Original Article
The Efficacy of Intensive Dietary Therapy Alone or Combined with Lovastatin in Outpatients with Hypercholesterolemia
N Engl J Med 1993; 328:1213-1219April 29, 1993
- Abstract
Background
A diet low in saturated fat and cholesterol is the standard initial treatment for hypercholesterolemia. However, little quantitative information is available about the efficacy of dietary therapy in clinical practice or about the combined effects of diet and drug therapy.
Methods
One hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once daily), both alone and together. A diet high in fat and cholesterol and a placebo identical in appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period.
Results
The level of low-density lipoprotein (LDL) cholesterol was a mean of 5 percent (95 percent confidence interval, 3 to 7 percent) lower during the low-fat diet than during the high-fat diet (P<0.001). With lovastatin therapy as compared with placebo, the reduction was 27 percent. Together, the low-fat diet and lovastatin led to a mean reduction of 32 percent in the level of LDL cholesterol. The level of high-density lipoprotein (HDL) cholesterol fell by 6 percent (95 percent confidence interval, 4 to 8 percent) during the low-fat diet (P<0.001) and rose by 4 percent during treatment with lovastatin (P<0.001). The ratio of LDL to HDL cholesterol and the level of total triglycerides were reduced by lovastatin (P<0.001), but not by the low-fat diet.
Conclusions
The effects of the low-fat-low-cholesterol diet and lovastatin on lipoprotein levels were independent and additive. However, the reduction in LDL cholesterol produced by the diet was small, and its benefit was possibly offset by the accompanying reduction in the level of HDL cholesterol.
Media in This Article
Table 1
Characteristics of the Study Participants, According to Type of Analysis.Table 2
Dietary Composition and Body Weight, According to Intention-to-Treat Analysis.Article Activity
- Article
In 1987, the Expert Panel of the National Cholesterol Education Program (NCEP) issued guidelines for the treatment of adults with hypercholesterolemia1. The first step in the treatment of patients with sustained elevation of levels of low-density lipoprotein (LDL) cholesterol is a diet low in saturated fat and cholesterol. The efficacy of such therapy, however, has not been clearly defined, because there have been few randomized, controlled trials of intensive dietary therapy in outpatients with hypercholesterolemia. Most previous studies1 of lipid-lowering diets have been conducted in institutional settings or under metabolic-ward conditions, in which adherence to a diet can be ensured. In this study, we have attempted to evaluate the efficacy of dietary therapy under the conditions of clinical practice. In addition, we have investigated the nature of the interaction between dietary and drug therapy.
We studied a free-living population of patients with moderate hypercholesterolemia who chose their own food. We attempted to maximize the effectiveness of the diet by means of extensive dietary advice, reinforcement, and monitoring. We chose the NCEP Step 2 diet1 because of its very low level of saturated fat (<7 percent) and cholesterol (<200 mg per day). Lovastatin (20 mg once daily) was an appropriate choice for the lipid-lowering drug since this agent has been extensively studied2-5 and is widely prescribed in the United States, accounting for 49 percent of the prescriptions for hypolipidemic drugs in 1991; two thirds of these prescriptions specified a dose of 20 mg of lovastatin per day6.
Methods
Patients
Of 186 patients screened for at least their lipid profile, 111 took part in this study. Each gave written informed consent, and the consent forms and study protocol were approved by each of the institutional review boards of the five participating lipid clinics. Forty-four patients were referred or were already known to the staff of the clinics, 22 were friends or relatives of clinic patients, and 39 joined the study because of media announcements or advertisements; information about the reason for participating was missing for 6 patients. The principal criterion for entry was an LDL cholesterol level between 160 and 200 mg per deciliter (4.14 and 5.17 mmol per liter) while the patient was following his or her current diet. Because the study design required following a high-fat, high-cholesterol diet without drug therapy for nine weeks, patients with clinically apparent atherosclerotic disease were excluded. Other major criteria for exclusion were active liver disease; a body weight 30 percent above ideal; poorly controlled hypertension (blood pressure above 160/95 mm Hg); in men, smoking more than 10 cigarettes a day; in premenopausal women, the ability to conceive, unless conception was unlikely, and treatment with oral contraceptives; and plasma triglyceride levels above 300 mg per deciliter (3.39 mmol per liter).
Study Design
The two treatments were the NCEP Step 2 low-fat, low-cholesterol diet and lovastatin (20 mg once daily) with the evening meal. The control interventions were a high-fat, high-cholesterol diet intended to resemble the average U.S. diet7 and a placebo identical in appearance to lovastatin. The study was double-blinded with respect to the administration of lovastatin and placebo. The dietary and drug treatments were given both alone and together, in four combinations: the high-fat diet with placebo, the low-fat diet with placebo, the high-fat diet with lovastatin, and the low-fat diet with lovastatin. Each patient received all four combinations in 1 of 12 sequences, with each combination being administered for nine weeks without intervening washout periods. The randomization schedule was balanced for both period and carryover effects. To familiarize the patients with the procedures for dietary records, a four-week run-in period during which the patients followed their usual prestudy diets preceded the four consecutive test periods. Thus, for each patient the total duration of the study was 40 weeks. The patients visited the clinic at weeks -4, -2, and 0 (run-in period) and weeks 3, 6, and 9 of each test period. The use of any lipid-lowering drugs was stopped six weeks before the start of the study.
