The safety of long-term low cholesterol levels

In their study, Strandberg and Strandberg found that during a 39-year follow-up of initially healthy men, aged 30 to 45 years (mean, 38 years), low serum cholesterol levels predicted better survival, better physical function, and better quality of life in old age, without adversely affecting mental functioning. The study population was comprised of 3,277 Finnish men from higher socioeconomic strata. The association of cholesterol and total mortality was significant and graded. Every mmol/L increase of baseline total cholesterol was associated with an in­creased risk of 11%.

This study confirms and extends the results of earlier shorter-term studies that cholesterol levels predict both cardiovascular and total mortality.^1-3 In the study cohort, lower cholesterol levels were associated with better long-term outcomes, and men with cholesterol levels in the lowest quintile had the lowest mor&shy;tality. An important objective of this study was to determine the safety of long-term low cholesterol levels. The results provide important and encouraging additional data regarding the benefits and safety of naturally low cholesterol levels. However, the study does not eliminate any concerns about the long-term safety of lowered cholesterol levels and that of cholesterol-lowering drugs. A limitation of the study findings is that the low total cholesterol levels in this Finnish population are not really that low by today’s standards or those commonly achieved with currently available HMG-CoA reductase inhibitor (statin) therapy. The total cholesterol level in the lowest group was less than 5.0 mmol/L (< 194 mg/dL), considerably higher than that currently recommended as a therapeutic goal for high-risk patients (LDL-cholesterol goal < 100 mg/dL or < 70 mg/dL).

Another important and encouraging finding in this study was that men with the lowest cholesterol levels had better physical functioning in old age and no associated adverse effects on mental functioning over the long term. There has been much debate as to whether low cholesterol and/or statin treatment over decades may be associated with adverse effects on mental functioning^4-7 and cancer. The finding that there was no adverse effect on mental function is an important observation, but again, the results apply to naturally low cholesterol levels and cannot be extrapolated to drug-induced low cholesterol levels. Statins have now been shown to reduce mortality in large clinical outcome studies for up to 8 years.⁸ Furthermore, the very low levels achieved with intensive therapy for periods up to 2 years are not associated with any increased adverse effects.⁹ How&shy;ever, there remains a lack of data to definitively address the concerns of some clinicians about the possible adverse effects of low cholesterol levels over the long term or the possible impact of statin therapy on memory loss and cognitive impairment. The idea that statins might adversely affect memory functioning has been based mostly on isolated case reports without causality being established and is not supported by data from the tens of thousands of patients in large-scale prospective studies.^10,11 In fact, statins may actually be beneficial in reducing cognitive impairment and the incidence of Alzheimer’s disease, although this remains speculative at the present time. A large clinical outcome trial in elderly patients, the PROspective Study of Pravastatin in the Elderly at Risk,¹¹ did not show a benefit for pravastatin (Pravachol) in reducing dementia in elderly patients. This trial lasted only 3 years, however, and the reduction in LDL was modest. Long-term randomized trials using potent statins to achieve and maintain low LDL cholesterols levels may definitively answer the question regarding the ability of statins to prevent Alzheimer’s disease.

Because this study was performed in a homogeneous upper socioeconomic strata male population, the results may not extrapolate to other groups such as women, the elderly, other ethnic groups, and low socio-economic status individuals.

The key take-home message from this study is that naturally low total cholesterol levels are associated with better long-term outcomes and no apparent adverse effects on mental functioning. These are very encouraging findings that confirm and extend the results of previous studies. How&shy;ever, the results cannot be extrapolated to the low cholesterol levels achieved with pharmacologic therapy or to groups that differ from the study population. Although the safety of statin therapy for lowering cholesterol has been established during treatment for at least as long as 8 years, the long-term safety of statins and that of significantly lowered cholesterol may not be known for another decade or more. However, it has now been almost 20 years since the first statin was introduced into clinical practice (lovastatin [Mevacor] in 1987) and 15- to 20-year safety data should appear soon.