Study to explain the reason for the variation in blood cholesterol responses to saturated fat
| ISRCTN | ISRCTN16727984 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16727984 |
| Secondary identifying numbers | BBSRC BB/P010245/1 |
- Submission date
- 01/08/2019
- Registration date
- 13/08/2019
- Last edited
- 10/07/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
The type of fat that we eat plays an important role in the development of heart disease. Diets high in saturated fats (found mostly in animal products such as meat and dairy foods) are related to higher levels of blood cholesterol (also known as Low Density Lipoprotein (LDL) cholesterol), which increase the risk of developing heart disease compared with diets high in unsaturated fats (found in vegetable oils). As a result, reducing intake of saturated fat to lower blood cholesterol levels has been a key dietary guideline to prevent heart disease for over 30 years. Studies have shown that there is significant variability between individuals in the extent to which blood cholesterol levels can be lowered by reducing the intake of saturated fat. However, very little is known about the factors that determine this variability in blood cholesterol levels between individuals, and the different ways in which people process saturated fat and regulate their blood cholesterol. The main aim of this study is to determine the factors that explain the individual variation in blood cholesterol response to saturated fat. In part 1 of this two-part study, the main aim was to measure the amount of variation in blood LDL-cholesterol in up to 150 healthy men in response to a high saturated fat diet consumed for 4 weeks, followed by a low saturated fat diet for a further 4 weeks. The latter diet was designed to meet the intake of saturated fat recommended by the UK government for the prevention of heart disease. These dietary interventions made it possible to identify and retain two groups of men who showed either a high or low blood LDL-cholesterol response to the reduction in dietary saturated intake, as defined by the top and bottom 10% of hyper-responders/or low-responders. In part 2 of this study, the aim is to study the metabolic characteristics of these two groups of men retained from part 1 in more depth, to investigate the possible underlying causes for the variation in their blood LDL-cholesterol response.
Who can participate?
Men aged 30-65 who participated in part 1 of the study (RISSCI-1) (responders and non-responders)
What does the study involve?
Participants are asked to repeat the same two dietary interventions as in part 1 (high and low saturated fat diet) for 4 weeks each, but undergo a more detailed investigation of their metabolism at the end of each diet, to help understand why some people’s blood LDL-cholesterol is more sensitive to changes in dietary saturated fat intake than others.
What are the possible benefits and risks of participating?
The knowledge gained from this study will help to show how and why dietary fats influence some peoples blood cholesterol level (a risk factor for developing heart disease) and not others. It will also help participants to understand how they personally respond to dietary fat. Potential risks (albeit small) include slight bruising/pain due to cannulation for blood sampling.
Where is the study run from?
1. University of Surrey (UK)
2. University of Reading (UK)
3. Imperial College London (UK)
When is the study starting and how long is it expected to run for?
August 2019 to August 2021
Who is funding the study?
Biotechnology and Biological Sciences Research Council (UK)
Who is the main contact?
1. Prof. Bruce Griffin
b.griffin@surrey.ac.uk
2. Prof. Julie Lovegrove
j.a.lovegrove@reading.ac.uk
Contact information
Scientific
Leggett Building
University of Surre
Guildford
GU2 &WG
United Kingdom
| Phone | +44 (0)1483 689724 |
|---|---|
| b.griffin@surrey.ac.uk |
Scientific
Hugh Sinclair Unit of Human Nutrition
University of Reading
Reading
RG6 6AP
United Kingdom
| Phone | +44 (0)118 378 6418 |
|---|---|
| j.a.lovegrove@reading.ac.uk |
Study information
| Study design | Multi-centre sequential dietary intervention study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Other |
| Study type | Other |
| Scientific title | Reading Imperial Surrey Saturated fat and Cholesterol Intervention (RISSCI): a metabolic phenotyping study (RISSCI-2) |
| Study acronym | RISSCI-2 |
| Study objectives | 1. It is predicted that men who show a greater reduction in blood LDL-cholesterol response (‘hyper-responders’) when changing from a high to a low SFA diet, will show a greater reduction in the absorption of dietary fat in their gut than low or ‘hypo-responders’. 2. It is believed that this effect may be explained, in part, by changes in the permeability of the gut lining, which may be increased by eating SFA. 3. Responders may also have a greater number of receptors on the surface of cells that remove LDL cholesterol from the blood (‘LDL-receptors’), most notably in the liver, when changing from a high to a low SFA diet. |
