The effect of cholesterol level on the health of older people is a matter of debate, probably because of the bidirectional association. We investigated this paradox in a long-term study. The baseline assessments of the Helsinki Businessmen Study (a cohort of mainly business executives, born 1919 to 1934) included the total cholesterol value and other cardiovascular risk factors from 1964 to 1973. These men were followed up for ≤46 years (through January 2010). During the follow-up period, the cholesterol value was assessed by self-report in 2000 (n = 1,292). Mortality was ascertained from the national registers, symptoms, and health-related quality of life with RAND-36 from questionnaires in 2000. A total of 3,277 healthy men without chronic diseases at baseline were included in the analyses. The median total cholesterol concentration at baseline was 6.5 mmol/L (251 mg/dl) (interquartile range 5.8 to 7.3 mmol/L, 224 to 282 mg/dl) and, in 2000, was 5.2 mmol/L (201 mg/dl) (interquartile range 4.6 to 5.9 mmol/L, 178 to 228 mg/dl). During the follow-up period, 1,773 men (54%) died. A strong and graded relation was found between the cholesterol level and total mortality, with the men with a cholesterol level ≤4 mmol/L (154 mg/dl) having the lowest mortality. In all, the men with the lowest cholesterol gained the most life years. However, no association was found with the cholesterol level in 2000 (when 16% were using statins) and subsequent mortality. The lowest (≤4 mmol/L) cholesterol value in midlife also predicted a higher score in the physical functioning scale of RAND-36 in old age. In conclusion, a low total cholesterol value in midlife predicts both better survival and better physical functioning in old age.
The effect of a low serum cholesterol value on total mortality, especially at an older age, has been a matter of debate and controversy. An elevated serum cholesterol level is a well-known risk factor for coronary heart disease in midlife and early old age; however, in late life, this association seems to disappear or even reverse. Furthermore, low or lowered total cholesterol might adversely affect mental functioning and health-related quality of life (HRQOL). Because cholesterol was measured in early midlife in the Helsinki Businessmen Study during the 1960s, we had an opportunity to test the associations among cholesterol, life years gained, and HRQOL in old age for ≤46 years of follow-up. We earlier reported the mortality and HRQOL data (RAND-36/Medical Outcomes Study Short-Form 36 physical and mental component summary scores) of this cohort up to 2002, showing a favorable effect of a low cholesterol level using 5 mmol/L (193 mg/dl) as a cutoff point. We have extended this follow-up period to 2010 to report the life years gained and have conducted a more detailed HRQOL analysis, in particular, examining the long-term effect of the lowest cholesterol value (≤4 mmol/L or 154 mg/dl). We also report on the effect of the cholesterol level measured in old age on subsequent mortality, as well as the effect of cholesterol-lowering medication started in old age, among this cohort.
Methods
In a long-term outcome study, a cohort of 3,490 healthy Finnish businessmen, born from 1919 to 1934 (the Helsinki Businessmen Study), aged 30 to 45 years at baseline, has been prospectively followed up since the 1960s to the present for cardiovascular risk factors, mortality, and HRQOL. Initially, the study cohort was a pragmatic health examination cohort conducted at the Institute of Occupational Health in Helsinki. From 1964 to 1973, these men participated in health checkup procedures that included clinical examinations and laboratory tests. Only 1 baseline measurement of serum total cholesterol was available. The Ethics Committee of the Helsinki University Hospital, Department of Medicine approved the follow-up procedures (the most recent application by the code HUS 429/13/03/01/09).
All participants were white men from the highest social class and were either businessmen or management executives with similar socioeconomic and employment status. The study population and examinations have been previously described in detail. The present study on mortality and cholesterol included the 3,277 men (94% of the total cohort) for whom the baseline serum total cholesterol level was available. The exclusion of the 612 men who participated in the 5-year intervention study during the 1970s did not alter the conclusions of the present study; thus, the results of the whole original cohort are presented.
In 2000, we sent a questionnaire to all survivors (n = 2,251), with 1 remailing for nonrespondents, and 1,820 (81%) responded. This questionnaire included questions about current diseases, medications, and the current cholesterol value by self-report. The Finnish version of the RAND-36 Item Health Survey, version 1.0 (practically identical to the Medical Outcomes Study Short-Form 36-item health survey ) was embedded in that questionnaire. The 8 scales of the RAND-36 (physical functioning, role limitations caused by physical health problems, bodily pain, general health, vitality, social functioning, role limitations caused by emotional problems, and mental health) evaluate different aspects of HRQOL. The RAND-36 as a postal questionnaire has been validated in the Finnish general population. The physical functioning score of this instrument has been shown to be a valid measure of mobility disability in epidemiologic studies of older people.
The participating men came to the laboratory between 9 and 11 a.m. after a 12-hour fast. During the 1960s and up to 1974, the serum cholesterol concentration was determined using the method of Huang et al ; subsequently, routine laboratory analyses with enzymatic methods have been used. According to our measurements, the cholesterol levels measured with older methods resulted in 8.3% greater values. Accordingly, a value of 5.0 mmol/L (193 mg/dl) in the 1960s would correspond to 4.6 mmol/L (178 mg/dl) measured with an enzymatic method. We used the corrected values in the present analyses; the conclusions nevertheless remained the same when the original values were used.
