Fenofibrate keeps lid on triglyceride in NASH patients receiving ACC inhibitor

For nonalcoholic steatohepatitis (NASH) patients with hypertriglyceridaemia, treatment with fenofibrate helps reduce the increases in triglyceride levels associated with acetyl-coenzyme A carboxylase (ACC) inhibition, as shown in a study.

In a cohort of 66 NASH patients with triglyceride elevation, 2 weeks of treatment with fenofibrate (145 mg daily; n=33) produced a more pronounced reduction in triglycerides as compared with icosapent ethyl (2 g twice daily; n=33). The median fasting serum triglyceride dropped from 190 mg/dL at baseline to 158 mg/dL at week 2 with fenofibrate (median change, –32 mg/dL; p=0.010) and from 177 mg/dL at baseline to 165 mg/dL at week 2 with icosapent ethyl (median change, –12 mg/dL; p=0.09). [Clin Gastroenterol Hepatol 2022;doi:10.1016/j.cgh.2021.12.044]

Fenofibrate continued to confer a superior triglyceride-lowering effect even when administered with the combination of the farnesoid X receptor agonist cilofexor (CILO; 30 mg daily) and the ACC inhibitor firsocostat (FIR; 20 mg daily). In a 6-week combination treatment phase, median triglyceride decreased by –2 mg/dL with fenofibrate as opposed to an increase of 41 mg/dL with icosapent ethyl.

In the subgroup of patients with baseline triglycerides <250 mg/dL, fenofibrate remained more effective than icosapent ethyl at mitigating triglyceride increases after 6 weeks of combination treatment (median change, 6 vs 39 mg/dL). Similar trends were observed in the subgroup of patients with baseline triglycerides ≥250 mg/d (–61 vs 99 mg/dL).

In terms of safety, all treatments were well tolerated. Most documented treatment-emergent adverse events (AEs) were grade 1–2 severity, and none of them led to treatment discontinuation. Of note, none of the patients developed hepatotoxicity, which was encouraging considering regulatory requirements to include liver disease as a contraindication to fibrate therapy, according to the investigators.

“These results complement a growing body of literature supporting the safety of fibrates in patients with liver disease, including NASH with advanced (F3–F4) fibrosis,” they said. [Liver Int 2021;41:1335-1343; N Engl J Med 2018;378:2171-2181; Hepatology 2019;70:LP5]

“After 6 weeks of combination treatment with CILO and FIR, no change from baseline in serum triglycerides was observed in the fenofibrate group, while an ~22.4 percent median increase was observed in the icosapent ethyl group. Changes in triglycerides were generally similar in subgroups defined by pretreatment triglyceride level (<250 or ≥250 mg/dL),” they added.

Moreover, the changes in serum triglycerides observed in this study are consistent with prior observations in patients with advanced fibrosis (F3–F4) due to NASH treated with FIR monotherapy. [Hepatology 2019;70:LP5]

These findings have important clinical implications, as the investigators pointed out, because prior studies have shown an increased risk of FIR-induced triglyceride elevation in patients with pre-existing hypertriglyceridaemia, particularly ≥250 mg/dL. [Gastroenterology 2018;155:1463-1473.e6]

While of insufficient duration to evaluate the impact of fenofibrate or icosapent ethyl on the potential hepatic benefits of CILO plus FIR treatment, “the present study provides both clinical and mechanistic support for the use of fenofibrate in the mitigation of firsocostat-induced serum triglyceride elevations in patients with NASH,” the investigators said.