SGLT2 inhibitor treatment is not associated with an increased risk of osteoporotic fractures when compared to GLP-1 receptor agonists: A nationwide cohort study

Abstract

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator.ResultsIn total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses.ConclusionThese results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

Effect of incretins on skeletal health

“…On the other hand, observational studies may have longer treatment duration. As shown in the recent epidemiological studies assessing GLP-1 RA and fractures, there are reported neutral outcomes compared to DPP4-i and SGLT-2i [30 ▪ ,31 ▪ ]. This is in alignment with previous studies and therefore treatment with GLP-1 RA in individuals with type 2 diabetes is perceived as fracture neutral [36,50,51].…”

“…Two propensity score matched cohort studies, based on Danish national registries, found no difference in fracture rates between users of DPP4-I and GLP-1 RA, or between users of sodium glucose co-transporter-2 inhibitors and GLP-1 RA when using these drugs as an add on to metformin [30 ▪ ,31 ▪ ]. However, there was an association towards lower fracture rates among those treated with the highest doses of GLP-1 RA compared to DPP4-I [30 ▪ ].…”

Association of metformin use with fracture risk in type 2 diabetes: A systematic review and meta-analysis of observational studies

“…The current use of metformin plus SGLT-2 inhibitor compared to the current use of metformin plus DPP-4 inhibitor was not associated with fractures in patients with type 2 diabetes ( 73 ). SGLT2 inhibitors + metformin combination treatment do not affect fracture risk compared to GLP-1 receptor agonists + metformin combination ( 74 ). SGLT2 and metformin combination therapy did not influence fracture risk compared with metformin monotherapy or other medications in patients with T2DM ( 75 ).…”

The associations of sodium‐glucose cotransporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors as add‐on to metformin with fracture risk in patients with type 2 diabetes mellitus

“…Additionally, the results of our study are supported by several other studies, including randomized controlled trials, all pointing towards a neutral effect of SGLT2 inhibitor use on fracture risk. [24][25][26][27][28][29][30] Our study used the CPRD database, which includes up to 19.9% (Aurum database) of the total population in the United Kingdom, 16 and did not find an increased fracture risk with SGLT2 inhibitor use versus DPP-4 inhibitor use in either Aurum or GOLD. This is also in line with a recent meta-analysis, 31 which included 11 large randomized clinical trials of this drug class in their meta-analysis on the association between SGLT2 inhibitor and fracture risk and concluded the CANVAS results were likely due to chance.…”