Long-term risk of total joint replacement associated with second-line glucose-lowering therapies in type 2 diabetes:...

To evaluate whether initiation of different second-line glucose-lowering therapies is associated with the risk of total joint replacement (TJR) among patients with type 2 diabetes (T2DM).

A retrospective, new-user, active-comparator cohort study was conducted using the TriNetX Global Health Research Network. Adults with T2DM initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), or dipeptidyl peptidase-4 inhibitors (DPP4i), with background glucose-lowering therapy not restricted, were identified. Three propensity score-matched pairwise comparisons were performed to balance baseline demographic and clinical characteristics. The primary outcome was TJR, with secondary outcomes including site-specific osteoarthritis (OA) diagnoses and major joint injections. Subgroup and sensitivity analyses were conducted to assess the robustness of findings.

In pairwise propensity score-matched analyses, the 10-year observed risk of total joint replacement (TJR) in the matched cohorts was 0.505% versus 0.674% for SGLT2i versus GLP-1 RA, 0.483% versus 0.891% for SGLT2i versus DPP4i, and 0.731% versus 1.038% for GLP-1 RA versus DPP4i. The corresponding hazard ratios were 0.85 (95% CI 0.73-1.00), 1.10 (95% CI 0.95-1.27), and 1.22 (95% CI 1.07-1.39), respectively. SGLT2i use was associated with lower risks of overall osteoarthritis (OA) than both GLP-1 RA and DPP4i, with stronger associations for knee OA than for hip OA. Among patients with pre-existing OA, SGLT2i remained associated with a lower risk of TJR than GLP-1 RA. Overall, associations were more evident for knee-related than for hip-related outcomes.

Among patients with T2DM initiating second-line glucose-lowering therapy, SGLT2i use was associated with more favorable OA-related outcomes, most consistently in comparison with GLP-1 RA. Comparisons with DPP4i were less consistent and were mainly limited to OA diagnostic outcomes rather than total joint replacement. These associations were more evident for knee-related than for hip-related outcomes, suggesting that the choice of second-line antidiabetic therapy may be associated with differences in clinically meaningful OA-related outcomes in real-world practice.