Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes

Abstract

Importance: Whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are associated with an increased risk of fractures in older adults with type 2 diabetes (T2D) outside of clinical trials remains unknown.

Objective: To examine the association of incident fracture among older adults with T2D with initiating an SGLT-2i compared with initiating a dipeptidyl peptidase 4 inhibitor (DPP-4i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA).

Design, setting, and participants: This is a population-based, new-user cohort study including older adults (aged ≥65 years) with T2D enrolled in Medicare fee-for-service from April 2013 to December 2017. Data analysis was performed from October 2020 to April 2021.

Exposures: New users of an SGLT-2i, DPP-4i, or GLP-1RA without a previous fracture were matched in a 1:1:1 ratio using 3-way propensity score matching.

Main outcomes and measures: The primary outcome was a composite end point of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days. After 3-way 1:1:1 propensity score matching, multivariable Cox proportional hazards regression models were used to generate hazard ratios (HRs) for SGLT-2i compared with DPP-4i and GLP-1RA and Kaplan-Meier curves to visualize fracture risk over time across groups.

Results: Of 466 933 new initiators of study drugs, 62 454 patients were new SGLT-2i users. After 3-way matching, 45 889 (73%) new SGLT-2i users were matched to new users of DPP-4i and GLP-1RA, yielding a cohort of 137 667 patients (mean [SD] age, 72 [5] years; 64 126 men [47%]) matched 1:1:1 for analyses. There was no difference in the risk of fracture in SGLT-2i users compared with DPP-4i users (HR, 0.90; 95% CI, 0.73-1.11) or GLP-1RA users (HR, 1.00; 95% CI, 0.80-1.25). Results were consistent across categories of sex, frailty (nonfrail, prefrail, and frail), age (<75 and ≥75 years), and insulin use (baseline users and nonusers).

Conclusions and relevance: In this nationwide Medicare cohort, initiating an SGLT-2i was not associated with an increased risk of fracture in older adults with T2D compared with initiating a DPP-4i or GLP-1RA, with consistent results across categories of frailty, age, and insulin use. These findings add to the evidence base evaluating the potential risks associated with SGLT-2i use for older adults outside of randomized clinical trials.

Figure 1.. Flow Diagram of the Study Population

We included patients aged 66 years and older with type 2 diabetes (T2D) who were newly prescribed a sodium-glucose cotransporter–2 inhibitor (SGLT-2i), dipeptidyl peptidase 4 inhibitor (DPP-4i), or glucagon-like peptide 1 receptor agonist (GLP-1RA) between April 1, 2013 (after the first SGLT-2i was approved in the US), and December 31, 2017. We set the age threshold to 66 years at cohort entry so that patients would have at least 1 year of Medicare eligibility before cohort entry. A total of 466 933 patients met the study inclusion and exclusion criteria: 62 454 (13%) SGLT-2i new users, 338 463 (73%) DPP-4i new users, and 66 016 (14%) GLP-1RA new users. After 1:1:1 3-way propensity score matching, we identified 45 889 matched sets of patients initiating SGLT-2i, DPP-4i, or GLP-1RA, for a total of 137 667 patients: 73% of SGLT-2i users were matched. Demographic information includes age, sex, race, and region. ESKD indicates end-stage kidney disease; PS, propensity score; T1D, type 1 diabetes.

Figure 2.. Kaplan-Meier Curves for Incidence of Fractures Within Matched Groups

The cumulative incidence of fractures within the 3 groups is shown in this Kaplan-Meier plot. We observed a total of 501 fracture events. There were 158 events in sodium-glucose cotransporter–2 inhibitor (SGLT-2i) users (incidence ratio [IR], 4.69 fractures per 1000 person-years) compared with 195 in dipeptidyl peptidase 4 inhibitor (DPP-4i) users (IR, 5.26 fractures per 1000 person-years) and 148 in glucagon-like peptide 1 receptor agonist (GLP-1RA) users (IR, 4.71 fractures per 1000 person-years). SGLT-2i use was not with associated fracture compared with DPP-4i (hazard ratio, 0.90; 95% CI, 0.73-1.11) or GLP-1RA use (hazard ratio, 1.00; 95% CI, 0.80-1.25).

Figure 3.. Forest Plot of Subgroup Analyses for Matched Fracture Outcome

We tested for the presence of effect modification in 3 relevant subgroups: (1) nonfrail, prefrail, and frail patients; (2) patients aged less than 75 years vs 75 years and older, and (3) baseline insulin users vs nonusers. The incidence rate (IR) of fracture increased with frailty, older age, and insulin use; there was no evidence of effect modification on the fracture outcome based on frailty status, age less than 75 years vs 75 years and older, or insulin use. DPP-4i indicates dipeptidyl peptidase 4 inhibitor; GLP-1RA, glucagon-like peptide 1 receptor agonist; HR, hazard ratio; SGLT-2i, sodium-glucose cotransporter–2 inhibitor; PY, person-years.