Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease

Randomized Clinical Trials on the Effects ofDietary Fat and Carbohydrate on PlasmaLipoproteins and Cardiovascular Disease

Frank M. Sacks, MD, Martijn Katan, PhD

Several dietary approaches have reduced cardiovas-cular events in randomized clinical trials. Replacingsaturated fat with polyunsaturated fat prevented cor-onary events in men, and a Mediterranean diet andfatty fish improved survival. None of these trials hadmuch impact on total fat intake but rather increasedvegetable oils, n-3 fatty acids, or many other plantfoods or nutrients that are linked to coronary preven-tion. The reductions in cardiovascular disease (CVD)caused by these dietary therapies compare favorablywith drug treatments for hyperlipidemia and hyper-tension. Improvement in blood lipid risk factors is animportant mechanism to explain the results of trialsof unsaturated fats. When saturated or trans unsat-urated fats are replaced with monounsaturated orn-6 polyunsaturated fats from vegetable oils, primar-ily low-density lipoprotein (LDL) cholesterol de-creases. The LDL to high-density lipoprotein (HDL)cholesterol ratio decreases. When carbohydrates areused to replace saturated fats, in a low-fat diet, LDLand HDL decrease similarly, and the ratio is not im-proved; triglycerides increase as well when carbohy-drate increases, except when low glycemic indexfoods are used. The n-3 polyunsaturated fats in fishoils suppress cardiac arrhythmias and reduce tri-glycerides, but they have little effect on LDL or HDLcholesterol levels. The theme should be that diet hasbenefits that come directly from foods, as well asfrom the reduction in saturated fats, cholesterol,meats, and fatty dairy foods. It is likely that manydiets could be designed that could prevent CVD. Thispotential diversity is crucial for engaging the diversecultures and tastes of people worldwide in cardio-vascular disease prevention. Am J Med. 2002;113(9B):13S–24S. © 2002 by Excerpta Medica, Inc.

In this article, we review the randomized clinical trialsthat determined the effects of diet on plasma lipopro-teins and cardiovascular disease (CVD). We discuss,

in order, the effect of amount and type of dietary fats andcarbohydrate on plasma lipid risk factors, effects on CVDthat are predicted by these effects on the lipid risk factors,and the observed effects of dietary fats on CVD; theseinclude polyunsaturated fats, low-fat diets, Mediterra-nean diet, vegetarian diet, fish and fish oil, and trans un-saturated fat. We end with a summary of the evidence,and conclusions on optimal diet therapy.

The randomized clinical trial has the potential to pro-vide a compelling rationale for accepting or rejecting atreatment. It is no less important for evaluating dietarytherapies than drug treatments for which it is the onlyacceptable study design. By randomizing the patients to adietary treatment or alternative, self-selection does notinfluence the test of efficacy. In a nonrandomized study,in which patients choose a dietary pattern, importantnondietary factors may be associated with the diet that ischosen. If the randomized trial is successfully conductedwith few dropouts and few patients lost to end point as-certainment, the results should fully and solely reflect thetrue effect of the diet. One drawback of clinical trials ofdiet in CVD is their high cost and impracticality for test-ing many nutrients and foods. Also, clinical trials may notlast long enough to detect such effects as those on cancerthat take more than a few years to make themselves seen.

An alternative to using CVD as an outcome in a dietarytrial is to select surrogate end points that are in the causalpath between a food or nutrient and CVD. Trials that usesurrogate end points are valuable, because cost, durationof study, and, at times, ethical issues are lessened. Plasmalipoproteins are important surrogate end points becauseof their strong link to the pathogenesis of atherosclerosisand their strong predictive association with coronaryheart disease (CHD). In this article, we review the estab-lished effects of dietary fats on plasma lipoprotein con-centrations. We also comprehensively review the effectsof dietary treatments on coronary death, myocardial in-farction, stroke, and all-cause mortality in randomizedclinical trials. We did not include trials that combineddietary therapy with other treatments or that primarilyused coronary arteriography rather than coronary deathor myocardial infarction as study end points. Elsewhere

From the Nutrition Department, Harvard School of Public Health, Bos-ton, Massachusetts, USA (FMS); and Wageningen Centre for FoodSciences, and Division of Human Nutrition and Epidemiology,Wageningen Agricultural University, Wageningen, the Netherlands(MK).

Requests for reprints should be addressed to Frank M. Sacks, MD,Nutrition Department, Harvard School of Public Health, 665 Hunt-ington Avenue, Boston, Massachusetts 02115. E-mail: [email protected].

© 2002 by Excerpta Medica, Inc. 0002-9343/02/$22.00 13SAll rights reserved. PII S0002-9343(02)00987-1

in this issue, Ascherio reviews the recent epidemiologicevidence on dietary fats and CHD.1 The evidence fromclinical trials and epidemiology are largely concordant;together they demonstate a strong relation between dietand CHD, and they provide a compelling rationale fordietary treatment.

