% 130–⬍160 29% 90–⬍105 27% 150–⬍200 33%
130–⬍160 14% 160–⬍190 13% 105–⬍120 20% 200–500 32%
Non–HDL-C ApoB Triglyceride during treatment
Cut Point ⬎160 1% ⬎190 7% ⬎120 36%
ApoB ⫽ apolipoprotein B; LDL-C ⫽ low-density lipoprotein cholesterol; HDL-C ⫽ high-density lipoprotein cholesterol.
entirely consistent with what the guidelines were designed to do in order to indicate the need for more aggressive treatment, because these subjects have more small, dense LDL or they have more VLDL. However, in these subjects the number of subjects achieving apoB goals has decreased from 30% of patients to only 17%, and it has increased to nearly 50% of patients who have an apoB of ⬎120 mg/dL. This clearly reflects that there are more atherogenic particles and most likely more small dense LDL. Thus, for baseline TG levels ⬎200 mg/dL, non-HDL targets are harder to reach than LDL cholesterol targets the higher the baseline TGs, thus achieving the objectives of including them in the guidelines. However, apoB goals are the most difficult to achieve and get more difficult, the higher the baseline TGs; this is consistent with more small, dense LDL and a greater burden of atherogenic particles. In patients with high TG levels, while 51% achieve non-HDL goals, only 17% achieve apoB targets. What about correlations between these parameters within these hypertriglyceridemic patient populations? Figure 2 shows data from approximately 4,500 patients who were at their primary goal of an LDL level of ⬍100 mg/dL. When these subjects were at the LDL goal of ⬍100 mg/dL, 84% of the time they were also at the non-HDL goal of ⬍130 mg/dL; the remaining 16% of patients were fairly close to this goal (between 130 and 160 mg/dL). However, when apoB is evaluated, only 30% of the time was it at the equivalent goal of ⬍90 mg/dL. In fact, the same percentage of patients had apoBs 2 cut points away (ie, ⬎120 mg/dL) from what is considered the optimal goal. Most of these
patients had apoB levels in the intermediate cut point (between 90 and 105 mg/dL). In Figure 3, the focus is the non-HDL goal, which is the recommended target for patients with moderate hypertriglyceridemia. Using a non-HDL goal of ⬍130 mg/dL, in the approximately 4,000 samples in this subset, it can be seen that almost all (97%) are also at the LDL cholesterol goal of ⬍100 mg/dL. Although there is an improvement in the number of patients who are at apoB goal from 30% to 34%, and a reduction of those ⬎2 cut points are away from optimal goal from 30% to 22%, more than two thirds of patients are not at apoB goal. What if patients are at their apoB goal of ⬍90 mg/dL? Whereas considerably fewer patients achieve this goal in this study, it is still very robust data (nearly 1,300 patients; Figure 4). These data clearly demonstrate that if an apoB goal of ⬍90 mg/dL is achieved, there is virtual assurance that 100% of the time the patient is going to be both at LDL and non-HDL goals of ⬍100 and ⬍130 mg/dL, respectively. What about the new, more aggressive, cut points promulgated in the recent update of the NCEP ATP III guidelines?2 The assessment is based on an LDL level of ⬍70 mg/dL as the primary cut point in very-high-risk patients (Figure 5). Although it is not easy to reduce LDL cholesterol to ⬍70 mg/dL, it was achieved in ⬎1,100 samples in our database; however, even in these subjects, the goals for non-HDL cholesterol of ⬍100 mg/dL and an apoB of ⬍90 mg/dL were achieved in just 70% of patients. Although most of those not achieving the goals were in the next cut-point range, 5% were 2 cut points higher.
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Figure 2. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein goal of ⬍100 mg/dL (n ⫽ 4,454): distribution of non– high-density lipoprotein cholesterol (non–HDL-C) and apolipoprotein B (apoB) relative to their goals.
Figure 3. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal of ⬍130 mg/dL (n ⫽ 3,884): distribution of LDL-C and apolipoprotein B (apoB) relative to their goals.