Dietary Therapy and Monitoring
The high-fat control diet was designed to provide approximately 40 percent of calories as fat, with 15 percent saturated, 14 percent monounsaturated, and 8 percent polyunsaturated fatty acids, and a cholesterol intake of 350 to 400 mg per day. The diets were individually prescribed on an isocaloric basis. For the control diet, patients were encouraged to consume whole-fat dairy products, eggs, red meats, bacon, organ meats, chicken with skin, cold cuts, mayonnaise, rich desserts, sauces, and high-fat snack foods. For the NCEP Step 2 diet, the consumption of these foods was limited and low-fat substitutes were recommended in accordance with the guidelines of the NCEP Expert Panel1. In this diet, less than 30 percent of the calories are derived from fat, with less than 7 percent saturated, 10 to 15 percent monounsaturated, and less than 10 percent polyunsaturated fatty acids, and the cholesterol intake is less than 200 mg per day1.
Dietary advice was provided by a coordinated group of registered dietitians certified by the University of Minnesota Nutrition Coordinating Center (Minneapolis). Extensive dietary counseling was given at the beginning of each period to encourage adherence to the newly assigned experimental diet, and was repeated at each subsequent visit. The patients were given dietetic scales and measuring cups and spoons and trained in estimating portion sizes with the use of uniform food models. At each visit except that at week -4, four-day diet diaries were completed by all patients and reviewed by the dietitians, who all used the same checklist and measuring aids. These diaries were first analyzed (usually within one week) by Professional Nutrition Systems (Kansas City, Kans.) to produce a composite diet score, the ratio of ingested saturated fat and cholesterol to calories (the RISCC rating)8. The RISCC rating is the cholesterol-saturated fat index of Connor et al.,9 adjusted for energy intake according to the following equation:
((1.01 × saturated fat [in grams]) + (0.05 × cholesterol [in milligrams])) / (kcal/1000)
This dietary analysis was returned to the dietitians before the patient's next visit and used only to help monitor adherence and to assist in counseling. Subsequently, the diet diaries for weeks 6 and 9 were encoded and analyzed by the Nutrition Coordinating Center; the values were averaged to determine for each period the nutrient composition and RISCC scores that were to be used in the statistical analysis of the study.
For the low-fat diet, the target RISCC score was 12 and the highest acceptable score was 15. For the high-fat diet, the target score was 26 and the lowest acceptable score was 22. The study protocol specified that any period lacking an acceptable RISCC score (average of scores for weeks 6 and 9, as analyzed by the Nutrition Coordinating Center) would be excluded from the analysis.
Measurement of Lipids, Lipoproteins, and Apolipoproteins
At each visit a sample of venous blood was drawn after an overnight fast of 12 to 14 hours and collected in EDTA (1 mg per milliliter); it was centrifuged within 4 hours, the plasma was separated, and the plasma sample was shipped at 4 °C to the central laboratory (Medical Research Laboratories, Cincinnati). Cholesterol and triglycerides were assayed enzymatically with a Hitachi 705 automated analyzer10. The laboratory followed the Standardization Program (Part III) of the Centers for Disease Control and Prevention (CDC) and the National Heart, Lung, and Blood Institute11. High-density lipoprotein (HDL) cholesterol was isolated with the modified procedure for precipitation with heparin and 2 mol of manganese chloride per liter12. The level of LDL cholesterol was calculated with the Friedewald equation13 for use during screening and for comparing values for week 6 with those for week 9 of each period.
At week 9 of each period, ultracentrifugation14,15 was carried out to isolate lipoproteins with densities of 1.006 and 1.125 kg per liter -- i.e., the combined fractions LDL plus HDL (density, >1.006) and the HDL3 subfraction, respectively. Calculation of differences then yielded the levels of very-low-density lipoprotein (VLDL) cholesterol, LDL cholesterol, and the HDL2 subfraction.
Also at week 9 of each period, competitive enzyme-linked immunosorbent assays16-19 were used to measure the apolipoproteins A-I, A-II, B, and E and lipoprotein(a). Internal quality control was evaluated throughout the study with the use of frozen pools at a minimum of two levels of each apolipoprotein. External quality control was assessed with the use of standardized assays for apolipoproteins A-I and B and lipoprotein(a) proposed by the CDC and the International Union of Immunological Societies20,21.
Apolipoprotein E isoforms were characterized (at any point) in the isolates produced by ultracentrifugation yielding lipids with a density below 1.006 kg per liter, by means of one-dimensional isoelectric focusing22. When interpretation was complicated by the presence of sialate isoforms, two-dimensional isoelectric focusing was performed23. If the amount of apolipoprotein E was insufficient for isoelectric focusing, Western blotting was used24.
Monitoring for Adverse Events
At each visit, the pulse rate, sitting blood pressure, and body weight were recorded, and the patients were questioned about adverse events, which were categorized as definitely, probably, possibly, probably not, or definitely not drug-related. Events in the first three categories were termed “drug-attributable.” Routine biochemical and hematologic analyses were performed by the central laboratory at the end of each period.
