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13 February 2018
Remnant cholesterol: a novel target for reducing lipid-related residual cardiovascular risk

The low risk of ischaemic vascular disease associated with APOC3 loss-of-function (LOF) mutations is mediated by low remnant cholesterol not low plasma low-density lipoprotein cholesterol (LDL-C) concentration.

Wulff AB, Nordestgaard BG, Tybjærg-Hansen A. APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk. Mediation and meta-analyses of 137,895 Individuals. Arterioscler Thromb Vasc Biol 2018; DOI: 10.1161/ATVBAHA.117.310473 [Epub ahead of print].
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate to what extent the low risk of ischaemic vascular disease (IVD) in APOC3 LOF heterozygotes is mediated by low plasma remnant cholesterol or low LDL-C levels.
Study design: Meta-analysis of 137,895 individuals in 6 studies reporting levels of triglycerides, remnant cholesterol and LDL-C, as identified by PUBMED searches. Mediation analysis of 75,725 individuals (260 heterozygotes for APOC3 loss-of-function mutations) in the Copenhagen studies.
Study population:  137,895 individuals; 776 were heterozygotes for an APOC3 LOF mutation. For the analysis of LDL-C levels, there were136,794 individuals and 774 LOF heterozygotes.  
Efficacy variable:
  • • IVD, defined as either ischaemic heart disease (IHD) or ischaemic cerebrovascular disease, estimated in the Copenhagen studies.

  • • Lipid levels: LDL-C (calculated measurement if plasma triglycerides were ≤4.0 mmol/L, direct measurement if plasma triglycerides were >4.0 mmol/L); nonfasting remnant cholesterol (defined as total cholesterol – [LDL-C + high-density lipoprotein cholesterol]), analyzed in the meta-analysis and the Copenhagen studies.
Methods:

Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for IVD and IHD as a function of APOC3 genotype with age as the time scale, for subjects in the Copenhagen studies. Models were adjusted for age (as the time scale), sex, smoking, hypertension, physical inactivity, and alcohol consumption. The median follow-up time was 34 years.

Mediation analysis was performed to determine the fraction of the low risk of IVD and IHD mediated by remnant cholesterol and LDL-C.

Results:
  • • The meta-analysis showed that APOC3 LOF heterozygotes had 43% (95% confidence interval [CI], 40%–47%) lower levels of remnant cholesterol and 4% (95% CI, 1%–6%) lower levels of LDL?C compared with noncarriers.

  • • In the Copenhagen studies, individuals with APOC3 LOF mutations had a 41% reduction in risk of IVD (hazard ratio, 0.59; 95% CI, 0.41–0.86; p=0.007) and a 36% reduction in risk of IHD (hazard ratio, 0.64; 95% CI, 0.41–0.99; p=0.04). Similar to that reported for the meta-analysis, individuals with APOC3 LOF mutations had 44% lower remnant cholesterol levels and 3% lower LDL-C levels compared with noncarriers.

  • • Concomitant lipid-lowering therapy did not significantly influence these differences.
  • • Mediation analyses showed that low levels of remnant cholesterol were responsible for 37% of the observed 41% lower risk of IVD and 54% of the observed 36% lower risk of IHD in individuals with APOC3 LOF mutations. In contrast, low LDL-C levels mediated 1% lower risk of IVD and 2% lower risk of IHD.
Conclusion: The low risk of IVD observed in APOC3 loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL?C to IVD risk was not masked by lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk.

COMMENT

The gene APOC3 encodes apolipoprotein CIII (apoCIII), which is a key inhibitor of triglyceride lipolysis and clearance of remnant triglyceride-rich lipoproteins. Previous studies have indicated a causal link between carriage of APOC3 LOF mutations, characterized by low plasma triglycerides and low levels of apoCIII, and reduced risk of IHD.1.2 Thus, a biologically plausible explanation is that lower levels of remnant cholesterol, for which plasma triglycerides are a marker, may be responsible for this reduced risk. Indeed, observational and genetic evidence supports an association between elevated levels of remnant cholesterol and risk for IHD.3,4 Other studies, however, implicated a possible role for lower LDL-C levels as a mediator of the reduced IHD risk in APOC3 LOF carriers.2,5 This study aimed to investigate and resolve this ongoing debate.

The results of this analysis clearly show that low remnant cholesterol is the key mediator of the reduced IVD risk in individuals with APOC3 LOF mutations, responsible for almost all of this reduction in risk (37% of the observed 41% lower risk of IVD, and 54% of the observed 36% lower risk of IHD in the Copenhagen studies). These findings therefore implicate remnant cholesterol as a novel target for pharmacotherapeutic intervention. Ongoing studies are evaluating the potential of different approaches, such as antisense inhibition and monoclonal antibody therapy targeting apoCIII, to reduce triglycerides and remnant cholesterol and prevent cardiovascular events.6,7

References

1. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.

2. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.

3. 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.

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 Apr 29;5(5). pii: e002765

5. Pollin T, Damcott CM, Shen H et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008;322:1702–5.

6. Graham MJ, Lee RG, Bell TA 3rd et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112):1479-90.

7. Khetarpal SA, Zeng X, Millar JS et al. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med 2017;23:1086-94.

Key words triglycerides; remnant cholesterol; APOC3 loss-of-function mutations; ischaemic vascular disease