Apolipoprotein B: A better measure of cardiac risk than LDL?

February 27, 2003

Thu, 27 Feb 2003 23:30:00

Montreal, QC - Measurement of apolipoprotein B could be a more reliable indicator of cardiovascular disease than the measurement of LDL cholesterol, according to a new review published this week in the Lancet.

The authors, led by Dr Allan Sniderman (Mike Rosenbloom Laboratory for Cardiovascular Research, Montreal, QC), report that four large prospective studies have shown that apolipoprotein B is superior to total cholesterol or LDL cholesterol to predict the risk of vascular disease. They also report that the ratio of apolipoprotein B/apolipoprotein A-1 is superior to the conventional LDL/HDL cholesterol ratio as an overall index of cardiovascular risk and that apolipoproteins are also thought to be more sensitive markers than LDL cholesterol for guiding treatment with statins.

One of authors, Dr Goran Walldius (AstraZeneca and the Karolinska Institute, Stockholm, Sweden) comments: "LDL cholesterol concentration is now used in clinical practice as the prime index of risk of vascular disease and the main target for therapy. However, data now suggest that values of apolipoprotein B and the apolipoprotein B/apolipoprotein A-1 ratio are more sensitive indices of risk of vascular diseaseand are more robust predictors of future vascular events for patients on statin therapythan concentrations of LDL cholesterol, non-HDL cholesterol, or the LDL/HDL cholesterol ratio. Thus, apolipoprotein-B-guided statin therapy should be more effective in prevention of vascular events than treatment guided by LDL cholesterol."

In their Lancet paper, the authors explain that LDL cholesterol is an estimate of the mass of cholesterol in the LDL fraction in plasma whereas apolipoprotein B is a measurement of the total number of atherogenic particles. "Results of many studies show that apolipoprotein B is a better marker of risk of vascular disease and a better guide to the adequacy of statin treatment than any cholesterol index," they state.

The largest of these studies is the Apolipoprotein-Related Mortality Risk Study (AMORIS), which was designed to compare concentrations of LDL cholesterol and apolipoprotein B as predictors of fatal acute myocardial infarction in 175553 adults followed up for 5.5 years. In this study, apolipoprotein B and apolipoprotein A-1 were highly significant predictors at any concentration of total cholesterol and triglycerides in both sexes and at all ages, whereas LDL cholesterol concentration was marginally significant in men, but not in women and not in older patients, Sniderman et al report. The strongest univariate predictor was the apolipoprotein B/apolipoprotein A-1 ratio, and in multivariate analyses, this ratio was better than any cholesterol ratio in both men and women at predicting cardiovascular risk, they add.


Apolipoprotein-B-guided statin therapy should be more effective in prevention of vascular events than treatment guided by LDL cholesterol.


They also claim that most studies of statins have found that apolipoprotein B values are more predictive of future coronary events than LDL cholesterol concentration when patients are on treatment, a finding that, they say, is clinically important in establishing the correct statin dose.

In general, statins produce closely similar percent reductions in concentrations of LDL cholesterol and apolipoprotein B, but in patients with small dense LDL, the number of LDL particles will be higher than LDL cholesterol, so on-treatment LDL cholesterol concentration will give an inaccurate impression of the extent to which atherogenic particle number has been reduced, and treatment guided by this value could result in undertreatment, they explain. "By measuring apo B, we can include small dense LDL in assessing risk. This is one of the most common abnormalities in lipid metabolism but is not measured accurately by just considering LDL," Sniderman commented to heartwire .

The authors note that in addition to apolipoprotein B's being substantially more effective in preventing cardiovascular events than treatment guided by LDL cholesterol, using apolipoprotein levels to guide statin therapy has further practical advantages, such as the simplicity of focusing on one rather than several variables and the lack of the necessity for fasting blood samples, which are required for LDL measurements. "This is not a trivial issue," Sniderman says: "By doing away for the need [for a patient] to be fasting when having lipid measurements taken, we would be making care much more accessible and patient friendly. This is substantial progress."

Sniderman et al conclude that measurement of apolipoproteins should now be introduced broadly into clinical practice. However, noting that the importance of cholesterol is densely entrenched within the medical profession and public, they say that "the pace of change will be determined, in part at least, by how resistant conventional belief is to emerging clinical evidence."

More evidence needed?

However, Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas), who heads up the US National Cholesterol Education Program (NCEP) guidelines committee, says there is not yet enough evidence to switch from LDL to apo B as the primary measurement to assess cardiovascular risk.

In an editorial published in Circulation at the end of last year, Dr Grundy noted that the most recent US guidelines (ATP III) placed more emphasis on measurements other than LDL as secondary targets of lipid-modifying therapy than did previous guidelines. In particular, non-HDL cholesterol (which includes LDL and the triglycerides-rich lipoproteins VLDL and IDL), which Grundy said correlates with apo B, was highlighted as a secondary target in persons with elevated triglyceride levels.

Grundy says there are several arguments in favor of using either non-HDL cholesterol or apo B instead of LDL in clinical cholesterol guidelines. These include the fact that both non-HDL and apo B are markers for all of the potentially atherogenic lipoproteins, and there is some evidence that these markers have greater predictive power over LDL. And he agrees that use of non-HDL cholesterol or apo B adds an element of simplicity to guidelines by combining all atherogenic lipoproteins into a single fraction.

But he says that ATP III chose not to replace LDL with non-HDL cholesterol or apo B as the primary target of therapy for several reasons. These include the fact that LDL currently represents the most robust target of therapy, and its designation as the primary target has been widely accepted. "Modifying the primary target without stronger evidence would introduce considerable confusion into the medical community."


Modifying the primary target without stronger evidence would introduce considerable confusion into the medical community.


Grundy says in the editorial that despite these arguments, ATP III recognized that increasing information points to an atherogenic role for lipoproteins other than LDL, and whether non-HDL cholesterol or total apo B may someday replace LDL cholesterol altogether as the primary target must depend on the acquisition of enough new data to justify a major conceptual shift in cholesterol management.

While Sniderman says he is heartened that the NCEP committee has taken on board the idea that LDL may not be the only important lipoprotein to measure, he still takes issue with several of Grundy's comments. He believes there is now sufficient evidence to justify a change to measuring apo B as the primary risk factor. "The AMORIS trial included 175000 patientshow much more evidence can be required?" he asks. "We believe that considerably more benefit could be achieved than that seen so far in clinical trials, and the 25% reduction in cardiac events so far shown with the statins could actually be increased to a 50% reduction if apo B were used to guide therapy," Sniderman commented to heartwire . He explained that changing to apo B would not affect evidence from the statin drug trials. "The same drugs that lower LDL best will also lower apo B best, but by using apo B we can identify those patients who need higher doses."


Physicians have the capacity to change, and patients won't be worried by progress.


"We have seen 25 years in which the emphasis has been on cholesterol. That is going to be hard to change. But the US guidelines have placed too much weight on continuity. This is not as desirable as evidence. Physicians have the capacity to change, and patients won't be worried by progress."

Grundy still not convinced

In an interview with heartwire on the current Lancet paper, Grundy said he was still not convinced by Sniderman's arguments. He pointed out that it is necessary to incorporate all the risk factorsnot just a single one like apo Binto the risk model to determine a person's absolute risk for CVD. "Since there are insufficient studies to relate apo B to all of the other risk factors, it is not possible to use apo B in global risk assessment at this time," he commented.

"In fact, apo B is correlated with some other risk factors, so you would have to subtract some of the risk associated with apo B when using it in global risk assessment. You don't have to do this with LDL since it is a completely independent risk factor," he noted. "This issue is much more complex than it appears on the surface. It is not a question of whether apo B or LDL is better in itself but whether apo B or LDL fit better in a total risk model," he added.

Sniderman responds

In response to these comments, Sniderman said he was uncertain exactly what Grundy was referring to regarding correlation of apo B with other risk factors. "Of course, we are not suggesting that nothing other than apo B be measured. Apo B does correlate with the cholesterol indices but that does not affect the evidence that it works better. LDL is the prime target picked by ATP III to judge the adequacy of statin therapy. Our review of the evidence indicates apo B is better. That is a straightforward comparison: one vs the other."


Our review of the evidence indicates apo B is better. . . . My personal view is we should go with the best evidence.


Noting that the ATP-III position is driven very much by the results of the Framingham study, Sniderman added: "The Framingham study has contributed enormously to our understanding of cardiovascular risk factors, but it is not the only study and it is not in all regards the best study. My personal view is we should go with the best evidence."

Related link

[HeartWire > News; Dec 13, 2001]


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