Statistical Analysis
The primary analysis was performed according to the intention-to-treat principle and included data for all periods for which end-of-period (week 9) data were available. In addition, a per-protocol analysis of changes in lipoprotein levels included only data on patients who completed all four test periods, and excluded data on study periods during which dietary goals were not achieved (see Dietary Therapy and Monitoring, above), as specified by the study protocol. For analyses of lipids, lipoproteins, and body weight, the values for week 9 were used to compare the treatments. Comparisons of nutrient intake were performed as described above.
A general linear-models approach was used25,26. An analysis-of-variance model included the investigator, treatment sequence, patient, and treatment as model variables, and the interaction between period and treatment to test for the goodness of fit. To assess the effect of diet and drug, the treatment effect was partitioned into the effects of the diet, drug, and diet-drug interaction. Additivity was tested by examining the diet-drug interaction.
In a post hoc analysis of the per-protocol data base, which had less statistical power than the primary analysis, some factors potentially affecting the responsiveness to diet were entered into the model individually; the homogeneity of the responsiveness to each factor was tested by examining the interaction between the factor and treatment. The factors assessed were sex, obesity (indicated by a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 27), previous treatment (i.e., whether the patient had previously received professionally prescribed dietary therapy for hypercholesterolemia), and apolipoprotein E phenotype (patients with the E4/E4 and E4/E3 phenotypes were pooled, and those with the rare E2/E2 phenotype were omitted).
Because of the multiple lipoprotein variables and interactions analyzed, the alpha value for interaction was set at 0.01. The relation between treatment and adverse events was determined with the standard chi-square statistic27. All P values are two-tailed.
Results
Of the 111 patients who entered the study, 97 completed all four test periods. Fourteen patients failed to complete the study; five patients did not complete it for personal reasons, three were lost to follow-up, two left the area, two had problems with following the diets, one had an adverse event, and one had an LDL cholesterol level above 200 mg per deciliter. The data on 6 of these 14 patients were not analyzable (i.e., there were no end-of-period data); data for a total of 17 periods were available for the other 8 patients. For the intention-to-treat analysis, the 6 patients with no analyzable data were excluded (leaving 105 patients). For the per-protocol analysis, only the 97 patients completing the study were included. Of these, 39 patients did not comply with the diets during 1 or more periods; thus, 53 of the 388 periods (97 × 4) were excluded from analysis, as specified in advance (see the Methods section). Tablet counts indicated that compliance with taking lovastatin and placebo was 97 to 99 percent during all four interventions. The base-line characteristics of the patients are shown in Table 1Table 1
Characteristics of the Study Participants, According to Type of Analysis..The average estimated nutrient composition of the diets consumed during the four interventions and the body weight at the end of each period are shown in Table 2Table 2
Dietary Composition and Body Weight, According to Intention-to-Treat Analysis.. There was no significant difference in dietary composition either between the two high-fat interventions or between the two low-fat interventions. However, there were differences (P<0.001) between the two diets not only in the levels of cholesterol and fat, as planned, but also in the total energy intake. The patients weighed an average of 1.4 kg less after the low-fat diet (whether with placebo or lovastatin) than after the high-fat diet (P<0.001 with and without lovastatin). In the 16 patients whose base-line body-mass index exceeded 30, this difference was 1.8 kg.Lovastatin exerts its full effect in less than nine weeks3,4. To determine whether this was true of the study diet, we compared the mean values for total, LDL, and HDL cholesterol at week 9 with those at week 6 during both the high-fat diet-placebo and low-fat diet-placebo treatments, using the per-protocol data. In all six comparisons, the difference was less than 2 percent, the week 6 values being lower in each case. Therefore, the nine-week periods in this study appear to have been long enough to achieve stable lipoprotein levels.
Effects on Lipoproteins
The mean lipid, lipoprotein, and apolipoprotein measurements obtained at the end of the four interventions in the intention-to-treat analysis are shown in Table 3Table 3
Lipoprotein Levels at the End of Each Intervention., as well as the mean values for the more important variables in the per-protocol analysis. The two methods of analysis produced similar results.As shown by the pairwise comparisons in Table 4Table 4
Percent Change in Lipid Levels between Interventions, According to Intention-to-Treat Analysis., the effects of both dietary and drug therapy were similar regardless of the presence or absence of the other treatment. There was no significant interaction between diet and drug in relation to any variable. Thus, the effects of the two treatments were additive.Both lovastatin and the NCEP Step 2 diet significantly reduced the levels of total and LDL cholesterol. The mean levels of HDL cholesterol and the HDL2 and HDL3 subfractions were higher during therapy with lovastatin and lower during dietary therapy. The diet did not affect the ratio of LDL to HDL cholesterol or the levels of VLDL cholesterol or triglycerides, all of which were significantly reduced by lovastatin. The diet slightly reduced the levels of apolipoproteins A-I and A-II; both diet and lovastatin reduced apolipoprotein B levels. There were no significant effects on lipoprotein(a) levels.
Because they had no significant interaction with dietary treatment, sex, obesity, previous treatment, and apolipoprotein E phenotype had no detectable effect on the response of any of the variables to diet.
