LDL cholesterol

What is being measured

Low-density lipoprotein transports cholesterol from the liver to the cells. If it remains in the blood for too long, it is deposited in the vessel wall, where — together with inflammatory cells — it forms the basis of atherosclerotic plaques. The structure of lipoproteins is described as follows: Cholesterol and lipoproteins.

As with the HDL The test measures the ‘cargo’ rather than the ‘load’: LDL cholesterol is the amount of cholesterol in a class of particles, not their number. And in most cases, it is not even measured, but calculated.

The figure on the report is often an estimate

The standard estimation formula calculates LDL by subtracting HDL and triglycerides from total cholesterol. Its accuracy was tested against direct measurement using 1,350,908 test results. For triglyceride levels below 400 mg/dl, the risk classification using the newer calculation method matched the measurement in 91.7 per cent of cases, whilst the older Friedewald formula matched it in 85.4 per cent. The greatest difference was observed with low LDL levels below 70 mg/dl and with high triglyceride levels.

The inaccuracy was greatest when triglyceride levels were high, and as is well known, triglyceride levels are strongly influenced by the last meal; see Triglycerides. It is the obvious conclusion that a test carried out whilst not sober would therefore also affect the calculated LDL; this study did not investigate this. The formula used by the laboratory in question is usually stated on the test results.

Reference range

• Approximately 50 to 130 mg/dl

Unlike with most laboratory test results, the reference range is the less reliable indicator in this case. Guidelines use target values that depend on overall risk rather than on where the population falls; which of these applies to an individual is a matter for the doctor to decide. The reason why target values exist at all but not for HDL is explained in the next section.

Why causality is established in this case

When it comes to HDL cholesterol, the trail leads nowhere: a strong indicator whose contribution to the underlying cause disappears when tested against genetic factors. With LDL, it is the other way round, and this difference is the real reason why this figure matters.

Separate meta-analyses of more than 200 prospective cohort studies, Mendelian randomisation studies and randomised trials, involving a combined total of over two million participants and over 20 million person-years, find a consistent, dose-dependent and log-linear relationship between LDL burden and the risk of disease. A reduction should lower the risk in in proportion to the absolute reduction and the duration of the lower exposure, provided explicitly that the reduction in LDL cholesterol is accompanied by a corresponding reduction in particle count and that no harmful side effects occur as a result of targeting the wrong mechanism .

The intervention section confirms this to be of the same order of magnitude. A meta-analysis of 26 randomised trials involving 170,000 participants found that for 1 millimole per litre reduction in LDL, a relative risk of 0.78 for serious vascular events and a 10 per cent lower overall mortality rate; a more intensive reduction compared with a less intensive one resulted in 15 per cent fewer events. A subsequent analysis of 327,037 participants found a 19 per cent reduction in the incidence of serious vascular events per millimole, regardless of baseline levels and irrespective of whether the participants had diabetes or kidney disease.

The second finding is the one of greater practical importance: the relative reduction did not depend on where a person started, and it was actually greater among younger people and those with a lower baseline risk. A low baseline risk is therefore not an argument for saying that a high value is irrelevant.

Not the tip, but the surface

From the proportionality of the relationship follows the key factor: not the highest value ever recorded, but the interplay between magnitude and time. This is precisely what is meant by the statement that the reduction in risk is proportional to the absolute reduction and regarding the duration of the reduced workload is. Anyone who has had elevated levels for years is in a different position to someone with a single high reading; this is the obvious interpretation of the proportional equivalence and not a separately measured comparison.

Why ApoB is the more accurate figure

Each atherogenic particle carries exactly one apolipoprotein B. ApoB therefore counts the particles, whilst LDL cholesterol measures their load, and the two differ when the particles carry different loads. This does not necessarily mean, however, that ApoB therefore leads to better treatment decisions; the analysis below shows the deviation, not its benefit.

Two people with the same LDL cholesterol level can therefore differ by half in terms of particle count, and this difference is precisely what the causal chain is based on. Non-HDL cholesterol – that is, everything apart from HDL – is the convenient middle ground: it appears on every test result without the need for any additional tests.

