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1 From the Human Nutrition and Lipids Joint Research Unit 476-INSERM, National Institute of Health and Medical Research/1260-National Institute of Agronomic Research, Faculty of Medicine Timone, Université de la Méditerranée, Marseille, France (SV-B, CD, OH, RP, M-JA-C, and DL); the Analytical Chemistry Laboratory, Faculty of Pharmacy, Marseille, France (CD and HP); the Cancer Research Centre, INSERM-CRLC Val d'Aurelle, Montpellier, France (MG); the Centre for Detection and Prevention of Arteriosclerosis, Timone University Hospital, Marseille, France (M-CB and PV); the Health Regional Observatory, Epidemiology and Social Sciences Applied to Medical Innovation Unit-379-INSERM, Marseille, France (PV); and the UMMM Metabolic Disease and Macronutrients Laboratory, Clermont-Ferrand, France (PG)
2 Supported by the French Research Ministry (AQS grant, SV's salary), INSERM (IDS grant), the Provence-Alpes-Côte d'Azur Regional Council, the Bouches du Rhône General Council, the CRITT-PACA, and the following companies: Rivoire & Carret Lustucru, Jean Martin, Le Cabanon, Boulangerie Coagulation Surgelés, Distplack Mariani, and Minoterie Giraud. 3 Reprints not available. Address correspondence to D Lairon, UMR 476-INSERM/1260-INRA, Human Nutrition and Lipids, Faculty of Medicine Timone, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. E-mail: denis.lairon{at}medecine.univ-mrs.fr.
ABSTRACT
Background: Epidemiologic studies link Mediterranean-type diets to a low incidence of cardiovascular disease; however, few dietary intervention studies have been undertaken, especially in primary prevention.
Objectives: In the Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms (Medi-RIVAGE) study, the effects of a Mediterranean-type diet (Med group) or a low-fat diet (low-fat group) on risk factors were evaluated in 212 volunteers (men and women) with moderate risk factors for cardiovascular disease.
Design: After the 3-mo dietary intervention, changes in many risk factors were evaluated. Dietary questionnaires and plasma nutritional markers were used to test compliance.
Results: Although the dietary goals were only partially reached, changes in dietary habits were observed in both groups (n = 169): protein, carbohydrate, and fiber intakes increased and fat quality (decreased saturated fat and increased monounsaturated or polyunsaturated fat) improved. BMI, total and triacylglycerol-rich lipoprotein (TRL) cholesterol, triacylglycerols, TRL triacylglycerols, apolipoproteins A-I and B, insulinemia, glycemia, and the homeostasis model assessment score were significantly lower after 3 mo. The reductions in total cholesterol, triacylglycerols, and insulinemia remained significant after adjustment for BMI. There was a trend for a diet-by-time interaction for LDL cholesterol (P = 0.09). Our data predicted a 9% reduction in cardiovascular disease risk with the low-fat diet and a 15% reduction with this particular Mediterranean diet.
Conclusion: After a 3-mo intervention, both diets significantly reduced cardiovascular disease risk factors to an overall comparable extent.
Key Words: Intervention trial • primary prevention • blood pressure • lipid metabolism • apolipoproteins
INTRODUCTION
Cardiovascular disease (CVD) is one of the leading causes of death in the Western world and is the third cause of mortality in developing countries, accounting for 25% of all deaths (1). Many studies have already shown the effect of specific nutrients or diets on cardiovascular disease risk factors or mortality. The Seven Countries Study by Keys et al in the 1960s showed a relation between saturated fat intake, fasting blood cholesterol concentrations, and coronary heart disease (CHD) mortality in various populations (2, 3), which suggests the protective effect of traditional Mediterranean-type diets. The more recent MONICA survey, conducted in Europe, confirmed the South-North gradient in CHD mortality and its relation to dietary habits (4). Even more recently, 3 cohort studies in Spain and Greece have provided data supporting a cardiovascular protective effect of Mediterranean diets (5-7). These studies, together with other reliable epidemiologic studies (8), provide the basis for the well-known traditional Mediterranean diet pyramid and healthy eating model (9).
