Long-term benefit of cholesterol reduction
ACP J Club 1993 Jan-Feb;118:21. doi:10.7326/ACPJC-1993-118-1-021
Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. Arch Intern Med. 1992 Jul;152:1399-410.
To determine mortality and incidence of coronary heart disease and cancer in a cohort of men followed after completion of a cholesterol reduction trial.
Cohort followed for 6 years after a 7.4-year randomized controlled trial.
13 lipid research clinics in North America.
3806 men, aged 35 to 59 years, with asymptomatic hypercholes-terolemia were given choles-tyramine (n = 1907) or placebo (n = 1899) for 7.4 years. Their health status was followed for an additional 6 years. Follow-up for mortality was 99%.
Assessment of risk factors
Cholesterol levels (total, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and plasma triglycerides) were measured annually during follow-up.
Main outcome measures
Incidence of coronary heart disease and neoplasms and mortality established by direct contact with participants and next of kin plus national data bases.
2 years after the trial, when participants were using lipid-lowering drugs at their discretion, the previously observed differences for serum lipid levels between cholestyramine and placebo groups were no longer observed. Fewer men taking cholestyramine died (68 during the trial and 75 after the trial) than those taking placebo (71 during the trial and 85 after the trial). The risk for mortality for cholestyramine compared with placebo did not differ at trial end or after complete follow-up (RR, 0.89; P = 0.33). The groups did not differ for number of deaths from cancer (46 vs. 44 deaths), trauma (11 vs. 8 deaths), or other illnesses (11 vs. 12 deaths). Nonsignificant trends toward increased benign neoplasms of the large intestine, cancer of the buccal cavity and pharynx, and incidence of gallbladder disease and surgery occurred in participants taking cholestyramine. The 19% in-trial reduction in incidence of coronary heart disease in the cholestyramine group did not continue after study medication was stopped.
The 6-year extended follow-up of participants in the Lipid Research Clinics study did not show any differences between participants who initially took cholestyramine compared with placebo for cardiovascular death, cancer death, or death from other illnesses or trauma.
Source of funding: National Heart, Lung, and Blood Institute.
For article reprint: Dr. B.M. Rifkind, Lipid Metabolism-Atherogenesis Branch, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Federal Building, Room 401, Bethesda, MD 20892, USA. FAX 301-496-9882.
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