Mechanism of Ketogenic Diet-Induced Hypercholesterolemia

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.

Study Overview

• Status: Recruiting
• Conditions: Hypercholesterolemia and Hyperlipidemia
• Intervention / Treatment: Behavioral: Ketogenic Diet; Behavioral: Control Diet

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 Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Frannie Wilkinson, M.A.; Phone Number: (314) 362-0590; Email: francesw@wustl.edu
• Study Contact Backup: Name: Max C Petersen, M.D., Ph.D.; Phone Number: 314-362-8352; Email: max.p@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Nikki Plassmeyer, M.A., R.D.N., L.D.; Phone Number: (314) 362-0590; Email: nikkip@wustl.edu
      • Contact: Max C Petersen, M.D., Ph.D.; Phone Number: 314-362-8450; Email: max.p@wustl.edu
      • Principal Investigator: Max C Petersen, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

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

Description

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 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Arm A will complete the Ketogenic Diet intervention first, followed by the Control Diet intervention after a 4-week washout period.	Behavioral: Ketogenic Diet; Participants will consume an isocaloric ketogenic diet for 4 weeks with all food provided as packed-out meals.; Behavioral: Control Diet; Participants will consume an isocaloric control diet for 4 weeks with all food provided as packed-out meals.
Experimental: B; Arm B will complete the Control Diet intervention first, followed by the Ketogenic Diet intervention after a 4-week washout period.	Behavioral: Ketogenic Diet; Participants will consume an isocaloric ketogenic diet for 4 weeks with all food provided as packed-out meals.; Behavioral: Control Diet; Participants will consume an isocaloric control diet for 4 weeks with all food provided as packed-out meals.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Max C Petersen, M.D., Ph.D., Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2025
• Primary Completion (Estimated): November 30, 2030
• Study Completion (Estimated): November 30, 2030

Study Registration Dates

• First Submitted: March 10, 2025
• First Submitted That Met QC Criteria: March 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: ketogenic diet; cholesterol; LDL-cholesterol; lipoprotein kinetics
• Additional Relevant MeSH Terms: Metabolic Diseases; Dyslipidemias; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Hypercholesterolemia; Hyperlipidemias; Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Diet, Carbohydrate-Restricted; Diet, Ketogenic
• Other Study ID Numbers: 202409091

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All raw data used to generate descriptive statistics presented in manuscripts incorporating results generated from this study will be included as supplemental data files as and when required. Fully de-identified raw data, including all outcome measures and tracer enrichments from kinetic studies will be available in .csv format, which can be manipulated by many free and commercial software packages. Individual-level data will be shared as allowed by informed consent agreements approved by the Institutional Review Board (IRB).
• IPD Sharing Time Frame: Data will be made available upon peer-reviewed publication of the study results or earlier as required by the study sponsor and/or funding sources.
• IPD Sharing Access Criteria: FAIR Data Sharing protocols will be applied so that the data will be Findable, Accessible, Interoperable, and Re-usable.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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