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Remnant Cholesterol and non-HDL – What’s that? Why bother?

 
In a previous article "Blood Cholesterol Testing - don't let the routine standard lipid panel fool you!" I talked about the standard lipid panel that doctors use to check your “bad” cholesterol, aka LDL level. In "Why you need to look beyond your “bad" cholesterol” - level" I’ve also gone into some depth on why a myopic focus on LDL-C can do more harm than good.
 
In this article I will talk about 2 relatively unknown cholesterol parameters and explain why you want to keep an eye on these…
 
The routine standard lipid panel checks your levels of:
 
- Total cholesterol 
 
- LDL-C (or just LDL, low-density lipoprotein cholesterol, the “bad" cholesterol)
 
- HDL-C (or just HDL, high-density lipoprotein cholesterol, the “good" cholesterol) 
 
- VLDL-C (or just VLDL, very-low-density lipoprotein cholesterol) 
 
- Triglycerides (a.k.a. blood fats)
 
If you have read my previous articles you know the limitations of LDL-C and the standard lipid panel. However, while the advanced lipid panel gives you much more accurate information on your health status, the standard lipid panel is not totally worthless if you know what to look for…The caveat is, what to look for - non-HDL-C and remnant cholesterol – are not printed in your standar lipid test results. And your doctor may not even know about non-HDL-C and remnant cholesterol! That’s why I had to write this article…
 

non-HDL-C

 
How to calculate it from the standard lipid panel:
 
non-HDL-C = Total cholesterol – HDL [1]
 
What is it?
 
non-HDL-C is all the cholesterol not carried in HDL. 
 
In addition to LDL-C, cholesterol is also carried in VLDL (very low-density lipoprotein cholesterol) and IDL (intermediate-density lipoprotein cholesterol), which are other lipoprotein particles that transport cholesterol in the blood stream.
 
Despite being a simple calculation, it is not printed on lab result reports and not routinely checked by doctors. Half of surveyed doctors don’t even know how to calculate it and two thirds don’t know what the non-HDL-C treatment goals are.[2]
 
What non-HDL-C level should you aim for?
 
The table below shows recommended non-HDL-C levels for three risk categories of people. The non-HDL goal is 30 mg/dL higher than the LDL-C goal.[3, 4]
 

If you have read my previous articles you know LDL-C itself is worthless, but I added it to the table for comparison with the non-HDL-C goal.
 
Why do you want to know your non-HDL-C level?
 
Non-HDL-C better reflects the increased cardiovascular risk associated with high apoB levels and small LDL particle size, which are hallmarks of obesity (see my previous articles that explain apoB and LDL particle size).[5] When triglyceride levels exceed 150 mg/dL, as is commonly seen in patients with the metabolic syndrome, obesity, diabetes and cardiovascular disease – in other words, the large majority of the general population - LDL particle number, apoB and VLDL levels increase without concomitant elevations in LDL-C.[5-7] Thus, non-HDL-C is more reflective of atherogenicity in persons with elevated triglycerides.[8] This constellation of increased triglycerides, reduced HDL-C, increased small dense LDL particles, and increased remnant cholesterol levels (primarily VLDL, see below), is known as atherogenic or ‘‘adiposopathic” dyslipidemia.[9]
 
The superiority of non-HDL-C over LDL-C (the “bad” cholesterol) has been proven in multiple studies. A meta-analysis demonstrated that on-treatment levels of non-HDL-C are more strongly associated with future risk of cardiovascular events than either apoB or LDL-C.[10] In an analysis of men enrolled in NHANES II, increasing obesity (assessed by BMI) was associated with higher triglyceride, total and non-HDL cholesterol levels, and lower HDL-C.[11] In middle-aged and older men, LDL-C did not vary with BMI and the elevation in total cholesterol was due mainly to an increased non-HDL-C level (i.e. an increase in cholesterol carried by VLDL and IDL particles).[11] NHANES III also showed that non-HDL-C is significantly more strongly correlated with obesity than LDL-C.[12] While total cholesterol and LDL-C generally correlate on a population level, this correlation is weaker in fatter people, in whom VLDL-C (which is included in the non-HDL-C measure) makes a larger contribution to total cholesterol.[13] Similarly, accumulation of visceral (abdominal) adipose tissue - which drives the metabolic syndrome and diabetes - is associated with the lipoprotein profile of obesity with a normal LDL-C despite elevated levels of atherogenic lipoproteins and cardiovascular risk.[14]
 
The EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study followed 21,448 participants aged 45 to 79 years without diabetes or heart disease at baseline, for 11 years. A total of 2,086 participants developed coronary heart disease during follow-up.[1] In this large study, which is representative of the contemporary Western population, it was found that non-HDL-C, TG, and the total cholesterol to HDL-C ratio were more strongly associated with risk of future coronary heart disease than was LDL-C.[1] Interestingly, the increased risk associated with elevated non-HDL-C levels, TG levels, or with an elevated total cholesterol to HDL-C ratio was present in all LDL-C categories, and especially in participants with low LDL-C levels.[1] In this study, LDL-C did not confer additional risk for heart disease, whereas at any given LDL-C level, non-HDL-C levels were associated with higher risk risk.[1] Similar results were reported in an earlier study which found that within each LDL-C category (<130 mg/dl, 130–159 mg/dl, >160 mg/dl), non-HDL-C (<160 mg/dl, 160–189 mg/dl, >190 mg/dl) was additionally predictive of heart disease events, but within each non-HDL-C category, LDL-C was not.[15] In these patient populations - which comprise a large proportion of the general population - reliance on LDL-C as a risk indicator and therapeutic target in these populations is grossly misleading. Even in non-obese men, only non-HDL-C is predictive of heart disease.[16] 
 
Several guidelines for management of dyslipidemia and cardiovascular disease have recently added non-HDL as a primary treatment target. The International Atherosclerosis Society (IAS) Position Paper on the management of dyslipidemia considers non-HDL-C as an alternative to LDL-C as target of therapy, and actually favors adoption of non-HDL-C as the major target of lipid-lowering therapy.[8] The IAS expects that in future guidelines non-HDL-C will replace LDL-C as the best treatment target.
 
The European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guideline states that non-HDL-C can provide a better risk estimation compared with LDL-C, in particular in patients with the metabolic syndrome or diabetes, who commonly have elevated triglyceride levels.[3]
 
Notably, the National Lipid Association (NLA) states that while non-HDL-C and LDL-C are co-primary treatment targets, non-HDL-C is the superior treatment target for modification.[9] Non-HDL-C levels and change during treatment of dyslipidemia are more strongly associated with reduced risk for atherosclerotic coronary heart disease (CHD) than changes in LDL-C, or on-treatment levels of LDL-C.[9]
 
Considering this, it is a shame that doctors don’t routinely check people’s non-HDL-C levels. And it’s an embarrassment that half of them don’t even know how to do this simple calculation!
 

Remnant cholesterol

 
How to calculate it from the standard lipid panel:
 
Remnant cholesterol = Total cholesterol – HDL – LDL
 
What is it?
 
Remnant cholesterol is all cholesterol not carried in HDL and LDL. [17]
 
What non-HDL-C level should you aim for?
 
There is currently less medical research available on remnant cholesterol than non-HDL-C, and therefore no formal guidelines exist yet for remnant cholesterol goals. However, as outlined below, in studies the lowest risk is observed in people who have remnant cholesterol levels below 19 mg/dL.
 
Why do you want to know your remnant cholesterol level?
 
In the fasting state (before breakfast), this constitutes cholesterol carried in very low-density lipoprotein VLDL and intermediate-density lipoprotein IDL) – which are known as “triglyceride-rich lipoproteins” - whereas in the non-fasting state, cholesterol in chylomicron remnants is also included.[18] However, even in the non-fasting state, calculated remnant cholesterol is mainly cholesterol in VLDL and IDL.[18] 
 
For calculated non-fasting remnant cholesterol, it has been shown that those with the highest versus lowest levels (over 43 versus below 15 mg/dL) have a 2.3-fold increased risk of ischemic heart disease.[19] In the Copenhagen City Heart Study and Copenhagen General Population Study, including 82 890 individuals, the risk of heart attack increased continuously with increasing remnant cholesterol, even when the analysis for remnant cholesterol was adjusted for LDL cholesterol.[20] When compared with individuals with non-fasting remnant cholesterol levels <19 mg/dL, the risks for heart attack were 1.8-fold for a those with a level of 19-38 mg/dL, 2.2-fold for 39-58 mg/dL, and 3-fold for those with a level of 58 mg/dL and higher.[20] When examining all-cause mortality, the risk increased continuously with increasing remnant cholesterol levels, but not with increasing LDL-C levels.[20] When compared with individuals with non-fasting remnant cholesterol levels 19 mg/dL, the risk for all-cause mortality was 1.4-fold in individuals with remnant cholesterol level of 58 mg/dL.[20] 
 
Bottom line, an increased triglyceride level (i.e. blood fat level), which is a marker of increased remnant cholesterol levels, is associated with increased all-cause mortality in individuals in the general population, whereas this is not the case for increased levels of total cholesterol (which is often a marker of LDL cholesterol).[21] Even in statin trials where subjects have achieved very low LDL-C levels, elevated remnant cholesterol is associated with residual risk of arteriosclerotic cardiovascular disease.[22, 23]
 

Summary

 
Non-HDL-C and remnant cholesterol are two great indicators of your cardiovascular disease risk, than you can easily calculate from your standard lipid panel. The figure summarizes how to calculate these parameters.
 
