New medications are in development for treating non-alcoholic fatty liver disease (NAFLD) at various stages, but work remains to determine how these new drugs should be used and for how long.
A. Sidney Barritt IV, MD, MSCR, Associate Professor, University of North Carolina, discussed the status of several of these medications undergoing trials now as part of The Liver Meeting® Post Graduate Course “A Hectic Day for a Hepatology Consultant.” The all-day course on Saturday offered clinicians the latest information to help with complex patient presentations and differential diagnoses. Each presentation centered around a different patient presentation and also offered presenters a platform to speak about related issues.
In a phase II clinical trial of nonalcoholic steatohepatitis (NASH) patients, elafibranor, a peroxisome proliferator activated receptor, showed to induce NASH resolution. The drug was well-tolerated, and secondary endpoints all showed metabolic syndrome improvements. Results justified a phase III clinical trial.
The phase II clinical trial of obeticholic acid, a farnesoid X nuclear receptor, in adult NASH patients decreased hepatic fat and may also improve insulin resistance and have other positive impacts on the metabolic syndrome. The trial was stopped early because of clear effectiveness, and the phase III trial is underway.
The ASK1 inhibitor Selonsertib was shown in its phase II trial to meet its primary endpoint of improved fibrosis stage, as 43 percent showed improved histology. Like the others, the phase III trial is ongoing.
A phase III trial for Cenicriviroc will take place despite the phase II trial not meeting the primary endpoint of improved histology. Cenicriviroc did appear to have an antifibrotic effect that justifies further investigation.
“The challenge of treating NASH continues even after FDA-approved medications come through,” Dr. Barritt said. “Are these going to be lifetime drugs, or will these be brief interventions so the patients can work on their lifestyle modifications? What will be the long-term cardiovascular risk, long-term cancer risk, and what will be the clinical trial efficacy versus real-world effectiveness?”
The patient featured in Dr. Barritt’s presentation was a 43-year-old asymptomatic non-drinking woman with abnormal alanine aminotransferase (ALT), diabetes (A1C of 7.2% that she says is “diet controlled”) and a body mass index of 31 Kg/m2. She’s not sure why she was referred, and a physical exam was significant for central adiposity but no stigmata of advanced liver disease or cirrhosis.
When treating patients such as the one in this case, Dr. Barritt told the audience, make sure to consider the whole patient and the cardiovascular and cancer risks. The No. 1 all-cause mortality in NASH patients is cardiovascular disease, followed by cancer and liver disease. All of these risk factors can be addressed in a complimentary manner, Dr. Barritt said.
Treating both cardiovascular disease and metabolic syndrome can mitigate cardiovascular disease, cancer and liver disease. It all starts with lifestyle modification, Dr. Barritt said, and it’s never too late to make the modifications.
“If patients are able to maintain weight loss, it can help both from an inflammatory perspective with NASH and from an anti-fibrotic perspective, too, “ he said. “The problem is that patients need to sustain this over long periods of time, but if a patient has a sustained weight loss of greater than 5%, they can reverse NASH. If the sustained weight loss is greater than 10%, they can reduce their fibrosis.”
The patient presented in the case had an ALT of 90, which led Dr. Barritt to emphasize that the clinicians know what “normal” and “abnormal” means to each clinician’s local lab. Where a lab gets its healthy population for reference can expand the range of normal, especially in areas with more obesity when compared to other areas.