Stimulating Fat Tissue Storage With Niacin to Reduce Fat Accumulation in the Liver.

Université de Sherbrooke36 enrolled

Overview

Metabolic dysfunction-associated steatotic liver disease (MASLD) (aka non-alcoholic fatty liver disease), commonly occurring in individuals with obesity and type 2 diabetes can lead to liver inflammation/ fibrosis. MASLD results from fat being disproportionately deposited in the liver. The goal of this mechanistic study is to investigate metabolic response in patients aged 50 to 80 years with non-alcoholic fatty liver disease, after niacin (vitamin B3) treatment. The main questions it aims to answer are: * Does Niacin lower the fat deposition in the liver? * Does Niacin raise White Adipose Tissue storage of dietary fatty acids? Researchers will compare Niacin to a placebo (a look-alike substance that contains no drug) to compare the metabolic response. Duration of study per participant: Up to 28 weeks

It will be a randomized crossover study with two 12-week treatment phases (niacin vs. placebo) with a 4-week washout period between the two treatment phases. The two 12-week treatment phases will be performed in random order. The treatment will be administered once daily, at the end of the largest meal. There will be a 3-week dose escalation: from 250mg (the first week) to 750mg from week 3 onward. The outcomes will be assessed at the end of each of these two treatment phases in all participants with metabolic visit A and B (i.e., a total of 4 metabolic visits). Each metabolic visit will last 9 hours: it will be a test meal with perfusion of stable tracers, blood sampling, PET acquisitions using radiopharmaceuticals (18FTHA and 11C-palmitate) and MRI acquisitions. The two visits A and B will be performed without and with acute administration of niacin with the test meal, respectively, to determine acute niacin-induced reduction in hepatic fatty acid flux. The two visits will be performed at four to seven-day interval, in random order during the last week of each of the treatment phase.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

QUADRUPLE

Interventions

Niacin (250mg)DRUG

Niacin will be orally taken once daily with the largest meal. There will be a 3-week escalation period from 250 mg to 750 mg: * Week 1: 250mg * Week 2: 500mg * Week 3 to Week 12: 750mg (3 x 250mg caplets)

Placebo Oral TabletDRUG

Placebo will be orally taken once daily with the largest meal. There will be a 3-week escalation period from 250 mg to 750 mg: * Week 1: 250mg * Week 2: 500mg * Week 3 to Week 12: 750mg (3 x 250mg caplets)

Eligibility

Sex: ALLMin age: 50 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * aged 50 to 80 years; * diagnosed with MASLD, defined as the presence of liver steatosis + abdominal obesity (as defined by the International Diabetes Federation country/ethnic group-specific criteria; * all women will be post-menopausal. Exclusion Criteria: 1. Presence of advanced fibrosis (i.e., ≥ F3 based on liver stiffness \> 10kPa) using vibration-controlled transient elastography (FibroScan), serum ALT \> 3 times the normal upper limit, or signs of portal hypertension \[106-109\]. 2. Other hepatic disease. 3. Previous diagnosis of diabetes. 4. Overt cardiovascular or renal disease, cancer (other than non-melanoma skin cancer), or other uncontrolled medical conditions. 5. Any contraindication to MRI. 6. Previous intolerance or allergy to nicotinic acid. 7. Having participated to a research study with exposure to radiation in the last two years before the start of the study. 8. Being allergic to eggs 9. Smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day.

Outcomes

Primary Outcomes

Prolonged small-dose niacin treatment does not lead to desensitization of the niacin-induced reduction in hepatic total fatty acids flux.

Total 6 h integrated uptake of circulating NEFAs, DFAs, and all FAs in liver: represents the sum of the rate of NEFA uptake integrated over 360 min for the entire organ and the rate of DFA uptake integrated over 360 min for the entire organ.

Time frame: Week 12, Week 28

Secondary Outcomes

Change in White Adipose Tissue (WAT) and lean tissue Dietary Fatty Acid (DFA) uptake

Determined from the same static (whole-body) acquisition image using oral administration of \[18F\]-Fluoro-6-Thia-Heptadecanoic Acid (FTHA)

Time frame: Week 12, Week 28

Change in total hepatic fatty acid flux

represents the sum of the rate of NEFA uptake and DFA uptake (PET scan using \[18F\]-FTHA and \[11C\]-palmitate

Time frame: Week 12, Week 28

Change in hepatic Non-Esterified-Fatty-Acid (NEFA) uptake oxidation, esterification and secretion into very low-density lipoprotein (VLDL)

\[11C\]-Palmitate PET. Calculated from the same multicompartmental equation using liver \[11C\]-palmitate kinetics

Time frame: Week 12, Week 28

Change in Endogenous Glucose production and meal glucose systemic flux

i.v. and oral stable isotope tracer

Time frame: Week 12, Week 28

Change in plasma NEFA flux

calculated from i.v. stable isotope tracer (mass spectrometry).

Time frame: Week 12, Week 28

Change in hepatic Triglyceride (TG) content

magnetic resonance imaging (MRI)

Time frame: Week 12, Week 28

Change in insulin secretion

Determined by measuring C-peptide kinetics following the liquid meal

Time frame: Week 12, Week 28

Change in hormonal response

Multiplex assay

Time frame: Week 12, Week 28

Change in metabolite response

Colorimetric assay

Time frame: Week 12, Week 28

Change in plasma distribution of DFA metabolites

calculated from i.v. and oral stable isotope tracers (mass spectrometry) incorporated into triglyceride-rich lipoproteins and NEFA.

Time frame: Week 12, Week 28

Change in glycerol turnover

calculated from \[1,1,2,3,3-2H\]-glycerol i.v.

Time frame: Week 12, Week 28

Change in total substrate utilisation

measured by using indirect calorimetry

Time frame: Week 12, Week 28

Change in insulin resistance /sensitivity

Determined by measuring circulating glucose, NEFA and insulin following the liquid meal.

Time frame: Week 12, Week 28

Circulating markers of hepatic inflammation

Measurement of Alanine aminotransferase (ALT), Aspartate transaminase (AST) and platelet count for calculation of fibrosis-4 which is an index for liver fibrosis.

Time frame: Week1, Week 12, Week 16, Week 28

Adverse events

Time frame: up to 28 weeks

Stimulating Fat Tissue Storage With Niacin to Reduce Fat Accumulation in the Liver.

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts