Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial

Abstract

Background: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs.

Methods: A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis.

Results: Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups.

Conclusions: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs.

Clinical trial registration: Clinicaltrials.gov NCT01379625.

Conflict of interest statement

Conflict of interest Melanie B. Gillingham, PhD and Cary O Harding, MD received a research grant for a murine study from Ultragenyx Inc.

S. B. Heitner, J. Martin, S. Rose, A. Goldstein, A. H. El-Gharbawy, S. Deward, M. R. Lasarev, J. Pollaro, J. P. DeLany, L. J. Burchill, B. Goodpaster, J. Shoemaker, D. Matern, and J. Vockley declare that they have no conflict of interest.

Note: Ultragenyx Pharmaceutical was not involved with the design or execution of this study and did not provide triheptanoin for the trial.

Figures

Fig. 1

Model for the proposed benefit of triheptanoin (C7) compared to trioctanoate (C8) among patients with long-chain fatty acid oxidation disorders (LC-FAODs). Trioctanoate provides three 8 carbon fatty acids (C8) that, once imported into the mitochondria, are oxidized to 4 acetyl- CoA molecules. Triheptanoate provides three 7 carbon fatty acids (C7) that, once imported into the mitochondria, are oxidized to produce 2 acetyl-CoA and one propionyl-CoA molecule. Propionyl-CoA is converted to D-methylmalonyl-CoA by mitochondrial propionyl-CoA carboxylase followed by conversion to succinyl-CoA by D- methylmalonyl-CoA isomerase and L-methylmalonyl-CoA mutase. Succinyl-CoA is an intermediate of the citric acid cycle (CAC) and can increase intermediate pool size of carbon substrates. LCFAO = long-chain fatty acid oxidation; MCFAO = medium-chain fatty acid oxidation; CPT- 1 = carnitine palmitoyltransferase 1; CACT = carnitine acylcarnitine translocase; CPT-2 = carnitine palmitoyltransferase 2; VLCAD = very- long-chain acylCoA dehydrogenase; TFP = trifunctional protein. Patients enrolled in this clinical trial had CPT2, VLCAD or TFP deficiency, including long-chain 3-hydroxy acylCoA dehydrogenase (LCHAD) deficiency, as indicated by red enzyme color

Fig. 2

Echocardiogram and treadmill results. Data are presented as individual change over 4 months, mean and 95% confidence intervals. a) Left ventricular (LV) ejection fraction increased after 4 months of triheptanoin (C7) supplementation but did not change in the trioctanoate (C8) group. b) End systolic volume decreased and c) there was a decrease in LV wall mass in the C7 treated group compared to the C8 group. d) All but one participant had normal cardiac function at baseline and at the end of 4 months of treatment (gray shaded area indicates the normal range). Individual participant EF at baseline and 4 months of treatment is shown. More participants in the C7 group had an increase in EF compared to the random increase and decrease in EF observed in the C8 group within the normal test/retest variability of resting echocardiograms. Data are presented as mean ± standard deviation e) Ventilation during the moderate intensity treadmill was similar between treatment groups suggesting that workload was similar. f) Systolic blood pressure was not different but g) Heart rate was significantly lower in subjects treated with C7 compared to subjects in the C8 group H) double product was not significantly different between groups

Fig. 3

Body composition and energy expenditure. Data are presented as mean ± standard deviation. Subjects were instructed to consume 20% of their estimated total energy needs from the assigned study oil over the 4-month treatment period. a) There was no difference between groups and no change in body weight over the course of the treatment period. Fat free mass (FFM) and fat mass (FM) are similar between groups at baseline (not shown) and at the end of study (b). c) Resting energy expenditure per kg of fat free mass (FFM) and d) Total energy expenditure per kg of FFM was not different between groups at the end of study. e) Respiratory quotient (VCO2/VO2) was similar between groups. RQ ranged from 0.8 to 1.0 after 10-h overnight fast suggesting participants were oxidizing a mix of carbohydrates and fat at rest. f) Lipid deposition of soleus intra-myocellular (IMCL) and extra-myocellular (EMCL) did not change over the course of the treatment period but liver lipid deposition significantly decreased in the C7 group compared to C8. g) There was no difference in oxidation of the 13C–oleic acid between groups. Label recovery peaked in all subjects about 4 to 6 h after the meal and returned toward baseline 12 h after the meal. There was no difference in RQ or oleic acid oxidation after the moderate intensity treadmill between treatment groups performed between 7 and 8 h after the oral load. h) Total fat oxidation was dramatically lower among subjects with an FAO disorder compared to published normal controls (18)