Triglyceride-Rich-Lipoprotein Cholesterol Predicts CV Events

Marlene Busko

June 01, 2015

AMSTERDAM, THE NETHERLANDS — Triglyceride-rich-lipoprotein (TRL) cholesterol could be "the next target" to lower a person's risk of cardiovascular events, said Dr Kausik Ray (University of London, UK), speaking here at the International Symposium on Atherosclerosis 2015[1].

Their research, based on data from the Treating to New Targets (TNT) trial[2], showed that higher levels of TRL cholesterol (which is calculated by subtracting non-HDL cholesterol from LDL cholesterol) were associated with an increased 5-year risk of a major cardiovascular event—coronary heart disease death, nonfatal MI, resuscitated cardiac arrest, or stroke—independent of LDL cholesterol.

Moreover, the increased risk of a cardiovascular event with higher levels of TRL cholesterol was significantly reduced with intensive 80-mg/day atorvastatin therapy.

Thus, TRL cholesterol "is a great marker of [cardiovascular] risk, [and] we know it's modifiable with higher-intensity statins," Ray summarized. "The fact that we can lower this [marker] and that the percentage lowering predicts outcome suggest it might be a future target beyond LDL cholesterol."

Ray said the marker will need to be validated in other patient populations. In response to a question from session comoderator Dr Eric Sijbrands (Erasmus University Medical Center, Rotterdam, the Netherlands), Ray noted that triglyceride levels failed to predict the risk of future cardiovascular events in the TNT cohort but TRL cholesterol did.

TRL-Cholesterol Quintiles and 5-Year CV Events

Epidemiologic studies have shown that higher lifetime levels of remnant cholesterol, "which is really TRL cholesterol, not just remnant cholesterol," are associated with a higher risk of ischemic heart disease and MI, Ray explained.

The researchers used data from the TNT trial to test three hypotheses. In a statin-treated population, is TRL cholesterol a marker of cardiovascular risk? Second, is the level of risk modifiable with high-dose vs low-dose (standard-dose) statin? Third, does TRL-cholesterol lowering independently predict a reduction in clinical events?

The TNT trial randomized just over 10,000 individuals with coronary heart disease (previous MI, previous or current angina, or previous coronary revascularization procedure) to an open-label run-in with low-dose atorvastatin followed by randomization to either 10-mg/day or 80-mg/day atorvastatin. The current study divided the TNT participants into quintiles of baseline TRL-cholesterol levels: <19 mg/dL, >19 to <24 mg/dL, >24 to <30 mg/dL, >30 to <39.5 mg/dL, and >39.5 mg/dL.

Ray and colleagues found that the run-in, low-dose atorvastatin reduced the median TRL-cholesterol level from 30 mg/dL to 27 mg/dL (P<0.0001). In the participants who were randomized to high-dose statin, median TRL-cholesterol levels were further reduced to 23 mg/dL (P<0.0001) by 3 months, a reduction that was maintained over time.

In participants who were randomized to low-dose atorvastatin, the 5-year risk of a cardiovascular event increased with increasing baseline levels of TRL cholesterol. The risk increased from 9.72% in quintile 1 (lowest TRL cholesterol) to 13.77% in quintile 5 (highest TRL cholesterol). Individuals with the highest TRL-cholesterol levels had a 49% greater risk of cardiovascular events at 5 years compared with those with the lowest levels (hazard ratio 1.49; 95% CI 1.15–1.92).

In patients who were randomized to high-dose atorvastatin, however, the 5-year risk of a cardiovascular event was similar in all quintiles of TRL cholesterol (7.36% to 9.76%).

With high-dose statin vs standard-dose statin, there was a 2% absolute risk reduction in the rate of the primary end point (5-year cardiovascular events) in patients in quintile 3 of TRL cholesterol, but there was a "huge 4% absolute benefit in the top two quintiles" of TRL cholesterol, Ray pointed out.

Five-Year Risk of a Cardiovascular Event (%)

Quintile of baseline TRL-cholesterol (mg/dL) Atorvastatin 80 mg/day Atorvastatin 10 mg/day Absolute relative risk HR (95% CI)
<19 9.76 9.72 +0.04 1.01 (0.77– 1.34)
>19 to <24 8.20 8.62 -0.42 0.98 (0.71–1.34)
>24 to <30 8.21 10.58 -2.38 0.71 (0.53–0.96)
>30 to <39.5 7.36 12.07 -4.71 0.59 (0.44–0.80)
>39.5 9.84 13.77 -3.92 0.69 (0.53–0.90)

In multivariable models, independent of reductions in LDL cholesterol, a reduction in TRL cholesterol of one standard deviation was associated with a lower risk of the primary outcome (HR 0.93, CI 0.864–0.999).

"This is the first demonstration that when you actually alter [TRL cholesterol] with drug therapy and you reduce it by one standard deviation independent of LDL change, there is an independent association with clinical events," Ray said. "This would suggest that future therapies that modify that fraction will independently lower risk."

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