PREDIMED shows association between remnant cholesterol and incident cardiovascular disease

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16 February 2021

Among overweight or obese high-risk primary prevention patients, levels of triglycerides (TG) and remnant cholesterol – but not low-density lipoprotein cholesterol (LDL-C) – associate with cardiovascular outcomes.

Castañer O, Pintó X, Subirana I et al. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. J Am Coll Cardiol 2020;76: 2712-24.

STUDY SUMMARY

Objective:

To evaluate the association of TG, LDL-C and remnant cholesterol with major cardiovascular events in older individuals at high cardiovascular risk enrolled in the PREDIMED (Prevención con Dieta Mediterránea) study.

Study design:

The PREDIMED study (1) was a multicentre randomized controlled trial comparing the efficacy of a Mediterranean diet enriched with extra-virgin olive oil, nuts versus control in older subjects at high cardiovascular risk.

Study population:

6,901 subjects (mean age 67 years, 43% male, mean body mass index [BMI] 30 kg/m2) in the PREDIMED study. Overall, 48% had diabetes, 41% were on a statin, and 3.8% were treated with fibrates. At baseline, mean LDL-C was 129 mg/dL (3.34 mmol/L), TG were 128 mg/dL (1.45 mmol/L), and mean remnant cholesterol levels were 25.7 mg/dL (0.66 mmol/L). In the study population, 963 (14%) had atherogenic dyslipidemia, defined as TG >150 mg/dL (>1.7 mmol/L) and high-density lipoprotein cholesterol [HDL-C] <40 mg/dL (<1.03 mmol/L) in men and <50 mg/dL (<1.29 mmol/L) in women.

Main study variables:

· The primary endpoint was a composite of major adverse cardiovascular events [MACE), defined as myocardial infarction, stroke or cardiovascular death.

· Lipids: TG and HDL-C were measured; LDL-C was calculated using the Friedewald formula if TG were <300 mg/dL; and remnant cholesterol was calculated as total cholesterol – (LDL-C + HDL-C).

Methods:

Cox proportional hazards models were used to investigate the association between baseline lipid levels and incident MACE. Adjustment was made for age, sex, dietary intervention, BMI, diabetes, physical activity, educational level, adherence to the Mediterranean diet, hypertension, alcohol intake, and statin or fibrate treatment.

Results:

Over a median follow-up of 4.8 years, there were 263 MACE events. Serum concentrations of TG, non-HDL-C and remnant cholesterol were associated with 4%, 5% and 21% increased risk of MACE, respectively per 10 mg/dL increase in each lipid level. Additionally, the presence of atherogenic dyslipidemia at baseline was associated with a 44% increase (Hazard ratio 1.44, 95% confidence interval [CI] 1.04-2.00, p=0.03) in risk of MACE (Table 1).

In contrast, neither baseline LDL-C nor baseline HDL-C were associated with incident cardiovascular disease.

Among patients with LDL-C levels >100 mg/dL or ≤100 mg/dL, high baseline remnant cholesterol (≥75th percentile or ~30 mg/dL or 0.78 mmol/L) was associated with a higher risk of MACE compared with individuals with lower remnant cholesterol levels.

Table 1. Association of baseline lipid levels with MACE in PREDIMED

Lipid	Hazard ratio (95% CI)	p-value
	Per 5 mg/dL increase
HDL-C	0.97 (0.91-1.04)	0.43
	per 10 mg/dL increase
LDL-C	1.01 (0.97-1.07)	0.58
Non-HDL-C	1.05 (1.01-1.10)	0.026
TG	1.04 (1.02-1.06)	<0.001
Remnant cholesterol	1.21 (1.03-1.33)	<0.001

Authors’ conclusion:

In overweight or obese subjects at high cardiovascular risk, levels of TG and remnant cholesterol, but not LDL-C, were associated with cardiovascular outcomes independent of other risk factors. Randomized controlled trials with hard cardiovascular outcomes are warranted to compare the benefit of interventions directed at lowering remnant cholesterol against standard cholesterol lowering therapy, particularly when LDL-C targets have been achieved.

COMMENT

This analysis of the PREDIMED study in high-risk individuals without clinical cardiovascular disease showed an association between increases in TG, remnant cholesterol and non-HDL cholesterol with risk for cardiovascular disease. Notably, a baseline remnant cholesterol value ≥30 mg/dL, which equated to the 75th percentile of the cohort, identified individuals at high risk of a cardiovascular event independent of LDL-C levels. Moreover, the presence of atherogenic dyslipidemia, defined in this report as TG >150 mg/dL and HDL-C <40 mg/dL in men and <50 mg/dL in women, was associated with 44% increase in the risk of cardiovascular events. The findings from this analysis are supported by evidence of the atherogenicity of remnant cholesterol from observational studies (2-4), post hoc data from the Treating to New Targets study (5), as well as findings from Mendelian randomization analyses (6,7). Indeed, in one report using a Mendelian randomization design, the increase in ischaemic heart disease risk associated with obesity was partly mediated through elevated levels of nonfasting remnant cholesterol (8).

These findings add support for TG-rich lipoproteins and their remnants (as identified by remnant cholesterol), as a contributor to cardiovascular risk, with a negligible role for LDL-C. Some caution is needed in the interpretation of these results, however, given that only 263 cardiovascular events were reported over the 4.8-year follow-up period. The observational nature of this study does not allow firm conclusions regarding the causality of remnant cholesterol for cardiovascular disease. Additionally, given that remnant cholesterol was calculated rather than directly measured, this may have overestimated the values reported and therefore biased the study results. Finally, the causality of LDL-C for cardiovascular disease is now established based on extensive data and therefore LDL-C remains the primary lipid target, as reinforced in treatment guidelines (9,10).

References

1. Estruch R, Ros E, Salas-Salvadó J, Covas MI, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018; 378:e34.

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

3. Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.

4. Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study. Clin Chem 2018;64:219-30.

5. Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT Trial. Circulation 2018;138:770-81.

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

7. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2015;36:539-50.

8. Varbo A, Benn M, Smith GD, et al. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ Res 2015;116:665-73.

9. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.

10. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.

Key words

PREDIMED, triglycerides, remnant cholesterol, cardiovascular risk