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GLP-1 receptor agonist use was associated with a reduced risk of progressing to cirrhosis and related complications in patients with diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), according to an analysis of Veterans Affairs data.

In a matched cohort study of more than 30,000 patients, use of a GLP-1 agonist was associated with a 14% lower risk of cirrhosis compared with DPP-4 inhibitors (9.98 vs 11.10 events per 1,000 person-years; HR 0.86, 95% CI 0.75-0.98), said researchers led by Fasiha Kanwal, MD, of the Baylor College of Medicine in Houston.

Patients prescribed GLP-1 agonists also had a 22% lower risk for cirrhosis complications (1.89 vs 2.55 events per 1,000 person-years; HR 0.78, 95% CI 0.59-1.04) and an 11% lower risk for all-cause mortality (21.77 vs 24.43 events per 1,000 person-years; HR 0.89, 95% CI 0.81-0.98), the findings in showed.

"This chemopreventive activity became apparent 18 to 24 months after treatment initiation and increased over time," Kanwal's team wrote. "In contrast, there was limited benefit in patients with established cirrhosis." In a matched analysis of patients with cirrhosis at baseline, the study found no associations between GLP-1 agonist use and any outcome.

"These data highlight the potential consequences of delaying treatment -- either by lack of access or by patient or healthcare professional choice -- on subsequent risk of cirrhosis complications," Kanwal and colleagues said.

The study authors analyzed data from 16,058 patients in the national Veterans Health Administration database with diabetes and MASLD who initiated a GLP-1 receptor agonist from 2006 to 2022, including 14,606 without cirrhosis at baseline (mean 60 years; 89% male) and 1,452 with cirrhosis at baseline (mean 67 years; 94% male).

Each GLP-1 agonist user was propensity score matched to a patient who initiated a DPP-4 inhibitor during the same month. The researchers calculated propensity scores using a logistic regression model and included factors such as age, sex, race and ethnicity, income, and alcohol and tobacco use.

More than half of the patients (55%) switched from one GLP-1 agonist to another during follow-up. Overall, 6.6% of patients received exenatide (Byetta), 27.7% dulaglutide (Trulicity), 35.7% liraglutide (Victoza), and 75.6% semaglutide (Ozempic) during the study period.

The primary outcome was a new diagnosis of cirrhosis. Secondary outcomes were cirrhosis complications including decompensation, hepatocellular cancer (HCC), liver transplant, or a composite of these complications, as well as all-cause mortality. The number of HCC cases -- 12 among those taking GLP-1 agonists and 13 in those taking DPP-4 inhibitors -- was too small for an accurate assessment of risk, Kanwal and colleagues said.

"We also found a stronger association between semaglutide use and outcomes than with other GLP-1 RAs [receptor agonists]," they added, "suggesting that the protective associations may become more pronounced as more effective GLP-1 RAs or dual/triple agonists become available."

DPP-4 inhibitors were the chosen control because they are a second- to third-line drug, like GLP-1 agonists, but with a different mechanism of action and little to no known effect on MASLD, the study authors explained. Nevertheless, DPP-4 inhibitors do have a small effect on GLP levels, they added, making it possible they have some protective effects on MASLD progression -- and making the current results potentially conservative.

Another limitation: MASLD was defined as at least two measurements of elevated alanine aminotransferase levels, so there was a potential for misclassification. In addition, the findings might not be generalizable to patients with MASLD who have persistently normal liver enzymes, Kanwal and colleagues explained.

Finally, the study included mostly male patients, "but we had more than 3,000 female patients without cirrhosis in the group, and the associations were similar in both sexes," the authors said.

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