Nicotinamide Riboside + Ketogenic Diet for Fatty Liver Disease

Overseen By Stephanie T Chung, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Diet medications

Disqualifiers: Liver disease, Non-MODY2 diabetes, Heart failure, others

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

Compensation: Varies

Number of Visits: 1

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: At least 30% of Americans have fatty liver disease. This means that they store too much fat in the liver. At the moment lifestyle changes are the only way to treat this problem. Objective: To test how (1) a low-carbohydrate diet and (2) a supplement called nicotinamide riboside (NR) affect how a person s body uses dietary fat. Eligibility: Men aged 18 to 65 and women aged 18 to 50 who are healthy volunteers with a body mass index (height to weight ratio) of 25 or more. Adults with maturity-onset diabetes of the young type 2 (MODY2) are also needed. Design: Participants with diabetes will have 1 screening visit and a 9-day clinic stay. Healthy volunteers will have 1 screening visit and 2 clinic stays of 1 to 2 weeks each. During screening, all participants will have a physical exam with blood and urine tests. They will have their heart rhythm measured while riding a gym bike. NR is a pill taken by mouth. Only healthy volunteers will take the NR, for 14 days at a time, during 1 clinic stay. During their other stay, they will take placebos; these are pills that look like the study supplement but contain no NR. During each clinic stay, all participants will eat a normal American diet. Then they will eat a ketogenic "low-carb" diet for 5 days. Participants will have many tests, including: Sleeping every night and having two 24-hour stays in a special room that measures the gases their body uses and produces. Drinking a high-fat shake, then remaining seated for 5 hours while their blood and breath are monitored. Having a substance injected into the arm and remaining seated for 3 hours while their blood is measured. Wearing monitors to measure their activity levels. Another monitor will measure their blood glucose levels. Having imaging scans. ...

Will I have to stop taking my current medications?

Yes, participants must stop taking prescription medications or other drugs or supplements that may affect energy metabolism or nutrient digestion or absorption.

What data supports the effectiveness of the treatment involving a ketogenic diet and nicotinamide riboside for fatty liver disease?

Research suggests that low carbohydrate ketogenic diets can rapidly decrease liver fat content and improve metabolic issues related to non-alcoholic fatty liver disease (NAFLD). Additionally, weight loss through dietary changes is strongly associated with improvements in liver health. ^{1 2 3 4 5}

Is the combination of a ketogenic diet and nicotinamide riboside safe for humans?

Research suggests that ketogenic diets, including variations like the Spanish Ketogenic Mediterranean Diet, are generally safe for treating conditions like metabolic syndrome and nonalcoholic fatty liver disease. However, specific safety data on the combination of a ketogenic diet with nicotinamide riboside is not provided in the available studies. ^{2 3 6 7 8}

How does the treatment of Nicotinamide Riboside and Ketogenic Diet for Fatty Liver Disease differ from other treatments?

This treatment is unique because it combines Nicotinamide Riboside, a vitamin B-3 supplement that boosts NAD+ levels to improve liver health, with a Ketogenic Diet, which is high in fats and low in carbohydrates, to potentially reduce liver fat and improve metabolism. Unlike other treatments, this approach targets both cellular energy production and dietary changes to address fatty liver disease. ^{9 10 11 12 13}

Research Team

Stephanie T Chung, M.D.

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria

This trial is for healthy men aged 18-65 and pre-menopausal women aged 18-50 with a BMI of 25 or more, including those with MODY2 diabetes. Participants should be weight stable and able to perform moderate cycling without heart issues. Exclusions include heavy alcohol use, liver disease indicators, significant medical conditions, drug use, certain psychological conditions, strict dietary restrictions, inability to follow study procedures or give consent.

Inclusion Criteria

Able to cycle at a moderate rate and intensity with a HR equal to or greater than 0.3(SqrRoot) (220-age-HRest)+HRest but not exceeding 0.4(SqrRoot) (220-age-HRest)+HRest with no signs of arrhythmia

I am an adult with MODY2, male (18-65) or female (18-50) and not in menopause.

I am a woman aged 18-50 and have not gone through menopause.

Exclusion Criteria

My hematocrit level is below 37%.

You are currently involved in a regular exercise program, doing more than 2 hours of intense activity each week, as reported by you.

