Dietary intervention studies to reduce risk factors related to cardiovascular diseases and cancer

PREVENTIVE

MEDICINE

16, 516-524 (1987)

Dietary Intervention Studies to Reduce Risk Factors Related to Cardiovascular Diseases and Cancer’ JAMES M. IACONO, PH.D. U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, P.O. Box 29997, Presidio of San Francisco, California 94129 This article reviews data obtained from a series of dietary intervention studies conducted in the United States, Finland, and Italy. The objectives were to determine the effects of reducing animal fat consumption while moderately increasing polyunsaturated fatty acid (PUFA), on blood pressure and lipoproteins. Although the diet was modified to improve risk factors related to cardiovascular disease, it is apparent that the dietary intervention would also apply to cancer. The results obtained for men and women, ages 35-65 years, indicate that plasma total cholesterol and low-density and high-density lipoprotein cholesterol were reduced; blood pressure was reduced among both normotensives and hypertensives; daily intake of meat and dairy products were not reduced but were much lower in fat; carbohydrates were substituted as fruits, vegetables, and grains, which provided more vitamins and minerals; and salt intake was maintained at a level of 8-12 g per day. From the data obtained for lowering blood pressure, it would appear that the requirement for PUFA is between 5 and 10 en%, which is somewhat higher than the recommended dietary allowances but lower than that recommended by health agencies. The results of these studies give support to current dietary recommendations to reduce the risk of cardiovascular disease as well as cancer by dietary intervention. 0 1987 Academic Press, Inc.

INTRODUCTION

There is little doubt that nutrition plays a major role in the long-term development of cardiovascular disease (CVD) and cancer. The Committee on Diet, Nutrition, and Cancer (6) appointed by the National Academy of Sciences in 1982 concluded that there was convincing evidence from epidemiological and animal studies that an increase in total dietary fat was associated with an increase in the incidence of cancers, particularly of breast and colon, two of the major occurring cancers, and that a decrease in fat intake decreased the incidence of these tumors. There is extensive literature relating diet to other chronic diseases such as hypertension, stroke, obesity, diabetes, osteoporosis, and dental caries. The solutions to these problems are multifactorial and have been shown to involve a number of nutrients, particularly fat. It is clear that a public health approach is required to solve many of these problems (2). Therefore, considerable research effort is required to overcome these problems in coming years. Examples of approaches to the solution of nutritional problems related primarily to CVD and which also apply to cancer are presented in this report. Health i Presented at the Workshop on New Developments on Dietary Fat and Fiber in Carcinogenesis (Optimal Types and Amounts of Fat or Fiber), American Health Foundation, New York, March 25-26. 1986. 516 0091-7435187 $3.00 Copyright All rights

8 1987 by Academic Press, Inc. of reproduction in any form reserved.

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groups are in agreement that the content and quality of fat in the diet are involved in CVD and cancer (1, 6), and it is this area that is discussed briefly. The focus of this article is on the results of a series of dietary intervention studies performed over the past 12 years in the United States, Finland, and Italy. The objective of these studies was to assess the “typical Western diet” at approximately 25 en% from fat, instead of the usual 40 en%, on blood pressure and blood lipids. The lower level of fat was consistent with intakes of total fat consumed in Mediterranean countries. The details of Mediterranean studies have been described in considerable detail by Keys and his collaborators in their extensive Seven Country studies (14, 15). One major difference in the data reported here is that the menus were devised to be similar to the typical Western diet, and this was accomplished by reducing the saturated fat to less than one-half the amount usually consumed (from 18-20 to 6-8 en%) and by moderately increasing the polyunsaturated fat (PUFA) from levels of aproximately 2-5 to 5- 10 en%. In general, carbohydrates (fruits, vegetables, and grains) were substituted for fats. Protein was maintained at a level of about 15 en% (12). The objective of these studies was to show that the total fat content of the diet could be reduced with a minimum of difficulty, while at the same time retaining the kind of diet usually consumed in Western countries. GENERAL