DIETARY FAT AND PLASMA LIPID RISKFACTORS

The causal relationship between total and low-density li-poprotein (LDL) cholesterol levels and CHD has beensupported strongly by a consistent body of evidence fromclinical trials2–5 and epidemiological studies.6 –9 Nationalhealth organizations advocate dietary changes that de-crease intake of saturated and trans-unsaturated fat andcholesterol to prevent CHD.10 The rationale is to reduceLDL concentration. However, diets affect not only LDLbut also high-density lipoprotein (HDL), triglycerides,which are independent lipid risk factors.11,12 Thus, as-sessment of the effects of diet on CHD should includeconsideration of the concomitant changes in HDL andtriglycerides. This leads to a controversy about whethercarbohydrate or unsaturated oils should replace the en-ergy from saturated and trans unsaturated fat.

Long-chain saturated fatty acids, commonly found inthe diet, increase LDL-cholesterol concentrations.13

Palmitic acid (C16:0), which is found in meats, dairy fat,and palm oil, is the most common saturated fatty acid.Palm oil is a major fat source in Latin America, Asia, andEurope, although not in the United States. Western dietswith dairy fat and meats also contain myristic acid,whereas other tropical oils, such as coconut or palm ker-nel oils, have mainly lauric acid. Myristic acid has thestrongest effect on LDL followed by lauric and palmiticacids. If saturated fat (e.g., 25 g or 10% of total dailyenergy intake [such as from about 100 to 150 g beef plus100 to 150 mL ice cream]) is replaced by carbohydrate,monounsaturated fat, or polyunsaturated fat, LDL willdecrease by an average of 13 mg/dL, 15 mg/dL, or 18mg/dL, respectively.13 Thus, monounsaturated fats re-duce LDL slightly more than does carbohydrate, andpolyunsaturated fatty acids have still more of this effect.Considering just the changes in LDL, any of these dietarychanges would be considered beneficial. Fish containsmall amounts of a special class of polyunsaturated fattyacids, the very long-chain n-3 fatty acids. These have littleeffect on LDL cholesterol, but they lower both fasting andpostprandial triglycerides.

The effects of dietary fat and carbohydrate on HDL arequite different from the effects on LDL. Low-fat, high-carbohydrate diets are well known to reduce HDL. Theratio of total or LDL cholesterol to HDL cholesterol doesnot change on a low-fat diet, because HDL is reduced asmuch as LDL. However, when unsaturated fat replaces

saturated fat, LDL decreases proportionately more thanHDL, and the LDL–HDL ratio decreases.13

Plasma triglyceride concentration has now been shownto be an independent risk factor for coronary disease,whether measured in the fasting12 or nonfasting states.14

Low-fat, high-carbohydrate diets increase fasting triglyc-eride levels when carbohydrate replaces saturated or un-saturated fat even when the unsaturated fat contains noneof the fish fatty acids that are so effective in loweringtriglycerides.13 There is a controversy regarding whetherhigh-fat compared with low-fat diets increase postpran-dial triglycerides.15,16 Acute high-fat intakes may indeedincrease postprandial lipid levels, but chronic substitu-tion of carbohydrate for fat does not appear to decreasepostprandial and 24-hour triglyceride levels, probablybecause the high-carbohydrate intake increases endoge-nous triglyceride synthesis and very low-density lipopro-tein secretion. However, this issue is still open, becausemeasuring postprandial lipoproteins is laborious, andthere is no clear agreement as to which are the mostatherogenic postprandial lipoprotein particles.

Dietary patterns illustrate the contrasting effects of car-bohydrate compared with fat on plasma lipid risk factors.The predicted effects on plasma lipids13 of 3 therapeuticdietary approaches are shown in Figure 1.13,17 They arecompared with a standard Western diet, similar to dietsin North American and Northern European countries:total fat 38%, saturated fat 17%, monounsaturated fat14%, polyunsaturated fat 7%, carbohydrates 42%, anddietary cholesterol 400 mg/day. The plasma lipid levelsare illustrative of patients who have mild hyperlipidemia,for whom diet is recommended as first-line treatment.The standard Step 1 lower fat approach reduces total fatintake to 30%, saturated fat to 10%, and dietary choles-terol to 300 mg, replacing the saturated fat mainly withcarbohydrate. Monounsaturated and polyunsaturated fatcontent is similar to the initial diet. The predicted effectson plasma lipids were computed by the Mensink and Ka-tan equations,13 derived from a meta-analysis of 27 well-controlled dietary trials lasting 3 to 8 weeks, under strictconditions. The quality and number of the individualstudies makes this analysis definitive. Total cholesteroldecreases by 5% on the 30% fat diet, and the LDL choles-terol decreases by 6%. However, these modest improve-ments contrast with a decrease in HDL of 9% and anincrease in triglycerides of 9%. A more stringent low-fatapproach is shown next, in which total fat is reduced to20% and saturated fat to 7%. Monunsaturated and poly-unsaturated fats are reduced by necessity to 10% and 5%,respectively, to achieve 20% total fat, and carbohydrate isincreased to 65%. Dietary cholesterol is reduced to 100mg/day commensurate with the reduction in meats andeggs. The predicted plasma lipid changes that occurredwith the 30% fat diet were intensifed; total cholesteroldecreases by 9%, LDL decreases by 12%, HDL decreases

A Symposium: Effects of Dietary Fat and Carbohydrate on Plasma Lipoproteins and CVD/Sacks and Katan

14S December 30, 2002 THE AMERICAN JOURNAL OF MEDICINE� Volume 113 (9B)

by 20%, and triglyceride level increases by 20%. Thus, astotal fat is reduced, the adverse changes in HDL and trig-lycerides become more prominent. Lastly, a Mediterra-nean dietary approach is shown that differs from the pre-vious 2 diets. Saturated fat is reduced, but it is replacedwith vegetable oils, such as olive, canola, corn, safflower,or sunflower oil, or oils from nuts, which contain mainlymonounsaturated and polyunsaturated fatty acids. Totalfat content remains at 38%, similar to what is eaten tra-ditionally in Greece.18 Dietary cholesterol is reduced to100 mg/day, concordant with this plant-based dietarypattern. The high unsaturated-fat diet decreases totalcholesterol by 11% and LDL by 13%. HDL decreases by7%, and triglycerides do not change. In summary, thesediets all lower LDL, but the low-fat diets decrease HDLproportionately more than they decrease LDL, and theyincrease triglycerides. The total cholesterol to HDL cho-lesterol ratio increases on the 30% or 20% fat diets butdecreases only on the Mediterranean diet. These findingsraise questions about the eventual effects of low-fat dietson CHD.19

TYPE OF CARBOHYDRATE

The usual mix of carbohydrates in the Western diet con-tains much refined polysaccharides, such as in bread andbaked goods, and sugars in juices and soda. These have ahigh glycemic index, causing glucose and insulin to in-crease substantially. Other types of carbohydrates that arein certain whole grains, beans, nuts, and vegetables have alower glycemic index, probably because the digestion andabsorption of the glucose is slow. These cause less of anincrease in serum glucose and insulin. Low glycemic in-dex is only partly explained by the fiber content of foods:thus, white bread and whole wheat bread have the sameglycemic index even though whole wheat bread is muchricher in fiber. An important determinant of glycemicindex is the glucose content of the carbohydrates in thefood, because only glucose increases serum glucose. As aresult, ordinary sugar, which is a disaccharide of fructoseand glucose, has a relatively low glycemic index, as hasmilk sugar, which consists of galactose and glucose.20

Lastly, the processing and intrinsic digestability of thefood has an influence. Some foods with a low glycemic

Figure 1. Predicted changes in plasma cholesterol and triglyceride concentrations caused by 3 types of diet treatment: 30% fat (step1), 20% low-fat, and Mediterranean. The standard Western and Mediterranean diets have 38% fat. The dietary changes are describedmore fully in the text. The meta-analysis of Mensink and Katan13 was used for changes in dietary fatty acids and that of Clarke et al17

for changes in dietary cholesterol. Note that the effects of carbohydrate on triglycerides are less if the carbohydrate comes fromlow-glycemic-index foods, as described in the text. HDL � high-density lipoprotein; LDL � low-density lipoprotein.


December 30, 2002 THE AMERICAN JOURNAL OF MEDICINE� Volume 113 (9B) 15S

index cause less of an increase in plasma triglycerides thando the more commonly eaten higher glycemic index car-bohydrates. HDL decreases when dietary fat is decreased,whatever the type of carbohydrate. A low-fat diet that istruly based on high-fiber, low– glycemic index foodsrather than the high– glycemic index, low-fat foods thatare a major part of contemporary low-fat diets may avoidthe undesirable effects on plasma triglycerides, serumglucose, and insulin. For example, the Dietary Ap-proaches to Stop Hypertension (DASH) diet, a 27%-fatdiet that emphasizes fruit, vegetables, and low-fat dairyproducts and which includes whole grains, poultry, fish,and nuts and contains only small amounts of sweets andsugar-containing beverages, did not increase fasting tri-glycerides compared with a typical US diet with 37% fat.21 The type of carbohydrate and its relevance to plasmalipid control, treatment of diabetes, and prevention ofCAD is discussed elsewhere in this issue by Jenkins et al.22

PREDICTED EFFECTS OF DIETARYTHERAPIES ON CORONARY DISEASE

Unfortunately, there are no satisfactory clinical trials thatevaluate the effect of a 30% fat (Step 1) or a 20% low-fatdiet on clinical CHD. The trials were either too small inpopulation or too short in duration to properly deter-mine the effects.23,24 Other trials included a low-fat dietas part of a multifactorial prevention program,25–28 sothat the dietary effect cannot be independently deter-mined, or used coronary angiography27–29 rather thanmyocardial infarction or coronary death to assess the ef-fect of the diet. Because there are no definitive clinicaltrials of a low-fat, high-carbohydrate diet on coronaryevents, it is of interest to calculate the predicted effects oflow-fat diets on coronary events from the known effectson plasma lipid risk factors. To do this, the epidemiologicrelation between change in LDL, HDL, and triglycerideand change in coronary disease risk is used.11,12,30 Theoverall predicted effects on CHD differ between men andwomen, because HDL and triglycerides are stronger riskfactors in women (Table 1 and Figure 2). In men, the20% or 30% fat diet produces no change in coronarydisease incidence, because the beneficial decreases in LDLare completely counterbalanced by adverse decreases inHDL and increases in triglycerides (Figure 2 and Table 1).In women, the 20% or 30% fat diets are predicted toincrease coronary incidence (Figure 2). In contrast, thehigh-unsaturated-fat diet is predicted to reduce coronaryincidence by 19% in men and 16% in women (Figure 2).

It is important to recognize that these predictions ofthe effect of diet on coronary disease incidence have theinherent limitations of epidemiology. However, it is justas important to recognize that neither the 30% nor the20% low-fat diets have been tested in a randomized clin-ical end point trial. The calculated advantage of the high-

unsaturated fat diet based on blood lipid effects is consis-tent with prospective epidemiological studies that di-rectly studied the relation between dietary fats andcarbohydrate on coronary rates (reviewed in this supple-ment by Ascherio1). The predicted null effect in menraises questions about futility of the low-fat intervention,whereas the predicted adverse effect in women raises fur-ther questions about safety.

CONTROLLED TRIALS OF DIETARYTHERAPY AND CORONARY EVENTS

High-Polyunsaturated Fat DietsIn the period 1956 to 1957, 4 research groups reportedthat polyunsaturated vegetable oils substantially reducedblood cholesterol concentrations when they replaced sat-urated fats,31–34 and predictive equations were designedby Keys et al.32 The polyunsaturated fatty acids studiedwere mainly the n-6 class and did not include the n-3polyunsaturated fatty acids from fish. Many subsequentstudies confirmed that polyunsaturated fatty acids are themost potent fatty acids for reducing LDL cholesterol.13

Corn, safflower, sunflower, and soybean oils were pre-scribed to hypercholesterolemic patients in the 1960s and1970s. The treatment was relatively simple for dietarytherapy, because patients were often instructed to drinkthe vegetable oils, as well as to use them in cooking orsalads. Four randomized clinical trials tested the effect

Table 1. Predicted Changes in Coronary Heart Disease (CHD)*

Blood Lipid30% Fat(Step 1) 20% Fat

HighUnsaturated Fat(Mediterranean)

LDL† plasma level �11 mg/dL �23 mg/dL �25 mg/dLCHD incidence �11% �23% �25%

HDL‡ plasma level �4 mg/dL �9 mg/dL �3 mg/dLCHD incidence

Men �8% �18% �6%Women �12% �27% �9%

TG§ plasma level �18 mg/dL �40 mg/dL �1 mg/dLCHD incidence

Men �3% �6% 0%Women �7% �17% 0%

HDL � high-density lipoprotein; LDL � low-density lipoprotein;TG � triglycerides.

* See Figure 1 for initial diet and plasma lipid concentrations.† �LDL � 1 mg/dL3 �CAD � 1%. (Data from N Engl J Med.30)‡ Framingham, Lipid Research Clinics Coronary Primary Prevention

Trial (LRC-CPPT), Multiple Risk Factor Intervention Trial (MRFIT),British Regional Heart Study combined; adjusted for other lipids.�HDL � 1 mg/dL3�CAD �2% in men, �3% in women. (Data fromCirculation.11)

§ Adjusted for other lipids, including HDL. �TG �88 mg/dL (1mmol/L) 3 �CAD �14% in men, �37% in women. Note that theeffects of carbohydrate on TG are less if the carbohydrate comes fromlow glycemic index foods, as described in the text. (Data from J Cardio-vasc Risk.12)



of soy and other unhydrogenated vegetable oils onCHD.35–38 Both linoleic and �-linolenic acids were in-creased in these trials. CVD events were significantly re-duced in 3 of them35,36,38 (Table 2). Overall, these trialssupport the relationship found in trials of drug therapythat coronary events are reduced by 2% for every 1%reduction in total cholesterol.2

The trial at the Wadsworth Hospital and Veterans Ad-ministration Center in Los Angeles35 was the most rigor-ous methodologically, had the most patients (846), andlasted the longest (8 years). The patients lived and re-ceived their meals at the domiciliary center, each dietgroup in a separate dining room. Moreover, the investi-gators established double-blind conditions. Adherence

was monitored and confirmed objectively by fatty acidmeasurements in the patients’ adipose tissue. A descrip-tion of the patients, the experimental and control diets,and serum cholesterol are shown in Table 3. Corn, soy-bean, safflower, and cottonseed oils were used in the ex-perimental diet, rather than the animal fat used in thecontrol diet. Linoleic acid, an n-6 polyunsaturated fattyacid, was the major fatty acid in the experimental diet.The patients were 65 years old on average; 74% were cig-arette smokers, 7% had a previous myocardial infarction,12% had angina pectoris, and 7% had a stroke. The ex-perimental diet reduced total cardiovascular end pointssignificantly by 31% from 22.7% to 15.6% (P � 0.01),and the combined end point of myocardial infarction,

Figure 2. Predicted effects on coronary artery disease of a 30% fat (Step 1) diet, a 20% low-fat diet, and a Mediterranean diet.Epidemiologic studies were used to predict the change in coronary heart disease from the changes in low-density lipoproteincholesterol, high-density lipoprotein cholesterol, and triglycerides caused by the diets (see also Figure 1).11,12,30 Diets are describedin the text. The changes in plasma lipids are shown in Figure 1. Solid bars � males (M); open bars � females (F).

Table 2. Clinical Trials of Diet Therapy to Reduce Coronary Events: Substitution of Polyunsat-urated Fat for Saturated Fat

NDietaryFat (%)

Duration(yr)

� Cholesterol(%)*

� CVD(%)†

Finnish Mental Hospital37 676 34 6 �15‡ �43‡

Oslo35 412 39 5 �14‡ �25‡

MRC soy oil36 393 46 4 �15‡ �12%Los Angeles34 846 40 8 �13‡ �34‡

CVD � cardiovascular disease; MRC � Medical Research Council.Trials with at least 2 years of average follow-up were included. See text for more information on the indi-

vidual trials.* Percentage change in serum cholesterol in the treatment group compared with the change in the control

group.† Percentage difference in coronary event rates in the treatment compared with the control group. CVD is

defined as myocardial infarction or sudden death for the Finnish, Oslo, and MRC trials, and myocardialinfarction, sudden death, or stroke for the Los Angeles trial.

