Risk of all–cause death and pancreatic events following GLP-1 RA initiation in people with obesity or type 2 diabetes: observations from a federated research network

TL;DR

This study finds that GLP-1 RA use is linked to a lower risk of death but a small increased risk of acute pancreatitis, especially early on, in people with obesity or type 2 diabetes.

Contribution

The study provides new observational evidence on the risk-benefit profile of GLP-1 RAs in a large population with obesity or type 2 diabetes.

Findings

GLP-1 RA use was associated with a 44.6% lower risk of all-cause death after 1 year.

There was a small increased risk of acute pancreatitis, particularly in the first 6 months of treatment.

The survival benefit was greater in younger individuals and those with cardiometabolic comorbidities.

Abstract

Limited data are available on the risk of pancreatic adverse events among people with obesity or type 2 diabetes mellitus (T2DM) initiating glucagon-like peptide-1 receptor agonist (GLP-1 RA).

Retrospective study utilizing data from a federated research network (TriNetX). Adult people (≥ 18 years) with a diagnosis of obesity (body mass index ≥ 30 kg/m2) or T2DM (ICD-10-CM: E11) between 2018 and 2024 were subdivided in two mutually exclusive cohorts: (1) GLP-1 RA Users; and (2) Non–GLP-1 RA Users. Primary outcomes were 1-year risk of all-cause death and a composite outcome (acute pancreatitis, chronic pancreatitis). Secondary outcomes included the individual components of the composite outcome and pancreatic cancer. Cox regression analyses were employed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) before and after 1:1 propensity score matching (PSM). Sensitivity analyses stratified follow-up into early (first 6 months) and late (last 6 months) phases. Subgroup analyses were performed based on age (≥ 65 or < 65 years), sex, and the history of smoking and alcohol use, hypertriglyceridemia, cholelithiasis, heart failure, and chronic kidney disease.

We identified 1,562,626 people who initiated treatment with GLP-1 RA (mean age 55.3 ± 14.0 years; 59.2% female) and 18,652,572 those who did not (mean age 50.6 ± 18.7 years; 54.5% female). Before PSM, GLP-1 RA Users were older, more frequently female, and exhibited a higher burden of endocrine, metabolic and gastrointestinal disorders. After PSM, GLP-1 RA use was associated with a substantially lower risk of all-cause death (HR 0.554, 95% CI 0.542–0.566), and small increased risk of the composite outcome (HR 1.062, 95% CI 1.023–1.102) and acute pancreatitis (HR 1.058, 95% CI 1.015–1.103), with no differences in chronic pancreatitis or pancreatic cancer. The excess risk of acute pancreatitis was more pronounced during the early phase of follow-up (first 6 months). Subgroup analyses showed a higher reduction in death and composite outcome among people aged < 65 years. Additional significant interactions were observed for all-cause death in females and in people with a history of smoking, alcohol use, heart failure, chronic kidney disease, or cholelithiasis.

GLP-1 RA use was associated with substantially reduced all-cause death but a small increased risk of acute pancreatitis, particularly during early treatment. The survival benefit was more pronounced in younger people and those with cardiometabolic comorbidities, highlighting the need for a careful risk–benefit evaluation when prescribing GLP-1 RAs in high-risk individuals.

The online version contains supplementary material available at 10.1186/s12933-025-02986-0.

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