Two new studies suggest that LDL cholesterol (LDL-C) may be not the main driver of atherosclerotic cardiovascular disease (ASCVD).
The findings instead implicate remnant cholesterol (remnant-C) and very-low-density lipoprotein (VLDL) cholesterol in the development of cardiovascular disease (CVD) and MI.
The PREDIMED study, conducted in Spain, examined the association of triglycerides and remnant-C with major cardiovascular events (MACE) in older individuals with high CVD risk. It found that levels of triglycerides and remnant-C were associated with MACE independently of other risk factors, but there was no similar association with LDL-C.
“These findings lead [clinicians] to consider in the clinical management of dyslipidemias a greater control of the lipid profiles as a whole, including remnant-cholesterol and/or triglycerides,” Montserrat Fitó Colomer, MD, PhD, of the Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute, Barcelona, said in an interview.
In a separate analysis, the Copenhagen General Population Study, which focused on 25,000 individuals who were not taking lipid-lowering therapy, looked at the role of VLDL cholesterol and triglycerides in driving MI risk from apolipoprotein B (apoB)–containing lipoproteins.
Bruce Jancin/Frontline Medical News
Dr. Borge G. Nordestgaard
“Elevated VLDL cholesterol explained a larger fraction of risk than did elevated LDL cholesterol, or elevated VLDL triglycerides,” Børge G. Nordestgaard, MD, DMSc, professor, University of Copenhagen, said in an interview.
Both studies were published online Nov. 30 in the Journal of the American College of Cardiology.
But in an editorial accompanying both reports, John Burnett, MD, PhD, from the University of Western Australia, Perth, and colleagues cautioned that it would be “premature to discard LDL-C based on PREDIMED.”
The findings are “insufficient to offset the mountain of literally hundreds of studies that uphold the value of LDL-C in prediction and intervention of ASCVD,” Dr. Burnett and coauthors wrote.
Similarly, the editorialists cautioned that, although the findings from the study by Dr. Nordestgaard and colleagues indicate that VLDL cholesterol is the “new kid in town for prediction, LDL cholesterol retains predictive power.” Clinical cardiologists should not “shelve LDL cholesterol and embrace VLDL and remnant cholesterol as the new oracles of ASCVD risk.”
In a comment, Dr. Burnett said, “The take-home message for clinicians in both papers is that LDL-C is the main lipid measurement to guide clinical decisions; however, residual risk of atherosclerotic cardiovascular disease remains, even after LCL-C is treated.
“Assessment of residual ASCVD risk with nontraditional lipid biomarkers, including VLDL cholesterol and remnant cholesterol, as well as lipoprotein (a) and apoB, may improve prognostication and help guide preventive treatments,” he added.
“Affordable and inexpensive”
In their report, the PREDIMED study authors explained that atherogenic dyslipidemia is characterized by “an excess of serum triglycerides” contained in VLDL cholesterol, intermediate-density lipoproteins, and their remnants, all of which are called “triglyceride-rich lipoproteins (TRLs).”
TRLs and remnant-C “have the capacity to cross the arterial wall,” and may therefore play a causal role in atherosclerosis development, they wrote.
The main PREDIMED trial compared a low-fat diet with the Mediterranean diet for the primary prevention of CVD in high-risk participants. Those enrolled in the trial “had a high prevalence of diabetes, obesity, and metabolic syndrome, conditions that are associated with insulin resistance, hypertriglyceridemia, and atherogenic dyslipidemia,” the authors wrote. “Thus, this cohort of subjects at high cardiovascular risk was well suited to investigate the association of triglycerides and TRLs with cardiovascular outcomes.”
The researchers investigated the role of triglycerides and remnant-C in incident CVD among these high-risk individuals, particularly those with chronic cardiometabolic disorders (prediabetes, type 2 diabetes, and poorly controlled diabetes), overweight and obesity, metabolic syndrome, and renal failure.
Their 6,901 participants (42.6% male, mean age 67 years, mean BMI 30.0 kg/m2) had a diagnosis of type 2 diabetes or at least three CVD risk factors including current smoking, hypertension, elevated LDL-C levels, low HDL cholesterol levels, elevated body mass index, or family history of premature coronary heart disease.
The primary study endpoint was a composite of adverse cardiovascular events (MACE): MI, stroke, or cardiovascular death. Participants were followed for a mean of 4.8 years, during which there was a total of 263 MACE events.
Multivariable-adjusted analyses showed that levels of triglycerides and remnant-C were both associated with MACE independent of other risk factors (hazard ratio, 1.04; 95% confidence interval, 1.02-1.06; and HR, 1.21; 95% CI, 1.10-1.33 per 10 mg/dl, respectively, both P < .001). Non–HDL cholesterol was also associated with MACE (HR, 1.05; 95% CI, 1.01-1.10 per 10 mg/dl, P = .026).
In particular, elevated remnant-C (≥30 mg/dL), compared with lower concentrations, flagged subjects at a higher risk of MACE, even if their LDL-C levels were at target (defined as ≤ 100 mg/dL).
Levels of LDL-C and HDL cholesterol were not associated with MACE.
“The indirect calculation of remnant-C is an affordable and inexpensive method, which could provide valuable data for clinical management,” Dr. Fitó Colomer said.
“The results of this study suggest that, in individuals at high cardiovascular risk with well-controlled LDL-C, triglycerides and mainly remnant-C should be considered as a treatment target,” she proposed.