In addition to the baseline cholesterol level, we have the self-reported cholesterol values in 2000 for 1,292 men (71% of the respondents in 2000), and in 2002 to 2003, serum samples were obtained from a random sample of 665 men, with these measured in Professor Miettinen’s Laboratory, Helsinki University. Both the self-reported values in 2000 and the laboratory measured values in 2002 to 2003 displayed a Gaussian distribution and were significantly correlated (r = 0.52, p <0.001) despite the more prevalent use of statins in 2002 to 2003 than in 2000.
The total mortality of the study cohort up to January 2010 was retrieved from the Central Population Register, which keeps a record of all Finnish citizens. The cause of death (available for 95% of all deaths) through December 2007 was determined from the countrywide computerized Cause-of-Death Register of Statistics Finland in which trained nosologists (unaware of the present study) coded the cause of death. The causes were categorized into 5 groups: cardiovascular, cancer, accidents, suicides, and other.
The baseline serum total cholesterol levels were divided into 7 groups at 1 mmol/L intervals as follows: ≤4.0 mmol/L (154 mg/dl) (n = 22), 4.1 to 5.0 mmol/L (155 to 193 mg/dl) (n = 202), 5.1 to 6.0 mmol/L (194 to 232 mg/dl) (n = 803), 6.1 to 7.0 mmol/L (233 to 270 mg/dl) (n = 1,170), 7.1 to 8.0 mmol/L (271 to 309 mg/dl) (n = 720), 8.1 to 9.0 mmol/L (310 to 347 mg/dl) (n = 255), and >9.0 mmol/L (347 mg/dl) (n = 105). The cholesterol level from 2000 was divided into 5 groups (few men had the highest cholesterol levels), with the lowest and highest groups being ≤4 mmol/L (154 mg/dl) and >7 mmol/L (270 mg/dl), respectively. The cholesterol-specific cumulative mortality was calculated using the Kaplan-Meier method, and the log-rank test was used to estimate the significance of differences between the groups. We examined mortality both from the year of the first visit (median 1968, range 1964 to 1973) and from 2000. The follow-up time extended until death or the end of the follow-up period (January 2010). Hazard ratios with their 95% confidence intervals for mortality were calculated using Cox’s proportional hazards regression. Cholesterol groups were compared for survival time, and RAND-36 scales using analysis of covariance. Statistical analyses were performed using NCSS (2004) (NCSS, Kaysville, Utah). Significance was defined as 2-sided p <0.05.
For the present study, we investigated (1) the effect of the baseline cholesterol level on mortality and life years gained through January 2010; (2) the effect of the cholesterol level and cholesterol-lowering drug use in 2000 on subsequent mortality from 2000 to 2009; and (3) the effect of midlife cholesterol level on detailed HRQOL in old age in 2000, with a high response rate. The median follow-up period was 39 years (interquartile range 30 to 42, maximum 46), denoting 113,425 person-years.
Results
The baseline characteristics of the study group in midlife and in 2000 (time of the HRQOL assessment and the start of old age mortality follow-up) are listed in Table 1 . During the follow-up period, a duration of ≤46 years, 1,773 men (54%) died. A graded, highly significant association was seen between both total mortality and cholesterol; thus, the lowest mortality was observed in men with baseline cholesterol ≤4.0 mmol/L (154 mg/dl) ( Figure 1 ). The age-adjusted mortality increased consistently with the baseline cholesterol, with the difference in the mean survival 5.5 years between the lowest and highest baseline cholesterol group ( Figure 2 ).
| Variable | Midlife (1964–1973) (n = 3,277) | Old Age in 2000 (n = 1,820) |
|---|---|---|
| Age (years) | ||
| Median | 42 | 74 |
| Interquartile range | 38–45 | 70–76 |
| Body mass index (kg/m 2 ) | ||
| Median | 25.7 | 25.5 |
| Interquartile range | 24.0–27.5 | 23.6–27.5 ⁎ |
| Blood pressure (mm Hg) | — | |
| Systolic | 135 (125–140) | |
| Diastolic | 85 (80–90) | |
| Total cholesterol (mmol/L) [mg/dl] | ||
| Median | 6.5 [251] | 5.2 [201] |
| Interquartile range | 5.8–7.3 [224–282] | 4.6–5.9 ⁎ [178–228] |
| Total cholesterol grouping † | ||
| ≤4.0 [154] | 3.7 [143] (22) | 3.6 [139] (127) |
| 4.1–5.0 [155–193] | 4.7 [181] (202) | 4.6 [178] (442) |
| 5.1–6.0 [194–232] | 5.6 [216] (803) | 5.5 [212] (478) |
| 6.1–7.0 [233–270] | 6.5 [251] (1,170) | 6.5 [251] (204) |
| 7.1–8.0 [271–309] | 7.5 [290] (720) | 7.6 [293] (41) |
| 8.1–9.0 [310–347] | 8.4 [324] (255) | — |
| >9.0 [347] | 9.8 [378] (105) | — |
| One-hour glucose (mmol/L) [mg/dl] ‡ | ||
| Median | 6.0 [108] | |
| Interquartile range | 4.9–7.4 [88–133] | |
| Triglycerides (mmol/L) [mg/dl] § | — | |
| Median | 1.3 [115] | |
| Interquartile range | 1.0–1.8 [89–159] | |
| Smoker | 41% ⁎ | 9% ⁎ |
† Data are presented as the mean (number of patients).
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