‡ P �0.05.



sudden death, or stroke was reduced by 34% (P � 0.04)(Table 4).35 Stroke was reduced by 41% (P � 0.055).However clear-cut these results appear, acceptance of thefindings was hampered by the lack of reduction in totalmortality. The significant reduction in deaths from car-diovascular causes, 48 deaths in the experimental dietgroup versus 70 in the control group, was partly mitigatedby a higher number of deaths from noncardiovascularcauses in the experimental compared with the controlgroup, notably 7 versus 2 cancers and 4 versus 0 traumas,as well as from an uncertain cause in 32 versus 25 pa-tients.35 Such imbalances in small numbers of noncardio-vascular causes of deaths have occurred in many muchlarger studies, and it is recognized better now than beforethat these are usually the result of chance.

A fascinating sidelight of the Los Angeles diet trial wasthat a pilot study was conducted to determine whetherreduction of saturated fat intake was more acceptable tothe patients if accomplished by increasing carbohydrateor unsaturated oils. The results of the pilot study offer arelevant commentary on the current dietary controver-sies, �30 years later:

The circumstances of this trial—in particular the factthat most of the subjects were not highly motivated to-ward self-deprivation—rendered it mandatory that bothdiets be highly palatable by conventional criteria. It ap-peared on culinary grounds that a staff skilled in dietetics. . . could achieve a diet closely simulating the conven-tional institutional diet if, and only if, the total amount ofdietary fat remained nearly unchanged. This restrictionled to a decision to test a replacement of the saturatedanimal fats and hydrogenated shortenings of the conven-tional diet by equal quantities of unsaturated fat in theform of vegetable oils in the experimental diet. . . . A pilot

study demonstrated that a varied and palatable diet couldbe developed in line with these specifications and that itwas acceptable to most potential subjects, whereas low-fat diets were rejected forthwith. The diet chosen forstudy offered the incidental advantage that if it were ul-timately found to be of value, it might be adopted by thegeneral public more readily than would a diet requiringgastronomic sacrifice [pp 3– 4].35

The Oslo Diet-Heart Study36 was a trial that replacedsaturated with polyunsaturated fat, mainly soybean oil, in412 men who had a myocardial infarction. It was not adomiciliary trial, and the men were taught to select ratherthan being given their meals. After 5 years, the experi-mental group had fewer recurrent myocardial infarctionsor sudden deaths than the control group (61 [30%] vs. 81[39%]; P � 0.05) and fewer cardiovascular deaths (38[18%] vs. 52 [25%]; P � 0.09). The experimental groupcontinued to experience these trends toward reduced car-diovascular mortality for an additional 6 years after thetrial ended.33 Unlike the Los Angeles dietary trial, non-cardiovascular deaths were equal in the 2 groups, andtotal deaths were fewer in the experimental than controlgroup (41 vs. 55; P � 0.13).

The British Medical Research Council conducted atrial of soybean oil in 393 men after myocardial infarc-tion, instructing them to drink 43 g/day of soybean oilwith fruit juice and to use another 43 g/day in cooking.36

After 4 years, reduction in recurrent myocardial infarc-tion or sudden death was not significant, 45 events in theexperimental group versus 51 in the control group.

Finally, the Finnish Mental Hospital Study carried outa crossover study in 2 hospitals, in which 1 of the hospitalsfirst fed to the residential patients a control diet and thenthe experimental diet, and the other hospital fed the dietsin the reverse order.38 The experimental diet replaced sat-urated with polyunsaturated fat, mainly soybean oil. Eachdiet period lasted 6 years, and, for the most part, the samepatients ate both diets. Coronary end points, CHD deathor myocardial infarction, were significantly lower duringthe soybean oil periods than during the control period(Table 2 and Figure 3). The coronary event rates at eachhospital showed the effects of the crossover, decreasing in1 and increasing in the other after the change in diets(Figure 3). In summary, replacement of saturated withpolyunsaturated fat in the diet reduced coronary eventrates in all 4 trials and significantly in 3 of them.

Polyunsaturated fat is prone to oxidation in vitro. Ifthis also occurs in vivo, it might increase susceptibility ofLDL particles to oxidative modification, which wouldmake them more atherogenic. However, the positive out-comes of randomized controlled trials suggest that oxi-dizability of polyunsaturated fatty acids may be less of afactor in the genesis of atherosclerosis and CAD in hu-mans than previously thought.

