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(Circulation. 1998;97:1087-1094.)
© 1998 American Heart Association, Inc.

Current Perspectives

Serum Cholesterol Distribution and Coronary Heart Disease Risk

Observations and Predictions Among Middle-aged Population in Eastern Finland

Pekka Jousilahti, MD; Erkki Vartiainen, MD; Juha Pekkanen, MD; Jaakko Tuomilehto, MD; Jouko Sundvall, MSc; ; Pekka Puska, MD

From the National Public Health Institute, Department of Epidemiology and Health Promotion (P.J., E.V., J.T., P.P.), Helsinki, Finland; National Public Health Institute, Unit of Environmental Epidemiology (J.P.), Kuopio, Finland; and National Public Health Institute, Department of Biochemistry (J.S.), Helsinki, Finland.

Correspondence to Dr Pekka Jousilahti, National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300 Helsinki, Finland. E-mail pekka.jousilahti{at}ktl.fi

	Abstract

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Background—The purpose of the present study was to assess the implications of cholesterol distribution and its change on coronary heart disease (CHD) mortality and disease prevention at a population level.

Methods and Results—In five independent risk factor surveys (1972, 1977, 1982, 1987, and 1992) in eastern Finland, serum cholesterol was measured in 27 721 randomly selected men and women aged 30 to 59 years. The association between cholesterol level and CHD risk and the prediction of the effect of different prevention strategies was estimated by use of logistic regression models. The entire cholesterol distribution of the population shifted markedly toward lower levels between 1972 and 1992. The proportion of subjects with a very high cholesterol level (8.0 mmol/L), also decreased markedly, from 16% to 3%. The risk of CHD death among subjects with cholesterol 8.0 mmol/L was 5-fold that of those individuals having cholesterol <5.0 mmol/L. Nevertheless, because CHD risk increases continuously as serum cholesterol increases, and because the number of people having only slightly or moderately increased serum cholesterol was large, most CHD deaths occurred among them. A 10% reduction in cholesterol levels in the entire population would subsequently reduce CHD mortality by 20%, as much as an effective treatment as a 25% decrease in serum cholesterol among all subjects with cholesterol >6.5 mmol/L and four times more than similar treatment of all subjects with cholesterol 8.0 mmol/L.

Conclusions—The community-based population strategy in cardiovascular disease prevention was effective in decreasing cholesterol levels among the entire population, including the subjects with the highest cholesterol values. The balanced application of both high-risk and population strategies is needed for the effective prevention of CHD.

Key Words: cholesterol • coronary disease • mortality • prevention

	Introduction

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Coronary heart disease (CHD) is the leading cause of death in most industrialized countries, and its importance as a major public health problem is increasing in developing countries.^{1 2 3} The role of serum cholesterol as one of the main risk factors for CHD, along with smoking and high blood pressure, was established in the 1960s and confirmed later by a large body of data from biochemical and epidemiological studies, as well as by clinical trials.^{4 5 6 7} It was also shown that a high use of saturated fat is the main determinant of serum cholesterol concentration, both in a population and in individuals.^{8 9} Major approaches used for the reduction of serum cholesterol and subsequent prevention of CHD are the high-risk strategy and the population strategy.

In the high-risk strategy, the healthcare system first defines indicators for high risk, then tries to identify the high-risk subjects, and finally applies preventive measures to the identified high-risk subjects. In the high-risk strategy, an individual intervention can be either educational and targeted to lifestyle changes or medical (usually pharmacological).

In the population strategy, the starting point is a community diagnosis, ie, assessment of the health situation, the major health problems, and the related risk factors in the population. The intervention is targeted to the entire community or at least to the majority of the population. The intervention method most often applied is health education, but other methods such as legislative regulations, development and promotion of healthy products, and price policy are also used. In some situations, pharmacological mass interventions may also be implemented.

