Semaglutide Takes the Stage as a Potential Tx for MASH

Semaglutide is currently a hot ticket item when it comes to glycemic control in type 2 diabetes and for weight loss, but does it have a role in the treatment of metabolic dysfunction-associated steatohepatitis (MASH, formerly known as non-alcoholic steatohepatitis [NASH])? A phase II trial suggests that it does, by teasing out anticipation of higher-powered studies for semaglutide alone or in combination with other treatments.

"This placebo-controlled, randomized phase II trial is the first study to assess the efficacy and safety of semaglutide 2.4 mg once weekly in patients with MASH-related compensated cirrhosis (fibrosis stage 4)," Rohit Loomba, PhD, MD, NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, and colleagues wrote in Lancet Gastroenterology & Hepatology. "There was no difference between semaglutide and placebo for the primary endpoint (fibrosis improvement without worsening of MASH) or the supportive secondary endpoint of MASH resolution."

Loomba et al did find, however, that "semaglutide led to reductions in liver enzymes, liver steatosis (but not stiffness), and levels of the exploratory hepatic collagen biomarker pro-collagen 3 peptide. Patients treated with semaglutide lost more weight, had lower concentrations of triglycerides and VLDL cholesterol, and those with type 2 diabetes also had reductions in HbA_1c levels, compared with placebo." They also did not find any new safety concerns—as expected, the main adverse events were mild to moderate and transient gastrointestinal events.

"However, addressing features of the metabolic syndrome is essential in individuals with MASH-related cirrhosis, as is weight loss in those who have overweight or obesity, and there was evidence of improvement in cardiometabolic parameters and non-invasive markers of liver injury with semaglutide treatment. The relatively small size of the current trial may have limited its ability to demonstrate an effect on fibrosis and NASH resolution," they wrote.

In 2021, Newsome et al, published the results of a phase II trial of patients with MASH with stage 1-3 (F1-F3) liver fibrosis, and as Fernando Bril, MD, from the department of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, noted in an accompanying commentary, "the non-alcoholic fatty liver disease (NAFLD; now known as metabolic dysfunction-associated steatotic liver disease [MASLD]) community was filled with excitement. Semaglutide had already shown to be successful at lowering HbA_1c, producing significant weight loss, and reducing cardiovascular outcomes in patients with diabetes. Achieving resolution of MASH without worsening of fibrosis was an excellent addition to its repertoire."

However, Bril pointed out that in that study, there was a knowledge gap—since patients with cirrhosis (F4) were excluded from Newsome et al’s study, how would they fare if given semaglutide?

This is what Loomba and colleagues were determined to find out, enrolling patients from 38 sites in Europe and the United States in their phase II, double-blind, randomized controlled trial.

"Adults with biopsy-confirmed MASH-related cirrhosis and body-mass index (BMI) of 27 kg/m² or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2.4 mg or visually matching placebo," Loomba and colleagues wrote. The participants were also stratified by having or not having type 2 diabetes.

Improvement in liver fibrosis by one stage or more without worsening MASH at 48 weeks was the primary endpoint of the trial, as assessed by biopsy in the intention-to-treat population. Researchers also assessed safety in all patients who had at least one dose of semaglutide.

From June 18, 2019, to April 22, 2021, there were 71 patients enrolled in the study—49 (69%) patients were female; the mean age of those in the study was 59.5 years; and their mean BMI was 34.9 kg/m² (SD 5.9); 75% of the patients had type 2 diabetes. Forty-seven patients were randomized to the semaglutide group and 24 to the placebo group.

As already pointed out, Loomba and colleagues found that there was no statistically significant difference between the two groups at 48 weeks in improvement in liver fibrosis and no worsening of MASH—five (11%) of 47 patients in the semaglutide group versus seven (29%) of 24 patients in the placebo group (odds ratio, 0.28; 95% CI, 0.06–1.24; P=0.087).

"There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (P=0.29)," Loomba and colleagues noted, adding that adverse events were similar between groups—42 (89%) of patients in the semaglutide group versus 19 (79%) in the placebo group, with serious adverse events affecting six (13%) versus two (8%), respectively.

