Glucagon-like peptide-1 receptor agonist use for type 2 diabetes and risk of upper extremity fragility fracture.

Abstract

Older adults with type 2 diabetes mellitus (T2DM) face an elevated risk of fragility fractures. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have grown in use for the management of T2DM over recent years, however, their potential skeletal effects remain incompletely understood. This study evaluated the association between sustained GLP-1RA use and the risk of upper extremity fragility fractures in this population. A retrospective cohort study was conducted using TriNetX, a global electronic health record platform. Adults of age ≥ 50 years with T2DM and active metformin use were included, excluding individuals with documented osteoprotective medication use. Patients were stratified by long-term GLP-1RA exposure (≥5 years of use). Cohorts were propensity-score matched at a 1:1 ratio, utilizing demographic (age, race, sex), clinical (comorbidities associated with fracture risk), and laboratory covariates (hemoglobin A1c). Pharmacotherapy initiation was defined as the initiation of metformin (control) or GLP-1RA therapy (exposure). Incidence of composite upper extremity fractures (distal radius, olecranon, proximal/distal humerus) was evaluated over the 5 years following pharmacotherapy initiation. Subgroup analyses were performed for high-risk populations and multivariate regression analyses evaluated the contribution of individual GLP-1RA agents to composite upper extremity fragility fracture risk. This study identified 194,205 patients, with 34,830 patients in the GLP-1RA cohort and 159,375 in the control cohort. Following matching, each cohort consisted of 32,116 patients. Over the 5 years following pharmacotherapy initiation, patients with and without GLP-1RA use were at similar risk of upper extremity fragility fracture. No significant differences were detected on high-risk subgroup analysis. This study did not identify any individual GLP-1RA agent to confer protection against upper extremity fragility fracture. While GLP-1RAs appear safe with respect to fracture risk, their hypothesized osteoprotective effects did not translate to clinically meaningful reductions in upper extremity fragility fracture incidence.