LDL-C
Patients (%)
100
non–HDL-C
99% 98%
80 60 40 20
1%
2%
0 LDL-C 100 to <130 mg/dL LDL-C <100 mg/dL non–HDL-C <130 mg/dL non–HDL-C 130 to <160 mg/dL Figure 4. Patients with triglyceride levels of 200 to 500 mg/dL at the apolipoprotein B (apoB) goal of ⬍90 mg/dL (n ⫽ 1,279): distribution of low-density lipoprotein cholesterol (LDL-C) and non– high-density lipoprotein cholesterol (non–HDL-C) relative to their Adult Treatment Panel III goals.
Stein et al/Assessment of Reaching Goals in Patients with Combined Hyperlipidemia
non– HDL- C
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Apo B
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100 80
70% 70%
60 40
30%
20
25% 5%
0 non– HDL- C <100 mg/dL non– HDL- C 100 to <130 mg/dL non– HDL-C >130 mg/dL Apo B >105 mg/dL Apo B 90 to < 105 mg/dL Apo B <90 mg/dL Figure 5. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III low-density lipoprotein cholesterol goal of ⬍70 mg/dL (n ⫽ 1,158): distribution of non– high-density lipoprotein cholesterol (non–HDL-C) and apolipoprotein B (apoB). (Adapted from Circulation.3)
Figure 6. Patients with triglyceride levels of 200 to 500 mg/dL at the Adult Treatment Panel III non– high-density lipoprotein cholesterol goal of ⬍100 mg/dL (n ⫽ 1,034): distribution of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). (Adapted from Circulation.3)
If one looks at the new non-HDL cholesterol goal (Figure 6), it is, as expected, a little better than the LDL cholesterol in these patients with mild to moderate TG elevation. The LDL cholesterol goal was achieved in approximately 80% of samples, and the remaining 20% achieved levels only slightly above goal. Eighty-five percent of the patients will be at the apoB goal, and the remaining 15% will be just 1 cut point higher, with no one very far from the optimal range. If the new guidelines are viewed in terms of an apoB level ⬍90 mg/dL—a goal unchanged from the original ATP III guidelines—it can be seen from Figure 7 that 64% of patients will be within the LDL cholesterol goal of ⬍70 mg/dL, and 70% will have non-HDL cholesterol ⬍100 mg/dL. There are very few discrepant patients in the ⬎100-mg/dL range. Finally, an alternative way to evaluate the same data is by taking the ATP III guidelines1 and then the newer modifications.2 To begin, we looked at when LDL cholesterol was ⬍100 mg/dL and determined the non-HDL cholesterol and apoB levels. In these samples, mean LDL was 78
mg/dL, mean non-HDL was 113 mg/dL, and mean apoB was 98 mg/dL. Thus, even the average apoB level was above the target of ⬍90 mg/dL. For the non-HDL cholesterol goal of ⬍130 mg/dL, approximately the same mean LDL cholesterol was found, a slightly lower mean non-HDL cholesterol, and a slightly lower mean apoB. However, when an apoB of ⬍90 mg/dL is taken, the mean LDL cholesterol is 66 mg/dL in these patients, the mean nonHDL cholesterol is 94 mg/dL, and the mean apoB is 80 mg/dL. When looking at the recently revised guidelines and the LDL cholesterol of ⬍70 mg/dL, the results are a mean LDL cholesterol ⬍60 mg/dL, a mean non-HDL cholesterol of 94 mg/dL, and a mean apoB of 84 mg/dL. For non-HDL cholesterol goals of ⬍100 mg/dL, the mean LDL cholesterol is 62 mg/dL, mean non-HDL cholesterol is 89 mg/dL, and, because non-HDL cholesterol is a harder target to reach when TGs are elevated, the mean apoB is 81 mg/dL. Similarly, an apoB target of ⬍90 mg/dL is very similar in terms of the levels of LDL and non-HDL cholesterol relative to what the new ATP III guidelines recommend (Figure 7).