Nevertheless, drastic changes in food habits in Mediterranean populations have recently occurred, and the traditional Mediterranean model now seems restricted to elderly people and rural areas (10). Indeed, even in Crete, the progressive upward trend in total and saturated fat intakes is concomitant with a marked increase in obesity and cardiovascular disease mortality (11).
Although individual nutrients common in the traditional Mediterranean diet have been individually tested in some studies (12-14), very few intervention studies have looked at a global diet (15). The Lyon Heart Study for secondary prevention of CHD (16, 17) showed the positive effect of a Mediterranean-type diet enriched with -linolenic acid (mainly in the form of margarine), the survival rate after a first myocardial infarction increasing markedly compared with that for the control group (low-fat diet). Moreover, the Indo-Mediterranean Diet Heart Study (18) showed that a Mediterranean-type diet (rich in -linolenic acid from fruit, vegetables, and nuts) was also of benefit for secondary prevention of CHD in non-Mediterranean populations. The Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) Study (19, 20), a primary prevention study in hypercholesterolemic subjects, showed the benefit of the -linolenic acid contained in a Mediterranean diet. Finally, a recently published trial in patients with the metabolic syndrome shows that a Mediterranean-type diet decreases insulin resistance and improves endothelial function (21).
As the only other primary intervention study in this field (21), the Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms (Medi-RIVAGE) intervention study is based on an overall daily diet instead of on a specific nutrient. In this study, we aimed to evaluate the effect of a Mediterranean-type diet compared with that of a low-fat (prudent) diet on CVD risk factors in subjects at moderate CVD risk. It should be pointed out that the 2 diets differed somewhat in food types and quality but that the expected macronutrient contents were not markedly different. Extensive biological investigations were performed with a special focus on lipid and lipoprotein variables. In this article we report the effects of the 3-mo Medi-RIVAGE dietary intervention on clinical and biochemical risk markers.
SUBJECTS AND METHODS
Subjects
The design and methods of the Medi-RIVAGE study were recently reported (22) in detail. Briefly, the participants were men and women aged 18-70 y who were visiting the Center for Detection and Prevention of Arteriosclerosis (CPDA) at La Timone University Hospital (Marseille, France) and who met at least one of the following eligibility criteria: fasting plasma cholesterol concentration of 6.5–7.7 mmol/L; triacylglycerol concentration of 2.1–4.6 mmol/L; glycemia (glucose concentration of 6.1–6.9 mmol/L); systolic and diastolic blood pressure between 140–180 and 90–105 mm Hg, respectively; body mass index [BMI (in kg/m2)] >27; smoking; sedentary; or family history of CVD (22). Subjects treated by hypolipemic or hypoglycemic drugs were excluded. Eligible volunteers provided signed informed consent as approved by the institution's ethics committee (ethics committee number 98/25).
Nutritional strategy
Details of diet composition at baseline and of dietary intervention strategy were previously described (22). Briefly, the participants were consuming a Western-type diet at entry. They were provided with nutritional recommendations by physicians and dietitians and received a booklet presenting either the recommended Mediterranean diet adapted from the traditional model (Med) or a commonly prescribed low-fat American Heart Association–type diet adapted by the CDPA (low-fat diet). The Med diet recommended nuts, whole-meal bread, cereals, and a variety of raw or cooked, fresh, or dried fruit and vegetables and legumes,. Olive oil was recommended as the main source of added fat. Fish was recommended 4 times/wk and red meat only 1 time/wk. Sheep and poultry were to provide the main source of meat, whereas cheeses were mainly to be from sheep and goats. Oat-bran–enriched pasta, tomato sauce, and olive oil were provided. In the low-fat group, recommendations were to eat more poultry than mammal meat, to avoid offal and saturated fat–rich animal products, and to eat fish 2–3 times/wk. The consumption of raw and cooked fruit and vegetables, low-fat dairy products, and vegetable oils was recommended.
