Clinical trial NCT06668168: The Causal Role of Ketone Bodies in Obesity-associated Disease Prevention - Combining Genetic Epidemiology with a Randomised Trial to Infer Causality
Official title: The CAUSAL ROLE of KETONE BODIES in OBESITY-ASSOCIATED DISEASE PREVENTION - COMBINING GENETIC EPIDEMIOLOGY with a RANDOMISED TRIAL to INFER CAUSALITY
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Nutrition
Obesity and Overweight
Lead sponsor: University of Bath
Sponsor class: OTHER
First posted: 2024-10-31
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

We will combine a tightly controlled, short-term RCT, with MR to link short-term responses to long-term endpoints. We 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.


Eligibility criteria: Inclusion Criteria:

* Body mass index: 25-45 kg/m2
* Fat mass index: : \>6 kg/m2 for males, \>9 kg/m2 for females

Exclusion Criteria:

* 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

Primary outcomes:
measure: Apolipoprotein B concentrations
timeFrame: From baseline to week 4
measure: Fasting glucose concentrations
timeFrame: From baseline to week 4
measure: Urinary albumin concentrations
timeFrame: From baseline to week 4
Secondary outcomes:
Other outcomes:
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