From Heartwire — a professional news service of WebMD

June 23, 2008 — An analysis of two studies that contributed to reducing low-density lipoprotein (LDL)-cholesterol levels to lower and lower targets has shown that on-treatment levels of non–high-density lipoprotein (HDL) cholesterol and apolipoprotein B were more closely associated with cardiovascular outcomes than levels of LDL cholesterol [1].

Demonstrating the superiority of non-HDL cholesterol or apoB over LDL cholesterol as a cardiovascular risk predictor during statin treatment, lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and colleagues state: "These data suggest that future guidelines should favor the use of non-HDL cholesterol or apolipoprotein B instead of LDL cholesterol as the primary treatment target, especially because targets are currently adjusted downward to very low LDL-cholesterol levels."

The findings, published in the June 10, 2008 issue of Circulation, are from a post hoc analysis of two studies: the Treating to New Targets (TNT) and Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials, both of which have been reported by heartwire and both of which were part of the transition to treating to lower LDL-cholesterol targets.

Making room for non-HDL cholesterol and apoB

Dr John LaRosa (State University of New York Health Sciences Center, Brooklyn), who was a coauthor of the study, noted that non-HDL cholesterol is already being used as a secondary target in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) guidelines in patients with elevated triglyceride levels. He told heartwire that the field is slowly moving toward measuring apoB for assessment of cardiovascular risk.

"When you use LDL cholesterol, you don't take into account the intermediate-density particles, things that have more triglycerides in them but still have a lot of cholesterol," he said. "These might not be an issue for people with very elevated LDL-cholesterol levels, but there are subgroups with borderline LDL levels and high triglycerides, and these people might be carrying around the intermediate particles where, while they don't contain as much cholesterol, they still have the potential to get caught in the walls of blood vessels and cause atherosclerosis."

LDL cholesterol remains the chief target of therapy in the management of cardiovascular disease risk. However, other targets, including non-HDL cholesterol, which is the sum of all the cholesterol in the proatherogenic lipoproteins, and apoB [apolipoprotein B], the major apolipoprotein of very low-density lipoprotein, intermediate-density lipoprotein, and LDL particles, have been proposed. In fact, hardly a major atherosclerosis meeting goes by without a scheduled debate over the relative merits of LDL cholesterol vs other apolipoproteins, particularly apoB. Elevated high apoB levels, it's often noted, are common in patients with diabetes, insulin resistance, or abdominal obesity, and some of these patients might have low LDL levels, thus creating a gap in treating these higher-risk patients.

With the TNT and IDEAL post hoc analysis, investigators sought to determine the relative association of apoB and non-HDL cholesterol with cardiovascular events. Both studies (TNT included 10,001 patients with stable coronary disease, and IDEAL included 8888 patients with a history of myocardial infarction [MI]) compared high-dose statin treatment with usual-dose therapy for the secondary prevention of cardiovascular events.

In the analysis, LDL cholesterol, non-HDL cholesterol, apoB, and total/HDL-cholesterol, LDL/HDL-cholesterol, and apoB/A1 ratios were all associated with the occurrence of major cardiovascular events, with non-HDL cholesterol and apoB having the strongest association among the variables.

Relationships between on-treatment levels of lipids and apolipoproteins and major cardiovascular events in TNT and IDEAL

In a comparison of the relative strengths of association of the study variables with major cardiovascular risk, investigators showed that when LDL and non-HDL cholesterol were included simultaneously in a hazards model, only non-HDL retained the positive association. Similar findings were observed in a model that included apoB and LDL cholesterol, with only apoB retaining the positive association. When apoB and non-HDL were included in a model, neither was significant due to colinearity, report investigators.

Direct comparisons of relationships with major cardiovascular events for on-treatment levels of LDL, non-HDL, and apolipoprotein B

Speaking with heartwire , LaRosa said that in this study, and from a practical standpoint, apoB and non-HDL cholesterol are equivalent in their association with cardiovascular risk. "Once you say that, non-HDL is probably a preferable measurement, because all you have to do is measure total cholesterol and HDL cholesterol, and subtracting the HDL cholesterol from total cholesterol, you have a very good indication of cardiovascular risk."