Adverse Events
One patient was withdrawn from the study because of a rash during the low-fat diet-lovastatin period. Twenty-five of the 111 patients reported 83 minor drug-attributable adverse events (as defined in the Methods section) that occurred outside the run-in period, which are summarized in Table 5Table 5
Drug-Attributable Adverse Events, According to Body System.. There were no significant differences between the interventions in the incidence of adverse events.Discussion
Effect of Dietary Therapy
According to analysis of standardized, quantitative dietary records, the diets actually consumed by the patients during each study period were close to those specified in the study protocol, with substantial differences between the high-fat and low-fat diets. Nevertheless, the 5 percent average reduction in the mean levels of total and LDL cholesterol produced by the low-fat diet in the presence or absence of lovastatin was much less than the reduction anticipated by the NCEP Expert Panel1. On the basis of metabolic-ward studies, the Expert Panel predicted an average reduction of about 50 mg per deciliter (1.29 mmol per liter) in the level of total cholesterol during the NCEP Step 2 diet; we observed a mean reduction in the total cholesterol level of only 15 mg per deciliter (0.39 mmol per liter). Our results, however, are consistent with those of many previous controlled studies in outpatients with hypercholesterolemia who received less intensive dietary treatment; most of these studies have shown marginal effects on plasma cholesterol levels28. The effectiveness of the NCEP Step 2 diet has not been previously determined in a controlled study of free-living U.S. outpatients with hypercholesterolemia who chose their meals. More pronounced effects of diets low in saturated fat and cholesterol have been reported in several studies of subjects in institutions or metabolic wards,28-31 presumably because dietary intake can be more readily controlled under those conditions.
The results of nutrient analysis suggested good dietary adherence; they were obtained by standard methods and were consistent. However, inaccuracies in dietary data may be due to the tendency of patients to report what the dietitian will want to hear, and patients may adhere to their diet better during the days they are completing the diary than at other times. For example, patients completing diet diaries often underestimate their true caloric intake32,33. These problems are inherent in any study in free-living subjects choosing their food. It is possible, therefore, that the differences between the compositions of the two diets were overestimated. The diets used in this study were intended to be isocaloric, but patients often spontaneously consume fewer calories and lose weight when placed on a low-fat diet34,35. Although there was a significant mean difference in weight of 1.4 kg, the estimated difference in energy of approximately 43,000 kcal (180 MJ) between the diets over the nine-week study period should have led to a weight difference of about 5 kg36 if no adaptation such as a change in basal metabolic rate or body water occurred.
Our study devoted considerable effort to encouraging dietary compliance: the diets were administered and monitored by a coordinated group of expert dietitians, certified by the University of Minnesota Nutrition Coordinating Center, who had access to a central dietary-monitoring program; the patients were selected because they were expected to comply, and were given dietary measuring equipment and trained in estimating portion sizes from uniform food models. Therefore, if the patients in this study were unable to comply adequately with the diets, the typical patients treated by most practitioners will probably have even more difficulty with compliance. Consequently, the results obtained in this study may overestimate the average effect of prescribing a highly restrictive lipid-lowering diet in routine clinical practice. Nevertheless, individual patients who are highly motivated may achieve results that are much better than average. In a recent study (the St. Thomas' Atherosclerosis Regression Study),37 a small group of patients with coronary disease who were selected on the basis of their responsiveness to cholestyramine had both a mean reduction of 16 percent in the LDL cholesterol level and improvement in the condition of their coronary lesions after they followed a diet similar to the NCEP Step 2 diet for three years.
The reduction in the level of LDL cholesterol produced by the NCEP Step 2 diet was matched by a similar percentage decrease in the level of HDL cholesterol, so that the ratio of LDL to HDL cholesterol did not change significantly. Weight loss temporarily reduces the level of HDL cholesterol, but the estimated mean decrease with a loss of 1.4 kg is only 0.4 mg per deciliter (0.01 mmol per liter)38. A reduction in the level of HDL cholesterol has been noted in some7,29,31,39,40 but not all37 previous studies of diets low in saturated fat and cholesterol. This reduction can probably be attenuated or reversed by exercise41 and, in obese subjects, by sustained weight loss38. Because many studies in defined population groups have shown that the level of HDL cholesterol is correlated inversely with the incidence of coronary disease,42 the net effect of dietary reduction of both LDL and HDL cholesterol levels on the risk of cardiovascular disease is unclear43. Metabolic-ward studies7,30,40 suggest that replacing saturated fat with monounsaturated fat, instead of replacing it with carbohydrates, lowers LDL cholesterol levels effectively while producing little change in HDL cholesterol levels. A diet of this type is palatable and traditional in Mediterranean countries, where coronary disease is relatively infrequent44. Further work is needed to improve the understanding of effects of diet on HDL cholesterol, to determine how best to maintain HDL cholesterol levels on an outpatient basis, and to optimize dietary therapy by measuring changes in coronary lesions37.
The Combined Effects of Diet and Drug Therapy
Our results show clearly that the effects of diet and lovastatin are independent of each other and additive. Cobb et al. reached a similar conclusion in their study of subjects given lovastatin under metabolic-ward conditions,31 but Clifton et al. have recently reported in a small study that dietary therapy was less effective in outpatients when the closely related drug simvastatin was administered39. The additional reduction in LDL cholesterol levels produced by a strict diet and lovastatin in a dose of 20 mg once a day appears equivalent to the reduction produced by doubling this dose2. On the other hand, the diet undercuts the small drug-induced increase in HDL cholesterol levels.
We conclude that the effects of a strict diet and lovastatin were independent and additive. However, the reduction in LDL cholesterol levels produced by diet was small, and its benefit was possibly offset by the accompanying reduction in HDL cholesterol levels.
Supported by a grant from Merck Research Laboratories.
We are indebted to the patients who participated in this study for their dedication to the demands of the protocol, and to Dr. M. Buzzard, J.R. Nelson, and M. Stevens (Nutrition Coordinating Center, Minneapolis) and L. Votaw and G. Peterson (Professional Nutrition Systems, Kansas City, Kans.) for their analysis of the dietary records.
Source Information
From the Heart Disease Prevention Clinic, Minneapolis (D.B.H., E.Q.); the Christ Hospital Cardiovascular Research Center, Cincinnati (E.A.S., S.H.); the University of Kansas Medical Center, Kansas City (C.A.D., W.S.H.); the Medical College of Georgia, Augusta (E.B.F., S.B.L.); George Washington University, Washington, D.β(V.T.M., B.K.B.); Merck Research Laboratories, Rahway, N.J. (J.A.T., A.M.T.); Medical Research Laboratories, Cincinnati (P.M.L.); and Professional Nutrition Systems, Kansas City, Kans. (J.H.). The following persons also participated in the study: Heart Disease Prevention Clinic, Minneapolis -- J. Peters and K. Gardner; Christ Hospital Cardiovascular Research Center, Cincinnati -- D.M. Black, G.E. Lamkin, and S. Ames; University of Kansas Medical Center, Kansas City -- P. Krehbiel and S. Horniman; Medical College of Georgia, Augusta -- T.T. Kuske and J.M. Greene; George Washington University, Washington, D.β -- D.B. Stoy and G. Gasparis; and Medical Research Laboratories, Cincinnati -- P.M. Steiner.
Address reprint requests to Dr. Hunninghake at the Heart Disease Prevention Clinic, 151 Variety Club Heart & Research Center, 401 E. River Rd., Minneapolis, MN 55455.
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Citing Articles
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Jeffrey G. Shanes. (2011) A Review of the Rationale for Additional Therapeutic Interventions to Attain Lower LDL-C When Statin Therapy Is Not Enough. Current Atherosclerosis Reports
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Jingbo Huang, Jiri Frohlich, Andrew P. Ignaszewski. (2011) The Impact of Dietary Changes and Dietary Supplements on Lipid Profile. Canadian Journal of Cardiology 27:4, 488-505
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James M. Shikany, Laura K. Vaughan, Monica L. Baskin, Mark B. Cope, James O. Hill, David B. Allison. (2010) Is Dietary Fat “Fattening”? A Comprehensive Research Synthesis. Critical Reviews in Food Science and Nutrition 50:8, 699-715
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Nusrat Shafiq, Meenu Singh, Sharonjeet Kaur, Pratibha Khosla, Samir Malhotra, Nusrat Shafiq. 2010. Dietary treatment for familial hypercholesterolaemia. .
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Dean Ornish. (2009) Mostly Plants. The American Journal of Cardiology 104:7, 957-958
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Neal D Barnard, Heather I Katcher, David JA Jenkins, Joshua Cohen, Gabrielle Turner-McGrievy. (2009) Vegetarian and vegan diets in type 2 diabetes management. Nutrition Reviews 67:5, 255-263
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Jeannette M. Schenk, Marian L. Neuhouser, Daniel W. Lin, Alan R. Kristal. (2009) A Dietary Intervention to Elicit Rapid and Complex Dietary Changes for Studies Investigating the Effects of Diet on Tissues Collected during Invasive Surgical Procedures. Journal of the American Dietetic Association 109:3, 459-463
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Catherine Buettner, Stewart H Lecker. (2008) Molecular basis for statin-induced muscle toxicity: implications and possibilities. Pharmacogenomics 9:8, 1133-1142
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Catherine Buettner, Roger B. Davis, Suzanne G. Leveille, Murray A. Mittleman, Kenneth J. Mukamal. (2008) Prevalence of Musculoskeletal Pain and Statin Use. Journal of General Internal Medicine 23:8, 1182-1186
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Ju Young Shin, Jerry Suls, René Martin. (2008) Are Cholesterol and Depression Inversely Related? A Meta-analysis of the Association Between Two Cardiac Risk Factors. Annals of Behavioral Medicine 36:1, 33-43
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Peter F. Wilson. 2008. Statins. .
