Clinical trial NCT05181553: Unravelling the Impact of Diet on Cardiovascular Health in Heterozygous Familial Hypercholesterolemia.
Official title: Unravelling the Impact of Diet on Cardiovascular Health in Heterozygous Familial Hypercholesterolemia: a Metabolomic Approach.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Familial Hypercholesterolemia
Nutrition, Healthy
Cholesterol, Elevated
Cholesterol; Metabolic Disorder
Cardiovascular Diseases
Keywords: familial hypercholesterolemia
diet
LDL-cholesterol
metabolome
cardiovascular disease
Lead sponsor: Laval University
Sponsor class: OTHER
First posted: 2022-01-06
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The proposed research will combine a dietary RCT (objectives 1, 2) and a cohort investigation (objective 3). The dietary intervention will be undertaken as a crossover RCT at the INAF (Université Laval) in Quebec City. Men and women with genetically-defined HeFH will consume in a random order a fully-controlled whole-food plant-based diet low in red and processed meats and high in plant foods (WFPB diet in further sections), and a standard North American diet (SAD diet; i.e. control diet), for 4 weeks each, and separated by a 4-week washout period. The first and second objective consist respectively to investigate the impact of a WFPB diet in place of a SAD on LDL-C concentrations and plasma metabolome.

The third objective consist to evaluate the association between the plasma metabolomic signature of a diet low in red and processed meats and high in plant foods and cardiovascular disease risk.
Primary purpose: PREVENTION

Brief summary: The investigators will first conduct a fully controlled dietary randomized crossover trial (RCT) including 50 adults with HeFH to investigate the impact of a whole food plant-based (WFPB) diet low in red and processed meats and high in plant foods, reflecting Canada's Food Guide, in place of a standard North-American diet on LDL-cholesterol (LDL-C) levels and the plasma metabolome. Such a robust design will also lead to the identification an objective proxy to healthy diet adherence: the metabolomic signature. Secondly, by leveraging a cross-sectional cohort of adults with HeFH, the investigators will evaluate the relationship between the metabolomic signature of the healthy diet and cardiovascular disease risk factors in HeFH.

Detailed description: The research combines a dietary RCT (objectives 1, 2) and a cohort investigation (objective 3), both including adults with genetically-defined HeFH.

The dietary intervention will be undertaken as a crossover RCT at the Institute on nutrition and functional foods (INAF, Laval University) in Quebec City. Participants (men and women with genetically-defined HeFH) will consume in a random order a fully-controlled whole food plant-based diet low in red and processed meats and high in plant foods, reflecting Canada's Food Guide principles (WFPB diet in further sections), and a standard North American diet (SAD diet; i.e. control diet), reflecting current dietary intakes of French-Canadians, for 4 weeks each, and separated by a 4-week washout period.

Once enrolled, participants will enter a 2- to 4-week run-in period at the beginning of which they will stop taking their lipid-lowering medication for the study duration (16 weeks). Other medications (e.g. anti-hypertensive drugs, oral contraceptives) will be allowed, but doses will have to remain constant during the study. At the end of the run-in, participants will provide a blood sample and complete a self-administered, validated web-based food-frequency questionnaire. Participants will be randomly assigned to either the WFPB-SAD or SAD-WFPB diet sequence, using a computer-assisted program. The randomization (1:1) will be stratified by sex (female vs male) and LDL-receptor (LDLR) genotype (receptor-negative vs others) in 8 blocks of 8 subjects. The two diets will be consumed for 4 weeks and separated by a 2- to 4-week washout period. During diet phases, all meals and foods will be provided to ensure optimal diet control using a 7-day cyclic menu. The WFPB diet emphasizes low intakes of red and processed meats and high intakes of whole plant-based foods with water as the drink of choice, as per Canada's Food Guide. The SAD diet reflects current dietary intakes of the French-Canadian adult population in terms of foods, nutrients, and diet quality, as characterized in recent surveys conducted in an age- and a sex-representative sample of adults from the Province of Quebec. An experienced food technician will prepare the diets. Each food and ingredient will be weighed with a precision of ±0.1 g.

During the diet phases, participants will visit the INAF clinical research unit three times weekly (Monday, Wednesday, Friday) to collect their meals and had the option to eat on-site under supervision. At that time, they will also be given their evening meals and the next day's packaged breakfast to take home. Weekend meals will be provided at the Friday visits. A checklist will be provided to all participants to identify the consumed foods. Alcohol, vitamin supplements, and natural health products will not be allowed. Tea and coffee (black) will be allowed (≤2 servings/day without daily fluctuations). Participants will be instructed to maintain their usual physical activity level. At the end of each diet, fasting plasma samples will be collected in ethylenediaminetetraacetic acid (EDTA) tubes. Parts of the samples will be stored at -80℃ for future ancillary analyses. Participants' anthropometry, body composition (DEXA scan), and blood pressure will be measured. To incorporate gender aspects associated with the intervention in knowledge transfer activities, subjects' appreciation of the diets and appetite sensation will be assessed using visual analog scales filled after each meal on day 7 and 28 of each diet.

Objective 1: To investigate the impact of a whole food plant-based diet low in red and processed meats and high in plant foods in place of a standard North American diet on LDL-C concentrations - the primary treatment target in HeFH management. This objective will output a convincing demonstration of the cholesterol-lowering effects of diet in adults with HeFH, supporting the effectiveness of dietary interventions in HeFH management. Investigators will compare post-diet LDL-C levels (primary outcome) using mixed models for repeated measures.

