Atherogenic lipoproteins and residual cardiovascular risk: the role of triglyceride-rich lipoproteins

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16 October 2017

Atherogenic apolipoprotein B-containing lipoprotein particle concentrations, in particular very low-density lipoprotein (VLDL) particles, were markers of residual cardiovascular disease risk in individuals with well controlled low-density lipoprotein cholesterol (LDL-C) levels on statin therapy.

Lawler PR, Akinkuolie AO, Chu AY, Shah SH, Kraus WE, Craig D, Padmanabhan L, Glynn RJ, Ridker PM, Chasman DI, Mora S. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc;6(7). pii: e005549. doi: 10.1161/JAHA.117.005549.

STUDY SUMMARY

Objective:

To understand the residual markers of lipid- and lipoprotein-related risk against a background of well controlled LDL-C levels by profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease (CVD) in two populations.

Study design:

The primary study population was derived from JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a primary prevention randomized controlled clinical trial of rosuvastatin 20 mg versus placebo.

Analyses were also performed using the CATHGEN (CATHeterization GENetics) population, an independent, prospective cohort of 4721 individuals referred for cardiac catheterization.

Study population:

Data from 11,984 subjects in JUPITER (mean age 66 years, 64% men, median baseline LDL-C 109 mg/dl (2.8 mmol/L), median baseline non-high-density lipoprotein cholesterol (non-HDL-C) 135 mg/dl (3.5 mmol/L) were analysed. In total, data from 2,149 subjects in the CATHGEN cohort with LDL-C <130 mg/dl (3.4 mmol/L) and triglycerides <500 mg/dl (5.6 mmol/L) were evaluated.

Efficacy variables:

The primary outcome was the primary endpoint of JUPITER, i.e. a composite incident CVD endpoint defined as the occurrence of either myocardial infarction, stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death. An expanded end point of CVD or all-cause mortality was also examined, consistent with JUPITER.

Methods:

Main results:

Among placebo-allocated subjects in JUPITER, the risk of a primary endpoint (adjusted hazard ratio [95%CI] per SD increment) was 1.19 (1.02-1.38) for total LDL particles and 1.21 (1.04-1.41) for total VLDL particles. Apolipoprotein (apo) B, non–HDL-C, and triglycerides, but not LDL-C were also associated with risk. Most VLDL-particle subfractions, as well as total VLDL-particle concentration and NMR-determined VLDL/CM triglycerides, were associated with increased risk of the primary end point.

For subjects on statin (median LDL-C 55 mg/dl or 1.4 mmol/L, and median triglycerides 102 mg/dl or 1.15 mmol/L), each SD increment in total VLDL-particle concentration was associated with residual risk for the primary and expanded endpoint, which was largely driven by small VLDL particles (Table). VLDL-cholesterol, but not VLDL/chylomicron triglycerides, was also associated with residual cardiovascular risk (Table). Prediction analysis showed that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures.

Table. Residual risk in the JUPITER on-statin treatment arm for primary and expanded endpoint per SD increment in each NMR variable (hazard ratio and 95% confidence interval; P: particle number)

	Primary endpoint	Secondary endpoint
NMR measure	Hazard ratio (95% CI)	Hazard ratio (95% CI)	p-value
Total LDL-P	1.02 (0.79-1.31)	1.07 (0.88, 1.31)	NS
Large	1.16 (0.88-1.53)	1.18 (0.95, 1.47)	NS
Small	0.87 (0.69-1.11)	0.87 (0.72, 1.05)	NS
IDL	0.98 (0.80-1.20)	0.98 (0.83, 1.15)	NS
Total VLDL-P	1.34 (1.05-1.71)	1.32 (1.08, 1.61)	p=0.006
Large	1.03 (0.81-1.32)	1.03 (0.85, 1.26)	NS
Medium	1.00 (0.78-1.28)	1.04 (0.84, 1.27)	NS
Small	1.68 (1.28-2.22)	1.56 (1.25, 1.95)	p<0.0001
VLDL-C	1.27 (1.01-1.61)	1.27 (1.05, 1.54)	p=0.014
VLDL/chylomicron-TG	1.04 (0.84-1.32)	1.10 (0.91, 1.34)	p=0.325

Similar findings were reported for the CATHGEN cohort; total VLDL-particle concentration was significantly associated with risk of MI (hazard ratio per SD increment 1.23, 95% CI 1.01, 1.51), driven by the small VLDL lipoprotein subclass.

Conclusion:

Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk

COMMENT

Guidelines have recognized the importance of the total burden of atherogenic apoB-containing lipoproteins, including LDL, to cardiovascular risk.1 In the setting of well controlled LDL-C levels, as in the on-statin study group in JUPITER, apoB-containing lipoproteins other than LDL may be more relevant contributors to residual cardiovascular risk.

This study used NMR spectroscopy to measure concentrations of both LDL and VLDL lipoproteins. The results show that in the setting of low LDL-C levels, VLDL lipoproteins, especially small VLDL lipoproteins are associated with more than 50% increase in the risk of cardiovascular events. Moreover, evidence that VLDL-cholesterol but not VLDL/chylomicron triglycerides are significantly associated with residual cardiovascular risk, implies that it is the cholesterol carried by these lipoproteins rather than the triglycerides content that confers this increased risk. This finding is supported by mechanistic studies, which show that remnants may cause atherosclerosis by accumulation in the arterial wall; observational studies, which have shown association between elevated levels of remnant cholesterol and increased risk of cardiovascular disease; and genetic studies which have shown that elevated levels of remnant cholesterol are causally associated with ischaemic heart disease.2-4 Indeed, there is recent evidence that beyond accumulation in the arterial wall, remnants may elicit an immune-inflammatory response in the arterial wall contributing to the development of atherosclerosis.5

Taken together, the findings from this study, as well as supportive evidence, provide a case for considering VLDL remnants, especially small remnant particles, as potential therapeutic targets in the management of residual cardiovascular risk.

References

1. Expert Dyslipidemia Panel, Grundy SM. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia. J Clin Lipidol 2013;7:561-5.

2. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo: Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42.

3. Varbo A, Benn M, Tybjærg-Hansen A. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.

4. Joshi PH, Khokhar AA, Massaro JM et al. Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies. J Am Heart Assoc 2016;5(5). pii: e002765.

5. Bernelot Moens SJ, Verweij SL, Schnitzler JG et al. Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans. Arterioscler Thromb Vasc Biol 2017;37;969-75.

Key words

: triglyceride-rich lipoproteins; very low-density lipoprotein particle; residual cardiovascular risk; JUPITER; risk prediction