You drink more than 300 mg of caffeine per day, according to what you tell us.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Baseline Diet

Participants consume a standard high-carbohydrate diet to establish baseline measurements

2 days

Part of clinic stay

Ketogenic Diet with NR or Placebo

Participants consume a ketogenic low-carb diet for 5 days, with healthy volunteers taking NR or placebo

5 days

Part of clinic stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketogenic Diet
• Nicotinamide Riboside
• Placebo
• Standard Diet

Trial Overview The trial examines the effects of a ketogenic diet and nicotinamide riboside (NR) supplement on fat usage in the body. Healthy volunteers will take NR pills for two weeks during one clinic stay and placebos during another. All participants will switch from a standard American diet to a low-carb ketogenic diet while undergoing various tests like physical exams, blood/urine tests, activity monitoring, glucose level tracking and imaging scans.

Participant Groups

Group I: Women with overweight or obesity Experimental Treatment 4 Interventions

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

Group II: Men with overweight or obesity Experimental Treatment 4 Interventions

To investigate whether NR supplementation augments the sleeping energy expenditure and fat oxidation rate during the ketogenic diet in men and women with overweight and obesity

Group III: MODY2 Patients Experimental Treatment 3 Interventions

To measure changes in sleeping energy expenditure and fat oxidation rate after transitioning from a baseline diet to an isocaloric ketogenic diet similar to our previous study in men

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

Findings from Research

Hypocaloric diets, especially low carbohydrate ketogenic diets, are effective in rapidly reducing liver fat and improving metabolic issues associated with non-alcoholic fatty liver disease (NAFLD).

Diets high in saturated fats are particularly harmful, as they increase liver fat and insulin resistance, while vitamin E supplementation can reduce liver fat and fibrosis but does not improve insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. Yki-Järvinen, H.[2018]

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing alongside obesity and metabolic syndrome, making it the most common chronic liver disease, which can progress to severe conditions like cirrhosis and liver cancer.

A ketogenic diet (KD), which is very low in carbohydrates, may help alleviate oxidative stress and restore mitochondrial function, suggesting it could be a potential therapeutic approach for managing NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review. Paoli, A., Cerullo, G.[2023]

In a study of 240 adults (120 with NAFLD and 120 without), low carbohydrate diets (LCDs) did not show a significant association with the risk of developing non-alcoholic fatty liver disease, suggesting that higher protein and fat intake alone may not contribute to NAFLD risk.

Patients with NAFLD had significantly higher intakes of protein, carbohydrates, and cholesterol compared to controls, indicating that while these dietary factors are prevalent in NAFLD, they do not correlate with the consumption of low carbohydrate diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence to low carbohydrate diets and non-alcoholic fatty liver disease: a case control study. Yaghoubi, F., Darand, M., Vasmehjani, AA., et al.[2023]

In a study of 74 patients with non-alcoholic fatty liver disease (NAFLD), both the low-carb high-fat (LCHF) diet and the 5:2 intermittent calorie restriction diet significantly reduced liver fat and body weight compared to standard lifestyle advice, with reductions of 7.2% and 6.1% in hepatic steatosis, respectively.

There was no significant difference in effectiveness between the LCHF and 5:2 diets, indicating that both can be tailored to individual preferences for treating NAFLD, while the 5:2 diet also improved LDL cholesterol levels and was better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. Holmer, M., Lindqvist, C., Petersson, S., et al.[2022]

Weight loss of at least 5-7% of total body weight is crucial for improving liver health in patients with non-alcoholic fatty liver disease (NAFLD), as it can lead to better liver enzyme levels and reduced liver fat.

A hypocaloric diet is the most effective dietary approach for weight loss in NAFLD management, while a Mediterranean diet can also improve liver fat levels even without weight loss, highlighting the importance of personalized dietary recommendations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary Approaches for Management of Non-Alcoholic Fatty Liver Disease: A Clinician's Guide. Aboubakr, A., Stroud, A., Kumar, S., et al.[2021]

In a study of 153,076 nondiabetic Koreans followed for an average of 4.1 years, fasting ketonuria was linked to a significantly lower risk of developing nonalcoholic fatty liver disease (NAFLD), with a hazard ratio of 0.81 compared to those without ketonuria.