In terms of nutrients, the quantity and quality of lipid intakes were the major differences between the 2 recommended diets. The Med diet recommendations accepted up to 35–38% of total energy as fat, whereas the low-fat diet recommendations limited fat intake to 30% of total energy. Moreover, in the Med diet, 50% of the energy provided by lipids was to come from monounsaturated fatty acids, 25% from polyunsaturated fatty acids, and 25% from saturated fatty acids; in the low-fat diet, 33% of energy was provided by each of the 3 lipid subclasses. Cholesterol was restricted to 200–300 mg/d in both diets. The recommended fiber intake was higher in the Med group (25 g/d) than in the low-fat group (20 g/d). The Med diet made specific mention of carotenoid intake (7 mg/d), a marker of fruit and vegetable intakes, whereas there was no specific recommendation concerning these micronutrients in the low-fat diet. Furthermore, to limit dairy food intake as in the traditional Mediterranean diet, the Med group subjects were instructed not to exceed a calcium intake of 800 mg/d. In the Med diet, 2 glasses of red wine/d were allowed for men and 1 glass/d for women; however, alcohol was to be avoided, especially for hypertriglyceridemic subjects, in the low-fat diet.
To ensure adequate compliance with dietary recommendations, dietitians used 3-d food records (at inclusion and after 3 mo) and 24-h unscheduled dietary recalls (once a month). The GENI program nutritional database was used (Micro6, Nancy, France), which is based on the French REGAL food database.
The physical activity of the participants was recorded on questionnaires. It did not differ between groups at inclusion (22) and did not change noticeably during the 3-mo intervention period, as was recommended (data not shown).
Endpoints
The endpoints were observed changes in the risk factors (clinical variables and biological markers) after 3 mo of dietary intervention. A DNA bank was also built to determine the polymorphisms of genes involved in lipoprotein metabolism or arteriosclerosis and to search for interactions between gene polymorphisms and responses to diets.
Weight and blood pressure were checked at entry and at the end of 3 mo. After the subjects fasted overnight, plasma concentrations of glucose, insulin, total cholesterol, LDL cholesterol, HDL cholesterol, TRL cholesterol, triacylglycerols, TRL triacylglycerols, fatty acids, carotenoids, vitamin B-12, folates, and apolipoprotein (apo) E, apo A-I, apo B, and apo C-III were measured at entry and at the end of 3 mo with the use of methods previously described (22). Insulin resistance was estimated by the homeostasis model assessment (HOMA) (22).
Statistical analysis
A sample size of 80 subjects in each group was calculated to have 90% statistical power to detect a difference of 0.5 mmol/L in blood cholesterol, with a 5% level of significance (two-tailed test).
The intention-to-treat principle was used to compare the Med and low-fat groups. The groups were defined according to the initial random assignment rather than according to reported compliance with the protocol (n = 169 at 3 mo). Continuous data are expressed as mean (±SD) values. Variables not normally distributed were tested with the Mann-Whitney U test. Associations were examined by using Pearson's (parametric data) and Spearman's (non parametric data) correlation analysis.
The data were analyzed by using repeated-measures 2-factor analysis of covariance. Time effect and diet interaction were determined as reported in the tables (P values for time and time-by-group interactions, respectively). The results were adjusted for baseline values if they were different and also for age, sex, tobacco, and BMI variation. Comparisons within groups were made by using the paired-samples t test. Comparisons between groups, at baseline, were made by using the independent-samples t test. Two-tailed P values < 0.05 were judged significant. SPSS for WINDOWS version 12.0 (SPSS Inc, Chicago, IL) was used for the statistical analysis.
RESULTS
A total of 232 subjects were invited to participate in the study (22); 212 (91.4%) subjects were included in the study (n = 102 in the Med group and 110 in the low-fat group). During the first 3 mo, 43 subjects dropped out [n = 14 (15.9%) in the Med group and 29 (35.8%) in the low-fat group]. The characteristics of the dropouts were not significantly different from those of the other subjects. Of the subjects (n = 169) followed at month 3, 42% were men and 58% women in the Med group, and 39.5% were men and 60.5% were women in the low-fat group. The mean age of the subjects was 50.8 (± 10.8) and 51.6 (± 10.3) in the 2 groups, respectively. Overall, 35% of the subjects were overweight (BMI: 25-30), 38% were obese (BMI > 30), 93% were hypercholesterolemic, 46% were hypertriacylglycerolemic, and 21% were hypertensive. There was no significant difference between the Med (n = 88) and low-fat (n = 81) groups with regard to energy intake and demographic, anthropometric, and clinical baseline data, with the exception of smoking [more smokers in the Med group (27.3%) than in the low-fat group (17.3%); P = 0.07] and LDL cholesterol (4.4 mmol/L in the Med group and 4.1 mmol/L in the low-fat group; P < 0.05) as previously reported (22).