Twenty-five years ago, Finland had the highest known CHD mortality rate in the world. Within Finland, coronary mortality was highest in the eastern part of the country, particularly in the North Karelia province.^{1 4} It was also found that levels of the main cardiovascular risk factors, particularly serum cholesterol, were higher in eastern Finland than was known in any other population. These observations led to the planning and launching of the North Karelia Project in 1972, the first comprehensive community-based program for cardiovascular disease prevention.¹⁰

The original aim of the North Karelia Project was to test the feasibility and the effects of a community-based program for the prevention of cardiovascular disease through general lifestyle and risk factor changes. The main intermediate objectives were to reduce the prevalence of smoking and to reduce serum cholesterol and blood pressure levels among the entire population, with a special emphasis on middle-aged men. Gradually, various activities aimed at CHD prevention in North Karelia were begun elsewhere in the country.¹¹

In this article, we will describe the 20-year change in serum cholesterol distribution, estimate the association between serum cholesterol and CHD mortality and assess the size of the regression-dilution bias in this estimate, assess the population-attributable risk of CHD mortality associated with different cholesterol levels, and predict the effect of different intervention strategies on cholesterol levels and subsequent CHD mortality among the middle-aged population in eastern Finland.

	Methods

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Study Populations
Five independent cross-sectional population surveys (in 1972, 1977, 1982, 1987, and 1992) were carried out to assess the levels and trends of cardiovascular risk factors in the provinces of North Karelia and Kuopio in eastern Finland.^{10 12} In 1972 and 1977, a randomly selected sample of 6.6% of the population born between 1913 and 1947 was drawn in both provinces. In 1982, 1987, and 1992, the sample included people aged 25 to 64 years; the samples were stratified according to the WHO MONICA protocol so that at least 250 subjects of each sex and each 10-year age group were chosen from both provinces.¹³ Subjects aged 30 to 59 years, which was the common age range in all five surveys, are included in the present analyses. Sample sizes and participation rates are given in Table 1. A total of 13 542 men and 14 179 women for whom we had complete data on cholesterol, systolic blood pressure, and smoking were included in these analyses. A subsample of 353 subjects aged 45 to 59 years from the 1992 study cohort was reexamined in 1995.

View this table: [in this window] [in a new window]   Table 1. Sample Sizes, Number of Participants,1 and Participation Rates by Study Year and Gender

Risk Factor Assessment and Prospective Follow-up
The survey methods followed the WHO MONICA protocol in 1982, 1987, and 1992 and were comparable to those methods in 1972 and 1977.^{12 13} The surveys included a self-administered questionnaire on health behavior and other related factors. The questionnaires were returned to the survey site, where specially trained nurses checked them to ensure that they were fully completed, measured blood pressure and other parameters, and took a venous blood specimen for determination of serum cholesterol.

Serum cholesterol was determined in 1972 and 1977 from frozen samples using the Lieberman-Burchard reaction (Auto Analyzer II-26a, Technicon Instruments Corp). In 1982, 1987, and 1992, an enzymatic assay method was used (CHOD-PAP Monotest, Boehringer-Mannheim). The enzymatic assay method gave 2.4% lower values than the Lieberman-Burchard method. The cholesterol values from 1972 and 1977 were corrected by this percentage. All cholesterol samples were analyzed in the same central laboratory.

The data on CHD mortality were obtained from the Central Statistical Office of Finland. ICD (the International Classification of Diseases, Injuries, and Causes of Death) codes 410 to 414 were classified as coronary deaths. Mortality data were linked to the risk factor data of the 1972, 1977, and 1982 study cohorts using the identification numbers assigned to every resident of Finland. The follow-up time of each subject considered in our present analyses was 10 years. The number of coronary deaths during the follow-up period was 463 among men and 76 among women.

Statistics
Linear regression analysis was done to test the change in serum cholesterol levels over time. The association between cholesterol level and CHD mortality was assessed by use of logistic regression models. All models were adjusted for age, smoking, and systolic blood pressure. Prediction of the effect of different interventions on serum cholesterol and subsequent CHD mortality was based on the same model and on an assumption that the levels of other risk factors will be the same as in 1992. The effect of the regression-dilution bias on the association between serum cholesterol and CHD mortality was assessed on the basis of repeated cholesterol measurements of the subsample of the 1992 study cohort. The subjects were classified in five groups according to their cholesterol values in the first measurement, and the size of the regression toward the mean was estimated on the basis of the cholesterol values in the second measurement.¹⁴ All analyses were performed with the use of the SAS statistical program.¹⁵

	Results

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During the period from 1972 to 1992, a considerable downward shift occurred in the entire serum cholesterol distribution (Fig 1 and 2). Mean cholesterol decreased from 6.78 to 5.90 mmol/L among men and from 6.72 to 5.55 mmol/L among women (Table 2). The proportion of subjects with cholesterol <5.0 mmol/L increased markedly between 1972 and 1992, from 6.3% to 20.3% among men and from 8.1% to 32.4% among women. In the same time period, the proportion of subjects with very high cholesterol (8.0 mmol/L)drastically decreased from 15.6% to 3.4% among men and from 16.1% to 2.1% among women. The proportion of subjects with cholesterol between 6.5 and 7.9 mmol/L also decreased.

View larger version (19K): [in this window] [in a new window]   Figure 1. Serum cholesterol distribution by study year, men aged 30 to 59 years.

View larger version (20K): [in this window] [in a new window]   Figure 2. Serum cholesterol distribution by study year, women aged 30 to 59 years.

View this table: [in this window] [in a new window]   Table 2. Mean and Distribution of Serum Cholesterol by Study Year and Gender

In the 10-year follow-up of the 1972, 1977, and 1982 survey cohorts, the odds ratio (adjusted for age, systolic blood pressure, and smoking) of CHD mortality associated with a 1-mmol/L change in serum cholesterol was 1.43 (95% CI, 1.33 to 1.54) among men and 1.34 (95% CI, 1.15 to 1.56) among women. The odds ratios of CHD mortality in subjects having cholesterol levels between 5.0 and 6.49 mmol/L, between 6.5 and 7.99 mmol/L, and 8.0 mmol/L compared with subjects having cholesterol levels <5.0 mmol/L were 1.64, 2.76, and 4.76 among men and 2.52, 4.25, and 5.22 among women, respectively (Figs 3 and 4). Among men, 44% of all CHD deaths occurred among those having cholesterol levels between 6.5 and 7.99 mmol/L, and 28% occurred among those having cholesterol levels 8.0 mmol/L. Among women, these proportions were 47% and 32%, respectively.

View larger version (20K): [in this window] [in a new window]   Figure 3. Distribution of serum cholesterol and coronary heart disease (CHD) deaths of men aged 30 to 59 years (1972, 1977, and 1982 cohorts combined) and odds ratio of CHD mortality associated with serum cholesterol.

View larger version (19K): [in this window] [in a new window]   Figure 4. Distribution of serum cholesterol and coronary heart disease (CHD) deaths of women aged 30 to 59 years (1972, 1977, and 1982 cohorts combined) and odds ratio of CHD mortality associated with serum cholesterol.

The predicted 10-year CHD mortality in the 1992 study population was 284 per 10 000 men and 42 per 10 000 women (Table 3). Among men, a 5% decrease in the entire cholesterol distribution would reduce the estimated 10-year CHD mortality by 10.2%. Similarly, a 10% and 15% decrease in cholesterol would reduce the estimated CHD mortality by 19.7% and 27.8%, respectively. A 25% decrease in serum cholesterol among men having cholesterol levels 6.5 mmol/L would decrease the mean cholesterol level by 8.5% and reduce the estimated CHD mortality by 22.5%. A 25% decrease in serum cholesterol among men having cholesterol levels 8.0 mmol/L would decrease the mean cholesterol level by 1.2% and reduce the estimated CHD mortality by only 4.9%. Among women, the estimated proportional changes in 10-year CHD mortality were slightly smaller than those of men.

View this table: [in this window] [in a new window]   Table 3. Effect of Different Intervention Strategies on the Mean and Distribution of Serum Cholesterol and on Predicted1 10-Year Coronary Heart Disease Mortality

Among the subsample of men with repeated cholesterol measurements, the difference in mean cholesterol levels between the first and fifth quintiles was 2.78 mmol/L in 1992 and 1.93 mmol/L in 1995. Among women, the differences were 3.09 and 2.07 mmol/L, respectively. The regression-dilution bias correction factors were 1.44 in men and 1.49 in women (Table 4). Thus, taking the effect of regression dilution into account, the association between serum cholesterol level and CHD mortality and the predicted decrease in CHD mortality associated with the decrease in serum cholesterol may be 50% larger than estimated without the correction.