Lipoprotein(a), once in a lifetime

Lp(a) is an LDL-like particle containing an additional protein and is largely genetically determined. A statement by the European Atherosclerosis Society notes that epidemiological and genetic studies involving hundreds of thousands of people support a causal and continuous association between Lp(a) concentration and cardiovascular events, even in the presence of very low LDL cholesterol. Elevated Lp(a) is also associated with aortic valve calcification; the data do not support a link with venous thrombosis.

Because the level is genetically determined, monitoring it over time is of little use; however, this is not substantiated in this statement, which does not comment on the matter. What it does say is that specific Lp(a)-lowering medicines have yet to demonstrate their clinical benefit . An elevated value therefore initially alters the assessment of the overall risk and, consequently, the other measures to be taken, rather than requiring treatment of the value itself.

What anabolic substances do

The study that illustrates this most clearly is a crossover trial involving eleven strength athletes: six weeks of oral stanozolol raised LDL cholesterol by 29 per cent, whilst six weeks of injected testosterone enanthate reduced it by 16 per cent. Two androgens, acting in opposite directions. The experiment does not distinguish the cause: the substance, the route of administration and 17-alpha-alkylation coincide in this case.

In strength athletes who self-administered several substances simultaneously, apolipoprotein B rose from 0.96 to 1.32 grams per litre. Over the same period, lipoprotein(a) fell from 189 to 32 units per litre.

These two figures point in opposite directions, and the study itself leaves open what this means for atherogenesis. A decrease in Lp(a) is, in itself, favourable, whilst an increase in ApoB is unfavourable, and the study does not measure which of the two changes carries greater weight. Anyone who looks solely at Lp(a) sees an improvement that does not actually exist.

A review of the research literature on anabolic steroids in sport lists a reduction in HDL and an increase in LDL amongst the effects described, and at the same time notes that most laboratory studies have not examined the actual doses used. In a long-term study of transgender people spanning five to six years, transmasculine participants experienced an increase in triglycerides and LDL, whilst HDL levels fell. The study observes these trends whilst the participants were on hormone therapy but does not demonstrate that they are the result of the therapy.

What this means in strength training

• Have your blood sugar measured whilst sober. High triglyceride levels in the test tube skew the calculated LDL level, and this effect is most pronounced precisely where accuracy is crucial.
• Have your ApoB levels checked once, at least for comparison. Someone with an LDL of 100 and an ApoB of 99 is in a different situation to someone with 66, yet the results look the same in both cases.
• Have your Lp(a) levels checked once. The value is genetically determined, and there is as yet no specific treatment for it; it alters the assessment of the overall risk.
• It’s not just the amount that counts – the duration does too. The reduction is effective in relation to the absolute reduction and the duration of the reduced load.
• Stanozolol and testosterone moved in opposite directions, by 29 per cent compared with a fall of 16 per cent. This comparison does not distinguish whether the route of administration, the substance or the alkylation is the decisive factor.

Classification

LDL is the laboratory parameter for which the effort involved in measuring it is most likely to pay off, for a reason that the neighbouring parameters do not have: cohorts, Mendelian randomisation and randomised trials all show the same dose-dependent relationship, and lowering it has been validated in randomised trials involving hundreds of thousands of participants . This conclusion is based on the assumption that as cholesterol levels fall, so does the number of particles.

However, the figure shown on the test results reflects less than it suggests. It is usually calculated; it measures the total mass rather than counting the particles, and for the same total mass, the particle count can vary by as much as half. Anyone who takes this matter seriously therefore measures ApoB once and Lp(a) once, and then looks at the trend rather than the third decimal place.

The issue that most affects this readership remains unresolved: the reduction in risk has not been investigated in strength-training athletes with cyclically elevated levels. The available data tend to support rather than contradict the idea that the proportional equivalence holds, as the relative reduction was actually greater among younger people and those with a lower baseline risk. Nevertheless, it is not measured against this group.

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