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Stephanie M. Winters, Hannah Visser, Anke H.M. Steerneman, Gregory Thomas, Michiel L. Bots, Geert J. van der Heijden. (2008) Is there a need for dietary measures to further reduce LDL cholesterol in patients with type II diabetes mellitus on statin therapy?. Primary Care Diabetes 2:1, 51-54
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Robert H. Knopp, Barbara Retzlaff, Carolyn Walden, Brian Fish, Brenda Buck, Barbara McCann. (2008) One-Year Effects of Increasingly Fat-Restricted, Carbohydrate-Enriched Diets on Lipoprotein Levels in Free-Living Subjects. Proceedings of the Society for Experimental Biology and Medicine 225:3, 191
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Martin B. Madsen, Anne-Mette Jensen, Erik B. Schmidt. (2007) The effect of a combination of plant sterol-enriched foods in mildly hypercholesterolemic subjects. Clinical Nutrition 26:6, 792-798
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Eric Brunner, Karen Rees, Kirsten Ward, Margaret Burke, Margaret Thorogood, Eric Brunner. 2007. Dietary advice for reducing cardiovascular risk. .
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2006. Dairy Foods and Cardiovascular Health. , 55-98.
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EJ Brunner, M Thorogood, K Rees, G Hewitt, Eric Brunner. 2005. Dietary advice for reducing cardiovascular risk. .
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Carolyn Berdanier. 2005. Drugs, Nutrients, and Hormones in Mitochondrial Function. , 455-506.
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Y Wady Aude, Pedro Mego, Jawahar L Mehta. (2004) Metabolic syndrome: dietary interventions. Current Opinion in Cardiology 19:5, 473-479
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Dean Ornish. (2004) Was Dr Atkins right?. Journal of the American Dietetic Association 104:4, 537-542
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Steven G. Aldana, Roger Greenlaw, Dean Thomas, Audrey Salberg, Tawnya DeMordaunt, Gill W. Fellingham, Andrew L. Avins. (2004) The Influence of an Intense Cardiovascular Disease Risk Factor Modification Program. Preventive Cardiology 7:1, 19-25
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Gregg C. Fonarow. (2003) In-hospital initiation of statin therapy in patients with acute coronary events. Current Atherosclerosis Reports 5:5, 394-402
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Rachel L Thompson, Carolyn D Summerbell, Lee Hooper, Julian PT Higgins, Paul Little, Diane Talbot, Shah Ebrahim, Rachel L Thompson. 2003. Dietary advice given by a dietitian versus other health professional or self-help resources to reduce blood cholesterol. .
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Serena Tonstad, Ingvar Hjermann. (2003) Journal of Cardiovascular Risk 10:2, 129-135
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Lyne Lalonde, Katherine Gray-Donald, Ilka Lowensteyn, Sylvie Marchand, Marc Dorais, George Michaels, Hilary A. Llewellyn-Thomas, Annette O'Connor, Steven A. Grover. (2002) Comparing the Benefits of Diet and Exercise in the Treatment of Dyslipidemia. Preventive Medicine 35:1, 16-24
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Richard M. Fleming. (2002) The Effect of High-, Moderate-, and Low-Fat Diets on Weight Loss and Cardiovascular Disease Risk Factors. Preventive Cardiology 5:3, 110-203
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Kathleen L. Keller, Angelo Pietrobelli, Shoshanna Must, Myles S. Faith. (2002) Genetics of eating and its relation to obesity. Current Atherosclerosis Reports 4:3, 176-182
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W. C. Willett. (2002) Dietary fat plays a major role in obesity: no. Obesity Reviews 3:2, 59-68
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Gregg C. Fonarow. (2002) Statin therapy after acute myocardial infarction: Are we adequately treating high-risk patients?. Current Atherosclerosis Reports 4:2, 99-106
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Roberto Aquilani, Stefano Boni, Sandro Verdirosi, Ornella Pastoris, Jole Assandri, Angelo Rossi, Vincenzo Paganini, Roberto Riccardi, Alberto Cajelli, Marcello Pernice, Manuela Verri, Maurizia Dossena, Franco Cobelli. (2002) An Organizational Model to Translate Nutritional Recommendations into Routine Clinical Practice in Secondary Prevention of Coronary Artery Disease. Preventive Medicine 34:2, 138-143
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Jill Rubin, Lars Berglund. (2002) Apolipoprotein E and diets: a case of gene-nutrient interaction?. Current Opinion in Lipidology 13:1, 25-32
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Kirsten F. Clemmer, Amy E. Binkoski, Stacie M. Coval, Guixiang Zhao, Penny M. Kris-Etherton. (2001) Diet and drug therapy: A dynamic duo for reducing coronary heart disease risk. Current Atherosclerosis Reports 3:6, 507-513
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Elaine Feldman. 2001. Cardiovascular Disease Risk - Prevention by Diet. .
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Manjiang Yao, Susan B. Roberts. (2001) Dietary Energy Density and Weight Regulation. Nutrition Reviews 59:8, 247-258
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Vanessa J Poustie, Patricia Rutherford, Vanessa J Poustie. 2001. Dietary treatment for familial hypercholesterolaemia. .
