RISSCI-1 Blood Cholesterol Response Study
Condition: Lipids; Lipid Metabolism; Healthy
Study type: Interventional

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.
    

Intervention name(s): High SFA diet (Diet 1); Low SFA diet (Diet 2)
Intervention type(s): Other; Other
Intervention description(s): 'Diet 1' will contain ~18% of its total energy as SFA .; 'Diet 2' will contain ~10% of its total energy as SFA. The SFA-replacement fats will be mixture of PUFA/MUFA.
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Dietary fat modification; Lipids; LDL cholesterol; Dietary fatty acids; Saturated fat