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Refining Our Measurements
New Study Links Small LDL Subclasses to Cardiovascular Disease Outcomes

March, 2013 – A groundbreaking new study by CHORI Senior Scientist Ronald Krauss, MD, and his colleagues shows for the first time a correlation between small low density lipoproteins (LDL) and not just cardiovascular disease (CVD) risk – but CVD outcome in patients on lipid lowering drug treatment [PLoS One. 2013;8(2):e56782. Epub 2013 Feb 27]. The study combined data from the 2001 High Density Lipoprotein (HDL)-Atherosclerosis Treatment Study (HATS), led by Greg Brown, MD, with new, more refined measures of HDL and LDL subclasses conducted by Dr. Krauss and his colleagues.

“While the sample size was not sufficient to look at individual treatment groups individually, we were able to look at the entire study population to see the relationship between these more refined measurements and cardiovascular outcomes independent of treatment status,” explains Dr. Krauss.
“We found a very strong relationship of a very specific form of small LDL subclass, which predicted the cardiovascular outcome in the HATS study independently of HDL levels and all other lipid measurements as well.”



"We found a very strong relationship of a very specific form of small LDL subclass, which predicted the cardiovascular outcome in the HATS study independently of HDL levels and all other lipid measurements as well."

The HATS was originally designed to test the benefits of two separate treatment approaches for reducing heart disease risk. The study utilized standard lipid measurements of HDL or "good" cholesterol, and LDL or "bad" cholesterol, as well as cardiovascular outcomes, such as reducing blockage of coronary arteries, or reducing heart attacks over time.

"The study was very well received because it showed that the statins plus niacin treatment substantially reduced the number of heart attacks," says Dr. Krauss. "Since then, the statin-niacin combination has received a great deal of attention, in part because the extent of improvement compared with placebo was enormous."

However, most of the focus has been on the improvement in HDL that was seen in HATS, rather than looking more comprehensively at the whole lipid profile. Dr. Krauss and his colleagues have addressed that gap by utilizing gradient gel electrophoresis to provide a much more refined assessment of the various LDL subfractions that have previously been associated with increased CVD risk. The results were unequivocal, showing that LDL-IIIb levels strongly correlated with cardiovascular outcomes.
“While we have identified this small LDL subclass as being associated with increased risk previously, this is the first time we have been able to use it to predict outcome in a drug intervention study.”
"People with higher levels of this LDL had worse outcomes, while people with lower levels had better outcomes, regardless of treatment," says Dr. Krauss.

Two very high profile clinical trials have recently tested whether adding niacin to statins reduces heart disease risk. Unlike HATS, both trials failed to show an added benefit. Both trials, however, actively selected only those patients with already very low LDL levels in order to focus specifically on the impact of niacin on HDL.

"What our study suggests, however, is that the reason HATS was so successful, and that these two trials were not, is that if the levels of very small LDL are already at rock bottom due to the statins, which can lower these particles as well, then there isn't an additional benefit of raising HDL with niacin," says Dr. Krauss.
"The idea is that the cardiovascular benefit seen in HATS may not have been driven by increasing HDL, but by decreasing small LDL."

The study also suggests that using a single biomarker may not provide the necessary information as to the effects of any given treatment. The two failed studies were designed very effectively to test the effect of niacin on HDL, while missing the opportunity to investigate the potential benefit of niacin on other biomarkers of cardiovascular disease risk.

"Our results really provide a model for using more refined lipoprotein measurements as biomarkers to screen compounds for those most likely to have long term benefit," says Dr. Krauss.

“If levels of the small LDL subclasses don't respond, it's an indication that another, as yet undefined treatment option, would be more appropriate and really, this is where we should be concerned: how to treat the people who don't get their LDL levels down to that lower risk level.”

Many people can't take statins, many people have a poor lipid response to statins, and of those who do respond adequately, there is still a substantial risk for poor cardiovascular outcomes.

"It's these individuals we should be testing for additional benefits, using more refined biomarkers like small LDL subclasses, to determine in what other ways we can reduce their levels, and by doing so, reduce heart disease risk," says Dr. Krauss.

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Monday, May 20, 2013 3:18 PM

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