GLP-1 therapy tied to lower mortality and liver decompensation in older adults with MASLD

Older adults with metabolic dysfunction-associated steatotic liver disease (MASLD) who started a GLP-1 receptor agonist had a 45% lower risk of death and a 28% lower risk of hepatic decompensation over up to 10 years compared with peers who did not, according to a study published recently in Age and Ageing.

The retrospective cohort analysis, led by researchers at Houston Methodist Research Institute, used electronic health records from the TriNetX US Collaborative Network, which spans 69 healthcare organizations. The team identified 44,196 adults 65 and older with MASLD who began a GLP-1 receptor agonist or tirzepatide and 384,672 who did not, then used propensity-score matching to build two balanced cohorts of 43,930 patients each. Semaglutide was the most prescribed agent, followed by tirzepatide and dulaglutide.

"Our findings suggest that the potential benefits of GLP-1-based treatments may extend well beyond weight loss," Eleftherios Mylonakis, M.D., Ph.D., the study's lead author and chair of the Department of Medicine at Houston Methodist, said in a news release.

Why older adults with MASLD are a GLP-1 evidence gap

MASLD, defined as fat buildup in the liver alongside at least one cardiometabolic risk factor, affects more than 25% to 30% of adults worldwide and is the leading cause of chronic liver disease, the authors wrote. Adults older than 65 with the condition have higher rates of advanced fibrosis, hepatic decompensation, liver cancer and liver-related death.

Trials showing that GLP-1 drugs reduce liver fat have mostly enrolled middle-aged adults and rarely examine frailty or functional capacity.

"Data to guide pharmacotherapy in older adults remain scarce, since pivotal trials underrepresent this age group or lack geriatric-specific analyses," Mylonakis wrote in the study.

Age also changes the risk calculation. Many older adults with MASLD have sarcopenia, frailty, multiple chronic conditions and complex medication regimens, and the lean mass lost during GLP-1-driven weight loss could worsen physical function and fall risk, according to the study.

What the study found on mortality, liver and cardiovascular outcomes

In the primary analysis, which began follow-up 90 days after the index date, the GLP-1 cohort recorded 1,997 deaths compared with 5,409 in the comparison group and 789 hepatic decompensation events compared with 1,511. All-cause hospitalization was modestly lower among GLP-1 users.

Major adverse cardiovascular events, defined as heart attack and stroke, were not significantly reduced in the primary analysis. A significant reduction (HR 0.89) emerged only in a sensitivity analysis that started follow-up on day 1.

The lower risk of hepatic decompensation held across subgroups defined by diabetes status, body mass index and metabolic dysfunction-associated steatohepatitis (MASH) status. Excluding tirzepatide weakened the mortality and decompensation associations (HR 0.68 and 0.83, respectively), but both remained significant, which the authors said suggests the results are not specific to dual GIP/GLP-1 agonism.

Bone, eye and gastrointestinal safety signals

GLP-1 users had a slightly higher risk of osteoporosis without fracture and of retinopathy, while differences in osteoporosis with fracture, sarcopenia and acute pancreatitis were not statistically significant. Among patients with gastrointestinal symptoms, GLP-1 users had fewer encounters on average (3.03 vs. 3.50), which the authors said suggests the symptoms were transient.

The researchers cautioned that higher coded rates of osteoporosis and retinopathy may reflect closer surveillance of GLP-1 users rather than true excess risk. Because the study was observational, residual confounding from factors such as frailty, disease severity and healthcare access may persist, and the analysis did not assess long-term safety.

What GLP-1 findings in MASLD mean for Medicare and payers

The findings add to a growing case for GLP-1 therapy in liver disease. The FDA granted accelerated approval to Wegovy (semaglutide) in 2025 for adults with MASH and moderate-to-advanced liver fibrosis, a condition the agency estimates affects about 6% of U.S. adults, or 14.9 million people, according to an FDA announcement.

Medicare access is also shifting. Under the temporary Medicare GLP-1 Bridge, Part D enrollees who meet BMI-based eligibility criteria can obtain Wegovy or Zepbound for a $50 copay through the end of 2026, ahead of a multi-year demonstration called the BALANCE Model that begins in 2027 and is voluntary for Part D plans, according to a KFF analysis.

“Alongside the benefits of GLP-1 treatment, we found more osteoporosis and retinopathy diagnoses in patients on GLP-1 therapy and no reduction in heart attack or stroke,” first author Tilemachos Koutouratsas, M.D., a clinical research fellow at Houston Methodist Research Institute, said in the news release. “Randomized trials in older adults may be needed to confirm these findings and to clarify who benefits and who needs closer monitoring.”