Nutritional data
As illustrated in Figure 1, the subjects noticeably altered their food consumption pattern in line with recommendations to the 2 groups. For almost all dietary variables, there were no significant time-by-group interactions; dietary changes in the Med group were not significantly different from those in the low-fat group (Table 1). Both groups decreased energy intake over the 3-mo study period. Alcohol intake decreased significantly in both groups, but the decrease was greater in the low-fat group than in the Med group (P for interaction = 0.02). In both groups, the percentage of energy provided by proteins and carbohydrates increased significantly, whereas that provided by total fat decreased. The percentage of energy provided by saturated fat decreased over time, whereas that provided by polyunsaturated fat increased. There was a significant interaction for percentage of fat provided by monounsaturated fat, which increased with the Med diet and decreased with the low-fat diet (P for interaction = 0.012). Ingested cholesterol decreased in both groups over the 3-mo period. Total, soluble, and nonsoluble dietary fiber intakes did not increase significantly in either group. In both groups, there was no variation in ß-carotene, folate, vitamin C, and vitamin B-12 intakes. Calcium intake decreased in both groups. There was a significant interaction for vitamin B-6 and vitamin E intakes (P for interaction = 0.011 and 0.027, respectively); vitamin B-6 increased with the Med diet and decreased with the low-fat diet, whereas vitamin E showed the reverse trend. Iron intake decreased in both groups, and there was a significant interaction for iron (P for interaction = 0.032).
FIGURE 1.. Mean intakes (g/d) of important food items at baseline and after a 3-mo dietary intervention in subjects fed a Mediterranean-type diet (Med group; n = 88) or a low-fat diet (low-fat group; n = 81) at baseline and at 3 mo.
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TABLE 1. Daily nutrient intakes of the sample by treatment group at baseline and after the 3-mo diet1
Nutritional biomarkers
Changes in plasma nutritional biomarkers after the 3-mo diet are shown in Table 2. After adjustment for BMI variation, we observed a tendency for increased plasma ß-carotene and lycopene concentrations over time (P = 0.10). Total plasma phenolic compounds showed a time-by-group interaction, with a significant increase in the Med group after 3 mo.
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TABLE 2. Plasma nutritional markers of the sample by treatment group at baseline and after the 3-mo diet1
For plasma fatty acids, we observed a significant time-by-group interaction for palmitoleic (16:1n–9) and stearic (18:0) acids. Docosahexaenoic acid (22:6n–3) significantly increased after 3 mo in both the Med and the low-fat groups (0.7% and 0.3%, respectively). Fish consumption (69.7 ± 48.7 and 72.4 ± 56.7 g/d in the Med and the low-fat group at 3 mo) was positively correlated with plasma eicosapentaenoic acid (r = 0.30, P < 0.01) and docosahexaenoic acid (r = 0.19, P < 0.05) concentrations. In both groups, no significant change was observed for plasma folate or vitamin B-12 concentrations after 3 mo.
Clinical endpoints
A small but significant decrease in BMI was observed after a 3-mo diet, in line with the moderate reduction in total energy intake (Table 3). A significant, although weak, increase was observed in diastolic blood pressure after 3 mo.
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TABLE 3. Mean BMI and blood pressure of the sample by treatment group at baseline and after the 3-mo diet1
Biochemical variables
After the 3-mo diet (Table 4), plasma total cholesterol significantly decreased, with a tendency for a group effect (P = 0.082) in the Med group (–0.4 mmol/L, or –7.5%) and in the low-fat group (–0.3 mmol/L, or –4.5%). There was a trend (P = 0.09) for a time-by-group interaction in LDL cholesterol and a trend for a main effect of group (P = 0.074): Med group (–0.5 mmol/L) and low-fat group (–0.2 mmol/L). After 3 mo, no change in HDL cholesterol was observed, whereas TRL cholesterol decreased significantly in both groups.
