Semaglutide Doesn't Improve Fibrosis in NASH-Related Cirrhosis

Carolyn Crist

March 29, 2023

Semaglutide didn't significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis compared with placebo, according to a phase 2 trial.

However, the glucagon-like peptide 1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low–density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

Dr Rohit Loomba

"Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis," lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, told Medscape Medical News.

"Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and non-invasive biomarkers of fibrosis," he said.

The study was published online March 16 in The Lancet Gastroenterology & Hepatology.

Analyzing Safety and Efficacy

Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) ≥ 27 were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement compared with seven patients (29%) in the placebo group (odds ratio [OR], 0.28; 95% CI, 0.06-1.24, P = .087).

There also wasn't a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution compared with five patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide vs placebo, although the difference wasn't significant. In the semaglutide group, three patients (6%) achieved both compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide vs placebo.

Some Improvements Seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase.

Body weight decreased by 8.83% in the semaglutide group compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren't significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial due to adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

"GLP-1 analogue exposure — among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes — for the treatment of diabetes appears to be well-tolerated and may be safe," Loomba said. "Further studies are needed in this study population."

Considering Next Steps

Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

Dr Fernando Bril

"As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients," Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, told Medscape Medical News.

Bril, who wasn't involved with this study, wrote an accompanying editorial in the journal.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

"This emphasizes that early diagnosis of patients with NASH is crucial," he said.

"Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease."

In further research, investigators may want to consider the lack of NASH resolution, a result that could be due to this study being underpowered, Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

"While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes," he said. "Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications."

At the same time, it's important to note that NASH can't be oversimplified as "a matter of weight," Bril said. Significant weight loss in the study didn't result in histologic improvement, which means other strategies are needed to treat the disease.

"Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis," he said. "In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH."

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Bril had no relevant disclosures.

Lancet Gastroenterol Hepatol. Published online March 16, 2023. Full text

Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape, MDedge, and WebMD.

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