Glucagon-Like Peptide-1 Receptor Agonists and Fragility Fracture Risk in Type 2 Diabetes.
Obesity, type 2 diabetes (T2D), and weight loss are associated with increased fragility fracture risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, yet their effects on skeletal outcomes remain uncertain.
To evaluate the association between GLP-1 RA initiation and 3-year fragility fracture risk compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) initiation among adults with T2D.
This comparative effectiveness study using retrospective target trial emulation examined data from the TriNetX Research Network (January 1, 2015, to December 31, 2022), a multicenter US electronic health record database. Adults aged 50 to 90 years with T2D who newly initiated a GLP-1 RA or DPP-4i were followed up for up to 3 years. A separate cohort stratified by T2D status was also analyzed. The database was queried on January 26, 2026, to generate a line-level analytic dataset.
Initiation of GLP-1 RAs vs DPP-4is.
The primary outcome was incident fragility fracture, defined as fractures after low-energy trauma (eg, fall from standing height). Cohorts were propensity score matched. Time-varying mediation analyses were used to evaluate the contribution of changes in body mass index and hemoglobin A1c.
After matching, 133 606 patients (66 803 per group; GLP-1 RA vs DPP-4i: mean [SD] age 63.2 [8.1] vs 63.8 [8.5] years; 35 195 [52.7%] vs 36 098 [54.0%] male) were included. Initiation of GLP-1 RA was associated with lower fragility fracture risk compared with DPP-4i initiation (hazard ratio [HR], 0.79 [95% CI, 0.76-0.83]; absolute risk reduction, 0.79% [95% CI, 0.60%-0.99%]; number needed to treat, 126 [95% CI, 101-168]). The largest risk reductions were observed with vertebral (HR, 0.68 [95% CI, 0.63-0.73]) and hip or femur (HR, 0.70 [95% CI, 0.63-0.79]) fractures. In a sensitivity analysis stratified by diabetes status, fracture risk reduction was observed among patients with T2D (HR, 0.91 [95% CI, 0.88-0.95]) but not among those without T2D (HR, 1.13 [95% CI, 1.04-1.23]; interaction P < .001). Mediation analyses showed that the direct association between GLP-1 RA use and lower fracture risk persisted (HR, 0.81 [95% CI, 0.76-0.86]).
This target trial emulation study of adults with T2D found that initiation of a GLP-1 RA was associated with lower 3-year fragility fracture risk compared with initiation of a DPP-4i, independent of changes in body mass index and hemoglobin A1c. Prospective studies are needed to establish causality and define long-term skeletal effects.
To evaluate the association between GLP-1 RA initiation and 3-year fragility fracture risk compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) initiation among adults with T2D.
This comparative effectiveness study using retrospective target trial emulation examined data from the TriNetX Research Network (January 1, 2015, to December 31, 2022), a multicenter US electronic health record database. Adults aged 50 to 90 years with T2D who newly initiated a GLP-1 RA or DPP-4i were followed up for up to 3 years. A separate cohort stratified by T2D status was also analyzed. The database was queried on January 26, 2026, to generate a line-level analytic dataset.
Initiation of GLP-1 RAs vs DPP-4is.
The primary outcome was incident fragility fracture, defined as fractures after low-energy trauma (eg, fall from standing height). Cohorts were propensity score matched. Time-varying mediation analyses were used to evaluate the contribution of changes in body mass index and hemoglobin A1c.
After matching, 133 606 patients (66 803 per group; GLP-1 RA vs DPP-4i: mean [SD] age 63.2 [8.1] vs 63.8 [8.5] years; 35 195 [52.7%] vs 36 098 [54.0%] male) were included. Initiation of GLP-1 RA was associated with lower fragility fracture risk compared with DPP-4i initiation (hazard ratio [HR], 0.79 [95% CI, 0.76-0.83]; absolute risk reduction, 0.79% [95% CI, 0.60%-0.99%]; number needed to treat, 126 [95% CI, 101-168]). The largest risk reductions were observed with vertebral (HR, 0.68 [95% CI, 0.63-0.73]) and hip or femur (HR, 0.70 [95% CI, 0.63-0.79]) fractures. In a sensitivity analysis stratified by diabetes status, fracture risk reduction was observed among patients with T2D (HR, 0.91 [95% CI, 0.88-0.95]) but not among those without T2D (HR, 1.13 [95% CI, 1.04-1.23]; interaction P < .001). Mediation analyses showed that the direct association between GLP-1 RA use and lower fracture risk persisted (HR, 0.81 [95% CI, 0.76-0.86]).
This target trial emulation study of adults with T2D found that initiation of a GLP-1 RA was associated with lower 3-year fragility fracture risk compared with initiation of a DPP-4i, independent of changes in body mass index and hemoglobin A1c. Prospective studies are needed to establish causality and define long-term skeletal effects.
Authors
Hamad Hamad, Wiener Wiener, Golzar Golzar, Kaur Kaur, Henein Henein, Kittredge Kittredge, Su Su, Kaelber Kaelber, Chan Chan, Yeaman Yeaman, Adams Adams, Bernthal Bernthal, Sheppard Sheppard
View on Pubmed