Figure: Illustration of what’s in non-HDL-C and remnant cholesterol.
 
 

Figure modified from Robinson JG. Are you targeting non-high-density lipoprotein cholesterol? J Am Coll Cardiol. 2009 Dec 29;55(1):42-4.

Since most doctors don’t know how to calculate non-HDL and its recommended levels, and probably have never heard about remnant cholesterol, you will have to be proactive and calculate these simple – yet powerful - parameters yourself.
 
The advanced lipid panel is more expensive than the standard lipid panel, and not always covered by health insurance. But, by finding out your levels of non-HDL-C and remnant cholesterol you will be far more informed about your health status than you would if you and your doctor just cared about your “bad” cholesterol. 
 
If your “bad” cholesterol level is high and your doctor prescribes you a statin without having found out your non-HDL-C and remnant cholesterol level (or without having had you get an advanced lipid panel) – which is common among the large majority of doctors who practice “one-size-fits-all-assembly-line-medicine” - run away as if your life depends on it because it may...!
 

References:

1.            Arsenault, B.J., et al., Beyond low-density lipoprotein cholesterol: respective contributions of non-high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women. J Am Coll Cardiol, 2009. 55(1): p. 35-41.

2.            Virani, S.S., et al., Barriers to non-HDL cholesterol goal attainment by providers. Am J Med, 2011. 124(9): p. 876-80 e2.

3.            Catapano, A.L., et al., ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis, 2011. 217(1): p. 3-46.

4.            Bays, H.E., et al., National Lipid Association Annual Summary of Clinical Lipidology 2015. J Clin Lipidol, 2015. 8: p. S1-S36.

5.            Bays, H.E., et al., Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol, 2013. 7(4): p. 304-83.

6.            Arsenault, B.J., S.M. Boekholdt, and J.J. Kastelein, Lipid parameters for measuring risk of cardiovascular disease. Nat Rev Cardiol, 2011. 8(4): p. 197-206.

7.            Adiels, M., et al., Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol, 2008. 28(7): p. 1225-36.

8.            Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel, An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report. J Clin Lipidol, 2014. 8(1): p. 29-60.

9.            Bays, H.E., et al., National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol, 2016. 10(1 Suppl): p. S1-S43.

10.          Boekholdt, S.M., et al., Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA, 2012. 307(12): p. 1302-9.

11.          Denke, M.A., C.T. Sempos, and S.M. Grundy, Excess body weight. An underrecognized contributor to high blood cholesterol levels in white American men. Arch Intern Med, 1993. 153(9): p. 1093-103.

12.          Gardner, C.D., M.A. Winkleby, and S.P. Fortmann, Population frequency distribution of non-high-density lipoprotein cholesterol (Third National Health and Nutrition Examination Survey [NHANES III], 1988-1994). Am J Cardiol, 2000. 86(3): p. 299-304.

13.          Wolf, R.N. and S.M. Grundy, Influence of weight reduction on plasma lipoproteins in obese patients. Arteriosclerosis, 1983. 3(2): p. 160-9.

14.          Yusuf, S., et al., Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet, 2005. 366(9497): p. 1640-9.

15.          Liu, J., et al., Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol, 2006. 98(10): p. 1363-8.

16.          Pischon, T., et al., Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation, 2005. 112(22): p. 3375-83.

17.          Varbo, A., M. Benn, and B.G. Nordestgaard, Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther, 2014. 141(3): p. 358-67.

18.          Nordestgaard, B.G., Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circ Res, 2016. 118(4): p. 547-63.

19.          Varbo, A., et al., Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol, 2013. 61(4): p. 427-36.

20.          Varbo, A., J.J. Freiberg, and B.G. Nordestgaard, Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem, 2015. 61(3): p. 533-43.

21.          Langsted, A., et al., Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med, 2011. 270(1): p. 65-75.

22.          Faergeman, O., et al., Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease. Am J Cardiol, 2009. 104(4): p. 459-63.

23.          Miller, M., et al., Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol, 2008. 51(7): p. 724-30.

Last modified on Monday, 19 June 2017 04:28
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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