Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread
Introduction
Hypercholesterolaemia is a major and modifiable risk factor for coronary heart disease. Dietary cholesterol and saturated fats raise serum cholesterol levels, although these can be reduced by consumption of 1 g or more daily of plant sterols or phytosterols.[1] These compounds occur naturally in vegetable oils and fats and are structurally similar to cholesterol, but are not synthesised by the human body [1]. They can be saturated using commercial processes to form compounds such as sitostanol [2]. Their exact mechanism of cholesterol-lowering is not fully understood, but they appear to inhibit the uptake of dietary and biliary cholesterol from the gut [3]. The cholesterol-lowering efficacy of dietary phytosterols varies depending on the dose and duration of administration, and possibly the type of underlying lipid disorder [2]. A recent Finnish study in mildly hypercholesterolaemic subjects demonstrated that consumption of ∼23 g/day of fat spread enriched with 10% hydrogenated sterols from wood pulp esterified with fatty acids reduced LDL-cholesterol levels by 10–14% compared with controls [4].
Cholesterol-lowering dietary advice usually reduces total cholesterol by only ∼5% [5] because compliance is poor. As a functional food, the use of sterol-enriched products might be expected to reduce cardiovascular risk in the majority of the population with modestly elevated but biologically undesirable cholesterol levels. In moderately hypercholesterolaemic patients, the combination of dietary therapy and use of plant sterols may avoid the need for cholesterol-lowering drug therapy in some patients, and allow treatment with lower doses of drugs in other patients. We therefore examined the effect of a fat spread enriched with sterols from vegetable oils, rather than wood pulp, on plasma lipid, lipoprotein and apolipoprotein concentrations in patients with heterozygous familial hypercholesterolaemia treated concurrently with a lipid lowering diet and an HMG-CoA reductase inhibitor (statin), and in moderately hypercholesterolaemic patients not taking any lipid-lowering drugs.
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Patients and methods
A randomised double blind controlled crossover trial design was used. Fig. 1 shows the patient flow through the trial. The two periods were consecutive without a washout period and were of 2 months duration. Patients were recruited from a hospital lipid clinic in Oxford over a 10-month period from June 1997. Two groups of patients, aged 18–69 years, were eligible for inclusion in the trial: (1) men and women with total cholesterol concentration ≥6.5 mmol/l not requiring lipid-lowering drug
Intervention
The study treatment and control fat spreads had the same fatty acid concentration and composition, and were specially prepared (Van den Bergh Foods, Purfleet, UK) and packed in individual blinded tubs for single day use. The fortified fat spread (25 g/day) provided 2.5 g/day of phytosterols. Soybean, rape seed, and sunflower seed oils accounted for ∼60, 30 and 5%, respectively, of the vegetable oil sterols, which were esterified with sunflower seed oil fatty acids to enhance their solubility in
Biochemical methods
Venous blood specimens were collected in EDTA vacutainers and centrifuged within 4 h of collection for measurement of lipids, lipoproteins and apolipoproteins (Diabetes Trial Unit Biochemistry Laboratory, Radcliffe Infirmary, Oxford, UK). Cholesterol was measured by an enzymatic colorimetric method (MPR2 CHOD-PAP kit with Preciset Cholesterol Standard, Boehringer Mannheim, Lewes, Sussex, UK). HDL cholesterol remained in solution after precipitation of LDL and VLDL-cholesterol with sodium
Statistical methods
The principal results were analysed using the statistical package SPSS. Patients who were randomised but withdrawn from the trial or lost to follow up were excluded from the crossover trial analyses. The triglyceride, plant sterol and sterol precursor concentrations were log transformed before analysis because the data were positively skewed. For continuously distributed variables, results at the end of the two 8-week periods were used to determine the statistical significance of paired
Results
A total of 106 patients were invited to participate in the trial, 63 agreed (31 with statin treated familial hypercholesterolaemia) and were subsequently randomly allocated to intervention. One ineligible patient with previously diagnosed untreated familial hypercholesterolaemia (total cholesterol concentration 12.5 mmol/l) requiring statin drug therapy was randomised in violation of the trial protocol and was withdrawn from the trial, and excluded from all analyses. Four patients withdrew from
Discussion
The study demonstrated that the sterol-enriched spread was effective in lowering total and LDL-cholesterol concentrations in patients with familial hypercholesterolaemia treated with an HMG-CoA reductase inhibitor and in those with type IIa hypercholesterolaemia taking no lipid-lowering drug therapy. In a parallel group analysis, LDL-cholesterol was reduced by 15% after 4 weeks use and by 10% after 8 weeks with no effect on HDL cholesterol or triglyceride. The trial was an unbiased blinded
Acknowledgements
We thank Dr D.R. Matthews for permission to study those patients that were under his care, and P. Dyson, S.M. Neil, Dr R Spivey, Dr H Turner for their help in conducting the trial, A. Fuller and K. Boschen for data entry, and Dr S.E. Manley for advice on biochemical analyses. Funding: The trial was sponsored by Unilever Research Vlaardingen, The Netherlands. Competing interests: G.W. Meijer is employed by Unilever.
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