Clinical trial NCT03270527: RISSCI-1 Blood Cholesterol Response Study
Official title: Reading Imperial Surrey Saturated Fat Cholesterol Intervention (RISSCI) Study. RISSCI-1 Blood Cholesterol Response Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Lipids
Lipid Metabolism
Healthy
Keywords: Dietary fat modification
Lipids
LDL cholesterol
Dietary fatty acids
Saturated fat
Lead sponsor: University of Surrey
Sponsor class: OTHER
Collaborators: name: University of Reading
name: Imperial College London
First posted: 2017-09-01
Enrollment: 109
Sex: MALE
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: Raised blood cholesterol (also referred to as blood LDL-cholesterol) is a major risk factor for developing heart disease. Dietary saturated fat is recognised as the main dietary component responsible for raising blood LDL-cholesterol, and reducing its intake has been the mainstay of dietary guidelines for the prevention of heart disease for over 30 years. However, there is very little evidence for a direct link between the intake of saturated fat and risk of dying from heart disease. One explanation for this, is that the link between saturated fat intake and heart disease is not a direct one, but relies heavily on the ability of saturated fat to raise blood LDL-cholesterol levels. This LDL cholesterol-raising effect of saturated fat is complex, and highly variable between individuals because of differences in the metabolism of dietary fat and cholesterol between people. The main aim of this study is to measure the amount of variation in blood LDL-cholesterol in healthy volunteers at the Universities of Surrey and Reading in response to lowering the amount of saturated fat in the diet to the level recommended by the government for the prevention of heart disease. This collaborative project between the Universities of Reading, Surrey and Imperial ('RISSCI-1' Blood Cholesterol Response Study') will permit identification of two subgroups of men who show either a high or low LDL-cholesterol response to a reduction in dietary saturated intake. These two groups of participants will be provided with an opportunity to participate in a similar follow-up study ('RISSCI-2') that will also take place at the University of Surrey and Reading. In this follow-up study, the participants will be asked to repeat a similar study protocol as for RISSCI-1, but undergo more detailed measurements to investigate the metabolic and genetic origins of how saturated fat is metabolised in the body and influences blood LDL-cholesterol (LDL-C).

Detailed description: The LDL cholesterol-raising effect of saturated fatty acids (SFA) is complex, and highly variable between individuals because of differences in the metabolism of dietary fat and blood cholesterol between people. While these differences in metabolism make it difficult to study how dietary SFA influences LDL-cholesterol in large numbers of people, they can be measured in the laboratory and used as biological markers to distinguish between people who respond well from those who will respond less well to moderate-fat diets, which are lower in SFA.

The main aim of this study is to measure the amount of variation in blood LDL-cholesterol in healthy male volunteers in response to the replacement of SFA with unsaturated fats, and to select LDL-C responders from non-responders for a subsequent metabolic study ('RISSC-2'). Estimate of statistical power and sample size for 'RISSCI-1': A decrease of 0.16 mmol/L (SD 0.54) in our primary outcome of fasting plasma LDL-C between the high- and low-SFA diets, as observed in a previous randomly controlled trial, will require a sample size of 92 participants, at 80% power and 5% significance level. An estimated attrition rate of 15% will increase this sample size to 106 participants. To recruit this sample of participants, we anticipate having to screen 150 volunteers (75 at each site).

Specific objectives:

1. Undertake a dietary intervention study to examine the effects of two, 4 week diets that differ in their composition of fatty acids. The first diet ('Diet 1') will contain \~18% of its total energy as saturated fatty acids (SFA), while the second diet ('Diet 2') will contain \~10% of its total energy as SFA. Blood, urine and stool samples taken at the beginning (week 0) and end of Diet 1 (week 4), and end of Diet 2 (week 8), will be analysed to measure blood LDL-cholesterol and other relevant blood, urine and faecal metabolites. The white blood cell buffy coat will also be isolated from the blood samples collected at the baseline visit to enable genotyping of relevant genes involved in the absorption and metabolism of dietary fat.
2. To examine the data for evidence of associations between the changes in blood LDL- cholesterol, and the physical and biochemical characteristics of the participants as possible determinants of the variation in serum cholesterol response. This will include measurement of a common genetic polymorphism in APOLIPOPROTEIN E, as an established determinant of variation in blood cholesterol in response to dietary SFA.
3. To identify two subgroups of individuals whose blood LDL-cholesterol either responds ('Responders') or show little or no response ('Non-responders') on changing from Diet 1 to Diet 2, for participation in the follow-up study ('RISSCI-2'), which will be conducted at the Universities of Surrey, Reading and Imperial College London. In this follow-up study, the participants will be asked to repeat a similar study protocol as for RISSCI-1, and undergo more detailed measurements to determine how saturated fat is metabolised in the body.