Persistent ketonuria was associated with the greatest reduction in risk for incident hepatic steatosis, suggesting that higher levels of ketones may play a protective role against liver fat accumulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fasting Ketonuria and the Risk of Incident Nonalcoholic Fatty Liver Disease With and Without Liver Fibrosis in Nondiabetic Adults. Kim, Y., Chang, Y., Kwon, MJ., et al.[2021]

In a pilot study of 5 patients with obesity-related fatty liver disease, a low-carbohydrate ketogenic diet for 6 months resulted in an average weight loss of 12.8 kg, indicating its potential effectiveness for weight management.

Post-treatment liver biopsies showed significant histological improvements in liver fat content, inflammation, and fibrosis, suggesting that this dietary approach may help reverse fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Tendler, D., Lin, S., Yancy, WS., et al.[2018]

The Spanish Ketogenic Mediterranean Diet (SKMD) significantly improved various health markers in 14 obese men over 12 weeks, including body weight, liver enzymes, and cholesterol levels, indicating its efficacy in treating metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD).

After following the SKMD, all participants were free of metabolic syndrome according to the International Diabetes Federation criteria, demonstrating the diet's potential as a safe and effective intervention for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study. Pérez-Guisado, J., Muñoz-Serrano, A.[2017]

A 12-week clinical trial involving 40 obese, insulin-resistant men found that supplementation with nicotinamide riboside (NR) at a dose of 2000 mg per day was safe, with no serious adverse events reported.

However, NR supplementation did not improve insulin sensitivity or metabolic parameters such as glucose metabolism, resting energy expenditure, or body composition, indicating that it may not be effective for enhancing metabolic health in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Dollerup, OL., Christensen, B., Svart, M., et al.[2023]

The combination of L-carnitine and nicotinamide riboside significantly reduced body weight gain (by 17%) and fat mass gain (by 22%) in mice on a high-fat diet over 21 weeks, indicating its potential as an effective treatment for obesity and non-alcoholic fatty liver disease (NAFLD).

This combined treatment improved liver metabolism by reversing harmful effects of a high-fat diet on key metabolic pathways, suggesting a novel approach to enhance fatty acid utilization and protect against obesity-related liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. Salic, K., Gart, E., Seidel, F., et al.[2021]

Nicotinamide riboside (NR) supplementation significantly reduced liver fibrosis in a diet-induced mouse model, indicating its potential as a preventative treatment for liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD).

NR was found to inhibit the activation of hepatic stellate cells, which play a key role in liver fibrosis, and also increased energy expenditure, suggesting a mechanism of action that may involve enhancing metabolic processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, an NAD+ precursor, attenuates the development of liver fibrosis in a diet-induced mouse model of liver fibrosis. Pham, TX., Bae, M., Kim, MB., et al.[2021]

In a study of 70 diabetic patients with nonalcoholic fatty liver disease (NAFLD), nicotinamide supplementation (1000 mg daily for 12 weeks) significantly reduced liver enzymes and improved metabolic markers like cholesterol and insulin resistance, although it did not affect liver steatosis or fibrosis scores.

Patients taking nicotinamide also reported a significant improvement in their quality of life, particularly in areas related to activity and fatigue, indicating that while it may not change liver fat levels, it can enhance overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide supplementation in diabetic nonalcoholic fatty liver disease patients: randomized controlled trial. El-Kady, RR., Ali, AK., El Wakeel, LM., et al.[2022]

Nicotinamide riboside (NR) has been shown to prevent and even reverse liver fibrosis in mice, indicating its potential as a protective treatment against liver damage.

The protective effects of NR are linked to its ability to activate Sirt1, which regulates the acetylation of Smads, thereby inhibiting the activation of hepatic stellate cells involved in liver fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. Jiang, R., Zhou, Y., Wang, S., et al.[2022]

References

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

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Investigating the Link between Ketogenic Diet, NAFLD, Mitochondria, and Oxidative Stress: A Narrative Review. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Adherence to low carbohydrate diets and non-alcoholic fatty liver disease: a case control study. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. [2022]

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

Dietary Approaches for Management of Non-Alcoholic Fatty Liver Disease: A Clinician's Guide. [2021]

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

Fasting Ketonuria and the Risk of Incident Nonalcoholic Fatty Liver Disease With and Without Liver Fibrosis in Nondiabetic Adults. [2021]

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

The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. [2018]

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

The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study. [2017]

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

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, an NAD+ precursor, attenuates the development of liver fibrosis in a diet-induced mouse model of liver fibrosis. [2021]

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

Nicotinamide supplementation in diabetic nonalcoholic fatty liver disease patients: randomized controlled trial. [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. [2022]