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Figure 7. Patients with triglyceride levels of 200 to 500 mg/dL at the apolipoprotein B goal of ⬍90 mg/dL (n ⫽ 1,279): distribiution of non– high-density lipoprotein cholesterol (non–HDL-C) and low-density lipoprotein cholesterol (LDL-C) relative to their Adult Treatment Panel III goals. (Adapted from Circulation.3) Table 5 Superiority of apolipoprotein B (apoB) as guide for both risk and treatment adequacy measurement ● ApoB is a better guide to both risk and adequacy of treatment than either lipid indexes ● ApoB is superior, especially in patients with lipid-poor (“small dense”) lipoproteins where lipid indexes underestimate risk ● The data shown indicate that at an LDL-C target of ⬍100 mg/dL and even ⬍70 mg/dL, a significant number of patients have elevated apoB (⬎90 mg/dL and even ⬎105 mg/dL) ● In patients with elevated triglyceride (TGs), although non–HDL-C is better than LDL-C, it still significantly underestimates atherogenic lipoprotein burden as judged by apoB ● When apoB is ⬍90 mg/dL, values for both LDL-C and non–HDL-C are both almost always below ATP III targets, and approximately half are less than the new cut points ● Current guidelines for LDL-C and non–HDL-C still leaves many patients with elevated apoB levels, especially those with elevated TG levels such as those found in the metabolic syndrome ● In patients with combined HLP and triglyerides 200–500 mg/dL, non–HDL-C, LDL-C, and apoB are not equivalent targets, and thus may not yield the same anticipated reduction in cardiovascular risk with therapy ● ApoB measurements should be incorporated into all end point trials, or measured on stored samples from completed trials to increase information as to possible new lower cut points ● ApoB should be incorporated into guidelines sooner rather than later because they provide a simpler, more reliable objective for clinicians ● ApoB can be more universally applied irrespective of TG levels ATP III ⫽ Adult Treatment Panel III; HDL-C ⫽ high-density lipoprotein cholesterol; HLP ⫽ hyperlipoproteinemia; LDL-C ⫽ low-density lipoprotein cholesterol.
Conclusion In summary, apoB is a better guide to determine both risk and adequacy of treatment than both currently recommended lipid indexes (LDL cholesterol and non-HDL cholesterol) (Table 5). It is superior in patients with mild to moderate hypertriglyceridemia where smaller and less lipidrich (dense) lipoproteins result in the 2 cholesterol indexes grossly underestimating risk. The data presented indicate that at an LDL cholesterol target of ⬍100 mg/dL, and even ⬍70 mg/dL, a number of high-risk patients will still have elevated apoB levels (even ⬎105 mg/dL) 2 cut points away from optimal. In patients with elevated TGs, although nonHDL cholesterol is certainly better than LDL cholesterol as a target, it still significantly underestimates the risk of lipoprotein burden as judged by apoB. When apoB is selected as the target with a goal of ⬍90 mg/dL, values for both LDL
and non-HDL cholesterol are almost always below the original ATP III targets, and more than half of them are below the revised 2004 cut points. ApoB can be more universally applied than either LDL or non-HDL cholesterol, because if apoB goal is reached, then so were goals for non-HDL and LDL cholesterol, irrespective of the baseline TGs. Thus apoB, which is now reliably measured and widely available, is easier for physicians to understand and implement than both LDL and non-HDL cholesterol; it should be incorporated into guidelines sooner, rather than later, because it provides a simple, more reliable objective for clinicians. To confirm the apoB/ apoB A1 ratio as the most reliable and predictive parameters for prospective risk assessment, we would strongly advocate that apoB and apoA1 measurements be incorporated into all end point trials or measured on stored samples from completed trials. This would also increase the information as to more possible optimal cut points.
Stein et al/Assessment of Reaching Goals in Patients with Combined Hyperlipidemia 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486 –2497. 2. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239. [erratum in: Circulation 2004;110:763]. 3. Grundy SM. Low density lipoprotein, non-high density lipoprotein and apolipoprotein B as targets of lipid lowering therapy. Circulation 2002; 106:2526 –2529. 4. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026 –2033.
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5. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budai A, Pais P, Varigos J, Lisheng L, for the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study). Lancet 2004;364:937–952. 6. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477– 484. 7. Genest J, Frohlich J, Fodor G, McPherson R, for the Working Group on Hypercholesterolemia and Other Dyslipidemias. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. Can Med Assoc J 2003;169;921–924. 8. Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of international reference material. Clin Chem 1994;40:586 –592.