Clinical trial NCT06894004: Mechanism of Ketogenic Diet-Induced Hypercholesterolemia
Official title: Mechanism of Ketogenic Diet-Induced Hypercholesterolemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hypercholesterolemia and Hyperlipidemia
Keywords: LDL-cholesterol
cholesterol
ketogenic diet
lipoprotein kinetics
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2025-03-25
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Very-low carbohydrate ketogenic diets can dramatically increase blood cholesterol levels, particularly in normal-weight people, for reasons that are not well understood. This study will enroll normal-weight adults, will identify "responders" who develop high cholesterol on a ketogenic diet, and will measure rates of production and removal of certain types of cholesterol-carrying particles called lipoproteins in responders. The results will clarify the mechanism by which a ketogenic diet can cause high cholesterol in certain susceptible people.

Detailed description: This study will evaluate the mechanism of ketogenic diet-induced hypercholesterolemia in susceptible normal-weight adults. The first stage of screening will identify eligible young adults who are normal-weight and at low cardiovascular risk. The second stage of screening will identify "responders" who demonstrate susceptibility to ketogenic diet-induced hypercholesterolemia by displaying an increase in LDL-cholesterol concentration after a 3-week screening ketogenic diet. Responders will be eligible to complete a randomized crossover clinical study at Washington University School of Medicine in St. Louis, MO. The randomized crossover study will involve isotope tracer studies of lipoprotein and cholesterol kinetics after two separate 4-week dietary interventions \[ketogenic diet and control diet\], conducted in random order with a 4-week washout period between interventions. All food will be provided to the participants as packed-out meals. Certain outcomes will use data from the screening process, comparing screen successes and screen failures to evaluate factors that could influence susceptibility to ketogenic diet-induced hypercholesterolemia.

Eligibility criteria: Inclusion Criteria:

1. age ≥ 18 and \< 40 years
2. BMI ≥ 18.5 and \< 25.0 kg/m2
3. baseline serum LDL-c \< 150 mg/dL (\< 3.9 mmol/L)
4. baseline serum TG \< 100 mg/dL (\< 1.1 mmol/L)
5. HbA1c ≤ 5.6%.

Exclusion Criteria:

1. personal or family history of familial hypercholesterolemia
2. current use of lipid-lowering drugs
3. currently on a ketogenic diet and unwilling to change diet
4. current tobacco use
5. hypertension
6. prediabetes or diabetes
7. elevated Lp(a) \> 6.5% of ApoB-containing lipoproteins at baseline
8. oral contraceptive use
9. contraindication to heparin
10. known atherosclerotic cardiovascular disease
11. unwilling to abstain from alcohol

Primary outcomes:
measure: VLDL-ApoB100 production rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
Secondary outcomes:
measure: VLDL-ApoB100 fractional catabolic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: IDL-ApoB100 production rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: IDL-ApoB100 fractional catabolic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: LDL-ApoB100 production rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: LDL-ApoB100 fractional catabolic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: VLDL-triglyceride production rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: VLDL-triglyceride fractional catabolic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: Plasma lipoprotein lipase activity
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: Plasma lipoprotein profile
timeFrame: At baseline, immediately after the screening ketogenic diet, immediately after the 4-week ketogenic diet intervention period, and immediately after the 4-week control diet intervention period.
measure: Whole-body lipolytic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: Relative contribution of systemic fatty acids to VLDL-triglyceride
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: Cholesterol synthetic rate
timeFrame: Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.
measure: Fat mass
timeFrame: Immediately after the screening ketogenic diet
measure: Fat-free mass
timeFrame: Immediately after the screening ketogenic diet
measure: Insulin sensitivity
timeFrame: Immediately after the screening ketogenic diet
measure: Thyroid function
timeFrame: Immediately after the screening ketogenic diet
measure: Adipokines
timeFrame: Immediately after the screening ketogenic diet
measure: Cholesterol absorption markers
timeFrame: Immediately after the screening ketogenic diet
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Max C Petersen, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: