Mechanism of Ketogenic Diet-Induced Hypercholesterolemia

Not Applicable

Recruiting

• Conditions: Hypercholesterolemia and Hyperlipidemia

• Registration Number: NCT06894004
• Lead Sponsor: Washington University School of Medicine

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.

Study Timeline

• Study Start: 2025-02-24
• Status Verified: 2025-03
• Study First Submitted: 2025-03-10
• Study First Submitted QC: 2025-03-18
• Last Update Submitted: 2025-03-18
• Study First Posted: 2025-03-25
• Last Update Posted: 2025-03-25
• Primary Completion: 2030-11-30
• Study Completion: 2030-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Primary Outcome Measures

Name	Time	Method
VLDL-ApoB100 production rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and VLDL-ApoB100 leucine isotopic enrichment and compartmental modeling

Secondary Outcome Measures

Name	Time	Method
VLDL-ApoB100 fractional catabolic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and VLDL-ApoB100 leucine isotopic enrichment and compartmental modeling
IDL-ApoB100 production rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and IDL-ApoB100 leucine isotopic enrichment and compartmental modeling
LDL-ApoB100 production rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and LDL-ApoB100 leucine isotopic enrichment and compartmental modeling
LDL-ApoB100 fractional catabolic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and LDL-ApoB100 leucine isotopic enrichment and compartmental modeling
IDL-ApoB100 fractional catabolic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and IDL-ApoB100 leucine isotopic enrichment and compartmental modeling
VLDL-triglyceride production rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and VLDL glycerol isotopic enrichment and compartmental modeling
VLDL-triglyceride fractional catabolic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and VLDL glycerol isotopic enrichment and compartmental modeling
Plasma lipoprotein lipase activity	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by assaying lipoprotein lipase activity in post-heparin plasma
Plasma lipoprotein profile	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.	Determined by standard clinical chemistry methods and by advanced lipoprotein profiling
Whole-body lipolytic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma palmitate isotopic enrichment
Relative contribution of systemic fatty acids to VLDL-triglyceride	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using plasma and VLDL-triglyceride palmitate isotopic enrichment and compartmental modeling
Cholesterol synthetic rate	Immediately after the 4-week ketogenic diet intervention period and immediately after the 4-week control diet intervention period.	Determined by using mass isotopomer distribution analysis of deuterium enrichment in plasma cholesterol after labeling the total body water pool with deuterium oxide
Fat mass	Immediately after the screening ketogenic diet	Determined by using dual-energy X-ray absorptiometry
Fat-free mass	Immediately after the screening ketogenic diet	Determined by using dual-energy X-ray absorptiometry
Insulin sensitivity	Immediately after the screening ketogenic diet	Determined by measuring fasting plasma glucose, insulin, and C-peptide
Thyroid function	Immediately after the screening ketogenic diet	Determined by measuring TSH, free T4, and free T3
Adipokines	Immediately after the screening ketogenic diet	Determined by measuring plasma leptin and adiponectin
Cholesterol absorption markers	Immediately after the screening ketogenic diet	Determined by measuring serum campesterol, sitosterol, and cholestanol

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States