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(Circulation. 1995;92:2396-2403.)
© 1995 American Heart Association, Inc.

Articles

Low Serum Cholesterol and Mortality

Which Is the Cause and Which Is the Effect?

Presented at the Society for Epidemiologic Research 27th Annual Meeting, Miami, Fla, June 15-18, 1994.

Carlos Iribarren, MD, MPH, PhD; Dwayne M. Reed, MD, PhD; Randi Chen, MS; Katsuhiko Yano, MD; James H. Dwyer, PhD

From the Institute for Health Promotion and Disease Prevention Research, Department of Preventive Medicine (C.I., J.H.D.), and the Atherosclerosis Research Institute, Department of Medicine (J.H.D.), University of Southern California School of Medicine, Los Angeles; the Buck Center for Research on Aging, Novato, Calif (D.M.R.); and the Honolulu (Hawaii) Heart Program, Kuakini Medical Center (R.C., K.Y.).

Background Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men.

Methods and Results The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor–adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (<180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3.

Conclusions These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.

Key Words: coronary disease • stroke mortality • cholesterol

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