Low-carbohydrate Diet and Low-Density Lipoprotein - Cholesterol (LDL-c) Interindividual Variability (REPETO)

Exploring True Interindividual Heterogeneity of Cardiovascular Disease (CVD) Risk Factors in Response to Low-carbohydrate Diets Using a Replicate Crossover Randomised Controlled Trial

Ketogenic diets are very low-carbohydrate diets that increase hepatic production of ketone bodies, which have several effects as substrates and signals. Ketogenic diets are used to manage some conditions (e.g., drug-resistant epilepsy), and their potential for managing many other conditions (e.g., cancer) is being actively explored. Indeed, the British Dietetic Association acknowledge the potential for ketogenic diets to improve glycaemic control to a greater extent than some other diets in people with type 2 diabetes. A lower fasting glucose is also relevant to future mortality in people without diabetes. Ketogenic diets are popular in the general population, with up to 15% of the UK following a low-carbohydrate diet. There is, therefore, great interest in ketogenic diets amongst people with and without health conditions. However, although the diet shows promising results in improving blood sugar levels, it has also shown to increase low-density lipoprotein-cholesterol (LDL-c) in some individuals, which has been linked to increased cardiovascular health risks. The aim of this project is to find the potential for personalised use of (or guidance to avoid) ketogenic diets for cardiovascular disease risk. To do that the investigators will ask participants to replicate 24 hours of a ketogenic diet and a control diet thrice each. This will allow the investigators to find variability between responses and have a better idea of individuals who could benefit (or not) from following the ketogenic diet.

Study Overview

• Status: Recruiting
• Conditions: Healthy
• Intervention / Treatment: Other: control diet; Other: Low carbohydrate diet

Detailed Description

The study will be a controlled feeding replicate randomised controled trial with 3 cycles, each involving the pair of diets [low carbohydrate (K) and control (C) diets]. There will be 6 x 1-day periods (3 days low carbohydrate and 3 days control). Twenty individuals (body mass index: 18.5-35 kg/m2) will be recruited and randomised into one of the 8 possible sequences:

1. KC KC KC
2. KC KC CK
3. KC CK KC
4. KC CK CK
5. CK CK CK
6. CK CK KC
7. CK KC CK
8. CK KC KC A week before the interventions start, participants will visit the laboratory so that the investigators can perform indirect calorimetry and collect a blood sample for genotyping. During the week before the interventions, participants will wear activity monitors to determine habitual physical activity. Before each visit, participants will be asked to come to the lab in a rested and overnight fasted state. During the first trial visit, participants will have a dual-energy X-ray absorptiometry (DEXA) body scan to determine body composition. During all 12 study visits the investigators will perform a venepuncture in an antecubital vein and will collect 20 mL of blood.

Additionally, the investigators will also collect urine samples. After odd visits (1st, 3rd, 5th, 7th, 9th and 11th), participants will be supplied with their respective meals for the day (low carbohydrate or control) and will be asked to not eat anything else during the day.

Finally there will be a wash-out period of 6 days between laboratory visits. To keep consistency between trial days, participants will be asked to replicate physical activity levels performed during the 24 hours before the first trial, and during diet day (before second visit), so that these can be replicated for the following visits.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bruno Spellanzon, PhD candidate; Phone Number: 447769407954; Email: bs954@bath.ac.uk

Study Locations

• United Kingdom
  • Bath and North East Somerset
    • Bath, Bath and North East Somerset, United Kingdom, BA2 7AY
      • Recruiting
      • University of Bath
      • Principal Investigator: Javier Gonzalez, PhD
      • Contact: Bruno Spellanzon, PhD candidate; Phone Number: 447769407954; Email: bs954@bath.ac.uk
      • Contact: Javier Gonzalez, PhD; Email: jg833@bath.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age: >18 years
• Body mass index: 18.5-35 kg·m-2
• Low-Density Lipoprotein-cholesterol <4.9 mmol/L
• Non-fasting triglycerides <2.3 mmol/L