LaRosa said this study provides the first data from randomized clinical-end-point trials looking at the association of apoB and non-HDL cholesterol, although there have been other population studies, but they will be just one part of a larger body of evidence that marks the shift toward measurements other than LDL cholesterol. Although the body of evidence supporting apoB and non-HDL cholesterol is not nearly as full as support for LDL reducing cardiovascular events, LaRosa said major trials would not need to be repeated. Researchers analyzing the data patient-by-patient would be able to determine whether the association between apoB, non-HDL, and cardiovascular risk exists in these studies, as the measurements have already been recorded.

Asked about concerns that the public is only starting to understand the importance of LDL cholesterol and what the change emphasizing apoB or non-HDL cholesterol might do to education efforts, LaRosa said this is a justifiable concern. However, in recent decades the focus has shifted from total to LDL cholesterol, and the public eventually will catch up in its understanding.

Pfizer sponsored the TNT and IDEAL studies. Dr. Kastelein has received research funding, consultant fees, and honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Schering-Plough, and Sankyo. Dr. LaRosa has received consulting fees from Pfizer, Merck, Bristol-Myers Squibb, and AstraZeneca, and lecture fees from Pfizer. The complete list of disclosures is available in the original article.

Source

1. Kastelein JJ, van der Steeg WA, Holme I, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002-3009.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

Study Highlights

• This post hoc analysis combined data from 2 prospective clinical trials in which patients with established coronary heart disease were randomized to receive usual-dose or high-dose statin treatment.
• The goal of the analysis was to compare the relationships of on-treatment levels of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I levels with the occurrence of cardiovascular events in patients treated with statins.
• The study sample consisted of 10,001 patients enrolled in the TNT and 8888 enrolled in the IDEAL trials.
• Patients were eligible only if they had clinically apparent coronary artery disease.
• All patients received statin therapy.
• Mean age of the pooled population was 61.3 ± 9.1 years; 81.0% were men.
• The main endpoint was a composite of coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal or nonfatal stroke.
• In models that included LDL cholesterol levels, both non-HDL cholesterol and apolipoprotein B levels were positively associated with cardiovascular outcome, but a positive relationship with LDL cholesterol levels was lost.
• In a model including both non-HDL cholesterol and apolipoprotein B levels, neither variable was significantly predictive of cardiovascular outcome because of collinearity.
• Compared with individual proatherogenic lipoprotein parameters, the total/HDL cholesterol ratio, and the apolipoprotein B/A-I ratio in particular, were each more closely associated with cardiovascular outcome.
• Reanalysis of the data with an endpoint of myocardial infarction led to the same pattern of findings.
• The investigators concluded that in patients treated with statins, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome vs levels of LDL cholesterol.
• These relationships were further strengthened when measurements of the antiatherogenic lipoprotein cholesterol fraction were included.
• The investigators further suggest that these findings support the use of non-HDL cholesterol or apolipoprotein B levels as novel treatment targets for statin therapy.
• However, they deem it premature to consider the ratio variables as clinically useful because no interventions have been proven to consistently reduce cardiovascular disease risk by raising plasma levels of HDL cholesterol or apolipoprotein A-I.
• Limitations of this analysis include lack of generalizability to patients without clinically evident coronary artery disease treated with statins; predominantly male, elderly sample; endpoint consisting of several types of atherosclerotic disease; and selection of patients with a narrow range of LDL cholesterol limits.

Pearls for Practice

• In models that included LDL cholesterol levels, both non-HDL cholesterol and apolipoprotein B levels were positively associated with cardiovascular outcome, but a positive relationship with LDL cholesterol levels was lost. In a model including both non-HDL cholesterol and apolipoprotein B levels, neither variable was significantly predictive of cardiovascular outcome because of collinearity.
• Compared with individual lipoprotein cholesterol values, the total/HDL cholesterol ratio, and the apolipoprotein B/A-I ratio in particular, were each more closely associated with cardiovascular outcome. This was true when a composite endpoint of coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal or nonfatal stroke, or an endpoint of myocardial infarction alone, was used.

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