Contrasting Ketogenic and Mediterranean Diets in Individuals With Type 2 Diabetes and Prediabetes: The Keto-Med Trial

The objective of this study is to compare two metabolically distinct diets, WFKD vs Med-Plus, in order to examine the potential benefits, and unintended consequences, of going beyond a focus on maximally avoiding added sugars and refined grains, to also avoiding legumes, fruits, and whole grains.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; PreDiabetes
• Intervention / Treatment: Behavioral: Mediterranean Diet (Med-Plus); Behavioral: Well-Formulated Ketogenic Diet (WFKD)

Detailed Description

The proposed randomized clinical trial will investigate differential population-specific effects of two low-carbohydrate (low-carb) diet patterns, addressing a gap in the evidence base in this area that will lead to 1) improved treatment strategies for common adverse clinical conditions, 2) improved health for these individuals, and 3) long-term decreases in health care costs. This impactful research will advance the field of personalized and precision medicine.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18
• Diagnosed with type 2 diabetes mellitus, OR prediabetes (defined as HbA1c </= 5.7% OR Fasting Glucose of >100 mg/dL)

Identify exclusion criteria.

• Weight < 110 lb
• BMI > 40
• LDL-C >190 mg/dL
• Blood pressure: SBP > 160 mmHg OR DBP: > 90 mmHg

Exclusion Criteria:

• Weight < 110 lb
• BMI ≥ 40
• LDL-C >190 mg/dL
• Systolic blood pressure (SBP) > 160 mmHg OR Diastolic blood pressure (DBP) > 90 mmHg
• Diagnosed with type 1 diabetes or history of ketoacidosis
• Uncontrolled and untreated diabetes (by discretion of study physician)
• Active cardiovascular disease (in past year with myocardial infarction, coronary stent or bypass surgery)
• Kidney disease (eGFR less than 50 mL/min per 1.73 m2)
• Liver disease (liver transaminase higher than 3 times the normal range for the laboratory)
• Symptomatic gallstones
• History of bariatric surgery
• Anemia
• Taking any of the following medications in past 3 months: SGLT-2 inhibitors, GLP-1 receptor agonist, Insulin, Amylin analog, Alpha-glucosidase inhibitor, Dopamine agonist, Bile acid sequestrant.
• Taking any medications for weight loss
• History of active cancer in the past 3 years except for squamous or basal cell carcinomas of the skin that have been medically managed by local excision
• Unstable dietary history as defined by major changes in diet during the previous month, where the subject has eliminated or significantly increased a major food group in the diet.
• Recent history of chronic excessive alcohol consumption defined as more than five 1.5-ounce servings of 80 proof distilled spirits, five 12-ounce servings of beer or five 5-ounce servings of wine per day; or > 14 drinks/week.
• Women: Pregnant currently or planning to become pregnant during the course of the study, and/or breastfeeding
• Regular/frequent use of smoking or chewing tobacco, e-cigarettes, cigars or other nicotine-containing products
• Regular use of prescription opiate pain medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mediterranean Diet (Med-Plus); Participants will follow a Mediterranean-type diet (Med-Plus) for 12 weeks. This diet will maximize the intake of vegetables, legumes, fruits and nuts, whole intact grains/cereals and fish; and minimize the intake of meat, poultry, and dairy. It will exclude added sugars and refined grains.	Behavioral: Mediterranean Diet (Med-Plus); Participants will follow the Med-Plus diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).
Experimental: Well-Formulated Ketogenic Diet (WFKD); Participants will follow a Well-Formulated Ketogenic Diet (WFKD) for 12 weeks. This diet will maximize the intake of non-processed beef, pork, and poultry (preferably organic/grass-fed), fish, heavy cream, low-lactose, high-fat cheeses, animal fats, oils (avocado, coconut, or other nut oils), non-starchy (above ground) vegetables and limited amounts of some fruits (berries). It will exclude legumes, grains, sugars, starchy (below ground) vegetables, most fruits, and polyunsaturated oils (soy, sunflower, peanut, cottonseed, canola, etc.). It will aim for an intake of 20 g of carbohydrates/day at start, with the goal to have no more than 50 grams/day to maintain ketosis.	Behavioral: Well-Formulated Ketogenic Diet (WFKD); Participants will follow the WFKD diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin A1c (HbA1c)	Change from baseline in HbA1c at 12 weeks of each phase	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiota composition	Change from baseline in alpha diversity at 12 weeks of each phase. We will be using number of observed sequence variants ("species") determined by standard 16S rRNA amplicon sequencing (V3-V5 region followed by DADA2 to define error-corrected sequence variants) as our primary metric of alpha diversity. Higher alpha diversity is better. The units are the # of sequence variants.	Baseline and 12 weeks
Microbiota function	Change from baseline in composite of short-chain fatty acids (SCFA) concentration (ug/g stool: acetate + propionate + butyrate) at 12 weeks of each phase.	Baseline and 12 weeks
LDL Cholesterol	Change from baseline in LDL cholesterol at 12 weeks of each phase.	Baseline and12 weeks
HDL Cholesterol	Change from baseline in HDL cholesterol at 12 weeks of each phase.	Baseline and 12 weeks
Triglycerides	Change from baseline in triglycerides at 12 weeks of each phase.	Baseline and 12 weeks
Fasting insulin	Change from baseline in fasting insulin at 12 weeks of each phase.	Baseline and 12 weeks
Blood pressure	Change from baseline in blood pressure at 12 weeks of each phase.	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Satisfaction with WFKD and Med-Plus diets	Average satisfaction level with meals at 12 weeks of each phase (WFKD compared to Med-Plus phase) using a 5-point Likert scale (1=not at all satisfied; 2=slightly satisfied; 3=moderately satisfied; 4=very satisfied; 5=extremely satisfied).	Baseline and 12 weeks
Adherence to diet protocols	Adherence to diet protocols 12 weeks of each phase in subjects with Diabetes compared to subjects with prediabetes, according to 3-day food records.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Stanford University

Publications and helpful links

General Publications

• Gardner CD, Landry MJ, Perelman D, Petlura C, Durand LR, Aronica L, Crimarco A, Cunanan KM, Chang A, Dant CC, Robinson JL, Kim SH. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial. Am J Clin Nutr. 2022 Sep 2;116(3):640-652. doi: 10.1093/ajcn/nqac154. Erratum In: Am J Clin Nutr. 2022 Dec 19;116(6):1904.
• Landry MJ, Crimarco A, Perelman D, Durand LR, Petlura C, Aronica L, Robinson JL, Kim SH, Gardner CD. Adherence to Ketogenic and Mediterranean Study Diets in a Crossover Trial: The Keto-Med Randomized Trial. Nutrients. 2021 Mar 17;13(3):967. doi: 10.3390/nu13030967.

Helpful Links

• Study description and summary of results

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2019
• Primary Completion (Actual): December 4, 2020
• Study Completion (Actual): December 6, 2020

Study Registration Dates

• First Submitted: January 9, 2019
• First Submitted That Met QC Criteria: January 17, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 18, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Prediabetes; Mediterranean diet; Ketogenic diet
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State; Glucose Intolerance
• Other Study ID Numbers: 49218

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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