The Causal Role of Ketone Bodies in Obesity-associated Disease Prevention - Combining Genetic Epidemiology With a Randomised Trial to Infer Causality
KETO-GENETIC
1 other identifier
interventional
69
1 country
1
Brief Summary
Excess weight increases the risk of several diseases including cardiovascular disease, type 2 diabetes, kidney disease and various cancers. There is a need for preventative strategies for obesity-associated disease, especially for people in the overweight and moderately obese ranges where pharmacological intervention may not be suitable. Low-carbohydrate (ketogenic) diets are popular for weight control. Ketogenic diets increase circulating ketones, which can have favourable effects on cardiometabolic health markers. However, the ketogenic diet has a nutrient composition associated with harms (high-saturated fat/red meat, and low-fibre). The net effects of ketogenic diets on long-term health are unclear. Ketone supplements can increase circulating ketones and could provide benefits of ketosis without needing to adhere to a potentially harmful diet. Establishing causality between complex exposures (e.g., diet) and long-term outcomes (e.g., disease), is challenging. The MRC \& NIHR Review of Nutrition and Human Health Research (2017) highlighted an "overreliance (as opposed to reasonable reliance) on observational studies" as a key barrier to progression in the field of nutrition and health. Randomised controlled trials (RCTs) facilitate causal inference, but for long-term outcomes are expensive, time-consuming, and often suffer from waning adherence. Mendelian randomization (MR) can estimate causal effects subject to key assumptions. A challenge to these assumptions includes complex behavioural exposures (e.g., diet), which could be intercorrelated with causal factors. Our proposal will address these limitations with a novel combination of study designs to establish causal effects of ketosis (via diet and supplementation) on obesity-associated disease risk in humans. The investigators will combine a tightly controlled, short-term RCT, with MR to link short-term responses to long-term endpoints. The investigators will examine the circulating (blood) and tissue-specific (adipose) transcriptomic and proteomic responses in the fasted and postprandial state in response to our dietary interventions and translate these to MR by identifying single-nucleotide polymorphisms from genome wide association studies. This approach overcomes limitations of RCTs and MR, as adherence to diets will be confirmed with controlled feeding, and intermediate molecular traits as exposure for MR are less likely to be intercorrelated with causal traits.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for not_applicable
Started May 2025
Longer than P75 for not_applicable
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 30, 2024
CompletedFirst Posted
Study publicly available on registry
October 31, 2024
CompletedStudy Start
First participant enrolled
May 6, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 6, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
January 1, 2030
July 31, 2025
July 1, 2025
2 years
October 30, 2024
July 28, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (3)
Plasma proteome
Plasma proteome at week 4 adjusted for baseline values
From baseline to week 4
Transcriptome of peripheral blood mononuclear cells
Transcriptome of peripheral blood mononuclear cells at week 4 adjusting for baseline values
From baseline to week 4
Transcriptome of adipose tissue
Transcriptome of subcutaneous abdominal adipose tissue at week 4 adjusting for baseline values
From baseline to week 4
Secondary Outcomes (3)
Apolipoprotein B concentrations
From baseline to week 4
Urinary albumin concentrations
From baseline to week 4
Fasting glucose concentrations
From baseline to week 4
Study Arms (3)
CONTROL
NO INTERVENTIONKETONE ESTER
ACTIVE COMPARATORKETOGENIC DIET
EXPERIMENTALInterventions
25g ketone ester 3x/day. The ketone ester will be a beta-hydroxybutyrate monoester \[(R)-3-hydroxybutyl (R)-3-hydroxybutyrate\].
Eligibility Criteria
You may qualify if:
- Body mass index: 25-45 kg/m2
- Waist circumference \>93.9 (males) or \>79.9 (females)
You may not qualify if:
- Glucose or lipid lowering medication
- Diagnosis of cardiovascular disease, renal failure, liver disease or type 2 diabetes
- Contraindications to a ketogenic diet (e.g., pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency)
- Unable to understand English language
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of Bathlead
- University of Bristolcollaborator
- Imperial College Londoncollaborator
Study Sites (1)
University of Bath
Bath, Bath, BA2 7AY, United Kingdom
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- RANDOMIZED
- Masking
- NONE
- Masking Details
- Outcome assessors will be masked to the group allocation when analysis is outsourced from the University.
- Purpose
- BASIC SCIENCE
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor of Nutrition and Metabolism
Study Record Dates
First Submitted
October 30, 2024
First Posted
October 31, 2024
Study Start
May 6, 2025
Primary Completion (Estimated)
May 6, 2027
Study Completion (Estimated)
January 1, 2030
Last Updated
July 31, 2025
Record last verified: 2025-07