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Rianne M Weggemans, Peter L Zock, Jose M Ordovas, Juan Pedro-Botet, Martijn B Katan. (2001) Apoprotein E genotype and the response of serum cholesterol to dietary fat, cholesterol and cafestol. Atherosclerosis 154:3, 547-555
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Robert H. Knopp, Barbara Retzlaff, Carolyn Walden, Brian Fish, Brenda Buck, Barbara McCann. (2000) One-Year Effects of Increasingly Fat-Restricted, Carbohydrate-Enriched Diets on Lipoprotein Levels in Free-Living Subjects. Proceedings of the Society for Experimental Biology and Medicine 225:3, 191-199
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Patrick H. Bowen, John R. Guyton. (2000) Nonpharmacologic and pharmacologic treatment of patients with low levels of high-density lipoprotein cholesterol. Current Atherosclerosis Reports 2:1, 58-63
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Akiko Takenaka, Yuko Matsumoto, Aika Nagaya, Kunio Watanabe, Shunji Goto, Bambang Suryobroto, Osamu Takenaka. (2000) Plasma cholesterol levels in free-ranging macaques compared with captive macaques and humans. Primates 41:3, 299-309
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Arne Astrup, Louise Ryan, Gary K. Grunwald, Mette Storgaard, Wim Saris, Ed Melanson, James O. Hill. (2000) The role of dietary fat in body fatness: evidence from a preliminary meta-analysis of ad libitum low-fat dietary intervention studies. British Journal of Nutrition 83:S1,
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Jose M. Ordovas, Ernst J. Schaefer. (2000) Genetic determinants of plasma lipid response to dietary intervention: the role of the APOA1/C3/A4 gene cluster and the APOE gene. British Journal of Nutrition 83:S1,
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Nilo B. Cater. (2000) Plant Stanol Ester: Review of Cholesterol-Lowering Efficacy and Implications for Coronary Heart Disease Risk Reduction. Preventive Cardiology 3:3, 121-130
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H.J.C. Swan. (2000) The framingham offspring study: A commentary. Journal of the American College of Cardiology 35:5, 13B-17B
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Lukas E. Spieker, Georg Noll, Manfred Hannak, Thomas F. Lüscher. (2000) Efficacy and Tolerability of Fluvastatin and Bezafibrate in Patients with Hyperlipidemia and Persistently High Triglyceride Levels. Journal of Cardiovascular Pharmacology 35:3, 361-365
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GEETA SIKAND, MOTI L KASHYAP, NATHAN D WONG, JEFFREY C HSU. (2000) Dietitian Intervention Improves Lipid Values and Saves Medication Costs in Men with Combined Hyperlipidemia and a History of Niacin Noncompliance. Journal of the American Dietetic Association 100:2, 218-224
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Neil J. Stone, Robert Kushner. (2000) EFFECTS OF DIETARY MODIFICATION AND TREATMENT OF OBESITY. Medical Clinics of North America 84:1, 95-122
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Sumit R. Majumdar, Jerry H. Gurwitz, Stephen B. Soumerai. (1999) Undertreatment of Hyperlipidemia in the Secondary Prevention of Coronary Artery Disease. Journal of General Internal Medicine 14:12, 711-717
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T T Nguyen, L C Dale, K von Bergmann, I T Croghan. (1999) Cholesterol-lowering effect of stanol ester in a US population of mildly hypercholesterolemic men and women: a randomized controlled trial.. Mayo Clinic Proceedings 74:12, 1198-1206
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1999. Dairy Foods and Cardiovascular Health. .
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Mary M. Flynn, Joseph M. Zmuda, Dragana Milosavljevic, Marjorie J. Caldwell, Peter N. Herbert. (1999) Lipoprotein response to a National Cholesterol Education Program step II diet with and without energy restriction. Metabolism 48:7, 822-826
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H.J.C Swan. (1999) The Framingham Offspring Study: a commentary. Journal of the American College of Cardiology 33:5, 1136-1140
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Daniel E. Hilleman, Jeffrey O. Phillips, Syed M. Mohiuddin, Kay L. Ryschon, Craig A. Pedersen. (1999) A population-based treat-to-target pharmacoeconomic analysis of HMG-CoA reductase inhibitors in hypercholesterolemia. Clinical Therapeutics 21:3, 536-562
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Jose M. Ordovas. (1999) The genetics of serum lipid responsiveness to dietary interventions. Proceedings of the Nutrition Society 58:01, 171-187
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S. Drummond, T. Kirk. (1998) The effect of different types of dietary advice on body composition in a group of Scottish men. Journal of Human Nutrition and Dietetics 11:6, 473-485
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Ernst J. Schaefer, Margaret E. Brousseau. (1998) DIET, LIPOPROTEINS, AND CORONARY HEART DISEASE. Endocrinology & Metabolism Clinics of North America 27:3, 711-732
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GEETA SIKAND, MOTI L KASHYAP, IVY YANG. (1998) Medical Nutrition Therapy Lowers Serum Cholesterol and Saves Medication Costs in Men with Hypercholesterolemia. Journal of the American Dietetic Association 98:8, 889-894