CHARACTERISTICS

OF THE STUDIES

Three of the studies performed in the United States were free-living studies, i.e., the subjects continued their usual activities but took their meals in the dining room at the U.S. Department of Agriculture’s Nutrition Research Center at Beltsville, Maryland, and took home preprepared meals for the weekend. Other U.S. studies were conducted in the metabolic unit at the U.S. Department of Agriculture’s Western Human Nutrition Research Center at San Francisco, California, where the subjects were in residence. Most of the studies were of the switchback design, having a stabilization period of 20 days, an intervention period of 4-6 weeks, and a switchback period of 4-6 weeks, depending on the study. The dietary intervention studies conducted in Finland and Italy were similar in design to the U.S. studies except that meals were prepared in the home. During the intervention period, Finnish families consumed the lower saturated fathigher PUFA diet. In Italy, families consumed the higher saturated fat-lower PUFA diets during the intervention period. During the switchback periods, families consumed their usual diets. Dietitians were assigned to teach the families how to weigh and measure all foods they consumed prior to the study and worked with the families twice a week during the study. No attempt was made to alter the usual diet of either group except for the change in the amount and quality of fat and the addition and/or deletion of certain foods. REDUCTION

OF BLOOD

LIPIDS

The reduction in saturated fat and cholesterol, and the increase in polyunsaturated fat in the diets, resulted in sharp reductions of plasma total cholesterol, mainly of the low-density lipoprotein (LDL) and high-density lipoprotein (HDL)

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fractions (9- 11) by the end of the intervention period. Depending on the study, a maximum decline of 15-25% in total plasma cholesterol occurred. During the switchback period, blood lipids usually returned to their initial levels. An example of the lipid-lowering effect of the intervention diet in one of the Finnish studies (9) is shown in Table 1. The effects of lower intakes of saturated fat and cholesterol and moderately higher intakes of PUFA on blood lipids were not unique, since these factors have been studied repeatedly. But, when all three dietary factors were imposed at the same time, the benefits were greater than have been observed previously. Consequently, blood lipids fell to a lower range in the United States and Finland and placed the families at lower risk for CVD and perhaps also at lower risk for cancer. The opposite effects were noted in the Italian study (11). The metabolic significance of HDL reduction, which occurred in the United States and Finland, is not understood but is thought to occur as a consequence of increasing the dietary PUFA. BLOOD PRESSURE REDUCTION

In all studies conducted in the three countries, systolic and diastolic blood pressure in normotensives and hypertensives (both men and women) was lowered when the diet contained the lower amounts of saturated fat and cholesterol and moderately increased levels of PUFA (12) (see Table 2). Blood pressure increased when the subjects returned to their typical diets. These data have been confirmed by a number of groups (20). What is still unclear is the mechanism of action by which the dietary components led to lowered blood pressure. The most likely explanation is that the higher level of PUFA leads to the formation of more favorable levels of prostaglandins (PGs) in kidney, which promote the increased excreTABLE 1 TOTALSERUMCHOLESTEROL,TRIGLYCERI~)ES,ANDHIGH-DENSITYLIPOPROTEIN(HDL) CHOLESTEROLCONCENTRATIONSATTHEENDOFTHESTUDYPERIODS~ Baseline period Men (n = 30) Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Women (n = 24) Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

263 185 54 124

k * * f

8* 8* 2* 18

239 2 8*

164 2 7* 56 e 3*

91 2 12

Intervention period bw&W 201 f 5 137 t 5 44 k 2

Switchback period

9

259 k 7* 183 f 7* 55 * 2* 99 t 11

188 * 8 125 f 7

231 2 lO* 156 * 9*

47 f 2 76 e 6

60 2 2* 76 t 7

96 f

Note. From Ref. (9). 0 Data are presented as means 2 SEM. To convert values for cholesterol and triglycerides to millimoles per liter, multiply by 0.02586 and 0.01129, respectively. * Significantly different from value for intervention period (P i 0.0001) by paired comparison test.

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TABLE 2 (*SEM;mmHg) RELATEDTOMODIFIEDFATDIETS,BELTSVILLE I-II AND NORTH KARELIA I-II n

Beltsville I Systolic Diastolic Beltsville II Normotensive group Systolic Diastolic Hypertensive group Systolic Diastolic North Karelia I Systolic Diastolic North Karelia II Reference group Systolic Diastolic Group 1 Systolic Diastolic Group 2 Systolic Diastolic