Hypothesis:

In accordance with the variation in blood LDL-cholesterol response, that many studies have reported previously following substitution of dietary saturated with unsaturated fats, the investigators hypothesise that consuming Diet 1 (a high saturated fat diet) for 4 weeks followed by diet 2 (a low saturated fat/high unsaturated fat diet) for a further 4 weeks, will: 1) produce a variable distribution of responses in LDL-cholesterol that will enable the study of associations between the participants' baseline characteristics as possible determinants of the observed variation in blood LDL-cholesterol response, and 2) identify two distinct subgroups of individuals who either respond or show little or no response in their blood LDL- cholesterol. These distinct groups will be defined by the top and bottom \~10% of change in the concentration of blood LDL-cholesterol.

Eligibility criteria: Inclusion Criteria:

* BMI of 19-32 kg/m2
* Fasting serum total cholesterol \< 7.5 mmol/l and triacylglycerol \< 2.3 mmol/l

Exclusion Criteria:

* Smokers
* Medical history of myocardial ischemia or stroke in the past 12 months;
* Diabetes (defined as fasting glucose \> 7.0 mmol/l) or other endocrine disorders; kidney, liver, pancreas or gastrointestinal disorders
* Hypertension (blood pressure \> 140/90 mmHg),
* Cancer
* Medication for hyperlipidaemia (e.g. statins), hypertension, inflammation or prescribed antibiotics within the last three months
* Drinking in excess of 14 units of alcohol per week,
* Anaemia (\<130 g/L haemoglobin), or planning on a weight-reducing regime
* Taking any dietary supplements known to influence lipids/gut microbiota (eg. plant stanols, fish oil, phytochemicals, natural laxatives, probiotics and prebiotics)
* Any other unusual medical history or diet and lifestyle habits or practices that would preclude volunteers from participating in a dietary intervention and metabolic study.

Primary outcomes:
measure: Changes in fasting total cholesterol (consisting of LDL-cholesterol and HDL) concentrations
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
Secondary outcomes:
measure: Fasting triacylglycerol
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: HDL immune functions
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: HDL anti-inflammatory and anti-oxidant (PON-1) properties
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: HDL capacity to promote cholesterol efflux (ex-vivo)
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Fasting insulin, glucose
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Adhesion molecules, markers of vascular function
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Inflammatory markers & adipokines
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: LDL-R gene expression
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Other relevant genes involved in the absorption and metabolism of dietary fat
timeFrame: Baseline
measure: Metabolomic analysis for the determination of the low molecular weight metabolite profiles in the biological fluids
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Changes in faecal bacterial population
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Weight
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Fat mass
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Fat free mass
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Waist circumference
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Hip circumference
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Blood pressure
timeFrame: Baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
measure: Fasting vascular stiffness
timeFrame: baseline, 4 weeks (after diet 1), 8 weeks (after diet 2)
Other outcomes:
measure: Genotyping for apolipoprotein E to determine the impact of this genotype on changes in the primary and secondary outcome measurements in response to dietary fat intake
timeFrame: Baseline
Locations:
city: Reading
country: United Kingdom
facility: Department of Food and Nutritional Sciences, University of Reading
state: Berkshire
city: Guildford
country: United Kingdom
facility: Department of Nutritional Sciences, University of Surrey
state: Surrey
Study officials:
affiliation: University of Surrey
name: Bruce Griffin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Reading
name: Julie Lovegrove, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vafeiadou K, Weech M, Altowaijri H, Todd S, Yaqoob P, Jackson KG, Lovegrove JA. Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. Am J Clin Nutr. 2015 Jul;102(1):40-8. doi: 10.3945/ajcn.114.097089. Epub 2015 May 27.
citation: Sellem L, Antoni R, Koutsos A, Ozen E, Wong G, Ayyad H, Weech M, Schulze MB, Wernitz A, Fielding BA, Robertson MD, Jackson KG, Griffin BA, Lovegrove JA. Impact of a food-based dietary fat exchange model for replacing dietary saturated with unsaturated fatty acids in healthy men on plasma phospholipids fatty acid profiles and dietary patterns. Eur J Nutr. 2022 Oct;61(7):3669-3684. doi: 10.1007/s00394-022-02910-2. Epub 2022 Jun 6.