Remnant cholesterol and risk of ischaemic stroke

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19 July 2019

High remnant cholesterol levels were associated with a higher risk of ischaemic stroke according to this report from the Copenhagen General Population Study.

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.

STUDY SUMMARY

Objective:

To investigate whether high remnant cholesterol concentrations are associated with increased risk of ischaemic stroke in the general population.

Study design:

Prospective, observational association study using data from the Copenhagen General Population Study over a 14-year follow-up. Results were validated using data from the Copenhagen City Heart Study over a 26-year follow-up.

Study population:

The Copenhagen General Population Study included 102,964 individuals with information on remnant cholesterol at baseline in 2003-2015. The Copenhagen City Heart Study was validated in 9,548 individuals recruited 1991-1994.

Efficacy variables:

· Ischaemic stroke, defined as International Classification of Disease [ICD]-8 codes 431–438; ICD-10 codes I61–I68 and G45. These data were collected from the national Danish Causes of Death Registry and the national Danish Patient Registry between 1976 and April 2018 and validated independently by two clinicians.

· Remnant cholesterol, calculated from a standard nonfasting lipid profile as: Total cholesterol – (LDL cholesterol + HDL cholesterol).

Methods:

Hazard ratios were estimated using Cox proportional hazard regression models. Multivariable adjustment was made for age, sex, hypertension, lipid-lowering therapy, smoking, and atrial fibrillation. Hazard ratios and confidence intervals (CIs) were corrected for regression dilution bias using measurements of remnant cholesterol from 4,400 individuals without lipid-lowering therapy with 1991–1994 and 2001–2003 examinations in the Copenhagen City Heart Study.

Results:

· Over the 14-year follow-up period, there were 2,488 verified ischaemic strokes.

· Step-wise higher remnant cholesterol concentrations were associated with step-wise higher ischaemic stroke risk. For each 1 mmol/L (39 mg/dL) higher remnant cholesterol there was a 43% (95% CI 23-67%) increase in risk of ischaemic stroke. Similar findings were reported for the validation analysis using data from the Copenhagen City Heart Study.

· Compared with individuals with low remnant cholesterol levels (<0.5 mmol/L or 19 mg/dL), a remnant cholesterol level ≥1.5 mmol/L (58 mg/dL) was associated with 1.99 (95% CI 1.49-2.67) higher risk of ischaemic stroke.

Conclusion:

Individuals with high remnant cholesterol concentrations had a higher risk of ischaemic stroke. These results indicate that randomised clinical trials on remnant cholesterol lowering in individuals with high concentrations, with the aim of preventing ischaemic strokes, are needed.

COMMENT

High levels of remnant cholesterol, i.e. the cholesterol content of triglyceride-rich remnant lipoproteins, is associated causally with an increased risk of ischaemic heart disease and mortality.1-4 There has, however, been debate as to whether high remnant cholesterol levels are also associated with an increased risk of ischaemic stroke.5 Statins are known to reduce ischaemic stroke risk, and while their predominant effect is lowering low-density lipoprotein cholesterol, they also lower triglycerides and remnant cholesterol.6 Therefore, at least some of the benefit of statins on ischaemic stroke may be mediated by reduction in remnant cholesterol.

This observational study, involving more than 100,000 individuals in the Copenhagen General Population Study, showed that stepwise higher remnant cholesterol concentrations were associated with stepwise higher risk of ischaemic stroke. Individuals with remnant cholesterol levels ≥1.5 mmol/L (58 mg/dL) had nearly 2-fold higher risk of ischaemic stroke than those with low levels (<0.5 mmol/L (19 mg/dL). While the large number of individuals included in this study strengthens the robustness of these findings it is also important to bear in mind the lack of information on ischaemic stroke subtypes, as well as the observational study design which precludes conclusions regarding causality.

While taking these caveats into account, the take home message is that this study supports a proportional association between high remnant cholesterol levels and risk of ischaemic stroke. These findings augur for large, randomised trials testing whether lowering of high levels of remnant cholesterol translates to reduction in the risk for ischaemic stroke.

References

1. 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.

2. 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. doi: 10.1161/JAHA.115.002765.

3. Jepsen AM, Langsted A, Varbo A et al. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem 2016;62:593-604.

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;64:219-23.

5. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388: 2532-61.

6. Varbo A, Nordestgaard BG. Remnant lipoproteins. Curr Opin Lipidol 2017;28:300–7.

Key words

remnant cholesterol; ischaemic stroke; Copenhagen General Population Study