STUDIES,

Baseline period

Intervention period

Switchback period

136 2 4 80 t 3

123 ? 3 73 2 2

129 k 3 83 f 2

132 k 3 87 f 2

123 2 4 81 2 4

120 f 4 81 f 2

145 k 6 99 * 5

126 2 4 88 xt 3

137 * 4 93 k 4

125 ? 2 77 2 1

117 2 2 74 k 1

125 ” 2 80 2 1

138 2 2 89 2 2

136 ? 2 87 5 2

138 k 2 88 k 2

138 2 3 89 2 2

130 k 2 81 k 1

137 t 2 85 + 2

139 k 2 90 5 2

137 t 3 87 k 2

138 f 3 86 ? 2

21

10 10 59

38 35 34

Note. From Ref. (12).

tion of salts and water, with the consequent reduction of blood pressure. Considerable animal data support this hypothesis, specifically with regard to PGE, (20). Data on the urinary excretion of PG metabolites are still unclear for humans, due mainly to technical problems associated with the methodology of estimating prostaglandins in urine. The salt content of the diet in all studies reported here was usually 8-12 g per day, an amount of salt usually consumed in the Western diet, and appeared to be unrelated to the blood pressure reduction. DIETARY INTAKE OF MEAT AND DAIRY PRODUCTS

The intakes of meat and dairy products were fairly similar during the lower total fat, lower saturated fat-higher PUFA dietary period in Finland (Table 3) (16) and during two resident studies in San Francisco (8). Cuts of meat were carefully trimmed of visible fat and low-fat dairy products were substituted for higher-fatcontaining products. A high-PUFA margarine was substituted for butter. The lowering of blood pressure and blood lipids occurred even though meat and dairy products were consumed at approximately the same levels usually consumed in the typical Western diet. It is obvious, therefore, that it was primarily

520

JAMES M. IACONO TABLE 3 MEAN DAILY CONSUMY~ION OF DIFFERENT FOOD ITEMS, IN GRAMS (n = 59) Food

Baseline

Dairy products Whole milk (4.4% fat) Regular milk (3.9%) Low-fat milk (2.9%) Skim milk (0.05%) Sour milk (0.05-o. 1%) Cream Cheese Other dairy products Fats Butter Margarine Oil Cereal products Rye products Wheat products Other products Meat Pork Beef Sausages Inner organs and blood Fish Eggs Vegetables Potatoes Roots Legumes Other vegetables Fruit and berries Fresh fruit Fruit juices Berries Beverages and other Coffee Tea Alcoholic drinks Mead, homemade beer Sugar, syrup, honey Other

193 147 98 255 16 225 12 14 26 69 61 7 1 287 144 117 26 167 43 63 55 6 24 29 216 116 38 5 57 260 116 45 99 858 633 7s 36 48 62 4

Intervention 750 5 5 28 290 360 45 17 39 1 34 4 286 160 105 21 167 14 89 60 4 43 27 262 98 42 9 113 369 202 53 114 926 632 81 35 112 65 1

Switchback 790 91 130 232 21 248 11 15 12 61 54 6 1 304 164 120 20 153 30 66 51 6 38 33 203 104 35 6 59 212 88 29 95 921 648 71 34 96 71 1

Note. From Ref. (16).

the lower saturated fat content of the animal products that had the profound fect on blood lipids. DiETARY INTAKE OF FRUITS, VEGETABLES,

Since the intervention

ef-

AND GRAINS

diets lowered the total percentage of calories from fat to

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25 from 40%, a net reduction of approximately 15 en%, and since calories from protein were maintained at about 15 en% during these studies, the calories substituted for fat came from carbohydrates in the form of fruits, vegetables, and grains. Assuming that an individual consumed 2,500 calories per day, this would result in a reduction of 375 metabolizable calories from fat (approximately 41 g). In place of fat, the 375 metabolizable calories came from carbohydrates (approximately 94 g). The usual Finnish diet already contains high amounts of carbohydrate because of the high consumption of grains, primarily as bread and rolls from whole wheat and rye products; therefore, no attempt was made to increase grain consumption in this diet. Fruits and vegetables, however, were increased during the intervention period (Table 3) (16). It is thought that the higher fiber content of the Finnish diet derived from whole grains is in some way effective in maintaining a lowered incidence of colon cancer (17). Fruits, vegetables, and grains were increased substantially during the intervention periods of the U.S. studies. Because of these increases, the vitamin and mineral content of the diet during the intervention periods was increased markedly (8). DISCUSSION

