Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial

Abstract

Objective: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies.

Methods: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise.

Results: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise.

Conclusion: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo.

Classification of evidence: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.

Figure 1. Flow diagram for the bezafibrate study

Figure 2. Fat metabolism

(A) Plasma palmitate concentration, (B) plasma free fatty acid (FFA) concentration, (C) palmitate oxidation, and (D) total fatty acid oxidation (FAO) at rest (gray) and during exercise at 50% to 60% of maximal oxygen uptake capacity (V̇o₂max) (black) without and with bezafibrate (green) in 10 patients with carnitine palmitoyltransferase II (n = 5) and very long-chain acyl-CoA dehydrogenase (n = 5) deficiencies. Values are mean ± standard error (SE). *p < 0.05 rest vs exercise; ^§p < 0.05 placebo vs bezafibrate. Dotted line indicates the mean fatty acid/palmitate oxidation at the 40th minute of exercise in 7 healthy controls exercising at 50% to 60% of V̇o₂max, and the shaded area is ±SE.

Figure 3. Exercise capacity

Perceived exertion (Borg) (A) and heart rate (B) during and at the end of exercise at 50% to 60% of maximal oxygen uptake capacity with placebo (closed circle) and bezafibrate (open circle) in 10 patients with carnitine palmitoyltransferase II (n = 5) and very long-chain acyl-CoA dehydrogenase (n = 5) deficiencies. Values are mean ± standard error.