Secondary outcomes include other atherogenic lipoproteins and lipids (apolipoprotein B, non-HDL-C, total-C, triglycerides, lipoprotein (a), LDL-C corrected for Lp(a), apolipoprotein A1, HDL-C) and other cardiovascular disease risk factors (C-reactive protein, fasting plasma glucose, fasting insulin, HbA1c, systolic and diastolic blood pressure, 10-year risk of cardiovascular disease).

Potential effect modification by key unmodifiable participant characteristics (sex, LDLR genotype, age) will also be tested. Sex and LDLR genotype were pre-specified.

Objective 2: To assess the impact of a diet low in red and processed meats and high in plant foods in place of a standard North American diet on the plasma metabolome. This objective serves a dual purpose as it will: 1. inform on the dietary impact on systemic metabolism, beyond its impact on LDL-C levels, further supporting the importance of healthy dietary habits in HeFH; and 2. allow the identification of an unbiased HeFH-specific plasma metabolomic signature of a diet low in red and processed meats and high in plant foods to be used as an objective proxy of diet adherence. To document post-diet differences in plasma metabolome and identify the metabolomic signature of the WFPB diet, investigators will derive a reproducible multi-metabolite model discriminating the post-WFPB/post-SAD metabolomic profiles.

Objective 3: To evaluate the association between the plasma metabolomic signature of a diet low in red and processed meats and high in plant foods and cardiovascular disease risk. The metabolomic signature will allow to infer how objective adherence to a healthy diet is associated with cardiovascular disease risk in a distinct, large cohort of free-living adults with HeFH. This will provide an innovative demonstration of the role of diet in long-term cardiovascular disease prevention in adults with HeFH, further supporting the importance of a healthy diet in this high-risk population. To evaluate the association between the plasma metabolomic signature of the healthy WFPB diet and cardiovascular disease risk in adults with HeFH, investigators will leverage a distinct cross-sectional cohort of adults with HeFH. Upon recruitment, participants underwent a complete clinical assessment and fasting blood samples were collected in EDTA tubes. Investigators will fit and standardize the WFPB multi-metabolite model (signature) to the cohort metabolomic data. The relationship between the WFPB multi-metabolite model (independent variable) and cardiovascular disease risk factors (plasma lipids, blood pressure, plasma glucose, insulin, HbA1c) will be assessed using linear regressions.

Results will fill key gaps on the short- and long-term influence of diet on cardiovascular health in HeFH.

Eligibility criteria: Inclusion criteria:

* Genetically-defined HeFH
* Premenopausal women with a regular menstrual cycle for \>3 months
* Postmenopausal women (without hormone replacement)

Exclusion criteria:

* Any cardiovascular disease-risk exacerbating conditions (age \>60 years, homozygous FH, personal history of cardiovascular disease, diabetes/anti-diabetic drug use, severe obesity, unstable body weight for \>3 months, uncontrolled hypertension, genetic hypertriglyceridemia),
* Allergies/aversions to components of the experimental diets
* Any condition that would interfere with optimal participation in the intervention.

Primary outcomes:
measure: Post-diet differences in LDL-C levels.
timeFrame: This analysis will compare LDL-C levels from plasma samples collected at the end (day 28) of each diet.
Secondary outcomes:
measure: Post-diet differences in other atherogenic lipoproteins and lipids
timeFrame: This analysis will compare levels of atherogenic lipoproteins and lipids measured from plasma samples collected at the end (day 28) of each diet
measure: Post-diet differences in other lipoproteins and lipids
timeFrame: This analysis will compare levels of other lipoproteins and lipids measured from plasma samples collected at the end (day 28) of each diet
measure: Post-diet differences in C-reactive protein levels.
timeFrame: This analysis will compare C-reactive protein levels (mg/L) measured at the end (day 28) of each diet.
measure: Post-diet differences in systolic and diastolic blood pressure
timeFrame: This analysis will compare systolic and diastolic blood pressure (mm Hg) measured at the end (day 28) of each diet.
measure: Post-diet differences in fasting plasma glucose
timeFrame: This analysis will compare levels of fasting plasma glucose (mmol/L) measured from plasma samples collected at the end (day 28) of each diet.
measure: Post-diet differences in fasting plasma insulin
timeFrame: This analysis will compare levels of insulin (pmol/L) measured from plasma samples collected at the end (day 28) of each diet.
measure: Post-diet differences in glycated hemoglobin (HbA1c)
timeFrame: This analysis will compare levels of glycated hemoglobin (HbA1c) (%) from plasma samples collected at the end (day 28) of each diet.
measure: Post-diet differences in 10-year risk of atherosclerotic cardiovascular disease
timeFrame: This analysis will compare 10-year risk of atherosclerotic cardiovascular disease (%) measured at the end (day 28) of each diet.
measure: Post-diet differences in plasma metabolomics profiles.
timeFrame: This analysis will compare metabolomic profiles from plasma samples collected at the end (day 28) of each diet.
Other outcomes:
measure: Post-diet differences in appetite sensation
timeFrame: Appetite sensation was measured at the end of the first (day 7) and the last week (day 28) of each diet. Changes between day 28 and day 7 will be calculated and compared between diet.
measure: Association between the plasma metabolomic signature of the healthy CFG diet and LDL-C levels
timeFrame: This analysis will leverage metabolomic profiles from plasma samples collected at the end (day 28) of each diet, but it is not part of the intervention time frame per se.
Locations:
city: Québec
country: Canada
facility: Institute on nutrition and functional foods, Laval University
state: Quebec
Study officials:
affiliation: Laval University
name: Jean-Philippe Drouin-Chartier
role: STUDY_DIRECTOR
References: