Emerging Therapies and Bariatric Treatment for MASLD and MASH

Drs Fontana, Abdelmalek, and Arab discuss new therapeutic options now being developed, as well as the continued role of bariatic therapies, including endobariatics as well as surgery, for the treatment of obese patients with MASLD or MASH.

Robert Fontana, MD, is a professor of medicine and director of the Transplant Hepatology Fellowship Program at University of Michigan Medicine in Ann Arbor, Michigan. Manal Abdelmalek, MD, FAASLD, is a professor of medicine and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) Clinical Research Program at Mayo Clinic in Rochester, Minnesota. Juan Pablo Arab, MD, is associate professor of medicine and the inaugural director of Alcohol Sciences at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University (VCU) Health in Richmond, Virginia.

MASH: Emerging Therapies and Individualized Bariatric Treatment

• MASH therapeutics: New options under investigation include dual and triple incretin agonists, FGF21 agents, and PPAR agents. Combination therapy trials are anticipated.
• Noncirrhotic MASH with clinical obesity: Endoscopic sleeve procedures may be considered after lifestyle interventions and pharmacotherapy fails, or medications are not tolerated. GLP-1–associated nausea and vomiting can limit treatment. Some 30% of patients using GLP-1s quit within the first year.
• Bariatric surgery: Consideration may be appropriate for substantial weight-loss needs and poorly controlled cardiometabolic disease. Some newer drugs achieve 20%–25% weight loss; treatment selection requires discussion of patient preferences, benefits, risks, and evolving long-term safety and outcomes data.

Dr Fontana:

Right now we have resmetirom, a thyroid hormone beta agonist. We have semaglutide, the GLP-1, and maybe vitamin E if maybe for whatever reason is a third-line agent. But JP, what's coming? We've heard about single receptor incretins, double receptor, triple. Can you give us just an overview of what you see happening in the next year or two in the field of MASH therapeutics?

Dr Arab:

Yeah, so there are more options coming. So we have these 2 drugs approved were the 2 first, but there is a significant number of new drugs coming, some on the family of the GLP-1. So single is GLP-1, but you have dual with glucagon or GIP or triple with combining GLP-1, glucagon, GIP. Some of these drugs have been already tested either for obesity, weight loss, or diabetes. So it makes sense that they may transfer, but there are other families too. Some of the important ones are the FGF21s. So there is actually a study in patients with cirrhosis and MASH that it was positive. And also the PPAR, so the pump PPR that has also been tested. So I think new families are coming and even the ones that we have are there.

And as Manal was mentioning, now the next step is going to be, well, we have all these drug that separately work. What happened if we combine this medication? So I think those trials are also going to come at some point, which is great for the field because finally we are having good therapeutic options for this population.

Dr Fontana:

So lots of potential new avenues, new pathways, et cetera. Well, that's quite exciting. Now what we also have in our toolbox as GI docs, is endoscopy. So at the same time of all this drug development, there's been quite a bit of improvements in endoscopic technique. So Manal, you're at Mayo, and I believe your center was one of the pioneers with endoscopic gastric sleeves. So tell us, where does that fit into your thinking? You see someone with MASH, they have cardiometabolic risk factors, maybe they're overweight. Should you be offering them endoscopic gastric sleeve or is it pure medicines? Where does it fit in?

Dr Abdelmalek:

So I do offer these options to my patients and we have to take a look at the patients holistically, not just from a liver-centric standpoint. If I see that patient who is otherwise young and a suitable surgical candidate who's got such poorly controlled diabetes, hypertension, dyslipidemia, and has more than 100% of their ideal body weight to lose, we know we're not going to get effective weight loss with resmetirom and maybe 10 to 15% with GLP-1s. Some patients are fortunate to get 20% weight loss, but for patients who have even more to lose than that and having cardiopulmonary complications of significant weight, potentially the right answer for the most significant weight loss is surgical interventions—Roux-en-Y gastric bypass, sleeve gastrectomy, maybe endobariatric procedures. So while it's important to treat the liver endpoint, I do believe there's a cohort of patients who could benefit from bariatric surgical procedures for those reasons.

And some of these reasons can potentially be life-threatening. A1Cs which are exorbitantly high, greater than 9, sometimes 11 or 13, I see in my practice and they're on multiple medications. Some patients need bigger guns and we should size them up for considerations of that and have an informed discussion and allow them to choose.

Dr Fontana:

So JP, I assume you have a similar phenotype of patients, particularly the more severe ones with the cardiometabolic endpoints already being met or coming. What's the response of patients to proposing bariatric surgery or maybe endobariatrics, which is a little less invasive? Are they enthusiastic or do they want to try a GLP-1 first? What's been your experience?

Dr Arab:

Yeah, my experience is patients prefer the medications before trying the surgery, but as Manal was mentioning, not everyone is going to respond to this medication. And the other thing that we need to consider is that many of these patients cannot tolerate the medications. So with GLP-1s, nausea and vomiting, it's a real issue. And if you follow these patients for some time, there is even a study showing that 30% of them are going to discontinue within the first year due to side effects. So I think, again, we need to be very individualized and trying to be very precise on who benefits from what.

For example, endoscopic sleeve gastrectomy could be a good idea in a patient with clinical obesity, with noncirrhotic MASH that has failed lifestyle intervention plus pharmacotherapy or cannot tolerate it. I think that's kind of a good gap filler in that sense. And then a straight bariatric surgery, you may consider BMI more than 35 or 40, very uncontrolled diabetes, where you really need to, and that patients that are in the verge of becoming cirrhotics and you really want to have a strong change quickly.

And I think again, that discussion needs to happen to the patient. Of course, I think most of my patients, they prefer the less invasive things first and you need to have that discussion, what are the pros and cons and what you can achieve. In the past with the initial drugs, we were able to achieve 5, 10% of body weight. Then we were able to achieve 10, 15. Now some of these drugs are able to achieve 20 to 25% of body weight, which is similar to what you can get with some of these bariatric interventions. So I think data is evolving. We'll need to have the long-term outcomes, the safety data to really strongly advise one over the other. But my guess is at the end it will be a discussion with the patient on what are the cons and pros on different options that not necessarily one is better than the other.

Dr Fontana:

So certainly it sounds like a personalized medicine approach is coming to our field and it's literally happening as we speak. That's been my experience as well, that patients really want to try something simple, oral or subcutaneous if they have to, first before they'll even go to a bariatric clinic or even within my own division, my endobariatric colleagues, they're a little bit hesitant. I think I find that a little bit of an easier sell, but still a little bit of hesitancy. So I tend to see the same thing, that it's more of a personalized approach here currently.