"The most common adverse events were nausea (21 [45%] versus four [17%]), diarrhea (nine [19%] versus two [8%]), and vomiting (eight [17%] versus none). Hepatic and renal function remained stable. There were no decompensating events or deaths," the study authors wrote.

The Silver Lining

But Bril pointed to, as did Loomba et al, a possible silver lining in the trial’s results.

"The good news is that semaglutide proved to be effective in patients with MASH-cirrhosis and BMI of 27 kg/m² or more in safely reducing weight (–8.83% versus –0.09% with placebo in 48 weeks), lowering HbA_1c in those with diabetes (–1.39% versus +0.24% with placebo), and improving several key metabolic parameters (e.g., triglycerides, liver fat, high sensitivity C-reactive protein). Treatment was safe; side-effects were mainly gastrointestinal, as expected," Bril wrote.

He also posed some thought-provoking ideas.

"But even if we agree that there is no real signal favoring placebo over semaglutide on liver fibrosis, an important question that stems from this study is why weight loss and metabolic improvements did not translate into histological improvement," Bril wrote, noting that perhaps "the study was not long enough to evidence changes in fibrosis. While studies before versus after bariatric surgery and other randomized controlled trials have shown a significant improvement in liver fibrosis in less than a year, it is possible that weight loss through GLP-1 agonism (not as pronounced as with bariatric surgery) may need a longer period of time to achieve fibrosis improvement, especially in light of the prolonged titration required for the drug (16 weeks in this study)."

Loomba and colleagues noted this as well.

"Trials investigating the treatment of MASH over a longer follow-up period are currently ongoing (e.g., NCT03439254) and could indicate whether a longer treatment duration has a significant effect on MASH and its components in patients with compensated cirrhosis," they wrote.

Bril also suggested that it is plausible that "the ability to induce improvements in liver fibrosis through weight loss may be lower when there is more pronounced liver fibrosis at baseline," he wrote. "In support of this, Pais and colleagues recently showed that despite significant weight loss after bariatric surgery, a significant proportion of patients continued to have advanced fibrosis around 4 years after surgery. The tipping point at which cirrhosis becomes irreversible remains unknown and a matter of debate.

"In this scenario, it is crucial to emphasize the importance of early diagnosis and treatment of patients with MASH to prevent the progression of fibrosis," he added. "Indeed, in patients with MASH without F4 fibrosis, semaglutide delayed the progression of liver fibrosis, results also observed with liraglutide in another trial. These results suggest that early use of GLP-1 agonists in patients at risk of liver disease may be warranted to change the natural history of the disease."

Bril concluded that, while the jury may still be out on semaglutide’s efficacy for patients with MASH with F4 fibrosis, "GLP-1 agonists may provide additional benefits at earlier stages of liver disease, including the possibility of delaying fibrosis prevention…initiating these drugs before the development of cirrhosis may be crucial, as we could be too late to the party at that point."

But maybe semaglutide in the treatment of MASH is not a solo act.

Loomba and colleagues noted that larger trials of semaglutide in this arena are needed.

"The phase IIb ATLAS trial indicated that a combination of cilofexor and firsocostat led to improvements in MASH activity and a reduction in fibrosis score in patients with bridging fibrosis or compensated cirrhosis (F3–4)," they wrote. "A combination of these treatments with semaglutide is currently under investigation (NCT04971785)."

Loomba et al acknowledged some trial limitations, namely "the use of a single pathologist to assess histology slides, which were permitted to be up to 12 months or 360 days old, with no re-read of baseline assessments at the end of trial. This approach was originally intended to evaluate secondary histology endpoints only. When the primary endpoint was changed during the trial, it was not feasible to alter the pathology procedures," they wrote. They also noted that the trial was conducted during the Covid-19 pandemic, which impacted both treatment arms, with resultant telephone or remote visits.

The study by Loomba et al was funded by Novo Nordisk.

Loomba is co-founder of LipoNexus Inc, and a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, AmgenArrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institutions have received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals.

Bril had no disclosures.

Loomba R, et al "Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: A randomised, placebo-controlled phase 2 trial" Lancet Gastroenterol Hepatol 2023; 8: 511–522.

Bril F "Semaglutide in NASH-related cirrhosis: too late to the party?" Lancet Gastroenterol Hepatol 2023; 8: 494-495.