Different Markers of Dyslipidemia Could Help Fine-tune CVD Prevention

Different cholesterol biomarkers may add important nuances to the prediction of cardiovascular events, new research suggests. Baseline levels of triglyceride-rich lipoprotein (TRL), for example, are strongly associated with both future MI and future peripheral artery disease. By contrast, small-dense low-density lipoprotein (sdLDL) particles are only predictive of MI.

The divergence in results for TRL and sdLDL was unexpected, senior author Aruna D. Pradhan, MD (Brigham and Women’s Hospital, Boston, MA). “These are both markers of atherogenic dyslipidemia, so I was surprised that they didn't seem to predict in identical ways,” she told TCTMD . “I would have thought that perhaps we'd be looking at two markers of the same clinical phenotype that would predict the same way, but that wasn't what we found.”

The study was published online ahead of print in the May 5, 2020, issue of the Journal of the American College of Cardiology.

TRL, sdLDL Correlations

For the study, Edward K. Duran, MD (Brigham and Women’s Hospital), Pradhan, and colleagues directly measured TRL and sdLDL cholesterol in baseline blood samples of 480 and 496 respective case subjects from the Women’s Health Study. All patients were followed for MI, ischemic stroke, PAD, a composite of coronary and cerebral vascular disease (nonfatal MI, nonfatal ischemic stroke, and death from CV causes), and total CVD (PAD plus coronary and cerebral vascular disease).

Across quartiles of both markers, the prevalence of modifiable risk factors for CVD trended upward, with more type 2 diabetes, hypertension, and current smoking among those in the highest quartile. Similarly, patients in the highest quartile had generally less-favorable lipid profiles, elevated body mass index, and greater basal inflammation. Triglyceride and HDL-cholesterol concentrations approached the clinical thresholds that jointly define atherogenic dyslipidemia in the highest quartile of both TRL and sdLDL.

TRL and sdLDL concentrations strongly correlated with each other (P < 0.001) as well as to triglycerides and total cholesterol.

The risk of both composite outcomes was higher across the upper quartiles of TRL and sdLDL cholesterol. For quartile 4 versus 1, for example, TRL was significantly associated with both MI (HR 3.05; 95% CI 1.46-6.39; P for trend = 0.002) and PAD (HR 2.58; 95% CI 1.18-5.63; P for trend = 0.019), whereas sdLDL was significantly associated with MI alone (HR 3.71; 95% CI 1.59-8.63; P for trend < 0.001). Both markers were weakly linked to ischemic stroke.

Similar patterns were seen for continuous exposures and, for TRL cholesterol, among subjects with low concentrations (< 100 mg/dL) of the atherogenic particle apolipoprotein B (apoB).

Further Confirmation Needed for Clinical Relevance

Pradhan predicted that the same study conducted in a population of both men and women would find similar results. “Women tend to develop insulin resistance in this profile later in life, so it may have to do with the fact that we have a population of middle-aged and older women,” she said. “Residual risk is a problem that's universal: it's there for men and women and for different ethnicities, and so it's a problem for everyone.”

For now, the study is scientifically relevant and “really invokes a lot of questions about how these conditions may differ,” Pradhan said. “It also may explain why triglycerides alone as a marker of risk and targeting therapy may not explain why some of the drugs that we're currently using to treat these patients with high triglycerides seem to be unlinked with how low your triglycerides get. It may be the wrong marker for the risk/benefit that we're getting from some of the therapies that we're using.”

Once the findings are replicated in other studies, “they could be used in identifying a patient who would most benefit from some of the new therapies that we're developing,” she said. For example, TRL in particular might be helpful in explaining the biologic effects of icosapent ethyl (Vascepa; Amarin) in reducing triglycerides, Pradhan explained. “In terms of unlocking the pathways that are involved, I think they can be very useful.”

As more cholesterol biomarkers emerge, however, she said that it will be important for clinicians to first become familiar with them before they can be used in clinical practice. “We don't want to burden physicians with measuring a lot of different markers until one or two or three emerge as a really reliable predictor,” Pradhan said. “But we also in medicine and in science need to be open to the idea that our understanding of biology changes and that's how scientific innovation and investigation affects clinical practice. So, it's important for clinicians to be ready for new markers that may emerge that are more important than others.”

Scientists, on the other hand, “look at gaps in knowledge, patients that are left behind, to try to figure out [if] there is something we can do to make their lives better, prevent them from having events,” she continued. “And in that context, we may need more markers and more reliable markers.”

‘Untying the Gordian Knot’

In an accompanying editorial, Gerald F. Watts, DSc, PhD, MD, and Dick C. Chan, PhD (both University of Western Australia, Perth, Australia), write that “these new indices of atherogenic dyslipoproteinemia may be most useful in managing residual [atherosclerotic cardiovascular disease (ASCVD)] risk, so predictive studies in high-risk patients receiving the best current standard of care are particularly relevant.”

Although “the benefits of TRL cholesterol and sdLDL cholesterol need to be distinguished from the simpler calculations of remnant cholesterol and non-HDL cholesterol, as well as measurement of apoB,” they write, “quantitative evidence of the superiority of the new assays needs to be demonstrated not only in observational but also in interventional studies. Their value will be in enabling clinical decisions on whether to treat or not to treat, or whether to intensify or not to intensify therapy. The clinical success of these assays will also depend on costs and physicians’ familiarity with their use.”

“In the absence of further evidence, the main challenger for untying the Gordian knot of atherogenic dyslipoproteinemia could well be the measurement of apoB concentration,” Watts and Chan conclude. “In a broader context, residual ASCVD risk has several determinants, including age, family history, smoking, hypertension, and diabetes, that need to be addressed. Precision medicine also mandates the use of biomarkers of inflammation, coagulation, platelet function, and oxidative stress, as well as genetic indices, including lipoprotein(a).”