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Stefanick, Marcia L., Mackey, Sally, Sheehan, Mary, Ellsworth, NancyHaskell, William L., Wood, Peter D., . (1998) Effects of Diet and Exercise in Men and Postmenopausal Women with Low Levels of HDL Cholesterol and High Levels of LDL Cholesterol. New England Journal of Medicine 339:1, 12-20
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Susan B. Roberts, F. Xavier Pi-Sunyer, Mark Dreher, Robert Hahn, James O. Hill, Ronald E. Kleinman, John C. Peters, Eric Ravussin, Barbara J. Rolls, Elizabeth Yetley, Sarah L. Booth. (1998) Physiology of Fat Replacement and Fat Reduction: Effects of Dietary Fat and Fat Substitutes on Energy Regulation. Nutrition Reviews 56:5, 29-41
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ARNE ASTRUP, SøREN TOUBRO, ANNE RABEN, ANNEBETH R. SKOV. (1997) The Role of Low-Fat Diets and Fat Substitutes in Body Weight Management. Journal of the American Dietetic Association 97:7, S82-S87
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Ari Palomäki, Kimmo Malminiemi, Timo Metsä-Ketelä. (1997) Enhanced oxidizability of ubiquinol and α-tocopherol during lovastatin treatment. FEBS Letters 410:2-3, 254-258
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MIA CLARK, GHASSAN GHANDOUR, NANCY HOUSTON MILLER, C.BARR TAYLOR, ALBERT BANDURA, ROBERT F. DeBUSK. (1997) Development and Evaluation of a Computer-Based System for Dietary Management of Hyperlipidemia. Journal of the American Dietetic Association 97:2, 146-150
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KATHERINE S. RHODES, LISA C. BOOKSTEIN, LAUREN S. AARONSON, NELDA M. MERCER, CARL E. ORRINGER. (1996) Intensive Nutrition Counseling Enhances Outcomes of National Cholesterol Education Program Dietary Therapy. Journal of the American Dietetic Association 96:10, 1003-1010
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Alfredo Quiñones Galvan, Andrea Natali, Simona Baldi, Silvia Frascerra, Tiziana Sampietro, Fabio Galetta, Giuseppe Seghieri, Ele Ferrannini. (1996) Effect of a Reduced-Fat Diet With or Without Pravastatin on Glucose Tolerance and Insulin Sensitivity in Patients with Primary Hypercholesterolemia. Journal of Cardiovascular Pharmacology 28:4, 595-602
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T Brosche. (1996) Effective lovastatin therapy in elderly hypercholesterolemic patients — an antioxidative impact?. Archives of Gerontology and Geriatrics 22:3, 207-221
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Gordon Schectman, Nancy Wolff, James C. Byrd, Janet G. Hiatt, Arthur Hartz. (1996) Physician extenders for cost-effective management of hypercholesterolemia. Journal of General Internal Medicine 11:5, 277-286
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H.J.C Swan, Bernard J. Gersh, Thomas B. Graboys, Daniel J. Ullyot. (1996) Task force 7. Evaluation and management of risk factors for the individual patient (case management). Journal of the American College of Cardiology 27:5, 1030-1039
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T Dolecek. (1996) Maximizing recruitment efforts in a drug lipid-lowering trial with dietary intervention to lower LDL cholesterol. Controlled Clinical Trials 17:1, 33-45
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I. U. Haq, W. W. Yeo, P. R. Jackson, L. E. Ramsay. (1995) The effects of dietary change on serum cholesterol. Proceedings of the Nutrition Society 54:03, 601-616
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S. TONSTAD, L. OSE, C. GØRBITZ, O. DJØSELAND, J. M. BARD, J. C. FRUCHART. (1995) Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolemia among postmenopausal women. Journal of Internal Medicine 238:1, 39-47
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Clinton D. Brown, Neal Azrolan, Lorraine Thomas, Kathleen G. Roberts, Andrew Bostom, Zhong H. Zhao, E.A. Friedman. (1995) Reduction of lipoprotein(a) following treatment with lovastatin in patients with unremitting nephrotic syndrome. American Journal of Kidney Diseases 26:1, 170-177
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Stevhn Haffner, Trevor Orchard, Evan Stein, Donald Schmidt, Patrice Labelle. (1995) Effect of simvastatin on Lp(a) concentrations. Clinical Cardiology 18:5, 261-267
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J. I. S. Robertson. (1994) Guidelines for the treatment of hypertension: A critical review. Cardiovascular Drugs and Therapy 8:4, 665-672
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Jean Dallongeville, Nicole Leboeuf, Chantal Blais, Jacynthe Touchette, Nathalie Gervais, Jean Davignon. (1994) Short-term response to dietary counseling of hyperlipidemic outpatients of a lipid clinic. Journal of the American Dietetic Association 94:6, 616-621
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JoséM. Silva, PolibioS. Silva. (1994) Sexless HDL. The Lancet 343:8890, 129-130
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L. H. Opie. (1993) Cholesterol confusion in primary prevention of coronary artery disease. Cardiovascular Drugs and Therapy 7:5, 779-784
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(1993) Treatment of and Screening for Hyperlipidemia. New England Journal of Medicine 329:15, 1124-1128
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Ernst J. Schaefer. (1993) New Recommendations for the Diagnosis and Treatment of Plasma Lipid Abnormalities. Nutrition Reviews 51:8, 246-252
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Sox, Harold C. Jr., . (1993) Screening for Lipid Disorders under Health System Reform. New England Journal of Medicine 328:17, 1269-1271
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