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Dietary Treatment of Hypercholestrolemia: Can We Predict Long-Term Success?

Department of Cardiology, Soroka University Medical Center (Y.H.), Beer-Sheva, ISRAEL
S. Daniel Abraham International Center for Health and Nutrition, Epidemiology and Health Services Evaluation Department, Faculty of Health Sciences Ben-Gurion University of the Negev (I.S.), Beer-Sheva, ISRAEL

Address reprint requests to: Yaakov Henkin, MD, Department of Cardiology, PO Box 151. Soroka Medical Center, Beer-Sheva, ISRAEL. E-mail: yaakovh{at}bgumail.bgu.ac.il

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Objective: To look for associations between changes in LDL cholesterol and baseline characteristics of patients receiving dietary therapy for hypercholesterolemia.

Methods: Ninety-six hypercholesterolemic individuals aged 30–65 from three primary care clinics and a worksite clinic received counseling by a physician and/or a dietitian for lifestyle and dietary modifications. Baseline nutritional intake was evaluated using three-day food diaries. Lipoprotein levels were evaluated at six weeks and thereafter every three months for one year. Partial (adjusted) correlations (ß) were calculated between baseline parameters (demographic, anthropometric, nutritional and laboratory) and changes of LDL cholesterol for the short and long term (three and 12 months).

Results: The average LDL cholesterol level decreased by 6 ± 10% (p < 0.001) at the end of 12 months. This reduction was positively correlated with baseline LDL cholesterol level (ß = +0.4, p = 0.001), and negatively correlated with the baseline BMI (ß = -0.2, p < 0.05) and saturated fat intake (ß = -0.3, p < 0.05). The differences between low and high subgroups of baseline LDL cholesterol, BMI and saturated fat intake became apparent only after six to twelve months of therapy and probably result from varying levels of adherence to the dietary regimen. A significant correlation was found between the change in LDL cholesterol after six weeks and the change in LDL cholesterol after 12 months (ß = 0.4, p < 0.001).

Conclusions: The probability of successfully reducing LDL cholesterol with dietary therapy can be predicted by baseline LDL cholesterol level, BMI and saturated fat intake, as well as by the response to dietary changes within six weeks of therapy.

Key words: hypercholesterolemia, lipoproteins, BMI, diet, adherence, prediction

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Current treatment guidelines for hypercholestrolemia recommend a therapeutic trial of a low-fat, low-cholesterol diet and other non-pharmacological treatments for at least three to six months before considering the use of drugs, especially in a primary prevention setting [1,2]. The expected average reduction in the low-density lipoprotein cholesterol (LDL cholesterol) levels using the Step I Diet are 3% to 14% [3–10] and an additional average reduction of 3% to 7% can be achieved by progressing to a Step II Diet [5,11–15]. However, the response of blood lipids and lipoproteins to dietary modification is highly variable and depends on a number of parameters, including the baseline lipoprotein levels and dietary habits, genetic factors and the degree of adherence to a modified diet [16–18]. It would therefore seem desirable to be able to predict which patients have the potential to achieve their target goals with diet as their sole therapy and which patients should receive early supplemental drug treatment.

The aim of our study was to identify associations between dietary changes in LDL cholesterol and the baseline demographic, clinical and nutritional characteristics. In addition, we evaluated the relationship between the short-term (six weeks) and longer-term (nine to 12 months) changes in LDL cholesterol during dietary therapy.

	SUBJECTS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Subjects
The study methodology has been described previously [19]. The purpose of the previously reported trial was to evaluate the incremental value of detailed nutritional counseling by a dietitian when added to general nutritional advice provided by physicians. Individuals with blood cholesterol levels above 5.2 mmol/L, aged 30–65 years, were recruited from cholesterol screening programs in a large industrial complex and in primary care clinics. Two lipoprotein analyses were performed at baseline for each participant at an interval of one to three weeks and the average of these two values was used for further therapeutic decisions. A third lipoprotein analysis was performed in cases where the difference between LDL cholesterol levels in the first two analyses exceeded 5%; an average of the two closest values was used in these cases. Thyroid stimulating hormone (TSH) level and a chemistry profile were also evaluated to exclude secondary hypercholesterolemia. Inclusion criteria to the study included LDL cholesterol levels >4.1 mmol/L in individuals with less than two risk factors, LDL cholesterol levels >3.4 mmol/L for individuals with two or more risk factors, or LDL cholesterol levels >2.6 mmol/L for individuals with co-existing CHD or other atherosclerotic cardiovascular disease. Exclusion criteria were any previous counseling by a dietitian, any unstable cardiovascular condition within the previous three years, pregnancy within the previous 12 months, chronic renal and/or liver disease, untreated hypothyroidism, malignancies and treatment by lipid-lowering drugs, thiazides, estrogen or corticosteroids. Individuals with LDL cholesterol >5.2 mmol/L and/or triacylglycerol >4.5 mmol/L were also excluded. All participants signed an informed consent form. The study was approved by the local Institute Review Board.

