Ten years prospective data from the Norwegian HUNT 2 study Journal of Evaluation in Clinical Practice February 2011; Vol. 18; No. 1; pp. 159-168 Halfdan Petursson MD, Johann A. Sigurdsson MD, Calle Bengtsson MD, Tom I. L. Nilsenand Linn Getz MD PhD FROM ABSTRACT: Total cholesterol is a frequently used variable in the risk estimates for cardiovascular disease (CVD) prevention. Some studies indicate that the predictive properties of cholesterol might not be as straightforward as widely assumed. Our aim was to document the strength and validity of total cholesterol as a risk factor for mortality in a well-defined, general Norwegian population without known CVD at baseline. These authors assessed the association of total serum cholesterol with total mortality, as well as mortality from CVD and ischaemic heart disease (IHD), in 52,087 Norwegians, aged 20 – 74. The subjects were followed-up at 10 years, giving 510,297 person-years in total. Results Among women: Elevated cholesterol reduced all-cause mortality by 6%. Elevated cholesterol reduced CVD mortality by 3%. The association with IHD mortality was not linear but seemed to follow a U-shaped curve, with the highest mortality below 5.0 [195 mg/dl] and greater than or equal to 7.0 mmol L-1 [271 mg/dl]. Among men, the association of cholesterol with mortality also followed a U-shaped pattern. Conclusion Our study provides an updated epidemiological indication of possible errors in the CVD risk algorithms of many clinical guidelines. If our findings are generalizable, clinical and public health recommendations regarding the dangers of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial. KEY POINTS FROM THIS STUDY: 1) As cholesterol has become an essential part of lay-peoples basic understanding of their health, and the prevalence of slightly elevated cholesterol levels is so high, we believe that it is important to re-examine old assumptions regarding cholesterol as a risk factor. 2) The common knowledge that total serum cholesterol is an important and strong, independent risk factor for cardiovascular disease (CVD) may be flawed. 3) The common knowledge that the lower the total cholesterol level, the better may also be flawed. 4) Campaigns aimed at the general public to not let their total cholesterol get above 5.0 mmol L-1 [195 mg/dl] may be flawed. 5) According to current authoritative CVD cholesterol guidelines, 75% of the adult Norwegian population would be deemed at risk for CVD and in need of clinical attention. Consequently, we have questioned the theoretical basis of the guidelines. 6) The aim of the present study was to document the strength and validity of total serum cholesterol as a risk factor for mortality, as defined by current CVD prevention guidelines. 7) The phrase U-shaped association indicates that higher mortality (or incidences) can be observed both in individuals with low and high levels of cholesterol compared with individuals with levels in between. 8) Among women, serum cholesterol had an inverse association with all-cause mortality as well as CVD mortality. [Which means elevated total cholesterol levels reduced CVD mortality rates]. 9) In women, the association with IHD mortality appeared to follow a U-shaped curve. [both low levels and high levels increased IHD mortality] 10) Among men, cholesterol did not seem to be linearly associated with mortality but rather the association followed a U-shaped pattern, with the lowest mortality appearing in the second cholesterol category (5.0 – 5.9 mmol L-1 [195 – 228 mg/dl]). This was apparent in all mortality categories. Consequently, cholesterol analysed as a continuous variable did not show a statistically significant linear association with mortality. 11) Having cholesterol levels above 5.5 mmol L-1 [213 mg/dl] was not associated with increased mortality, either among smokers or among non-smokers. 3 12) Smoking was strongly associated with increased mortality in all mortality categories among both sexes. 13) We found total cholesterol to be an overestimated risk factor for CVD prevention. 14) Our results contradict the guidelines well-established demarcation line (5 mmol L-1 [195 mg/dl]) between good and too high levels of cholesterol. They also contradict the popularized idea of a positive, linear relationship between cholesterol and fatal disease. 15) Guideline-based advice regarding CVD prevention may thus be outdated and misleading, particularly regarding many women who have cholesterol levels in the range of 5 – 7 mmol L-1 [195-271 mg/dl]. 16) Our finding of significant discrepancies between epidemiological data and clinical guidelines, suggesting a linear relation between total cholesterol and mortality from CVD is in accord with other studies. 17) In contrast to cholesterol, the detrimental effect of smoking was clearly evident even after stratifying for cholesterol levels. This emphasizes the importance of smoking as a CVD risk factor compared with cholesterol. 18) Based on epidemiological analysis of updated and comprehensive population data, we found that the underlying assumptions regarding cholesterol in clinical guidelines for CVD prevention might be flawed: cholesterol emerged as an overestimated risk factor in our study, indicating that guideline information might be misleading, particularly for women with moderately elevated cholesterol levels in the range of 5 – 7 mmol L-1 [195-271 mg/dl]. 19) Many individuals who could otherwise call themselves healthy struggle conscientiously to push their cholesterol under the presumed danger limit (i.e. the recommended cut-off point of 5 mmol L-1) [195 mg/dl], coached by health personnel, personal trainers and caring family members. Massive commercial interests are linked to drugs and other remedies marketed for this purpose. It is therefore of immediate and wide interest to find out whether our results are generalizable to other populations.