The cholesterol paradigm: is less really always better?

New data published in Frontiers of Endocrinology challenges the cholesterol paradigm of ‘less is always better’, especially for older people.

Is ‘as low as possible’ appropriate?

Cholesterol – can it be too low?

This question is raised again by a recent analysis of 903 participants in the Chinese Longitudinal Healthy Longevity Survey (CLHLS).1 It reports a significant inverse association between total cholesterol levels and all-cause mortality. A stratification according to the total cholesterol concentration at baseline (low: <3.40; medium: 3.40–4.39; high: ≥4.39 mmol/L) showed a lower mortality in the medium (HR = 0.72, 95% CI: 0.53-0.97) and high group (HR = 0.7 1, 95% CI: 0.52-0.96) compared to the lowest. When cholesterol concentration was used as a continuous variable, it was found that the risk of death increased by 12% when cholesterol was reduced by 1 mmol/l. People in the middle and high categories had a 10.1% and 13.0% higher 2-year survival probability than those in the lowest category, respectively.

The analysis was controlled for potential influencing factors by including nutritional status or physiological data in the model. Interestingly, the correlation was unaffected by this and pre-existing conditions such as diabetes, heart disease and strokes were not significantly linked to all-cause mortality. The predictive value of traditional risk factors for mortality may decrease in older people compared to younger population groups, the study authors explain, referring to earlier studies.

They emphasise the need for further research to validate these results and conclude: 'Our results add to the growing evidence that questions the “lower is better” paradigm for cholesterol levels in older adults.' According to their data, the optimal range could be between 3.40 and 5.18 mmol/l (131-200 mg/dl).

However, since the physiological functions of cholesterol change with age, the correlation between cholesterol levels and overall mortality may differ depending on age, and age-specific treatment recommendations would be useful, according to the authors.1

What are the risks associated with particularly low cholesterol levels?

Cholesterol plays an important role in the regulation of many cellular processes, is crucial for the fluidity and permeability of cell membranes, plays a role in gene transcription, and is the basis of all steroid/sex hormones and vitamin D analogues.2 It is found in practically all cells of the body. In the body's most cholesterol-rich organ, the brain (which contains almost 25% of the total), it is an important component of the myelin sheath and thus important for brain health.3

The aforementioned study has some limitations, but its observations are consistent with those of other, sometimes very large studies with longer follow-up periods. An older longitudinal study published in the Lancet reported a protective association between high total cholesterol and higher life expectancy (due to lower mortality from cancer and infection) in people aged 85 and older.4 The Honolulu Heart Program concluded that low cholesterol concentrations over a long period of time increased the risk of death.5 The authors, for whom the result was unexpected, summarised: 'These data cast doubt on the scientific justification for lowering cholesterol to very low levels (< 4.65 mmol/l or 180 mg/dl) in older people.'

A recent 10-year prospective study from Korea found a U-shaped association between total cholesterol and all-cause mortality in 75–99-year-olds.6 A cholesterol level of 210–249 mg/dL was associated with the lowest mortality risk, which is above the recommended level.1

Strong criticism of target levels that are too low and a lack of evidence

When the new European guideline on lipid lowering was published in 2019, its ‘as low as possible’ paradigm was already the subject of critical discussion from various quarters. In an article published by the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft, AkdÄ), it was stated that ‘the new guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) significantly expand the group of people with hyperlipidaemia who require drug treatment. The boundary between primary and secondary prevention has been removed, and the LDL target levels have been significantly reduced again. Ezetimibe and PCSK9 inhibitors have been given a class 1 recommendation without any new and convincing evidence of a favourable risk-benefit ratio or cost-effectiveness."7

In particular, the questionable level of evidence and the fact that the task force is not independent were criticised. In this context, the AkdÄ article pointed out that only two of the 21 authors stated no conflicts of interest with pharmaceutical companies – one author even had conflicts of interest with 48 pharmaceutical companies.

Almost 70% of the contributors had conflicts of interest with manufacturers of PCSK9 inhibitors. Significant conflicts of interest with industry were also highlighted within the ESC (75.5% of its total annual income of €71.9 million came directly or indirectly from industry). 'This raises serious questions about whether professional associations should be producing guidelines at all,' the article concluded.7 It added that 'In our opinion, [this guideline] can at best be described as a position paper of an industry-related professional association.'

Sources
  1. Hu, F. et al. Association between total cholesterol and all-cause mortality in oldest old: a national longitudinal study. Front. Endocrinol. 15, (2024).
  2. Schade, D. S., Shey, L. & Eaton, R. P. Cholesterol Review: A Metabolically Important Molecule. Endocr Pract 26, 1514–1523 (2020).
  3. Vitali, C., Wellington, C. L. & Calabresi, L. HDL and cholesterol handling in the brain. Cardiovascular Research 103, 405–413 (2014).
  4. Weverling-Rijnsburger, A. W. et al. Total cholesterol and risk of mortality in the oldest old. Lancet 350, 1119–1123 (1997).
  5. Schatz, I. J. et al. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet 358, 351–355 (2001).
  6. Yi, S.-W., Yi, J.-J. & Ohrr, H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci Rep 9, 1596 (2019).
  7. [In German] AKDAE, Neue europäische „Leitlinie“ zur Lipidsenkung: As low as possible? Arzneimittelkommission der deutschen Ärzteschaft (2020).