medwireNews: Glucagon-like peptide (GLP)-1 receptor agonists may lower the risk for progression to cirrhosis and death versus dipeptidyl peptidase (DPP)-4 inhibitors in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, US research suggests.
However, Fasiha Kanwal (Baylor College of Medicine, Houston, Texas) and colleagues report in JAMA Internal Medicine that “[t]he protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.”
The study included data for 16,058 people with MASLD (also known as nonalcoholic fatty liver disease) and type 2 diabetes who initiated a GLP-1 receptor agonist (exenatide, dulaglutide, liraglutide, or semaglutide) between 2006 and 2022.
Of these, 14,606 patients (mean age 60.6 years, 89.1% men) had no history of cirrhosis at baseline, while the remaining 1452 patients (mean age 67.0 years, 93.7% men) already had cirrhosis.
In the patients without cirrhosis, the rate of progression to cirrhosis was 9.98 events per 1000 person–years, which was significantly lower than the 11.10 events per 1000 person–years observed in an equal number of propensity-score matched patients who initiated a DPP-4 inhibitor (sitagliptin, saxagliptin, linagliptin, or alogliptin) in the same month.
The difference between the two groups corresponded to a significant 14% lower risk for cirrhosis with GLP-1 receptor agonists versus DPP-4 inhibitors. “This chemopreventive activity became apparent 18 to 24 months after treatment initiation and increased over time,” Kanwal et al remark.
The risk for cirrhosis complications, a composite of decompensation, hepatocellular carcinoma (HCC), or liver transplant, was a nonsignificant 22% lower with GLP-1 receptor agonist use than with DPP-4 inhibitor use (1.89 vs 2.55 events per 1000 person–years), while the corresponding risk for all-cause mortality was a significant 11% lower (21.77 vs 24.43 events per 1000 person–years).
The researchers note that the risk reductions were similar regardless of age, sex, BMI, diabetes complications, or Fibrosis-4 score, but may vary according to the GLP-1 receptor agonist used. Specifically, the use of semaglutide was associated with a lower risk for progression to cirrhosis whereas there was no association between the use of dulaglutide or liraglutide and MASLD outcomes.
Kanwal and co-authors say this suggests “that the protective associations may become more pronounced as more effective GLP-1 [receptor agonists] or dual/triple agonists become available.”
In the patients with cirrhosis at baseline, there was no significant difference between GLP-1 receptor agonist users and DDP-4 inhibitor users in the risk for cirrhosis complications overall (18.64 vs 15.31 events per 1000 person–years), or for decompensated cirrhosis (14.45 vs 13.32 events per 1000 person–years), HCC (5.32 vs 3.20 events per 1000 person–years), or all-cause mortality (54.75 vs 61.9 events per 1000 person–years).
The investigators conclude that their findings “support the need for long-term randomized clinical trials to test the benefits of GLP-1 [receptor agonist] use for primary prevention of cirrhosis in patients with MASLD.”
They add: “While cirrhosis is a clear risk factor for HCC and reducing cirrhosis by GLP-1 [receptor agonist] use should prevent HCC, an independent confirmation of this relationship requires even larger studies than this one. In the meantime, the presence of MASLD can help with the prioritization of GLP-1 [receptor agonist] therapy in persons with diabetes.”
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