Table 3. Clinical Trial of a High-Polyunsaturated-Fat Diet

Experimental Control

N 424 422Baseline characteristics

Age 65 years 66 yearsPrevious myocardial infarction 7% 7%Angina 12% 12%Stroke 7% 6%Smokers 74% 76%Serum cholesterol 233 mg/dL 234 mg/dL

Diet analysis during the trialTotal fat 39% 40%Polyunsaturated fat 17% 5.5%Linoleic acid 15% 4%Linolenic acid 2% 0.5%Monounsaturated fat 16% 15%Saturated fat 8% 19%Cholesterol 365 mg 653 mg

Serum cholesterol change �16% �3%

From Circulation.35



Clinical Coronary End Point Trials with aLow-Fat DietOnly 2 clinical coronary end point trials tested the effectof a low-fat diet without involving other treatments, suchas blood pressure– or plasma lipid–lowering medica-tion.23,24 Both trials enrolled patients with myocardialinfarction soon after they left the hospital. Reduction insaturated fat was intended to reduce total fat intake, andcarbohydrate-rich foods were recommended. Neithertrial showed a significant benefit (Table 5). However,both are unsatisfactory tests of the low-fat hypothesis,because the diets lowered serum cholesterol only mini-mally, the durations of 2 years in the 1989 study24 or 3years in the 1965 study23 years were insufficient for lipidtreatments to produce a reduction in coronary events, orthey had a very small sample size23 (Table 5). Because it iswell established that reduction of saturated fat lowers se-

rum cholesterol, it is likely that dietary adherence was lowin both studies.

Mediterranean Diet (Lyon Heart Study)The effect of a Mediterranean-style diet on coronarydeath after myocardial infarction was studied in the LyonDiet Heart Study.39 – 41 The dietary instruction startedrelatively early, 2 weeks, after the acute myocardial infarc-tion. The control group received Step 1 dietary advice.The Mediterranean diet replaced animal fat with polyun-saturated vegetable oil rich in �-linolenic acid, an n-3fatty acid that is the mother compound of the n-3 poly-unsaturated fatty acids from fish but that does not sharetheir effect on plasma triglycerides. Total fat was similarin both groups at 31% of energy. Meat, butter, and creamwere reduced, and legumes, bread, fruits, and vegetableswere increased (Table 6). Dietary cholesterol intake de-creased. Dietary adherence was proved by higher serum

Table 4. Clinical Trial of a High-Polyunsaturated-Fat Diet: Clinical Cardiovascular End Points

Experimental(N � 424)

Control(N � 422)

Risk Reduction(%) P Value

MI, definite 27 (6.4%)* 40 (9.5%) 32 NSSudden death 18 (4.2%) 27 (6.4%) 33 NSStroke 13 (3.1%) 22 (5.2%) 41 0.055Fatal cardiovascular 48 (11.3%) 70 (16.6%) 31 �0.05Nonfatal cardiovascular 37 (8.7%) 49 (11.6%) 24 NSTotal cardiovascular† 66 (15.6%) 96 (22.7%) 31 0.01MI, sudden death, stroke 60 (14.2%) 87 (20.6%) 34 0.04

MI � myocardial infarction; NS � not significant.* Number (percent) patients with event.† Myocardial infarction, sudden death, stroke, cerebral hemorrhage, limb amputation.From Circulation.35

Figure 3. Effects of a high-polyunsaturated-fat diet on coronary heart disease (CHD): the Finnish Mental Hospital Study.38 Acrossover study was conducted in 2 hospitals, the patients in 1 (hospital K) receiving the control diet first and then the experimentaldiet, and the patients in the other (hospital N) receiving the experimental diet first and then the control diet. In each hospital,coronary death and myocardial infarction (MI) rates were lower during the polyunsaturated fat diet.



levels of oleic acid, �-linolenic acid, eicosapentaenoicacid, and antioxidant vitamins. Particularly in view ofthese changes in dietary fat intake, it was surprising thatthere were no changes in plasma lipid levels. The trial wasstopped after a mean duration of 27 months, with highlysignificant reductions in coronary death in the Mediter-ranean diet group.39 Adherence to the assigned diets con-tinued for another 19 months after the trial ended, for atotal of 46 months of treatment. All-cause mortality wasreduced from 12% to 6%, coronary death from 9% to 3%,and nonfatal myocardial infarction from 12% to 4%, allstatistically significant39 (Figure 4). Cancer incidence wasalso reduced from 6% to 2%41 (Figure 4). Thus, a Medi-terranean dietary approach that did not reduce total fatbut improved many other aspects of the diet (Table 6)prevented death, recurrent coronary events, and cancerin patients after myocardial infarction (Figure 4). Per-haps the clinical benefits would have been even greater if

the diet improved the lipid profile as expected. The resultssupport several other hypotheses on diet and heart dis-ease, including benefits of �-3 fatty acids in general (�-linolenic acid in particular), monounsaturated fats, anti-oxidant vitamins, and fiber.

Indian Vegetarian DietThe Indian Heart Study42 tested the effect of fish andplant foods, including fruit, vegetables, legumes, and nutsin patients with acute myocardial infarction. The diets ofthe experimental and control groups both were reducedin meats, eggs, butter, hydrogenated oils and increased invegetable oils. Total fat intake was 24% to 26% of energyin both groups. This trial is unique in that it began thedietary intervention while the patients were in the hospi-tal only 2 to 3 days after the acute myocardial infarctionand that a significant reduction in coronary events of 36%occurred in the experimental group after only 12 weeks of

Table 5. Clinical Trials of Diet to Reduce Coronary Events: Low-Fat Diets

NDietary Fat(% energy)

Duration(yr)

Effects of the Low-FatDiet

Cholesterol CHD

London23 264 22% vs. 41% 3 �5% �5%DART24 2,033 32% vs. 35% 2 �3.5% �9%

CHD � heart disease; DART � Diet and Reinfarction Trial.Trials with �2 years of average follow-up were included.

