Should the beneficial impact of bezafibrate on fatty acid oxidation disorders be questioned?

Bastin, Jean; Bonnefont, Jean‐Paul; Djouadi, Fatima; Bresson, Jean‐Louis

doi:10.1007/s10545-014-9775-7

Cited by 11 publications

(5 citation statements)

References 15 publications

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“…A randomized, double-blind, crossover study of bezafibrate in patients with CPT II and VLCAD deficiencies showed lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations, but no changes in fatty acid oxidation, or heart rate during exercise (Ørngreen et al, 2014). The bases for the apparently conflicting findings have been discussed between the respective research groups (Bastin et al, 2015;Ørngreen et al, 2015); however, the benefit of treatment with bezafibrate remains unresolved.…”

Section: Clinical Phenotype and Therapies In Etf Pathologymentioning

confidence: 99%

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Henriques

Olsen

Gomes

et al. 2021

Gene

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Section: Clinical Phenotype and Therapies In Etf Pathologymentioning

confidence: 99%

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Henriques

Olsen

Gomes

et al. 2021

Gene

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“…Conversely, a 3-month, randomized, double-blind, crossover study involving a bezafibrate clinical trial in patients with CPT-2 and VLCAD deficiencies failed to demonstrate improvement in clinical symptoms or in some physical abilities [ 15 ]. Hence, the clinical efficacy of bezafibrate for FAODs is still controversial [ [16] , [17] , [18] ].…”

Section: Introductionmentioning

confidence: 99%

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan

Yamada

Shiraishi

Oki³

et al. 2018

Molecular Genetics and Metabolism Reports

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IntroductionFatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs.Materials and methodsThis trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires).ResultsThe frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed.ConclusionIn this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations.

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“…Moreover, they can ameliorate disease phenotype, including cardiac pathology, in various mitochondrial disease and RASopathy murine models (89)(90)(91). However, there have been mixed results from clinical trials of selected fatty acid oxidation disorders and mitochondrial myopathies and toxicity concerns raised, which are species specific (92)(93)(94)(95)(96)(97). Bezafibrate treatment in the Mmut -/-Tg INS-Alb-Mmut mice improved survival, restored the mitochondrial ultrastructure and metabolic activity of BAT (improved 18 F-FDG uptake in the PET study), and increased Ucp1 expression in the WAT of treated animals, associated with an increased 18 F-FDG uptake in subcutaneous fat tissue in a distribution pattern similar to the expanded subcutaneous fat depots seen in patients.…”

Section: Discussionmentioning

confidence: 99%

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation

Manoli,

Sysol,

Head

et al. 2024

JCI Insight

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A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model ( Mmut –/– Tg INS-Alb-Mmut ). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

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Should the beneficial impact of bezafibrate on fatty acid oxidation disorders be questioned?

Cited by 11 publications

References 15 publications

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan

Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation

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