Although there are substantial differences among the traditional diets in the United States, Finland, and Italy, the results of these joint studies provide convincing evidence of the predominant effect of diet on serum lipid levels and blood pressure in free-living populations. There appears to be a similarity between the dietary recommendations of health groups concerned with CVD and cancer prevention in terms of the quantity and quality of dietary fats. For both CVD and cancer, it is recommended that fat be reduced to about 30 en% (1, 6). Based on the data in the literature, however, lower plasma lipids were reported when energy intake from fat was lower than 30%. Early examples of the above were demonstrated at Kyushu, Velika Krsna, Montegiorgio, and Crevalcore, towns studied in the Seven-Country studies (see Fig. 1) (14). Information on cancer incidence from epidemiological reports (4), animal data (3), and intervention studies reported here suggest that the total calories from fat consumed in these areas varied from 10 to 30%. The information from most experimental animal studies (4, 18, 19) and epidemiological studies (4) supports the concept of lowered tumorigenesis in animals and people on lower-fat diets. The request for a clinical trial in patients with earlystage breast cancer to determine whether the cancer can be inhibited by reducing the dietary fat to about 20 en% with the quality of fat at a ratio of 1: 1: 1 for saturated, monounsaturated, and polyunsaturated fatty acids appears, therefore, to be reasonable (3). It is too early to make sound recommendations for types of dietary fatty acids for the prevention of cancer. Although it would be reasonable to assume that once tumorigenesis is initiated, the growth of the tumor would be enhanced by PUFA for cell membrane proliferation, the data for both human and animal cancers appear to be confusing when one attempts to recommend the type of fat that would reduce tumor formation and growth (6). This is particularly the case when n-6

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JAMES M. IACONO

F

22 F’NLAND SATU?ATED

F: A.

llIllljillll13~39’/. MONOEN

POLVENE

FIG. 1. Average percentage of calories from fat for men, ages 40-59 years, from towns studied in the Seven Country studies. Average percentage of dietary calories provided by saturated, monoene, and polyunsaturated fatty acids. (From Ref. 14).

fatty acids (linoleic acid series) are increased in the diet, which increases tumorigenesis, or when the ratio of n-3 (linolenic acid series)lnd dietary fatty acids is increased. In the latter case, the n-3 fatty acids appear to inhibit tumor growth, for example, through the inhibition of cyclooxygenase and lipoxygenase pathways of PG synthesis by the n-3 fatty acid, eicosapentaenoic acid (13). However, it is still too soon to make clear judgments on the role of n-3 fatty acids in cancer prevention. Recent data suggest that total fat content of the U.S. diet has decreased from about 40-44 to about 38-39 en% (5), and the ratio of polyunsaturated to saturated fatty acid has risen from about 0.2 to 0.4. During this period, there has been a reduction of CVD in the United States (21), while there has been little change in the incidence of cancer (7). A serious effort needs to be made to identify a biological marker that can be measured in people to give some indication of propensity to cancer, as is the case for atherosclerosis (lipoprotein), high blood pressure (pressure measurement), and thrombosis (blood clotting, platelet aggregation). Until a biological marker is identified for cancer assessment, we are subject to the interpretation of epidemiologic data for cancer incidence and the results of animal intervention studies, which may or may not point the way to the initiation and progression of cancer in humans. A number of mechanisms by which alterations in dietary fat may influence the tumorigenesis process have been proposed. These include fecal bile acid excretion, membrane structure and function, cell membrane fluidity, hormonal secretion of the affected tissue, caloric consumption and utilization, the role of antioxidants, prostaglandin synthesis, and integrity of the immune system. All of these mechanisms are under scrutiny (6).

