‘Remnant’ Cholesterol Linked With CVD Risk, Even When LDL Levels Are Low

Advanced lipoprotein profiling among individuals with low LDL cholesterol levels suggests that triglyceride-rich remnant particles, specifically small very low-density lipoprotein (VLDL) particles, are associated with an increased risk of incident cardiovascular events.  

Among individuals with a median LDL cholesterol of 55 mg/dL on statin therapy, each standard-deviation (SD) increase in small VLDL particles increased the risk of MI, stroke, hospitalization for unstable angina, revascularization, or cardiovascular death by approximately 70%. For individuals with the most elevated VLDL particles, those in the highest tertile, the risk of cardiovascular events was more than 3.5 times higher compared with those with the lowest levels of VLDL particles.

The researchers, led by Patrick Lawler, MD (Brigham and Women’s Hospital, Boston, MA), suggest these atherogenic remnant particles might represent a potential target for reducing residual risk in patients maximally treated with statin therapy. 

In the decades since statins and other lipid-modifying agents were introduced, LDL cholesterol levels have decreased in both primary and secondary prevention, senior investigator Samia Mora, MD (Brigham and Women’s Hospital), told TCTMD. “Then the question is, though, why are some people still having events?”

In primary prevention, approximately 1 in 10 patients managed with statin therapy to lower LDL cholesterol levels will have a clinical event over a 5-year period, Mora continued. In secondary prevention, approximately 1 in 5 patients will have a recurrent event. One theory is that, in the past, the risk associated with other lipids or lipoproteins might have been eclipsed by those high LDL cholesterol levels, say the researchers. 

“Many people think, well, your LDL cholesterol is very low, I don’t need to do anything else related to lipids and now we can look at other pathways related to cardiometabolic disease,” said Mora. “The question we asked was whether there were any other lipid measures of risk that we could identify. Maybe LDL cholesterol is not the best way to measure cardiovascular risk?”

JUPITER Study Includes Patients With Low LDL Cholesterol

For the study, published July 21, 2017, in the Journal of the American Heart Association, the researchers performed nuclear magnetic resonance spectroscopy to quantify the concentrations of LDL and VLDL particle subclasses in 11,984 patients participating in the JUPITER trial. In that study, patients with an LDL cholesterol level of less than 130 mg/dL and a high-sensitivity C-reactive protein (CRP) level of 2.0 mg/L or more were treated with rosuvastatin 20 mg.  

The researchers measured the distribution of lipoproteins subfractions, such as small, medium, and large LDL and VLDL particles, at baseline and 1 year after treatment with rosuvastatin. To TCTMD, Mora noted that the pattern of risk associated with the lipoproteins and lipid profile, especially VLDL particles, differed before and after statin use.

For example, at baseline, each 1-SD increase in total LDL and VLDL particles was associated with an increased risk of major cardiovascular events, as was each 1-SD increase in the concentration of large- and medium-sized VLDL particles. In contrast, prior to statin therapy, small VLDL particles were not associated with an increased risk of events. 

The question is, though, why are some people still having events? Samia Mora

“However, after the patients were on statins, statins reduced all the particles that were part of the VLDL remnant pathway, but the risk related to them also differed,” said Mora. “The largest risk was related to the smallest VLDL particle—it was the very small VLDL particles that carried the increased risk when patients were on statins.”

Additionally, each 1-SD increase in the size of VLDL cholesterol, which means less small VLDL particles, was associated with a 38% reduction in risk of incident cardiovascular disease. The risk associated with the small VLDL particle was driven by the cholesterol within the particle, not by the triglycerides, according to the researchers. The results were confirmed in a second cohort of 2,149 patients referred for cardiac catheterization in the CATHGEN registry.

The lipoprotein measures also significantly improved risk prediction when added to a risk model built with standard clinical and lipid measures, report the researchers.

Clinical Significance of Findings

Seth Martin, MD (Johns Hopkins Medical Institution, Baltimore, MD), who was not involved in the study, told TCTMD that small VLDL particles are believed to be atherogenic and that as LDL cholesterol levels are reduced, these particles “become a more predominant fraction of the total atherogenic lipoprotein load.”

“Regarding residual risk assessment, that is risk assessment while on statin therapy, it was interesting that the small VLDL particle stood out as such a strong predictor,” said Martin. “The question is whether this is something best treated with drug therapy or lifestyle.”

He noted that LDL cholesterol levels were predictive for incident cardiovascular events even at low levels (adjusted HR 1.15 for each 1-SD increase; 95% CI 1.00-1.32), but apolipoprotein B (apoB) and non-HDL cholesterol were not, which was surprising. He added that in the primary prevention setting for global risk assessment, no single biomarker—LDL cholesterol, apoB, or non-HDL cholesterol—can compare with a global integrator of risk like coronary artery calcium (CAC).

As for a potential mechanism, Mora said it’s possible the very small remnant particles, such as VLDL, are small enough to penetrate the arterial wall. Smaller, pathology-based studies have shown that these small VLDL particles can be found within the arterial wall in atherosclerosis.

Regarding the clinical applications, Mora said a full spectroscopy lipoprotein assessment might be warranted in patients maximally treated on statins who continue to have clinical events. Future studies can determine if patients with a high concentration of small VLDL particles might benefit from more aggressive therapy, such as a PCSK9 inhibitor, she said.

Additionally, in patients with a family history of cardiovascular disease who are still concerned about their risk even though their LDL cholesterol levels are low, an assessment of these atherogenic lipoproteins might be warranted to determine if they too could benefit from additional therapy, said Mora.