View this table: [in this window] [in a new window]   Table 4. Mean Serum Cholesterol at Baseline in 1992 and in 1995 in Five Categories of Baseline Cholesterol Level

	Discussion

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In the past 20 years, serum cholesterol levels have decreased markedly in eastern Finland. Our results demonstrate that the entire cholesterol distribution shifted substantially toward lower values. The population-based strategy applied was also effective in markedly reducing the proportion of high-risk individuals with high cholesterol levels. It is obvious that the high-risk approach alone would not have been appropriate in eastern Finland in the 1970s. Depending on the chosen cutoff point for cholesterol alone, half or more of the middle-aged population should have been considered as high-risk individuals in the early 1970s. Applying individual intervention, including pharmacological therapy, would have been difficult to implement, if not impossible, and intolerably expensive. Also, the cholesterol-lowering drugs available at that time were not optimal,¹⁶ and even today, we have only limited information on their long-term efficacy and safety in the prevention of CHD in healthy individuals.

The population strategy has been criticized for being either ineffective in risk reduction or for not using a sufficiently well-targeted intervention.^{17 18} Even though some projects have shown little effect on cholesterol reduction, there are also successful examples, as our results from eastern Finland show. One possible reason for unsuccessful risk reduction may be a lack of community participation and support. CHD risk increases continuously as serum cholesterol increases, starting from a relatively low level, and no natural cutoff point can be found.⁶ In Western societies, very large proportions of the populations still have cholesterol levels that are higher than optimal, and therefore most people can benefit from cholesterol reduction. Furthermore, no serious side effects have surfaced when serum cholesterol has been reduced through dietary means.¹⁹

The methods used to reduce high cholesterol levels in the population of eastern Finland were mainly health education and the development and promotion of low-saturated-fat food products. Health education campaigns were conducted using a large variety of channels, including television, newspapers, the healthcare system, schools, and voluntary organizations.¹⁰ Low-saturated-fat products were developed and marketed in collaboration with local and national manufacturers. Cholesterol measurements were also used, with the aim of having every person know his/her own cholesterol value. The primary target of measurement was not to screen high-risk subjects for individual intervention but rather to motivate people to adopt a healthier lifestyle that was promoted in the community.

In Finland, the consumption of saturated fats used to be very high and the consumption of polyunsaturated fats very low. In the early 1970s, 21% of energy intake came from saturated fats and only 3% from polyunsaturated fats.²⁰ In 1992, the proportions of saturated fats and polyunsaturated fats in the total energy intake were 16% and 5%, respectively. In the past 20 years, we can identify four major changes that can explain the observed decrease in saturated fat consumption: (1) introduction and promotion of low-fat milk and (2) oil-based soft margarine in the 1970s, (3) introduction of fat-free milk in the early 1980s, and (4) introduction of low-fat oil- and water-based margarine in the late 1980s. Even though the main target group for the population intervention was middle-aged men, the dietary changes promoted spread throughout the entire population and a decrease in serum cholesterol can be observed in both sexes, in all age groups, and in both low and high socioeconomic groups.^{21 22}

As in many other studies,^{4 5 6 7} our study demonstrates the strong association between serum cholesterol and CHD mortality. The risk of coronary death was 3-fold greater among subjects having cholesterol levels between 6.5 and 7.9 mmol/L and 5-fold greater among those having cholesterol levels 8 mmol/L than among subjects having cholesterol <5.0 mmol/L. However, even in eastern Finland, where the number of high-risk subjects in the 1970s and early 1980s was greater than in most other populations, the majority of the coronary deaths did not occur among subjects with the highest relative risk but rather among those having only moderately increased relative risk. In the future, due to the already observed change in the serum cholesterol distribution, an even larger proportion of coronary deaths will occur among those subjects who have only slightly or moderately increased serum cholesterol. Thus, the critical issue in the near future will be how to prevent CHD in the large number of people at moderate risk.