| Ethics approval(s) | 1. Approved 25/07/2019, University of Reading Ethics Committee (Whiteknights House, Whiteknights, PO Box 217, Reading, RG6 6AH; Tel: +44 (0)118 378 7119; Email: m.j.proven@reading.ac.uk), ref: UREC 19/29 2. Approved 12/08/2019, University of Surrey Ethics Committee (Research and Innovation Services, Senate House, University of Surrey, GU2 7XH; Tel: +44(0) 1483 689103; Email: s.bird@surrey.ac.uk), ref: UEC 2019 051 FHMS |
| Health condition(s) or problem(s) studied | Heart disease risk |
| Intervention | Participants will undergo, sequentially, a high (18%) SFA diet (Diet 1) followed by a low (10%) SFA diet (Diet 2) for 4 weeks each. Metabolic assessments will be conducted at the end of Diets 1 and 2. To comply with current UK dietary recommendations, Diets 1 and 2 will both contain ~35% energy from total fat. These diets will be consumed within the homes of free-living participants, by the substitution of ~40g of habitual fat, with either SFA-rich or mono/poly-unsaturated fatty acid-rich (MUFA/PUFA) cooking oils, spreads and snack foods, while maintaining their habitual diet (consistent intake of protein and carbohydrates, including dietary fibre). This will be achieved using a dietary exchange model developed for the 'DIVAS' study (Vafeiadou K et al (2015) Am J Clin Nut 102, 40-8). The diet is identical to the diet used in Part 1 of this two-part intervention study. |
| Intervention type | Behavioural |
| Primary outcome measure | 1. Lipid profile (Total Cholesterol (TC), LDL-C, HDL-C and triacylglycerol (TAG)) measured via direct quantification and/or auto-analyser at baseline, the end of diet 1 and at the end of diet 2 2. Dietary fat absorption, measured by feeding a manufactured fat that has been labelled with safe stable isotope tracer that can be traced in the body and can be used to measure how much is excreted in the stool, at the end of diet 1 and at the end of diet 2 |
| Secondary outcome measures | 1. Gut permeability measured using the urinary recovery of ingested carbohydrates provided as part of a drink, at baseline, the end of diet 1 and at the end of diet 2 2. LDL-receptor expression measured in peripheral blood mononuclear cells (PBMC) via PCR at baseline, the end of diet 1 and at the end of diet 2 3. Gut microbiota composition measured in stool samples using NGS/FISH at baseline, the end of diet 1 and at the end of diet 2 4. Endogenous cholesterol synthesis measured by measuring serum phytosterols, a biomarker of this process, using GCMS at baseline, the end of diet 1 and at the end of diet 2 5. Serum deconjugated bile acids measured using targeted UPLC-MS at baseline, the end of diet 1 and at the end of diet 2 7. Metabolomic signatures in urine, plasma and stool measured using 1H-NMR & UPLC-MS metabonomics at baseline, the end of diet 1 and at the end of diet 2 8. Markers of inflammation and endothelial function measured using commercially available kits (e.g. ELISA) at baseline, the end of diet 1 and at the end of diet 2 9. HDL composition/function measured via cell-based cholesterol efflux capacity assay at baseline, the end of diet 1 and at the end of diet 2 |
| Overall study start date | 01/08/2019 |
| Completion date | 14/08/2021 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 30 Years |
| Upper age limit | 65 Years |
| Sex | Male |
| Target number of participants | n=36 |
| Total final enrolment | 36 |
| Key inclusion criteria | 1. Hyper- and hypo-responsive males, defined as the participants (derived from the first stage of the project, RISSCI-1: https://clinicaltrials.gov/ct2/show/NCT03270527) exhibiting changes in serum LDL-cholesterol in response to a lowering of SFA intake in the top and bottom 10% of a larger cohort (n=150) 2. Middle-aged men (30-65 years) 3. BMI 19-32 kg/m2 4. Fasting serum total cholesterol < 7.5 mmol/l and TAG < 2.3 mmol/l |
| Key exclusion criteria | 1. Smokers 2. Medical history of MI or stroke in the past 12 months 3. Diabetes (defined as fasting glucose > 7.0 mmol/l) or other endocrine disorders 4. Medication for hyperlipidaemia (e.g. statins) or prescribed antibiotics within the last three months 5. Drinking in excess of 14 units of alcohol per week, anaemia (<130 g/L haemoglobin) 6. Planning a weight-reducing regime or taking any dietary supplements known to influence lipids/gut microbiota (e.g. plant stanols, fish oil, phytochemicals, natural laxatives, probiotics and prebiotics) 7. Unwilling to regularly consume study intervention products (butter/spreads, oils, dairy, snacks) 8. Any other unusual medical history or diet and lifestyle habits or practices that would preclude participants from participating in a dietary intervention metabolic study |
| Date of first enrolment | 13/08/2019 |
| Date of final enrolment | 30/08/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Stag Hill Campus
Guildford
GU2 7XH
United Kingdom
Harry Nursten Building
Reading
RG6 6AP
United Kingdom
South Kensington Campus
London
SW7 2AZ
United Kingdom
Sponsor information
University/education
Stag Hill
Guildford
GU2 7XH
England
United Kingdom
| Phone | +44 (0)1483 689724 |
|---|---|
| b.griffin@surrey.ac.uk | |