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TABLE 4. Cardiovascular disease risk factors of the sample by treatment group at baseline and after the 3-mo diet1
In both groups Apo-AI and Apo-B were significantly lower over the 3-month period with no time-by-group interactions. Apo-E and Apo-CIII did not change after 3 mo. Plasma triacylglycerol and TRL-triacylglycerol concentrations significantly decreased after 3 mo.
Glycemia, insulinemia, and HOMA score decreased significantly after 3 mo, with no time-by-group interactions (Table 4). Moreover, significant effects of BMI were found on total cholesterol, triacylglycerols, glycemia, insulinemia, and HOMA score: P = 0.028, = 0.014, < 0.001, < 0.001, and < 0.001 by using a 2-factor (time and BMI) repeated-measures analysis of covariance. After adjustment for BMI variation, the time effect remained significant for total cholesterol (P = 0.032), triacylglycerols (P = 0.039), and insulinemia (P = 0.014).
DISCUSSION
The Medi-RIVAGE study aimed to determine the effect of a Mediterranean diet and of a commonly prescribed low-fat diet on risk factors for cardiovascular disease. Aimed at a reduction in cardiovascular disease risks in our population, the study strategy was to globally modify dietary habits without particular focus on any specific nutrient, as is usual in intervention studies. This strategy was evaluated by using dietary questionnaires and measuring plasma nutritional markers. In both diet groups, we observed noticeable changes in food intake (Figure 1). The most important changes in the Med group were increases in fruit, vegetables (including legumes), olive oil, nuts, and fish and reductions in other vegetable oils, dairy products, and meat. In the low-fat group, the main changes observed were increases in fruit, vegetables, and fish and decreases in meat and dairy products. These changes in food intake had the effects of reducing protein intake, of increasing the relative proportion of carbohydrates, of decreasing ingested cholesterol, and of reducing total fat with a marked improvement in fat quality (Table 1). For some fatty acids we found a significant variation after a 3-mo diet in the Med and low-fat groups, and the increase in fish consumption observed was corroborated by higher plasma docosahexaenoic acids. Fiber intakes tended to increase after a 3-mo diet, especially in the Med group (2.1 g/d), as consistent with recommendations to increase intakes of whole-grain food products and legumes. We observed a trend toward increases in total carotenoids ingested, which was confirmed by the measurement of the plasma nutritional markers, which reflected the increase in vegetable and fruit intakes. To summarize, whereas the 2 diets compared were based on somewhat different consumption patterns of some foodstuffs (especially olive oil, whole grains, legumes, and nuts), they did not generate markedly different supplies of macro- or micronutrients.
Although we observed noticeable changes in dietary habits in both groups, the objectives set for the subjects were not fully met. Indeed, dietary records and nutritional markers showed insufficient intakes of several nutrients. Lipid intakes, especially monounsaturated fatty acids, remained insufficient in the Med group, whereas lipid intakes remained too high in the low-fat group; fiber intake did not reach the intake recommended for the Med group (25 g/d). This can be explained by the fact that subjects in both groups did not fully follow the dietary recommendations. It is difficult to recruit subjects who will be strictly compliant with dietary recommendations. Moreover, because the subjects lived in the Mediterranean area, those in the low-fat group may have unintentionally altered the recommended low-fat diet toward a kind of "moderate" Mediterranean diet pattern, which resulted in a reduction in differences between the 2 groups. It is noteworthy that we observed a 2-fold lower dropout rate in the Med group after 3 mo, which highlighted a better compliance with the Mediterranean diet pattern, as recently checked by others (23).
