RCT of Caloric Restriction vs. Alternate-Day Fasting in Non-Alcoholic Fatty Liver Disease

Obesity Clinical Trial

Official title: A Randomized Controlled Trial of Caloric Restriction vs. Alternate-Day Fasting in Patients With Non-Alcoholic Fatty Liver Disease

Status Terminated

Clinical Trial Summary

Non-alcoholic fatty liver disease (NAFLD) in patients with diabetes (T2DM) is increasing in prevalence and can lead to cirrhosis. Lifestyle intervention with caloric restriction (CR) is the cornerstone of treatment but remission is variable. Alternatively, the PI has shown alternate day fasting (ADF) is safe and well tolerated in obese patients and there might be additional beneficial effects. The objective is to combine the expertise of the PI with this novel intervention and the expertise of Dr. Cusi in NAFLD to explore the effects of ADF vs CR in patients with NAFLD and T2DM to test the following hypotheses:

H1: In patients with NAFLD and T2DM, the ADF intervention will result in more favorable metabolic changes than CR:

H1a: Hepatic triglyceride by MRS will decrease more with ADF than CR (Primary Outcome) and remain lower following a period of free living H1b: There will be greater improvements in glucose homeostasis following ADF vs CR H1c: There will be greater improvement in lipid metabolism following ADF vs CR and changes in ketone metabolism will predict changes in hepatic triglyceride content H2: ADF will have similar safety and tolerability and result in a similar degree of weight loss in participants with NAFLD and DM compared to CR

Clinical Trial Description

Rationale:

Non alcoholic fatty liver disease (NAFLD) has a prevalence of up to 80% in patients with T2DM and obesity and can lead to steatohepatitis (NASH) and fibrosis as well as cirrhosis and hepatocellular carcinoma. As NAFLD is associated with increased risk of cardiovascular disease and mortality and as NAFLD-induced liver disease is anticipated to be the most common indication for liver transplantation over the next decade, treatment options are desperately needed but very few are available.

Weight loss with caloric restriction (CR) is the preferred treatment of NAFLD, however successful maintenance of a significant weight loss is difficult to achieve. Additionally, despite significant association between degree of weight loss and improvements in NASH and NAFLD, there is extensive overlap in the response among populations. This suggests that it may not be weight loss in general, but rather the mechanistic underpinnings of the weight loss that potentiate the therapeutic effects. A study comparing dietary carbohydrate restriction vs CR in obese subjects with NAFLD found that, despite similar weight loss between groups, there was greater hepatic triglyceride reduction with carbohydrate restriction and this reduction was highly correlated with plasma ketone concentrations. Hence, although weight loss is ostensibly important, there might be additional factors beyond just weight loss per se causing the improvements in NASH. Therefore, rather than weight loss, reduction in intrahepatic triglyceride will be the primary endpoint of this proposal.

Progression to NASH and beyond is largely due to a spectrum of metabolic abnormalities including ectopic hepatic fat accumulation, insulin resistance, and abnormal lipid metabolism. A recent animal study showed blunted ketogenesis in NASH and suggested the overall etiology was due to inefficient oxidation and disposal of free fatty acids in the liver. A fasting paradigm, or facilitating times of ketosis that could then normalize lipid metabolism, might be one of the additional factors beyond weight loss that ensures improvements in NAFLD and NASH.

Intermittent fasting (IF) is a dietary intervention whereby food is restricted for varying timeframes, including alternate day fasting (ADF) where no or very few calories are given for a day or more with ad lib feeding in between. In animal models, IF has been shown to have numerous beneficial effects, many in excess of those seen with CR. In a mouse model of NAFLD, IF resulted in improvements in hepatic steatosis and inflammation along with gene expression changes showing enhanced activation of lipid oxidation and reduction of lipid synthesis. These benefits may be due to "flipping the metabolic switch" from glucose to ketone utilization for primary cellular energy needs. Data are only beginning to emerge on the effects of IF in humans, and very few studies have focused on ketone production as a mediator of positive outcomes. There are no data on the effect of ADF on NAFLD.

Specific Aims:

SA1: To compare the effect of ADF vs CR on metabolic changes including liver fat, glucose homeostasis, lipid metabolism, and inflammation in patients with NAFLD and T2DM SA1a: To determine changes in hepatic triglyceride by MRS after 4 weeks of ADF and after 4 weeks of ad lib diet SA1b: To determine changes in glucose homeostasis SA1c: To determine changes in whole body lipid metabolism and inflammation SA2: To determine the safety, tolerability, and effectiveness on weight loss of ADF vs CR SA2a: To determine safety of ADF SA2b: To compare changes in body weight, body composition, physical activity, physical functioning and physical fitness SA2c: To determine effect on eating behaviors, hunger/satiety, and body image SA2d: To determine effect on cognition and quality of life ;

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Fatty Liver
• Liver Diseases
• NAFLD
• Non-alcoholic Fatty Liver Disease
• Obesity

• NCT number: NCT03365531
• Study type: Interventional
• Source: University of Florida
• Status: Terminated
• Phase: N/A
• Start date: March 1, 2018
• Completion date: July 1, 2019