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Finally, a careful approach must be taken to avoid giving incorrect or premature dietary recommendations to the population at large. Dietary recommendations to individuals and to the general public should be consistent for good overall health and cleared by diverse expert groups so that they are based on fact. The recommendations must also be achievable and within the capability of the dietary practices of individuals and population groups. Dietary recommendations should provide guidance to the public to prevent or reduce the initiation and progression of degenerative diseases. REFERENCES 1. AHA Committee Report, Rationale for the diet-heart statement of the American Heart Association. Circulation 65, 839A-854A (1982). 2. Blackburn, H., and Ernst, N. Diet and mass hyperlipidemia: A public health view, in “Nutrition, Lipids and Coronary Heart Disease” (R. Levy, B. Rifkind, B. Dennis, et al., Eds.), p. 309. Raven Press, New York, 1979. 3. Carroll, K. K., and Kalamegham, R. Lipid components and cancer, in “Environmental Aspects of Cancer: The Role of Macro and Micro Components of Foods” (E. Wynder, G. Leveille, J. Weisburger, and G. Livingston, Eds.), p. 101. Food and Nutr. Press, Westport, CT, 1983. 4. Carroll, K., and Khor, H. Dietary fat in relation to tumorigenesis. Prog. Biochem. Pharmacol. 10, 308-353 (1975). 5. Carroll, M., Abraham, S., and Dresser, C. “Dietary Intake Source Data: United States, 1976-80.” Vital and Health Statistics, Series 2, No. 231, DHHS Publ. No (PHS) 83-1681, National Center for Health Statistics, Public Health Service. U.S. Govt. Printing Office, Washington, DC, 1983. 6. Committee on Diet, Nutrition and Cancer. “Diet, Nutrition and Cancer.” National Acad. Press, Washington, DC, 1982. 7. Doll, R., and Peto, R. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J. Narl. Cancer Inst. 66, 1192-1308 (1981). 8. Dougherty, R. M., Fong, A., and Iacono, J. M. Improvement of the nutrient composition of the USA diet when the fat content is reduced. Fed. Proc. 46, 1002. 9. Ehnholm, C., Huttunen, J., Pietinen, P., Leino, U., Mutanen, M., Kostiainen, E., Pikkarainen, J., Dougherty, R., Iacono, J., and Puska, P. Effect of diet on serum lipoproteins in a population with a high risk of coronary heart disease. New Engl. J. Med. 307, 850-855 (1982) 10. Ehnholm, C., Huttunen, J., Pietinen, P., Leino, U., Mutanen, M., Kostianinen, E., Iacono, J., Dougherty, R., and Puska, P. Effect of a diet low in saturated fatty acids on plasma lipids, lipoproteins, and HDL subfractions. Arteriosclerosis 4, 265-269 (1984). 11. Ferro-Luzzi, A., Strazzullo, P., Scaccini, C., Siam, A., Sette, S., Mariani, M., Mastranzo, P., Dougherty, R., Iacono, J., and Mancini, M. Changing the Mediterranean diet: Effects on blood lipids. Amer. J. C/in. N&r. 40, 1027-1037 (1984). 12. Iacono, J., Puska, P., and Dougherty, R. Studies on the effect of dietary fat on blood pressure. Ann. Clin. Res. 16 (Suppl. 43), 116-125 (1984). 13. Karmali, R., and Marsh, J. Antitumor activity in a rat mammary adenocarcinoma: The effect of cyclooxygenase inhibitors and immunization against prostaglandin E,. Prostag/andins Leuk. Med. 20, 283-286 (1985). 14. Keys, A. (Ed.). Coronary heart disease in seven countries. Circulation 41 (Suppl. l), 1-211 (1970). 15. Keys, A. “Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease.” Harvard Univ. Press, Cambridge, MA, 1980. 16. Pietinen, P., Dougherty, R., Mutanen, M., Leino, U., Moisio, S., Iacono, J., and Puska, P. Dietary intervention study among 30 free-living families in Finland. J. Amer. Diet. Assoc. 84, 313-318 (1984). 17. Reddy, B., Hedges, A., Laakso, K., and Wynder, E. Metabolic epidemiology of large bowel cancer, fecal bulk and constituents of high-risk North Americans and low-risk Finnish population. Cancer 42, 2832-2838 (1978).

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18. Reddy, B., Cohen, L., McCoy, G., Hill, I?, Weisburger, J., and Wynder, E. Nutrition and its relationship to cancer. Ah. Cancer Res. 32, 237-345 (1980). 19. Roebuck, B., Yager, J., Jr., Longnecker, D., and Wilpone, S. Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res. 41, 3961-3966 (1981). 20. Weinsier, R., and Norris, D. Recent developments in the etiology and treatment of hypertension: Dietary calcium, fat, and magnesium. Amer. J. Clin. Nutr. 42, 1331-1338 (1985). 21. Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute. Decline in coronary heart disease mortality, 1968-78, in “Report of the Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute,” Vol. 2, p. 157. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publ. No. 81-2035, Bethesda, MD, 1981.