Nevertheless, changes in risk factors in the low-fat group were comparable and even more satisfactory than those reported by others during short-term intervention studies with the low-fat American Heart Association–recommended diet (24). In the Medi-RIVAGE study, several variables were significantly different after a 3-mo dietary intervention, such as total and TRL cholesterol, triacylglycerols, TRL triacylglycerols, apo A-I, apo B, glucose, insulin, and HOMA score. Interestingly, the reduction in LDL cholesterol after 3 mo tended to be greater with the Med diet (P = 0.09 for time-by-group interaction) than with the low-fat diet, which agreed with the observations of the MARGARIN (20) and the Indo-Mediterranean (18) studies. Conversely, the biochemical variables did not change noticeably during the Lyon Diet Heart study (16). Dietary factors may explain these results. The Med diet provided greater intakes of soluble fibers (from fruit, vegetables, legumes, and cereals) and monounsaturated fatty acids (oleic acid from olive oil), which are known independently to have a cholesterol- and LDL cholesterol–lowering effect (25-28). Olive oil intake was recently shown to be related to reduced rates of myocardial infarction (29). Fiber-rich diets (28) and a high consumption of fruit and vegetables have been related to a reduced occurrence of CHD (5, 6).
The beneficial changes in total and LDL-cholesterol that we observed in both groups agree with those reviewed by Sacks and Katan (30), for both a low-fat and a Mediterranean-type diet. However, we found no increase in fasting triacylglycerols, as observed with high-carbohydrate, low-fat diets (30), which was likely due to the limited nature of the modification observed in dietary intakes and with the limited reduction in dietary energy and related weight loss, all of which are limiting factors for carbohydrate-induced hypertriglyceridemia. The reduction in plasma triacylglycerol (mainly in the form of TRLs) observed only in the Med group may have been due mainly to a high intake of fish and long-chain n–3 fatty acids (31, 32) and more probably to changes in postprandial lipoprotein metabolism induced by meals rich in olive oil (33) or dietary fibers (34).
An important point to consider in data interpretation is body weight and BMI reduction, which, although moderate, may improve some cardiovascular disease risk factors (35). After adjustment for BMI variation for variables showing an interaction with BMI, decreases in total cholesterol, triacylglycerols, and insulin after 3 mo remained significant. This suggests that the significant changes still observed for these variables, after adjustment for weight loss, result from an independent effect of diet quality alteration. This agrees with the recent observation that the Mediterranean diet is associated with decreased insulin resistance in patients with metabolic syndrome (21).
We observed no improvement in systolic or diastolic blood pressure with the dietary interventions. It is possible that the large number of normotensive subjects present (79% of total) or the limited duration of the interventions prevented such an observation, because several epidemiologic studies have reported reduced blood pressure linked to Mediterranean dietary patterns (36, 37).
In conclusion, the diets tested during the Medi-RIVAGE study, a Mediterranean-type diet or commonly prescribed low-fat diet, show measurable efficiency in reducing key cardiovascular risk factors. In line with most recent theories on optimal eating patterns for prevention of CHD (38) and according to Law's concept (39), the observed lowering in plasma cholesterol actually indicates a reduction in cardiovascular risk of 9% with the low-fat diet and 15% with the Mediterranean-type diet. The Medi-RIVAGE intervention study thus provides support to early (2-4) or recent (5-7, 21) observational studies linking adherence to the traditional Mediterranean diet and reduced cardiovascular disease mortality and reinforces the notion of its efficacy in primary as well as secondary prevention.
ACKNOWLEDGMENTS
We are indebted to N Rousset and S Loviconi (CDPA dietitians); MF Alliaud and AM Lorec (laboratory supervisors); M Senft, J Leonardi, B Lyan, C Bideau, D Iniesta, N Peyrol, and JF Lesgard (laboratory technicians); and A Lanteaume and A Loundou (statisticians).
DL, MG, and PV coordinated the study. SV-B, CD, and DL wrote the manuscript. MG was responsible for the nutritional strategy. M-CB recruited the subjects and conducted the clinical evaluations. CD, SV-B, PG, and M-JA-C were involved in the laboratory work and data interpretation. PV, OH, and SV-B were involved in the statistical analyses. HP and RP were involved in the blood analyses. All authors contributed to the final report. None of the authors declared a conflict of interest.
REFERENCES