| Website | https://www.surrey.ac.uk/ |
University/education
Hugh Sinclair Unit of Human Nutrition
Harry Nursten Building
Reading
RG6 6AP
England
United Kingdom
| Phone | +44 (0)118 378 6418 |
|---|---|
| j.a.lovegrove@reading.ac.uk | |
| Website | https://www.reading.ac.uk/ |
University/education
Faculty of Medicine
South Kensington Campus
London
SW7 2AZ
England
United Kingdom
| Phone | +44 (0)20 7594 0728 |
|---|---|
| j.swann@imperial.ac.uk | |
| Website | https://www.imperial.ac.uk |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- UKRI - Biotechnology And Biological Sciences Research Council, BBSRC UK, BBSRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/05/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The study protocol will be submitted upon approval by the UoS which remains outstanding. Publication of primary and secondary outcomes in research journals and presentations at major conferences Progress update 11/01/2021: The human dietary interventions were completed and samples for analyses collected and stored at the Universities of Surrey and Reading in February 2020 (2 months behind schedule). COVID-19 lockdown March 23rd 2020: The Universities of Surrey and Reading and Imperial College London and research laboratories were closed until September, with a phased re-opening and limited access after this period. This, together with staffing issues, has produced an estimated 12-month delay in the expected 'intention to publish date'. (added 11/01/2021) Progress update 08/03/2022: The dietary intervention studies for RISSCI-2 were completed at the Universities of Surrey and Reading in February 2021. The study received a 6-month no-cost extension from its sponsor/funder (BBSRC) because of COVID-19-related lockdowns, during which the universities of Surrey and Reading were closed (April-September 2020) or access was restricted (NovemberDecember 2021). Analysis is still ongoing on one primary outcome measure (stable-isotope labelled plasma palmitate) and one secondary outcome measure (faecal bile acids). Data analysis on other outcomes is ongoing. We anticipate completion of these measurements by May 2022 and paper submission and publication before the end of 2022. Note: the results from the dietary intervention of the preliminary study (RISSCI-1) are in the second round of peer review for the European Journal of Nutrition), with the main results to be submitted in May/June 2022. Publication of RISSCI-2 results will follow this. (added 08/03/2022) Updated 11/09/2023: The study protocol has been attached. Updated 10/07/2024: Results from the preliminary RISSCI-1 study have been published (https://pubmed.ncbi.nlm.nih.gov/35668120/), and the second manuscript is in its second round of peer review (Am J Nutr). RISSCI-2 progress update: The dietary intervention studies for RISSCI-2 were completed at the Universities of Surrey and Reading in February 2021. The study received a 6-month no-cost extension from its sponsor/funder (BBSRC) because of COVID-19-related lockdowns, during which the universities of Surrey and Reading were closed (April-September 2020) or access was restricted (November/December 2021). Statistical analysis of the primary outcome measure in RISSCI-2 (stable-isotope labelled plasma palmitate) is now complete and the first manuscript for the RISSCI-2 study is in preparation. The researchers anticipate completion and submission of this manuscript in October 2024 and publication online by May 2025. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 5 | 25/11/2019 | 11/09/2023 | No | No |
Additional files
Editorial Notes
10/07/2024: The publication and dissemination plan was updated. The intention to publish date was changed from 31/07/2024 to 01/05/2025.
11/09/2023: The following changes were made to the trial record:
1. The recruitment start date was changed from 12/08/2019 to 13/08/2019.
2. The publication and dissemination plan was updated.
3. Uploaded protocol (not peer-reviewed) as an additional file.
4. The intention to publish date was changed from 31/03/2024 to 31/07/2024.
15/03/2023: The intention to publish date was changed from 31/03/2023 to 31/03/2024.
12/07/2022: The intention to publish date was changed from 31/07/2022 to 31/03/2023.
08/03/2022: The following changes were made to the trial record:
1. The overall end date was changed from 14/02/2021 to 14/08/2021.
2. The publication and dissemination plan was updated.
3. The plain English summary was updated to reflect these changes.
13/07/2021: The following changes were made to the trial record:
1. The total final enrolment was added.
2. The intention to publish date was changed from 01/07/2021 to 31/07/2022.
11/01/2021: The following changes were made to the trial record:
1. The overall end date was changed from 01/04/2020 to 14/02/2021.
2. The intention to publish date was changed from 01/07/2020 to 01/07/2021.
3. The publication and dissemination plan was updated.
4. The plain English summary was updated to reflect these changes.
13/08/2019: Ethics approval details added.
06/08/2019: Trial's existence confirmed by ethics committee.
