Semaglutide Shows Promise for MASH Resolution, Severe Fibrosis: Naim Alkhouri, MD

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide (Ozempic), are yet to receive FDA approval for the treatment of metabolic dysfunction–associated steatotic liver disease (MASLD) and metabolic dysfunction–associated steatohepatitis (MASH). Multiple ongoing trials, however, are demonstrating the great potential for these drugs to influence MASH resolution and benefit those with more severe fibrosis.

In this last installment of his interview, Naim Alkhouri, MD, FAASLD, DABOM, chief medical officer, chief of transplant hepatology, and director of the Steatotic Liver Program at Arizona Liver Health, spoke to the exciting research in this area and where there is room to grow. Thus far, studies such as the ongoing ESSENCE trial have shown patients’ liver health improve, among other benefits. And this is just the beginning, Alkhouri noted, as more developments are on the horizon.

This transcript has been lightly edited; captions were auto-generated.

Transcript

How do you envision the role of GLP-1s evolving in MASH treatment, and what evidence or gaps need to be addressed to support their broader adoption?

We have very promising data with the GLP-1 receptor agonist, semaglutide, in a phase 3 trial called the ESSENCE trial to treat patients with biopsy-proven MASH and significant fibrosis—so F2 and F3 fibrosis. After treating these patients for 72 weeks with semaglutide, with the obesity dose of 2.4 mg weekly, we achieved MASH resolution in about 63% of patients, with the delta from placebo of 29%; and then we achieved fibrosis improvement in 37% of patients, with the delta from placebo of 14.5%. We achieved the 2 primary efficacy end points in terms of improvement in liver histology; that was very promising.1

Patients lost, on average, about 10% of their total body weight, and there was improvement in liver enzymes and some biomarkers of liver health. Based on these data, we anticipate that the FDA may grant approval at the end of this year for semaglutide, specifically to treat MASH with significant fibrosis.

I think the gaps that we still have are related to tolerability. Patients that go on a GLP-1, sometimes they have [gastrointestinal] side effects, and we estimate that after 1 year of treatment, 20%-30% of patients are no longer on a GLP-1 because of tolerability issues we've had, also issues with insurance coverage sometimes. And hopefully these issues are being resolved now.

We also see the efficacy, especially on fibrosis, and when we're talking about a 14.5% delta from placebo, it's great that this was significant, but I think we can improve this delta. The goal is to get up to a 50% difference, and I think by then the majority of patients will be considered responders.

I think we have a lot of work to do, but I think this is a major step forward with having GLP-1 approved to treat MASH because they will help with weight loss, with diabetes control, with dyslipidemia, and most importantly, we have long-term data showing benefits on cardiovascular outcomes in patients with diabetes and in patients with obesity, and this will be the majority of patients with MASLD and MASH. This will be a new and welcome addition to what we can do today.

I suspect that many patients will not tolerate the GLP-1 and can go on resmetirom [Rezdiffra], which is the other FDA-approved medication. I also suspect that some patients will have an initial response to GLP-1s, but over time may still have progressive disease, and then we can add resmetirom on top of GLP-1 therapy. The future is looking better than ever, but knowing what's coming next, I think we're going to continue to improve on the efficacy rates and improve tolerability also, and again, be able to reverse the disease and hopefully 1 day cure it completely and get to a point where we can take patients off medications.

References

1. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. Published online April 30, 2025. doi:10.1056/NEJMoa2413258