Lipids Beyond Good and Bad Cholesterol

For many patients, and some practitioners, cholesterol is still described in 2 words: good and bad. HDL is good, LDL is bad, and the goal is to raise one and lower the other. This simplification was once useful, but it now obscures more than it reveals. Modern lipid science focuses on particles rather than cholesterol content, on causation rather than association, and on a small number of markers that carry most of the useful information. Understanding them allows practitioners to read a lipid profile accurately and to discuss risk honestly.

Cholesterol travels in particles

Cholesterol and triglycerides do not dissolve in blood, so they travel inside lipoproteins, particles with a fatty core and a surface of proteins and phospholipids.

Each atherogenic particle, VLDL, IDL, LDL and lipoprotein(a), carries one molecule of apolipoprotein B, apoB. Measuring apoB therefore gives a count of atherogenic particles. Atherosclerosis begins when these particles enter the artery wall and are retained there, so the number of particles, and the time they have circulated, determines much of the risk.

LDL: causal, with overwhelming evidence

A European Atherosclerosis Society consensus reviewed genetic studies, epidemiological cohorts and randomised trials and concluded that LDL is a cause of atherosclerotic cardiovascular disease, with a consistent dose response: the lower the LDL, and the longer it has been lower, the lower the risk. People with genetic variants causing lifelong low LDL have markedly reduced cardiovascular risk; people with familial hypercholesterolaemia have markedly increased risk. Meta analyses of statin trials found that each 1 mmol/L reduction in LDL cholesterol reduced major vascular events by about a fifth.

HDL: a marker, not a target

Low HDL cholesterol is associated with higher cardiovascular risk, but raising it has not reduced risk. Genetic variants that raise HDL cholesterol do not lower heart disease risk, and several drugs that raised HDL substantially failed to reduce cardiovascular events. Very high HDL levels have even been associated with increased mortality in some studies. Low HDL is best understood as a marker of insulin resistance and metabolic dysfunction, not as a problem to be corrected directly.

Triglycerides and remnants

Raised triglycerides reflect increased triglyceride rich lipoproteins and their remnants, which carry cholesterol and are atherogenic. Triglycerides are strongly influenced by insulin resistance, refined carbohydrate, sugar, alcohol, obesity and poorly controlled diabetes. Very high levels, above about 10 mmol/L, increase the risk of pancreatitis and need urgent attention.

Better measures of atherogenic burden

Non HDL cholesterol, calculated as total cholesterol minus HDL cholesterol, captures cholesterol in all atherogenic particles, including remnants. It is available from any standard lipid profile and does not require fasting.

ApoB counts atherogenic particles directly. It is particularly useful in people with raised triglycerides, diabetes, obesity or metabolic syndrome, in whom LDL cholesterol can underestimate particle number because the particles are small and dense. European guidelines recommend apoB as an alternative risk marker, especially in these groups.

Lipoprotein(a)

Lipoprotein(a) levels are largely determined by genetics and remain relatively stable through life. High levels increase the risk of heart attack, stroke and aortic valve stenosis. European guidance recommends measuring it at least once in adulthood to identify people with very high levels, who have substantially increased risk. Lifestyle changes and most lipid lowering medicines have little effect on it, although specific therapies are in development. Knowing a person’s level helps refine their overall risk and informs the intensity of management of other risk factors.

Familial hypercholesterolaemia: do not miss it

Familial hypercholesterolaemia is a common inherited condition, affecting roughly 1 in 250 to 300 people in many populations, causing very high LDL from birth and premature cardiovascular disease. Clues include LDL cholesterol above about 4.9 mmol/L (190 mg/dL) in adults, a family history of early heart disease or high cholesterol, and physical signs such as tendon xanthomas. Diagnosis allows early treatment and cascade testing of relatives, which can be lifesaving. It cannot be managed by diet alone.

Practical points on testing

• Fasting is not routinely required for a lipid profile, according to international laboratory and atherosclerosis guidance, except when triglycerides are very high or a previous non fasting result was abnormal.
• Acute illness temporarily lowers LDL and raises triglycerides; testing is best done when well.
• Lipid values should be interpreted within an overall cardiovascular risk assessment, using a validated calculator appropriate to the population.

What changes lipids

Dietary change typically lowers LDL cholesterol by a modest amount, variable between people. For people at high cardiovascular risk or with familial hypercholesterolaemia, medication is usually necessary alongside diet.

Statins: evidence and communication

Statins are among the most extensively studied medicines, with consistent reductions in cardiovascular events in people at elevated risk. Muscle symptoms are the most commonly reported side effect. In blinded trials where patients who had stopped statins because of side effects took statin and placebo in alternating months, most of the symptom burden was present on placebo too, suggesting that many attributed symptoms are not caused by the drug itself. Genuine statin related muscle problems do occur and should be taken seriously.

Decisions about starting, continuing or stopping statins belong with the prescribing doctor and the patient. The practitioner’s role is to support lifestyle measures, to help patients understand their risk, and to raise concerns or side effects with the prescriber rather than advising changes to medication independently.

An illustrative case

A 44 year old woman has an LDL cholesterol of 5.6 mmol/L. She eats a healthy Mediterranean style diet, exercises regularly and has a normal weight. Her father had a heart attack at 49 and her brother has high cholesterol. She is interested in managing her cholesterol through diet and supplements alone.

The practitioner recognises features of possible familial hypercholesterolaemia and encourages her to discuss this with her doctor, who refers her to a lipid clinic. Genetic testing confirms the diagnosis, and treatment is started, with testing offered to her children. Her diet remains an important part of her care. A practitioner who focused only on diet would have missed the diagnosis that mattered most.

Beyond 2 words

The lipid profile tells a richer story than good and bad cholesterol. Reading it through particles, causation, non HDL cholesterol, apoB and lipoprotein(a), and recognising familial hypercholesterolaemia, gives practitioners a clearer picture of risk and a better basis for the conversations that follow.