- Click here for explanation of classification scheme.

To determine the extent to which diet could substitute for statins in achieving target LDL-cholesterol concentrations.

LDL-cholesterol of >4.1mmol/L.

• History of cardiovascular disease, untreated hypertension (>140/90mm Hg), diabetes, or renal or liver disease.
• Taking medications known to influence serum lipid levels. 

Recruitment

Hyperlipidemic patients attending the Risk Factor Modification Center and newspaper advertisements.

Design

Randomized crossover.

Blinding used

Statin medication and placebo were dispensed in identical containers by the hospital pharmacy marked with the subject's name. The statistician held the code for the placebo or lovastatin tablets provided in the control and statin treatment groups, respectively. The randomization of the tablets was assigned by using a pseudo-random number-generating facility within the SAS statistical software package. 

The laboratory staff responsible for the analysis was blinded to treatment and received the samples labeled with name codes and date. 

Intervention 

A very-low-saturated fat diet vs. the same diet plus 20mg of lovastatin vs. a diet high in plant sterols.

Statistical Analysis

The results were expressed as means ± SEs. The data were analyzed with a two-factor (diet and time) repeated-measures analysis of variance by using the three treatments and weeks zero, two, and four and with the diet-by-time interaction. After the establishment of a significant F-test, the significance of the pair-wise differences between treatments at each time point was assessed by least-squares means, with Tukey-Kramer adjustment for multiplicity of comparisons. Fisher's exact test for 2x2 contingency tables was used to assess whether the statin or portfolio diet was significantly different in achieving treatment goals in terms of LDL-cholesterol reduction. The cutoffs used for LDL-cholesterol were <3.4 and 2.6mmol/L. An additional analysis was also carried out, which included all participants who had completed only one or two of the three phases. 

 

 

Timing of Measurements

Weights and blood pressures were done weekly and blood draws bi-weekly at baseline through week four and bloods were drawn at zero, two and four weeks of each treatment period. 

A seven-day diet history was obtained the week before the one-month treatment periods. Menu checklists were returned at weekly intervals during the four-week diet periods with the previous week's exercise. Satiety ratings were done weekly. Fecal frequency was recorded for the seven-day of week four. 

Dependent Variables

• Serum was obtained after 12-hour overnight fasts and was analyzed for total cholesterol, triacylglycerol, and HDL cholesterol after dextran sulfate magnesium chloride precipitation. LDL-C levels were calculated, serum apoplipoprotein (apo) A-I and apo B were measured by nephelometry. 
• Blood pressure was measured twice in the non-dominant arm with a mercury sphygmomanometer by the same observer
• Satiety was rated by using a nine-point bipolar semantic scale, where -4 was excessively hungry, zero was neutral and four was discomfort due to excess food intake.

  Independent Variables 

• The subjects ate their own low-saturated-fat therapeutic diets for one month before starting the study. These diets were close to the current NCEP guidelines of < or equal to 7% of energy from saturated fat and <200 milligrams of cholesterol per day. They were then randomized to each of three one-month treatments with a two to six-week washout period between the treatments. The diets were a very-low-saturated-fat dairy and whole-wheat cereal diet (control diet), the control diet plus a statin (statin diet), or a diet containing viscous fibers, plant sterols, soy foods, and almonds (portfolio diet). All foods which were available in supermarkets and health food stores were provided, except for fresh fruit and vegetables. All the diets were weight-maintaining based on estimated caloric requirement. 
• The diet portfolio had four main components: Margarine enriched in plant sterol esters (1.0g per 1,000kcal), viscous fibers (~10g per 1,000kcal) from oats (4.24g), barley (1.36g), and psyllium (4.15g), soy protein (21.4g per 1,000kcal) and 14g whole almonds per 1,000kcal. Okra and eggplant were also included as vegetable sources of viscous fibers (0.39 and 0.24g) with 100 and 200g of these vegetables to be eaten on alternate days. Psyllium contributed 40% of the total viscous fiber. Soy protein was given as soy milk and soy meat analogues, including soy burgers, soy dogs and soy deli slices. 
• Skim milk, fat-free cheese, yogurt, egg substitute, and liquid egg white were used in the control diet to achieve low intakes of saturated fat. A high-fiber intake was provided via whole-wheat breakfast cereals (2.0g total dietary fiber per 1,000kcal), bread (2.5g total dietary fiber per 1,000kcal) and wheat bran that was added to muffins containing a high amount of dairy protein (7.25g total dietary fiber per 1,000kcal). Sunflower oil (9g per 1,000 kcal) and safflower oil (5g per 1,000kcal) high in monounsaturated fatty acids were also incorporated into the control diet to balance fatty acid profile of the portfolio diet. 
• Self-taring electronic scales were provided to all subjects. The subjects were asked to weigh all food items consumed in the week before and during the study period. During the study, all foods to be eaten by the participants were provided initially by courier and then at weekly clinic visits. The exceptions were fruit and low-calorie non-starch-containing vegetables, which the participants were instructed to obtain from their local stores and were reimbursed. The subjects were provided with a seven-day rotating menu plan on which they checked off each item as eaten and confirmed the weight of the foods. The same menu plan was used for all participants, but the menu could be modified to suit individual preferences provided that the goals were met. Non-caloric beverages were not restricted. Commercial dishes were provided ready for microwave or oven cooking and packs of instant soups were provided to be reconstituted with boiling water. Compliance was assessed from the completed weekly checklists and from the return of uneaten food items. 
• 20mg lovastatin tables were crushed and delivered in Vegicap capsules. Identical placebo capsules containing lactose and blue food coloring were also prepared. Subjects were asked to take one capsule (20mg lovastatin or placebo) daily in the evening for the 28 days of the study and to return the containers for capsule count at the end of the month. 

 

Control Variables

 

 

Initial N

55 (not further described)

Attrition (final N)

34 (20 males, 14 post-menopausal women) completed all three phases. 46 completed the first phase and 43 the second phase 

Age

58.4±8.6 years (range 36-71)

Ethnicity

European (16 males, 13 female), Indian sub-continent (two males), Chinese (one male), African-American (one female) and Hispanic (one male)

Other relevant demographics

Anthropometrics

(e.g., were groups same or different on important measures)

There was no significant difference at baseline for blood pressure or lipids. The body mass index was 27.3±3.3 (range 20.5-35.5)

Location

Toronto, Canada

 

Variables	Treatment Group Measures and Confidence Intervals	Control Group + Statin Measures and Confidence Intervals	Control Group Measures and Confidence Intervals	Statistical Significance of Group Number Differance
Body weight (kg)	76.2	76.4	75.9	P=0.702
Total Cholesterol* (mmol/L)	5.5b	4.97b	6.23a	P=0.001
LDL	3.17b	2.91c	4.13a	P=0.001
HDL*	1.15	1.17	1.11	P=0.221
Triacylglycerols (mmol/L)	2.04	1.96	2.18	P=0.007
Apo A-I	1.46	1.47	1.45	P=0.883
Apo B*	1.09b	1.02c	1.34a	P=0.001
Total: HDL*	4.74b	4.41c	5.76a	P=0.001
LDL: HDL*	2.85b	2.39c	3.80a	P=0.001
Apo B: Apo A-I*	0.76b	0.70c	0.74a	P=0.001
Systolic blood pressure (mm Hg)	116	117	116	P=0.741
Diastolic	72	73	73	P=0.053
10-year CHD risk (percentage)**	8.4b	7.7b	10.7a	P=0.001

Number significance of the time-by-treatment interaction in the general linear model

* the main effect of diet was significant (P<0.05)

** According to the Framingham study cardiovascular disease risk equation

^a,b,c Values are significantly different, P<0.05

Other Findings

Compliance was good: 93% ate all of the calories as provided and 98% of the capsules were taken. All of the participants believed that they were eating as much food as they were capable of without experiencing discomfort. Fecal frequency was greater with the portfolio diet (P<0.001) than with the other treatments although the actual increase was < one bowel movement in two days. 

A diet that combines a number of cholesterol-lowering foods may provide an option for reducing mild-to-moderate elevations in serum LDL cholesterol in persons without pre-existing cardiovascular disease. This option is relevant for those who are prepared to make significant dietary and lifestyle changes. 

Attrition rate was 38% and intent-to-treat statistics were not used.