In the past 25 years, mortality from CHD in the middle-aged population of eastern Finland has decreased to less than half its previous level.²³ It has been estimated that the majority of the decrease in coronary mortality was associated with the change in the major known cardiovascular risk factors: smoking, blood pressure, and cholesterol.^{23 24} About half of the decrease in coronary mortality associated with risk factor change was explained by the decrease in serum cholesterol alone. Despite the marked decrease, however, mean cholesterol levels among the population in eastern Finland are still high compared with many other populations.²⁵

We can estimate that if the proportion of saturated fat from the total energy intake could be reduced from the 16% level seen in 1992 to the recommended 10% level, it will decrease the mean serum cholesterol level by 0.5 to 0.6 mmol/L.⁸ Such a decrease in serum cholesterol would subsequently reduce CHD mortality by at least 20%. This is equivalent to the mortality decrease expected after effective treatment, ie, a 25% decrease in serum cholesterol among all subjects with cholesterol levels >6.5 mmol/L, and four times more than the expected mortality decrease after similar treatment of all subjects with cholesterol levels >8.0 mmol/L. In reality, the expected effect of the high-risk strategy in CHD prevention would be even smaller because only a fraction of all subjects with high serum cholesterol can be found and successfully treated.

The definition of high risk is an arbitrary decision. It is particularly difficult when risk factors are continuous, as with serum cholesterol, and an artificial cutoff point must be used. Nor is the identification of high-risk subjects easy, and it may be costly when biochemical and other clinical measurements are used for screening. High risk is also often associated with a low socioeconomic status and a low educational level. Therefore, subjects who have the highest risk may be less willing to participate in a screening program, and they may also be less able to comply with the given individual interventions. When pharmacological treatment of high serum cholesterol is compared with dietary changes, reducing saturated fat intake has other positive health effects besides its effect on cholesterol levels. A low-fat diet usually includes fewer calories and salt, more fiber, and has a higher content of vitamins and antioxidants.

Even though the high-risk strategy does not remarkably decrease the burden of CHD in the population, it can have great importance for individuals with the highest risk. In recent years, effective and most likely safer cholesterol-lowering drugs have been developed. The effect and cost-effectiveness of these new drugs, the statins, has already been shown in the secondary prevention of CHD.^{26 27 28 29 30} They are also recommended for the reduction of very high cholesterol levels, particularly among patients with familial hypercholesterolemia.

On the basis of the results of the recently completed West of Scotland Coronary Prevention Study and some ongoing trials, cholesterol-lowering drugs may eventually be recommended for primary prevention of CHD in those individuals who have only moderately increased cholesterol levels.^{31 32} If these drugs had been available in the 1970s, a very large proportion of the population in eastern Finland would have met the criteria for cholesterol-lowering drug treatment; however, such treatment would not have been feasible, at least economically. Even now, we may face a problem if the major emphasis is placed on pharmacological treatment of high serum cholesterol instead of on promoting additional dietary changes in the population. As an example, CHD mortality is increasing in the formerly socialistic countries of Europe, as well as in many developing countries.^{3 33} In these countries, large-scale use of cholesterol-lowering drugs is economically unfeasible for the healthcare systems, and the drugs are also too expensive for the vast majority of individual citizens. Thus, the more limited the resources are, the more important is the effective control of serum cholesterol through dietary means.

Population and high-risk strategies, however, are not necessarily competing alternatives but instead may be complementary. If the serum cholesterol distribution of the entire population were moved toward lower values, then also in primary prevention of CHD drug treatment of the small fraction of the population with high individual risk could be medically and ethically justified, and also cost-effective. The recent observation of the cholesterol-lowering effect of vegetable oil–based margarine fortified with oil-soluble natural sterol also provides a new approach for cholesterol control both in entire populations as well as among high-risk individuals.³⁴

In conclusion, the community-based cardiovascular disease prevention strategy adopted and implemented in eastern Finland during the past 25 years has resulted in a drastic decrease in serum cholesterol levels among the entire population, including those subjects with the highest cholesterol levels. Because the number of people who have only moderately increased serum cholesterol is great, most coronary deaths occurred among them, despite their relatively lower coronary mortality risk compared with subjects with very high serum cholesterol values. Therefore, at a population level, the potential public health impact of community-based control of serum cholesterol and subsequent decrease in coronary mortality is much greater than what can be achieved through individual interventions among high-risk subjects alone. The balanced application of both high-risk and population strategies is needed for the effective prevention of CHD.

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