Studies Relegate LDL to Lesser Role in Atherosclerotic Disease

— Is VLDL cholesterol a better prognosticator?

by Nicole Lou, Staff Writer, MedPage Today December 1, 2020

LDL cholesterol turned out not to be the main lipid contributor to atherosclerotic cardiovascular disease (ASCVD) in two studies.

Serum remnant cholesterol — the cholesterol carried on very low-density lipoproteins (VLDLs) and/or intermediate-density lipoproteins (IDLs), approximated by subtracting LDL and HDL from total cholesterol — was implicated in heart risk in both the primary prevention PREDIMED trial cohort from Spain and the Copenhagen General Population Study (CGPS).

Both reports were published in the December 8 issue of the Journal of the American College of Cardiology.

The two studies yielded complementary results despite the former showing no role of LDL in major adverse cardiovascular events (MACE), and the latter giving LDL “some credit, even if it seems dwarfed by the effect of VLDL cholesterol,” according to an accompanying editorial led by John Burnett, MD, PhD, of the University of Western Australia in Perth.

“What do these studies mean for the clinical cardiologist? For example, should we now shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk? Not so fast,” Burnett and colleagues wrote.

They argued that PREDIMED alone is “insufficient to offset the mountain of literally hundreds of studies and independent types of experiments that uphold the value of LDL cholesterol in prediction and intervention of ASCVD. In contrast, CGPS indicates that although VLDL cholesterol is the new kid in town for prediction, LDL cholesterol retains predictive power.”

It may be that in the future, the routine lipid profile is supplemented by remnant cholesterol and other new lipid biomarkers to improve prognostication and help guide preventive treatments, the editorialists suggested.

PREDIMED

Treatment of high triglycerides and remnant cholesterol could help in primary prevention for some high-risk individuals, according to an observational analysis of the PREDIMED primary prevention diet trial.

Whereas neither LDL nor HDL cholesterol levels showed ties to MACE over a median 4.8 years, other lipids did have significant associations with these events:

  • Triglycerides (per 10 mg/dL): adjusted HR 1.04, 95% CI 1.02-1.06
  • Non-HDL cholesterol (per 10 mg/dL): adjusted HR 1.05, 95% CI 1.01-1.10
  • Remnant cholesterol (per 10 mg/dL): adjusted HR 1.21, 95% CI 1.10-1.33

“Remnant-C [cholesterol] was the major cholesterol fraction contributor to MACEs in our cohort of participants at high cardiovascular risk but who had no previous CVD; these subjects had moderately elevated triglyceride concentrations and a high frequency of statin treatment,” wrote Montserrat Fitó, MD, PhD, of Hospital del Mar Medical Research Institute in Barcelona, Spain, and colleagues.

People with atherogenic dyslipidemia, or triglycerides >150 mg/dL and HDL cholesterol <40 mg/dL in men or <50 mg/dL in women, were also at increased risk of MACE (HR 1.44, 95% CI 1.04-2.00).

The threshold of remnant cholesterol ≥30 mg/dL identified people at higher risk of MACE regardless of whether LDL cholesterol was on target at ≤100 mg/dL. Incidence of MACE was lowest in those with low remnant cholesterol, again independently of LDL cholesterol, according to Fitó’s group.

“From the present data, it could be inferred that treatment of residual risk, measured as triglycerides or remnant-C, was probably more beneficial than further reducing LDL-C in high-risk subjects in primary prevention not eligible for statin treatment or already treated with moderate- or high-dose statins,” study authors suggested.

Only modest lowering of triglyceride and remnant cholesterol is achieved with high-intensity statins, PCSK9 inhibitors, and ezetimibe (Zetia), they said, adding that larger triglyceride reductions are possible with icosapent ethyl (Vascepa) and newer agents such as RNA-based antisense inhibitors of ApoC-III and ANGPTL3 genes.

“Nevertheless, it remains to be tested in randomized clinical trials whether this approach would be superior, in terms of CVD prevention, to a more intensive LDL-C lowering strategy, particularly in subjects at high CVD risk with elevated triglycerides, even when risk-specific LDL-C targets have been reached,” Fitó and colleagues cautioned.

PREDIMED participants were older people at high cardiovascular risk who had been randomized to the Mediterranean diet or a low-fat diet. The present observational analysis included 6,901 people (mean age 67 years, BMI 30 kg/m2, 43% men, 48% with diabetes) from the troubled trial.

Study results may not be generalizable to populations outside Spain, the investigators noted.

Copenhagen General Population Study

In a separate study, the remnant cholesterol, carried on VLDLs in particular, was the major contributor to ASCVD risk associated with triglyceride-rich lipoproteins, the CGPS group reported.

Each 39 mg/dL higher level of lipids correlated with higher MI risk over a median 11 years as follows:

  • VLDL cholesterol: adjusted HR 2.07, 95% CI 1.81-2.36
  • VLDL triglycerides: adjusted HR 1.19, 95% CI 1.14-1.25
  • IDL cholesterol: adjusted HR 5.38, 95% CI 3.73-7.75
  • LDL cholesterol: adjusted HR 1.86, 95% CI 1.62-2.14

VLDL cholesterol explained 50% of the MI risk from elevated apoB-containing lipoproteins, whereas IDL and LDL cholesterol together accounted for only 29% of MI risk, according to Børge Nordestgaard, MD, DMSc, of Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark and colleagues.

“Thus, in CGPS, directly measured VLDL cholesterol emerged as the most important MI risk factor, ahead of systolic blood pressure, smoking, and IDL + LDL cholesterol,” Burnett and colleagues commented.

“Our data illustrate that elevated levels of VLDL cholesterol can explain a large part of residual risk of MI when LDL cholesterol is relatively low. Therefore, the current focus on mainly LDL cholesterol reduction likely needs to be re-evaluated with more focus on reduction of triglyceride-rich remnants,” Nordestgaard’s group said.

VLDL triglycerides did not appear to contribute anything to the increased risk of MI from elevated concentrations of apoB-containing lipoproteins.

The study included 25,480 people who entered the CGPS free of lipid-lowering therapy or prior MI.

Also associated with MIs was plasma apoB, a surrogate measure of atherogenic apoB-containing lipoproteins such as LDL and VLDL (adjusted HR 2.21 per 100 mg/dL, 95% CI 1.90-2.58).

Like the aforementioned PREDIMED analysis, the CGPS analysis was observational and therefore left room for possible residual confounding and reverse causation. The generalizability of these study results was questionable, given that only White people were included, Nordestgaard and colleagues acknowledged.

Disclosures

The study from Spain was supported by grants from the Instituto de Salud Carlos III- FEDER, Fundació La Marató de TV3, and Agència de Gestió d’Ajuts Universitaris i de Recerca.

Fitó and Burnett had no disclosures.

The study from Denmark was funded by grants from the Danish Heart Foundation and the Novo Nordisk Foundation.

Nordestgaard reporting consulting with AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutics.

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