Low serum cholesterol and mortality from injuries and suicide
ACP J Club. 1993 Jan-Feb;118:23. doi:10.7326/ACPJC-1993-118-1-023
Lindberg G, Råstam L, Gullberg B, Eklund GA. Low serum cholesterol concentration and short term mortality from injuries in men and women. BMJ. 1992 Aug 1;304:277-9.
To determine whether total serum cholesterol levels are associated with mortality from injuries and suicide.
Cohort of men and women followed for 20 years.
A geographically defined part of the county of Värmland, Sweden.
Residents contacted in 1964 and 1965 as part of a global health survey who were ≥ 25 years old at study start. 78% (26 693) of the men and 81% (27 692) of the women participated. Those who died before the age of 45 were excluded from the analysis. Complete data were available for > 98% of participants.
Assessment of risk factors
At screening, blood samples were taken from nonfasting participants, and total serum cholesterol concentrations were measured. Age-adjusted quartiles of cholesterol concentration were determined for each 5-year age stratum. Cancer diagnoses were taken from the Swedish cancer register. 3 time periods (0 to 6 y, 7 to 13 y, and ≥ 14 y) were used for analysis.
Main outcome measure
All deaths listed in the Swedish mortality register as caused by injuries or suicide.
During follow-up, 376 men and 139 women died of injuries. Of these, 146 men and 44 women committed suicide, 226 men and 92 women died from accidents, and 4 men and 3 women were murdered. In the first follow-up period (0 to 6 years), the relative risk (RR) for death from injuries in men with the lowest quartile for age-adjusted cholesterol compared with men in the highest quartile for cholesterol was 2.75 (95% CI 1.52 to 4.96; P < 0.05). When the data were divided into suicide and nonsuicide accidental deaths for the same period, the RR for suicide in men in the lowest cholesterol quartile was 4.22 (P < 0.05). The groups did not differ for accidental death. When 2758 men with cancer were taken out of the analysis, the RR for suicide was 4.10 (P < 0.05). For the other 2 periods, cholesterol levels were not associated with death from injuries, suicide, and accidents for men. For women there was no association between cholesterol levels and mortality from injuries, suicide, and accidents at any period.
Total serum cholesterol concentration was inversely associated with a short-term increased risk for suicide in men older than 45 years.
Source of funding: Värmland County Council.
For article reprint: Dr. G. Lindberg, Centre for Public Health Research, 651 82 Karlstad, Sweden. FAX 46-54-111-338.
If the 1980s brought a consensus that lowering serum cholesterol reduces one's risk for coronary heart disease, the 1990s have heralded a re-appraisal of the presumed safety of cholesterol-lowering treatments. The possibility that cholesterol reduction may increase mortality from causes other than heart disease began to receive serious attention in 1990 when meta-analyses of cholesterol-lowering trials showed that coronary heart disease benefits may be offset by increased rates of noncoronary heart disease deaths (1, 2). These studies found that cholesterol-lowering treatments were associated, albeit inconsistently, with increased cancer mortality and death from suicides and violence. The absence of preformed hypotheses and biological mechanisms raises suspicion that such findings may be spurious, but the strong design of the clinical trials encourages attribution of increased noncoronary heart disease mortality to the treatment prescribed. The 3 studies abstracted here pertain to these controversial issues.
The report of the Coronary Primary Prevention Trial by the Lipid Research Clinics Investigators provides an additional 6 years of follow-up past the planned 7.4 year duration of the trial. Because the randomized treatments (cholestyramine and placebo) were no longer being provided, the extended follow-up can only help to determine whether beneficial or adverse effects increase or diminish over time. Although the in-trial reduction in coronary heart disease disappeared with follow-up, the absence of any increase in cancer mortality or death from suicide or trauma is reassuring. Nevertheless, the men who were treated experienced small but nonsignificant increased rates for certain tumors.
The other 2 papers use the alternative strategy of examining epidemiologic associations between serum cholesterol concentration and mortality from various causes. Neaton and colleagues' study of men in the Multiple Risk Factor Intervention Trial is the largest of its kind, having several hundred thousand participants and over 20 000 deaths to study. Lindberg and colleagues provide the most thorough examination to date of the relation between serum cholesterol and non-illness-related causes of death (suicides, accidents, and violence). Nevertheless, because cholesterol levels were not manipulated, these epidemiologic studies cannot establish whether any observed associations between cholesterol level and mortality are causally linked.
The 2 papers by Neaton and Lindberg and their colleagues, as well as a recent meta-analysis of 18 other epidemiologic studies (3), focus on the relation between low serum cholesterol and increased mortality from causes other than coronary heart disease. They permit refinement of our emerging understanding of this unanticipated phenomenon. Specifically, the increased risk for cancer death in men with low cholesterol is reproducible and appears to be specific for lung, pancreas, and liver cancer; leukemia; and lymphoma (and not colon or breast cancer). Low serum cholesterol is associated with increased risk for death from hemorrhagic stroke, chronic obstructive lung disease, and cirrhosis. Finally, men with low cholesterol die at increased rates from other causes, principally suicide. The importance of many of these adverse associations is limited, however, by recognition that they appear to exist only when the cholesterol level is below 4.14 mmol/L (160 mg/dL).
Jacobs (3) and Lindberg and their colleagues provide information on similar relations in women. Notably, high serum cholesterol in women is a less potent predictor of cardiovascular disease, yet low cholesterol, as in men, is associated with an approximately 40% increase in death from assorted noncoronary causes.
Although it is widely agreed that high serum cholesterol promotes atherosclerosis and heart disease, Neaton, Jacobs (3), and their colleagues feel that low cholesterol is not causally related to deaths from various noncoronary causes. Instead, as described at length, the investigators postulate that various confounding factors explain these adverse associations. Among these confounding factors, however, preclinical cancers, alcohol consumption, and smoking are shown not to account for low cholesterol. Data, including mortality associations, are not available to support other postulated mediating factors (e.g., nutritional status, dietary β-carotene, and socioeconomic factors).
Together, the findings of the epidemiologic studies indicate that associations between low cholesterol and increased noncoronary heart disease mortality are robust. Although low cholesterol may be only indirectly related to cancer, liver and chronic lung disease, and trauma- or suicide-related mortality, a causal role cannot be ruled out at present. The findings of clinical trials, despite some reassuring data from the new Coronary Primary Prevention Trial, also indicate that cholesterol reduction may increase noncoronary heart disease mortality. It is becoming increasingly difficult, therefore, to assert that serum cholesterol reduction is always safe, and, indeed, Hulley and colleagues (4) have called for a suspension of screening and treatment for primary heart disease prevention (i.e., they suggest that cholesterol-lowering treatment should be reserved for very-high-risk individuals). Nonetheless, a new consensus regarding the wisdom of widespread cholesterol reduction has not been reached. For the time being, a reasonable approach might involve continued general adherence to present treatment recommendations but with added hesitancy to treat isolated hypercholesterolemia.
Matthew F. Muldoon, MD
University of Pittsburgh Pittsburgh, Pennsylvania, USA