Table 6. Mediterranean Diet to Prevent Death After Myocardial Infarction: Changes in Foods,Nutrients, and Coronary Risk Factors

Increased Decreased Unchanged

Dietary changesFruits Meats Total fat (31%–33%)Vegetables Butter, cream Cheese, poultry, fishBeans CholesterolBreadVegetable oilFiber

Body weight UnchangedBlood pressure Unchanged

Dietary fatty acid changesOleic acid Linoleic acid�-Linolenic acid Saturated fatEPA, DHA

Blood levelsAscorbic acid Linoleic acid Cholesterol, LDL, HDL�-Tocopherol Trans fatty acidsOleic acid Platelet aggregation�-Linolenic acidEPA, DHA

DHA � docosahexaenoic acid; EPA � eicosapentaenoic acid; HDL � high-density lipoprotein; LDL � low-density lipoprotein.

Adapted from Lancet.39



treatment. Perhaps the early timing of the interventionafter myocardial infarction caused the rapid reduction incoronary events. After 1 year of treatment, significant de-creases occurred in all-cause mortality by 45%, in coro-nary deaths by 42%, and in nonfatal myocardial infarc-tion by 38%. The vegetarian diet also reduced ventricularectopy. Fruit and vegetable intake was 3 times higher inthe experimental than in the control group. The experi-mental group had higher intake of polyunsaturated fats,fiber, vitamins C and E, carotene, and potassium and hadlower intake of saturated fats and cholesterol; carbohy-drate intake shifted from refined to complex sources. Inthe experimental compared with the control group, bodyweight, LDL cholesterol, triglycerides, blood pressure,and serum glucose significantly decreased, and HDL cho-lesterol increased. The patients in the experimental groupwho lost �0.5 kg after 1 year had greater reductions inserum cholesterol, triglycerides, glucose, and blood pres-sure and had fewer recurrent cardiovascular events thanthose who lost �0.5 kg. Thus, a vegetarian diet initiatedsoon after acute myocardial infarction reduced deathsand recurrent cardiovascular events.

Fish and Fish OilThe Diet and Reinfarction Trial (DART) tested the effectof increased intake of fatty fish for 2 years in 2,033 Welshmen after acute myocardial infarction.24 The patientswere asked to eat mackerel, herring, kipper, sardine,salmon, or trout twice weekly, beginning 6 weeks aftermyocardial infarction. Those who could not eat fatty fishtook fish oil capsules (20% n-3 fatty acids), 1.5 g daily.This small amount of fatty fish or fish oil significantlyreduced total mortality from 12.8% to 9.3% (�29%; Fig-ure 5) and coronary mortality from 11.4% to 7.7%

(�33%). Nonfatal myocardial infarction was not affectedsignificantly, 3.2% in the control group versus 4.8% inthe fish group. This trial tested 2 additional dietary inter-ventions, reduced fat and increased fiber, and neithershowed any tendency to produce benefit (Table 5). TheDART study24 and the Lyon Heart Study41 both suggestthat n-3 fatty acids protect against death after myocardialinfarction. These results have recently been much rein-forced by the Gruppo Italiano per lo Studio della Soprav-vivenza nell’Infarto Miocardico (GISSI) trial, a random-ized controlled trial in 11,324 Italian patients surviving arecent myocardial infarction.43 Treatment with 1 g/day ofn-3 polyunsaturated fatty acids from fish lowered theoverall risk of death and of coronary death from 6.8% to4.8% (�2%) (Figure 5). In both trials24,43 the death ratebegan to lessen in the fish or fish oil group as early as 3months after treatment was started.

Figure 4. The effect of a Mediterranean diet on total mortality, coronary disease events, and cancer in men after acute myocardialinfarction (MI): the Lyon Heart Study.39 – 41 See text for description and Table 6 for changes in diet and coronary risk factors.Numbers in bars are the number of events. Percentages over the open bars are percentage risk reduction with P value.

Figure 5. Summaries of trials of fatty fish or fish oil to preventcoronary artery disease. See text for additional results.



Several actions of n-3 fatty acids that could explaintheir beneficial effect after myocardial infarction are re-duction of plasma triglycerides,44 accelerated clearance ofchylomicrons and very low-density lipoprotein,45 in-creased HDL,46 and reduced blood pressure.47 The n-3fatty acids also have an antiarrhythmic action,48 increas-ing the threshold for ventricular fibrillation.49 Dietary in-take of �-3 fatty acids was very low in persons who expe-rienced sudden death.50 This antiarrhythmic action ofn-3 fatty acids may have been the dominant mechanismfor prevention of death after acute myocardial infarctionin the Lyon Heart Study,40 the DART study,24 and theGISSI study.43

