Veterans Study Underscored Benefits of Starting Treatment Early
HOUSTON — Treatment with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) showed promise in lowering the incidence of cirrhosis and mortality in veterans with metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes, as long as the drug was initiated early in the course of the disease.
That’s according to a cohort study of about 16,000 VHA patients. Baylor College of Medicine-led researchers called for confirmation of the chemopreventive benefits of GLP-1 RSs by clinical trials. Also participating in the study were investigators from the Michael E. DeBakey AMC in Houston, the Corporal Michael J. Crescenz VAMC in Philadelphia and the VA Palo Alto, CA, Healthcare System.
Of the study participants, 1,452 had cirrhosis, and 14,606 did not. The authors advised in JAMA Internal Medicine that GLP-1 RA use was associated with a statistically significant reduction in the risk of progression to cirrhosis and its complications in patients with MASLD and diabetes vs. use of an active comparator treatment. “The chemopreventive benefit was limited to patients who initiated GLP-1 RAs earlier in the disease course; patients who started GLP-1 RAs after they had already progressed to cirrhosis did not have lower rates of progression to hepatic decompensation or hepatocellular cancer,” they added.1
Background information in the articles notes that metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis, and GLP-1 RAs are effective in improving liver inflammation in patients with MASLD.
The current study sought to determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD.
Data for the research came from the national VHA Corporate Data Warehouse and Central Cancer Registry. Included were patients with MASLD and diabetes who were seen at 130 VHA hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between Jan. 1, 2006, and June 30, 2022. The study team followed patients from baseline until one of the study outcomes or the end of the study period (Dec. 31, 2022), whichever came first.
The researchers propensity score-matched each GLP-1 RA new user in 1:1 ratio to a patient who initiated a DPP-4i during the same month. For patients without cirrhosis, the primary outcome was designated as progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, while secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC or liver transplant and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality.
Participants without cirrhosis initiating GLP-1 RAs had a mean age of 60.56 and were 89.1% male; those with cirrhosis had a mean age of 66.99 and were 93.7% male at baseline.
Results indicated that, in patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs. 11.10 events per 1,000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). The researchers reported that similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of the composite outcome of cirrhosis complications (1.89 vs. 2.55 events per 1,000 person-years; HR, 0.78; 95% CI, 0.59-1.04) and mortality (21.77 vs. 24.43 events per 1,000 person-years; HR, 0.89; 95% CI, 0.81-0.98). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis.
Early Treatment Best
“The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course,” the authors emphasized.
MASLD is the fastest-growing cause of cirrhosis and its complications, including HCC. “While antiviral treatments have greatly reduced cirrhosis-related sequelae of chronic viral hepatitis, studies have found the opposite trend for patients with MASLD,” the study pointed out, adding that clinical trial evidence for chemo prevention of cirrhosis or its complications in MASLD were lacking.
GLP-1 RAs are currently used to treat Type 2 diabetes and obesity, because the medications reduce body weight, glycemia and inflammation, which reduce the risk of MASLD progression, the article noted. Furthermore, previous randomized clinical trials have shown histological resolution of steatohepatitis, while other ongoing efforts are looking at cirrhosis prevention.
Yet, the researchers caution, “Even when the trials are complete, they may be underpowered to assess other outcomes, including decompensation or HCC.”
They advised that patients with MASLD who have not yet developed cirrhosis “represent an important population for observational studies to investigate the associations of GLP-1 RAs” based on retrospective cohort studies from Europe that have limited applicability. “Most patients in these studies were treated with older GLP-1 RAs, leaving gaps in the knowledge about cirrhosis prevention with the newer agents,” the researchers wrote. “In this study, we analyzed data from a large cohort of US patients with MASLD and diabetes to comprehensively assess the associations between GLP-1 RA use and the risk of developing cirrhosis and its complications, including HCC.”
The study described how chemo preventive activity became apparent 18 to 24 months after treatment initiation and increased over time. “In contrast, there was limited benefit in patients with established cirrhosis,” it stated. “These data highlight the potential consequences of delaying treatment—either by lack of access or by patient or health care professional choice—on subsequent risk of cirrhosis complications.”
The authors suggested that their results “fill an important gap in the understanding of cirrhosis chemo prevention among a large population of patients with MASLD but without cirrhosis. We were unable to assess whether there was an association with decreased HCC incidence due to the small number of cases. While prior work has established an association between cirrhosis and HCC, an independent establishment of the relationship between GLP-1 RA use and reduced HCC will need further study. Notwithstanding, we did find an association with other complications and with overall mortality.”
They also explained that the reduction in mortality associated with GLP-1 RA use (2.66 events per 1,000 person-years) actually exceeded the association with cirrhosis prevention (1.12 events per 1,000 person-years). “The former is consistent with prior retrospective studies and randomized trials of patients with diabetes and obesity. The present data suggest that among patients with MASLD, GLP-1 RAs may offer other survival benefits than those conferred by slowing the risk of liver disease progression,” they pointed out.
They added that both GLP-1 RAs and DPP-4is affect GLP levels, with the GLP-1 RAs being much more effective, explaining, “It is possible that DPP-4is have some protective effects on MASLD progression, rendering the present results potentially conservative estimates. We also found a stronger association between semaglutide use and outcomes than with other GLP-1 RAs, suggesting that the protective associations may become more pronounced as more effective GLP-1 RAs or dual/triple agonists become available.”
“While cirrhosis is a clear risk factor for HCC and reducing cirrhosis by GLP-1 RA use should prevent HCC, an independent confirmation of this relationship requires even larger studies than this one,” the researchers concluded. “In the meantime, the presence of MASLD can help with the prioritization of GLP-1 RA therapy in persons with diabetes.”
- Kanwal F, Kramer JR, Li L, et al. GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. JAMA Intern Med. Published online September 16, 2024. doi:10.1001/jamainternmed.2024.4661