Exclusion Criteria:

• weight instability (>5% change in body mass within last 3 months)
• smoker
• diagnosis of hypercholesterolaemia or any other lipid-related disease
• diagnosis of diabetes
• diagnosis of atherosclerotic cardiovascular disease
• elevated fasting glucose (>5.4 mmol/L)
• dietary intolerances or allergies or to other study procedures
• diagnosis of gastrointestinal disorders
• any other condition/medication that could introduce bias to the study
• already following a ketogenic diet
• not willing to follow a ketogenic diet
• unable to understand English language

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Sequence 1; Participants will follow a 1) low-carbohydrate diet, wash-out, 2) control diet, wash-out, 3) low-carbohydrate diet, wash-out, 4) control diet, wash-out, 5) low-carbohydrate diet, wash-out, 6) control diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 2; Participants will follow a 1) low-carbohydrate diet, wash-out, 2) control diet, wash-out, 3) low-carbohydrate diet, wash-out, 4) control diet, wash-out, 5) control diet, wash-out, 6) low-carbohydrate diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 3; Participants will follow a 1) low-carbohydrate diet, wash-out, 2) control diet, wash-out, 3) control diet, wash-out, 4) low-carbohydrate diet, wash-out, 5) control diet, wash-out, 6) low-carbohydrate diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 4; Participants will follow a 1) low-carbohydrate diet, wash-out, 2) control diet, wash-out, 3) control diet, wash-out, 4) low-carbohydrate diet, wash-out, 5) low-carbohydrate diet, wash-out, 6) control diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 5; Participants will follow a 1) control diet, wash-out, 2) low-carbohydrate diet, wash-out, 3) control diet, wash-out, 4) low-carbohydrate diet, wash-out, 5) control diet, wash-out, 6) low-carbohydrate diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 6; Participants will follow a 1) control diet, wash-out, 2) low-carbohydrate diet, wash-out, 3) control diet, wash-out, 4) low-carbohydrate diet, wash-out, 5) low-carbohydrate diet, wash-out, 6) control diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 7; Participants will follow a 1) control diet, wash-out, 2) low-carbohydrate diet, wash-out, 3) low-carbohydrate diet, wash-out, 4) control diet, wash-out, 5) control diet, wash-out, 6) low-carbohydrate diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat
Other: Sequence 8; Participants will follow a 1) control diet, wash-out, 2) low-carbohydrate diet, wash-out, 3) low-carbohydrate diet, wash-out, 4) control diet, wash-out, 5) low-carbohydrate diet, wash-out, 6) control diet	Other: control diet; Diet will have macronutrients split with 50% carbohydrates, 15% protein and 35% fat. Also there will be a 0.66 ratio saturated:unsaturated fat; Other: Low carbohydrate diet; Diet will have macronutrients split with 8% carbohydrates, 15% protein and 77% fat. Also there will be a 0.66 ratio saturated:unsaturated fat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasted plasma Low-density lipoprotein cholesterol (LDL-C) concentrations	Variable will be used to establish whether there is true inter-individual heterogeneity in response to 24 hours of a low-carbohydrate diet. Measured in mmol/L.	Pre and post following each intervention/control diet for 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasted glucose plasma glucose concentration	Variable measured to establish whether there is true inter-individual heterogeneity in response to 24 hours of a low-carbohydrate diet. Measured in mmol/L	Pre and post following each intervention/control diet for 24 hours

Collaborators and Investigators

• Sponsor: University of Bath
• Investigators: Principal Investigator: Javier Gonzalez, PhD, University of Bath

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: May 5, 2026
• First Submitted That Met QC Criteria: June 25, 2026
• First Posted (Actual): June 30, 2026

Study Record Updates

• Last Update Posted (Actual): June 30, 2026
• Last Update Submitted That Met QC Criteria: June 25, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Diet, Carbohydrate-Restricted
• Other Study ID Numbers: 8791-12081

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No