Study Design
Subjects who conformed to the study inclusion criteria were referred by the study nurse for additional evaluation by a physician who had received specific training in providing dietary advice for cholesterol reduction. All participants were instructed to complete a three-day dietary diary, including two regular weekdays and one weekend day. Each counseling session was scheduled for 30 minutes, during which the physician re-evaluated the patient’s risk factors, performed a modified physical examination, and provided counseling relating to smoking cessation, physical activity, weight control and dietary modifications conforming to the Step I diet. Emphasis was given to selecting lean meats, poultry, fish and low-fat dairy products; limiting the consumption of eggs, glucose and margarine, and increasing the intake of fruits and vegetables. Educational literature, including general information on hypercholesterolemia, guidelines for healthy nutrition as well as some specific dietary recommendations (prepared by a local HMO) was provided to the participants. The three-day food diaries were available to the physician during this evaluation if specifically requested.

Within three weeks after meeting the physician, half the subjects (dietitian group) were randomly assigned to receive additional evaluation and counseling by one of the study’s dietitians. The other participants (physician group) continued their usual care by the physician only. Counseling by the dietitians provided a more detailed analysis of eating habits and nutrient intake (guided by the diaries), and more specific dietary recommendations. Guidance in understanding nutritional labeling and strategies for making food choices outside the home were also provided. Where necessary, progression to a more stringent (Step 2) diet was offered. Each participant received two to four individual counseling sessions within the initial three months by the study nurse, as dictated by his/her individual progress. A fasting lipoprotein profile (one blood sample at every visit) was measured at six weeks and three months, and every three months thereafter for one year. At each phase, the participants were informed of their results and received additional re-enforcement for dietary compliance by the study nurse. Participants who had initially received counseling by a physician only, and had not reached their LDL cholesterol target goal after three months, were referred to a dietitian for additional counseling. Overall, 102 patients had received counseling by a dietitian by the end of the follow-up period, while 34 patients, who had reached their LDL cholesterol target goal by month three, had continued follow-up by a physician and nurse only. The results of the initial study [19] revealed that, at three months, the average decrease in LDL cholesterol was 7 ± 11% in the physician group and 12 ± 10% in the dietitian group (p < 0.004). However, at 12 months, both diet groups lost about half of the original LDL cholesterol decrease, and the difference between the two groups became clinically and statistically insignificant.

In the current study, we compared the short-term (six weeks and three months) and longer-term changes in blood lipoproteins to the average of the baseline lipoprotein levels (calculated as described above). The average of the lipoprotein levels at nine and 12 months was calculated and considered to represent the "longer-term" changes. Since the differences in the LDL cholesterol changes between the two groups by the end of the study were not statistically significant, we combined the results of all patients for the present analysis with adjustments to this factor.

Laboratory and Dietary Analysis
Blood samples were taken following an overnight fast of at least 12 hours, separated by centrifuge in a central laboratory within two hours of collection and tested within 24 hours in duplicate runs. Plasma total cholesterol, triacylglycerol levels and high-density lipoprotein (HDL) cholesterol were measured by enzymatic colorimetric methods [20–22]. LDL cholesterol was calculated using the Friedwald equation [23].

Evaluation of the baseline dietary intake was performed using the average daily intake of individual nutrients from the three-day dietary recall diaries. Nutrient composition of daily intake was computed using an ACCESS-based computer program developed at The S. Daniel Abraham International Center for Health and Nutrition at Ben-Gurion University of the Negev [24]. This program uses the United States Department of Agriculture (USDA) and United Kingdom (UK) nutrient databases modified and extended to meet Israeli food composition for the analysis of nutrient content.

Statistical Methods
Paired t test analysis was used to compare the blood lipid and lipoprotein changes across periods of follow-up (one and one-half, three and 12 months). Partial correlation coefficient (ß) was performed by linear regression analysis for calculating the correlation of baseline predictors to LDL percent reduction, adjusted for the dietary-advisors’ groups. These groups were composed of either those who were advised only by physicians or those who were advised by dietitians at any stage of the study. Analysis of variance test (unianova) by the General Linear Model (GLM) procedure was used to compare the short- and longer-term LDL changes between groups, stratified at their median baseline characteristics point (BMI, LDL cholesterol, dietary intake) and adjusted for the dietary-advisors’ groups. Multiple linear regression was tested to assess predictors of LDL changes over a one year period. The model included the following factors: BMI, age, treatment group, baseline plasma lipids (HDL cholesterol, LDL cholesterol, total cholesterol, triglyceride) and baseline dietary intake (protein, carbohydrates, saturated fatty acids). Baseline energy intake was added to control for factors such as underreporting bias in the dietary recall diaries [25]. All the nutrient components were natural log transformed to improve distribution normality.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Of the 612 individuals screened, 202 (33%) were referred for additional evaluation. Of these, a total of 66 individuals were excluded from the study: 14 because of previous dietary counseling, 16 due to co-existing illness and/or use of contraindicated medications, 28 who had a lipoprotein profile that did not meet the inclusion criteria and eight who refused to participate in the study. Thus, 136 patients were enrolled into the study and received dietary counseling. Of these, 102 had received counseling by a dietitian by the end of the follow-up period, while 34 patients had continued follow-up by a physician and nurse only.

During the follow-up period, 18 participants dropped out of the study: six because of an acute coronary syndrome or other new evidence of atherosclerosis, one because of intestinal obstruction that required prolonged treatment and 11 who refused to continue follow-up. An additional 22 patients who had not achieved their LDL cholesterol target goals within six months of dietary therapy had begun using lipid-lowering medications before completion of the one-year follow-up period and were also excluded from the final analysis. Comparison of the 96 subjects who completed the study to the 22 patients who dropped-out prior to completion of the study, revealed that the two groups were not significantly different in age, gender, risk-factor prevalence, baseline BMI and baseline lipoproteins, except for a lower baseline LDL:HDL ratio in the drop-out group (5.0 ± 1.0 vs. 4.7 ± 1.1, p = 0.04).

Table 1 shows the baseline characteristics of the participants. Table 2 presents the mean percent changes in lipids and lipoproteins after 12 months follow-up for all the study population. Total cholesterol, LDL cholesterol and the LDL:HDL cholesterol ratio decreased while the HDL cholesterol and triacylglycerols increased, compared to their baseline levels. Changes in weight were minor (-2.4 ± 4.2 kg, p = 0.07).

Further analysis of the relationship between the baseline BMI and the percent changes in LDL cholesterol was performed by dividing the study population into high and low BMI groups according to the median BMI (26 kg/m², Fig. 1). After three months of follow-up, the low and high BMI groups showed similar LDL cholesterol changes compared to baseline (-10 ± 11% vs. -9 ± 10%, p = 0.6). At the 12-month follow-up, the low BMI group continued at a similarly lower LDL cholesterol level (-9 ± 9% compared to baseline). However, the high-BMI group had an LDL cholesterol level that was only -4 ± 11% below the baseline, representing a 5% absolute increase compared to the three-month LDL cholesterol level (p = 0.001). Similar discrepancies between short-term and longer-term response to diet were found for the subgroups of low and high baseline plasma LDL cholesterol (Fig. 2) and saturated fat intake (Fig. 3).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Percent changes in LDL cholesterol throughout 12 months of follow-up in the high (>26) and low (26) baseline body mass index (BMI) subgroups. *p = 0.001 for the difference between the two subgroups.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Percent changes in LDL cholesterol throughout 12 months of follow-up in the higher (4.59mmol/L) and lower (<4.59mmol/L) baseline LDL cholesterol subgroups. *p = 0.001 for the difference between the two subgroups.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Percent changes in LDL cholesterol throughout 12 months of follow-up in the high (>11%) and low (11%) baseline saturated fatty acid (SFA) intake subgroups. *p = 0.01 for the difference between the two subgroups.

Evaluation of the relationship between short-term and longer-term lipoprotein changes revealed a positive and significant association between the percent changes in LDL cholesterol after six weeks and after one year (ß = 0.3, p = 0.001). In order to further characterize predictors of longer-term dietary success, we defined a 10% decrease in LDL cholesterol at 12 months as representing a clinically significant dietary achievement. We then divided the patients into a group of "achievers" (n = 36) and a group of "non-achievers" (n = 60). Fig. 4 shows that the difference in LDL cholesterol decline between the two groups is already obvious after six weeks of follow-up (-9 ± 10% vs. -3 ± 11%, p = 0.03). Analysis of various six-week cutoffs as predictors of longer-term success suggests that a 5% reduction in LDL cholesterol at six weeks is the most suitable predictor for longer-term dietary achievement, as seen by the largest probability ratio between success and failure after three and 12 months. Patients who had succeeded in reducing their LDL cholesterol by at least 5% after six weeks of therapy had a 60% probability of reducing their LDL cholesterol by at least 10% after three months and a 45% probability of such a reduction after 12 months of follow-up. In contrast, patients who had failed to reduce their LDL cholesterol by at least 5% after six weeks of therapy had only a 24% probability of reducing their LDL cholesterol by at least 10% after three months and an 18% probability of such a reduction after 12 months of follow-up.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Percent changes in LDL cholesterol throughout 12 months of follow-up in the group of "achievers" (10% decrease in LDL cholesterol at 12 months) and "non-achievers" (<10% decrease in LDL cholesterol at 12 months). *p = 0.03 for the difference between the two subgroups. **p = 0.002 for the difference between the two subgroups.

	DISCUSSION

Higher baseline BMI and nutritional intake of saturated fat were associated with less long-term success in reducing LDL cholesterol. In a manner similar to that of the baseline LDL cholesterol, there were no significant differences in the LDL cholesterol response after three months between patients below and above the median of BMI and saturated fat intake. However, overweight individuals (BMI > 26) and those with a higher saturated fat intake (above 11% of total fat energy) had lost most of their initial success in LDL cholesterol reductions during longer-term follow-up and had returned to within 4% of their baseline LDL cholesterol level. In contrast, the groups with a BMI and saturated fat intake below the median had retained their initial accomplishment on longer-term follow-up. Unfortunately, we did not evaluate dietary intake data at the end of the study. However, we feel that the difference between the groups is related to a difference in long-term compliance to a cholesterol-lowering diet. While speculations are risky without additional metabolic and psychosocial data, it seems plausible that the eating habits of overweight and high SFA consuming individuals may be more difficult to change in the long-term.

Lipoprotein changes occur gradually in response to diet and it is therefore recommended to wait for three to six months before contemplating drug therapy in low-risk patients [1]. A six-week lipoprotein analysis is recommended for providing feedback to the patient and the therapist regarding the patient’s progress. Although the average LDL cholesterol decrease at six weeks was less than half its peak value at three months, we found a significant correlation between the two values. In addition, LDL cholesterol changes at six weeks provide reasonable prediction of the longer-term changes in LDL cholesterol. Assuming a 10% decrease in LDL cholesterol to represent a clinically meaningful response to diet, we found that a decrease in LDL cholesterol of 5% or greater at six weeks is associated with a 45% chance of achieving >10% decrease at longer-term follow-up. In contrast, individuals with a smaller decrease in LDL cholesterol at six weeks are much less likely to achieve such success

Some limitations of our study need to be noted. Since the study intended to conform to the NCEP guidelines as closely as possible, some patients who had achieved their LDL cholesterol target levels with physician counseling alone, did not receive additional counseling by a dietitian. However, the long-term changes in LDL cholesterol were not significantly different between this group of patients and those that did receive counseling by a dietitian [19]. In addition, the results of our analyses were similar when analyzing the "dietitian group" separately. Thus we feel that analyzing all the patients as one group was justified. Another possible limitation results from the fact that interaction with the dietitians was confined to the initial three months and did not involve spouses. It may be speculated that periodic counseling by dietitians for longer time periods may improve adherence and modify the results. Finally, since many of our participants were recruited from screening programs at the worksite, the proportion of women and elderly individuals was small and did not enable evaluation of the effects of age and gender on outcome.

In conclusion, we found an association between baseline BMI and LDL cholesterol levels and the longer-term changes in LDL cholesterol during medical dietary therapy and with the baseline BMI, LDL cholesterol level and the intake of saturated fat. We speculate that overweight individuals, as well as those with a lower baseline LDL cholesterol level and high saturated fat intake, have problems adhering to a long-term low-fat diet, despite satisfactory initial declines in the LDL cholesterol levels. The longer-term lipoprotein response to medical dietary therapy can be reasonably predicted by the LDL changes after six weeks of therapy. Whether these findings can be utilized for the early identification of hypercholesterolemic individuals who might better benefit from early pharmacological lipid-lowering therapy should be evaluated in additional studies.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Our appreciation to Edna Oxman for her editorial assistance.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Dr. Shai is currently at the Nutrition and Epidemiology Departments, Harvard School of Public Health, Cambridge, MA.

Received September 9, 2002. Accepted April 26, 2003.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 

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