Metabolic Flexibility Predicts Response to Saroglitazar in Liver Transplant Recipients With Metabolic Dysfunction–associated Steatotic Liver Disease

Metabolic flexibility is the ability to match biofuel availability to utilization, with carbohydrates being the major fuel source in the fed state and fatty acids in the fasted state.1 Metabolic dysfunction–associated steatotic liver disease (MASLD) after liver transplantation (LT) is common and associated with reduced metabolic flexibity.2 The current analysis aimed to evaluate the impact of saroglitazar, a dual peroxisome proliferator-associated receptor γ/δ ligand, on metabolic flexibility in LT recipients using data from a phase 2A, single-center, open-labeled study that evaluated the safety and efficacy of saroglitazar 4 mg/d for 24 wk in 15 LT recipients with MASLD.3 Saroglitazar has previously demonstrated efficacy for treatment of MASLD in non-LT.4 The study design, enrollment criteria, and cohort have been described previously (ClinicalTrials.gov identifier: NCT03639623).3 Metabolic flexibility was measured at baseline and end of treatment (EOT) using whole room calorimetry for 18 h continuously and expressed as a respiratory quotient (RQ).2 Study participants were given a standardized meal after 6 h in the whole room calorimeter with an additional 12 h of continuous measurements. Peak RQ represents maximal carbohydrate metabolism and occurs in the postprandial state, whereas trough RQ represents maximal fatty acid metabolism occurring in the fasted state. No statistically significant differences in RQ curves were noted from baseline to EOT (n = 15; Figure 1A). The cohort was subsequently divided into study participants who responded (reduction in MRI proton density fat fraction; n = 9) and those who did not (no change/increase in MRI proton density fat fraction; n = 4) to determine the interaction between response to saroglitazar and metabolic flexibility. One patient was excluded from the analysis presented in Figure 1B as they did not have EOT MRI. At baseline, patients who responded to therapy (n = 9) had better metabolic flexibility than nonresponders (n = 5; Figure 1B). Study participants who responded to saroglitazar (versus those who did not) had a shorter time to peak (275 ± 82 versus 388 ± 82 min, P = 0.04), signifying a more rapid transition to maximal carbohydrate metabolism following a standardized meal. LT recipients responding to saroglitazar also had lower fasting RQ, reflecting greater fatty acid utilization in the fasting state, compared with nonresponders who had a greater reliance on carbohydrates (higher fasting RQ) during the fasting state. An improvement in time to peak was noted in responders (275 ± 82 to 246 ± 65 min) and nonresponders (388 ± 82 to 281 ± 97 min) from baseline to EOT; however, this did not reach statistical significance. Otherwise, no significant differences were noted in RQ from baseline to EOT when patients were stratified according to treatment response.FIGURE 1.: Impact of saroglitazar on metabolic flexibility. A, Metabolic flexibility, depicted as respiratory quotient (RQ), was similar in the 15 liver transplant recipients at baseline and week 24 (end of therapy) in patients treated with saroglitazar. B, Study participants who had reduction in liver fat as measured by MRI PDFF from baseline to the end of therapy (study responders; n = 9) had better metabolic flexibility compared with patients who did not have any reduction in liver fat (study nonresponders; n = 5). PDFF, proton density fat fraction.Metabolic flexibility is a strong predictor of future metabolic health1,5 and can potentially be used as a biomarker to identify which patients are likely to respond to MASLD therapy. Lack of response in patients with reduced metabolic flexibility may be due to a high metabolic burden that may be too much to overcome. Although the present study lacked a placebo arm and had a modest sample size, it does provide innovative data that have the potential to lead to personalized care of LT recipients, where patients are matched with the likelihood of pharmacological response to optimize patient outcomes.