Trans Unsaturated Fatty Acids, Serum Lipids,and CHDInformation on the effects of dietary trans fatty acids onserum lipids and CHD has increased tremendously dur-ing the past 10 years. Trans unsaturated fatty acids areformed from the naturally occurring cis unsaturated fattyacids during the hydrogenation process that takes liquidvegetable oil, such as soybean, and makes solid or semi-solid margarine or shortenings for frying or baking. Mosttrans unsaturated fatty acids in the diet are the analoguesof oleic acid, the main cis monounsaturated fatty acid inthe diet. Among all dietary fats, trans fatty acids haveunique effects on serum lipids. LDL increases and HDLdecreases when oleic acid is replaced by trans fatty acids,both when these are isomers of the same chain length andwhen they are longer-chain isomers formed by hydroge-nation of fish oils.51–53 As soon as this information wasknown, people asked whether foods that contain transunsaturated fatty acids, such as margarines, truly do havebenefits over food that contain saturated fat, such as

butter. When you replace 10% of energy intake from sat-urated fat with trans fatty acids, there is no change inLDL, and there is about a 7 mg/dL (15%) decrease inHDL. Thus, LDL stays high, and HDL decreases precipi-tously. This is worse than the effects of carbohydrate,which decreases both LDL and HDL. By combining thechanges in total cholesterol and HDL cholesterol into aratio, the trans fatty acids can be compared convenientlywith the other dietary fatty acids. This analysis is based on8 carefully controlled trials. Trans fatty acids have theworst effects on blood lipids among all dietary fatty acids,even saturates (Figure 6). Monounsaturated and polyun-saturated fatty acids reduce the ratio, whereas carbohy-drates have a negligible effect. These adverse effects oftrans unsaturated fatty acids on cholesterol and HDLagree with epidemiologic findings of increased risk ofCHD in people who consume these fatty acids, as de-scribed by Ascherio.1 This evidence of a harmful effect oftrans fatty acids on coronary disease has been sufficient toconvince a large part of the fats and oils industry in Eu-rope to get rid of trans fatty acids in packaged foods andmost margarines. Most Dutch retail margarines are nowfree from trans fatty acids, and the same trend is takingplace in a large part of the world. The United States islagging behind in this respect, although McDonald’s andFrito-Lay are progressively reducing the trans fatty acidcontent of their foods. The term “partially hydrogenated”on the label indicates the presence of trans fatty acids.Nonetheless, both in Europe and the United States, thereare still large amounts of trans fatty acids in the frying fatsused in restaurants and in baked goods, including cook-ies, snacks, and pastries. This is now the major source oftrans fatty acids, in Eastern Europe, Western Europe,North America, and South America, so there is still quite

Figure 6. The effect of trans unsaturated fat compared with other unsaturated fats on the ratio of total cholesterol to high-densitylipoprotein (HDL) cholesterol. In each instance, saturated fat (10% of total daily calories) is replaced by the same amount ofunsaturated fat. Carb � carbohydrate; Mono � monounsaturated fat; Poly � polyunsaturated fat; Trans � trans unsaturated fat.51



a bit of work left to do to improve the food supply toprevent CHD.

SUMMARY AND CONCLUSIONS

Dietary effects on plasma lipids are the following:

● Decreasing saturated fat lowers LDL cholesterol.● Replacing saturated fat with carbohydrate lowers HDL

as much as it lowers LDL. Triglycerides are increasedwith common high glycemic index sugars andstarches.

● Fish oil fatty acids do not lower LDL cholesterol but dolower triglycerides.

● Replacing saturated fat with monounsaturated orpolyunsaturated fat lowers HDL only slightly and doesnot increase triglycerides.

● Trans unsaturated fats produced by hydrogenatingvegetable oil increase LDL and decrease HDL.

● The most favorable overall changes in plasma lipidconcentrations are produced by replacing saturatedand trans unsaturated fats with unhydrogenatedmonounsaturated or polyunsaturated fats.

Dietary therapy that reduced CVD in clinical trials areas follows:

● Replacing saturated fat with polyunsaturated vegetableoil

● Mediterranean diet after myocardial infarction● Indian vegetarian diet after myocardial infarction; and● Fish oil after myocardial infarction.

(No randomized clinical trials of low-fat diets of suffi-cient duration and size were available.)

The standard dietary approach recommended for cor-onary disease prevention that increases carbohydratesand reduces saturated fat has never been tested satisfac-torily in a randomized clinical trial. The reductions inHDL and the increases in triglycerides caused by carbo-hydrate would be predicted to diminish or eliminate anybenefits on coronary disease gained by lowering LDL.Prospective epidemiologic studies also do not show re-duction in risk with carbohydrates. It is possible, but notproven, that low-fat diets could be effective in preventingcoronary disease if they are based on whole grain cereals,legumes, fruits, and vegetables and are low in rapidly ab-sorbed refined carbohydrates. In contrast, several dietaryapproaches reduced coronary events in randomized clin-ical trials. Replacing saturated fat with polyunsaturatedfat prevented coronary events in men. In men who had anacute myocardial infarction, a Mediterranean diet andfatty fish improved survival. None of these trials hadmuch impact on total fat intake but rather increased veg-etable oils, n-3 fatty acids, or many other plant foods ornutrients that are linked to coronary prevention. The re-

ductions in rates of CVD caused by these dietary thera-pies compare favorably with drug treatments for coro-nary patients. The theme should be that diet has benefitsthat come directly from foods, as well as from the reduc-tion in saturated fats, cholesterol, meats, and fatty dairyfoods. It is likely that many diets could be designed withthese principles that can prevent CVD. This potential di-versity is crucial for engaging the diverse cultures andtastes of people worldwide in coronary disease preven-tion.

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Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease