Dietary Intervention for Cardiovascular Risk

(GRADY Trial)

Overseen By Jennifer Wilcox

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Must be taking: Aspirin

Must not be taking: Antibiotics, Probiotics

Disqualifiers: Heart failure, Renal failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

170 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Our group has recently identified the association between gut-flora-mediated carnitine and phosphatidylcholine metabolism, specifically trimethylamine-N-oxide (TMAO), and cardiovascular risk. This study investigates the ability for dietary intervention to modulate TMAO levels.

Will I have to stop taking my current medications?

The trial requires participants to either stay on their current aspirin regimen or stop taking aspirin for 1 week before starting the study. Other medications are not specifically mentioned, so it's best to discuss with the study team.

Is the dietary intervention for cardiovascular risk generally safe for humans?

The fasting-mimicking diet (FMD), which is a type of dietary intervention, has been shown to be safe in healthy volunteers, leading to weight loss and improved metabolic health without reported adverse effects. This suggests that similar dietary interventions may be generally safe for humans. ^{1 2 3 4 5}

How does the MeLT dietary intervention differ from other treatments for cardiovascular risk?

The MeLT dietary intervention is unique because it focuses on reducing levels of trimethylamine N-oxide (TMAO), a compound linked to cardiovascular risk, by limiting caloric intake and animal-derived protein consumption. This approach is different from traditional treatments as it specifically targets gut microbiota metabolism, which is not addressed by conventional cardiovascular therapies. ^{1 4 5 6 7}

What data supports the effectiveness of the treatment for reducing cardiovascular risk?

Research shows that reducing levels of TMAO, a compound linked to higher cardiovascular risk, can be achieved through dietary interventions like the fasting-mimicking diet and grape pomace polyphenols, which significantly lowered TMAO levels in studies. These findings suggest that similar dietary approaches in the trial may help lower cardiovascular risk by reducing TMAO levels. ^{1 4 5 8 9}

Who Is on the Research Team?

Wilson Tang, MD

Principal Investigator

The Cleveland Clinic

Stanley L. Hazen, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

The GRADY trial is for men and women over 18 who are willing to modify their diet for 12 weeks and can either stay on aspirin or avoid it a week before and during the study. It's not suitable for those with recent infections, antibiotic use within two months, past stomach surgeries, pregnancy, significant chronic illnesses, or recent probiotic/yogurt consumption.

Inclusion Criteria

I can stay on or stop taking aspirin as needed for the study.

Willing to sign consent form and follow the study protocol, which may include 12-weeks of dietary modification.

Exclusion Criteria

I have had weight loss surgery.

I do not have serious ongoing illnesses like heart failure or kidney problems.

Any condition which, in the judgment of the Investigator, would place a patient at undue risk by being enrolled in the trial, or cause inability to comply with the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dietary interventions to modulate TMAO levels, including Mediterranean Low-TMAO and Therapeutic Lifestyle Changes diets

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• MeLT Dietary intervention
• MeLT dietary intervention with TMAO
• TLC Dietary intervention

Trial Overview This study tests if changing your diet can affect levels of TMAO, a gut flora metabolite linked to heart disease risk. Participants will try one of three diets: MeLT Diet alone; MeLT Diet plus TMAO; or TLC (Therapeutic Lifestyle Changes) Diet.

How Is the Trial Designed?

Group I: TLC Dietary intervention Experimental Treatment 1 Intervention

Therapeutic Lifestyle Changes (TLC) diet. Used in cohorts 1, 2 and 3.

Group II: MeLT dietary intervention with TMAO Experimental Treatment 1 Intervention

Mediterranean Low TMAO diet with TMAO levels reported. Used in cohort 1 only.

Group III: MeLT Dietary intervention Experimental Treatment 1 Intervention

Mediterranean Low-TMAO (MeLT) diet. Used in cohorts 1, 2 and 3.

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Published Research Related to This Trial

Trimethylamine-N-oxide (TMAO), produced by gut bacteria from certain dietary precursors, is linked to the development of metabolic dysfunction-associated fatty liver disease (MAFLD), particularly when consuming high-nutrient diets like red meat and eggs.

Excess TMAO levels can disrupt liver energy metabolism and contribute to MAFLD by affecting bile acid metabolism and increasing oxidative stress, highlighting the need for strategies to lower TMAO concentrations as a potential treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trimethylamine-N-Oxide Pathway: A Potential Target for the Treatment of MAFLD. Li, X., Hong, J., Wang, Y., et al.[2021]

The oral carnitine challenge test (OCCT) effectively identifies individuals who produce high levels of the metabolite TMAO, which is linked to cardiovascular disease, outperforming fasting plasma TMAO measurements.

In a study involving 57 participants (23 vegetarians and 34 omnivores), omnivores were found to be 10 times more likely to be high TMAO producers, suggesting dietary habits significantly influence TMAO production and highlighting the potential for personalized dietary guidance in CVD prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Wu, WK., Chen, CC., Liu, PY., et al.[2022]

A novel liquid chromatography-mass spectrometry (LC/MS) method was developed to measure trimethylamine N-oxide (TMAO) levels in serum, showing high precision and accuracy, which could enhance clinical practice and nutraceutical research.

After 8 weeks of treatment with grape pomace extract, both intervention groups significantly reduced TMAO serum levels by approximately 78%, indicating the efficacy of this nutraceutical formulation in lowering cardiovascular risk in overweight/obese subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Grape Pomace Polyphenols With or Without Pectin on TMAO Serum Levels Assessed by LC/MS-Based Assay: A Preliminary Clinical Study on Overweight/Obese Subjects. Annunziata, G., Maisto, M., Schisano, C., et al.[2020]

A 5-day fasting-mimicking diet (FMD) significantly reduced plasma levels of trimethylamine N-oxide (TMAO) by twofold in healthy volunteers, indicating a potential benefit in lowering cardiometabolic disease risk.

Participants on the FMD also experienced an average weight loss of 2.8 kg, improved insulin sensitivity, and elevated ketone bodies, while the vegetable intake group showed only minor metabolic changes, highlighting the efficacy of FMD over simply increasing vegetable consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting-Mimicking Diet Reduces Trimethylamine N-Oxide Levels and Improves Serum Biochemical Parameters in Healthy Volunteers. Videja, M., Sevostjanovs, E., Upmale-Engela, S., et al.[2022]

In a study involving male C57BL/6 mice, dietary trimethylamine N-oxide (TMAO) worsened glucose tolerance in those fed a high-fat diet, leading to increased fasting insulin levels and insulin resistance after 4 weeks.

The negative effects of TMAO were linked to changes in liver gene expression related to insulin signaling and inflammation in adipose tissue, indicating that TMAO may contribute to metabolic dysfunction in high-fat diet conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. Gao, X., Liu, X., Xu, J., et al.[2022]

In a study of 4,131 older adults, higher levels of trimethylamine N-oxide (TMAO) were linked to an increased risk of developing atherosclerotic cardiovascular disease (ASCVD), particularly in individuals with impaired kidney function.

Among 1,449 participants with a history of ASCVD, elevated TMAO levels were also associated with a higher risk of recurrent cardiovascular events, indicating that TMAO may play a significant role in both the onset and recurrence of heart-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults. Lee, Y., Nemet, I., Wang, Z., et al.[2022]

An 8-week vegan diet significantly reduced plasma TMAO levels and improved glucose tolerance in 23 participants with obesity or dysglycemia, indicating potential benefits for cardiometabolic health.

After returning to an unrestricted diet for 4 weeks, TMAO levels rebounded, highlighting the importance of dietary choices in managing metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of an 8-Week Vegan Diet on Plasma Trimethylamine-N-Oxide and Postchallenge Glucose in Adults with Dysglycemia or Obesity. Argyridou, S., Davies, MJ., Biddle, GJH., et al.[2023]

A short-term high-fat diet (55% fat) in 10 healthy, nonobese young men did not significantly increase fasting plasma levels of TMAO, a compound linked to heart disease.

However, the same diet led to significantly higher postprandial TMAO levels at each hour after a high-fat meal, indicating that while fasting levels remain stable, the body's response to fat intake can elevate TMAO production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. Boutagy, NE., Neilson, AP., Osterberg, KL., et al.[2018]

A novel nutraceutical formulation, Taurisolo®, significantly reduced serum levels of TMAO and oxidative stress biomarkers in a study of 213 participants, with reductions of up to 75.80% in TMAO after 8 weeks of treatment.

Taurisolo® also decreased oxidized LDL and reactive oxygen species, suggesting it may be an effective strategy for preventing atherosclerosis, especially since conventional treatments do not target TMAO levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taurisolo®, a Grape Pomace Polyphenol Nutraceutical Reducing the Levels of Serum Biomarkers Associated With Atherosclerosis. Annunziata, G., Ciampaglia, R., Maisto, M., et al.[2021]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Trimethylamine-N-Oxide Pathway: A Potential Target for the Treatment of MAFLD. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of Grape Pomace Polyphenols With or Without Pectin on TMAO Serum Levels Assessed by LC/MS-Based Assay: A Preliminary Clinical Study on Overweight/Obese Subjects. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Fasting-Mimicking Diet Reduces Trimethylamine N-Oxide Levels and Improves Serum Biochemical Parameters in Healthy Volunteers. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Longitudinal Plasma Measures of Trimethylamine N-Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community-Based Older Adults. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation of an 8-Week Vegan Diet on Plasma Trimethylamine-N-Oxide and Postchallenge Glucose in Adults with Dysglycemia or Obesity. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Taurisolo®, a Grape Pomace Polyphenol Nutraceutical Reducing the Levels of Serum Biomarkers Associated With Atherosclerosis. [2021]