Use of sodium-glucose co-transporter 2 inhibitors, changes in body mass index and risk of fracture: A population-based cohort study

Dalem, Judith van; Werkman, Nikki C C; Bergh, J.P. van den; Rossi, Bernardette; Viggers, Rikke; Eastell, Richard; Burden, Andrea M.; Stehouwer, Coen D.A.; Klungel, Olaf H.; Brouwers, Martijn C.G.J.; Driessen, Johanna HM

doi:10.1016/j.diabres.2022.109993

Cited by 9 publications

(11 citation statements)

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“…In observational studies, the relative fracture risk for SGLT2 inhibitors was compared with other hypoglycemic drugs currently in use, such as DPP-4 inhibitors, (11)(12)(13)(14)(15) sulphonylurea, (16) and GLP-1 receptor agonists, (17)(18)(19) and most studies yielded negative results. (46) Compared with observational studies, which may be subject to potential confounders and draw relative risks, the MR study is less likely to be affected by confounders and directly evaluate the causal effect of SGLT2 inhibition on fracture risk.…”

Section: Discussionmentioning

confidence: 99%

“…(4) Additionally, in trials evaluating the effects of other SGLT2 inhibitors, such as dapagliflozin, (5,8) empagliflozin, (6,9) and ertugliflozin, (10) no significant increased risk of bone fractures was reported. In real-world studies, treatment with SGLT2 inhibitors showed a similar fracture or fall risk compared with other hypoglycemic drugs currently in use, such as dipeptidyl peptidase 4 (DPP-4) inhibitors, (11)(12)(13)(14)(15) sulphonylurea, (16) and glucagon-like peptide 1 (GLP-1) receptor agonists. (17)(18)(19) Although meta-analyses of randomized controlled trials (RCTs) and observational studies have also shown that the overall risk was not increased in SGLT2 inhibitor users, (20)(21)(22)(23)(24)(25) these results do not eliminate concerns about the potential increased risk of fractures caused by SGLT2 inhibitors in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

Dai

Zheng

Zhu

et al. 2023

Journal of Bone and Mineral Research

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This study aims to evaluate the causal effect of sodium‐glucose cotransporter 2 (SGLT2) inhibition on bone mineral density (BMD), osteoporosis, and fracture risk using genetics. Two‐sample Mendelian randomization (MR) analyses were performed utilizing two sets of genetic variants as instruments (six and two single‐nucleotide polymorphisms [SNPs]) associated with SLC5A2 gene expression and glycated hemoglobin A1c levels. Summary statistics of BMD from the Genetic Factors for Osteoporosis consortium (BMD for total body, n = 66,628; femoral neck, n = 32,735; lumbar spine, n = 28,498; forearm, n = 8143) and osteoporosis (6303 cases, 325,717 controls) and 13 types of fracture (≤17,690 cases, ≤328,382 controls) data from the FinnGen study were obtained. One‐sample MR and genetic association analyses were conducted in UK Biobank using the individual‐level data of heel BMD (n = 256,286) and incident osteoporosis (13,677 cases, 430,262 controls) and fracture (25,806 cases, 407,081 controls). Using six SNPs as the instrument, genetically proxied SGLT2 inhibition showed little evidence of association with BMD of total body, femoral neck, lumbar spine, and forearm (all p ≥ 0.077). Similar results were observed using two SNPs as instruments. Little evidence was found for the SGLT2 inhibition effect on osteoporosis (all p ≥ 0.112) or any 11 major types of fracture (all p ≥ 0.094), except for a nominal significance for fracture of lower leg (p = 0.049) and shoulder and upper arm (p = 0.029). One‐sample MR and genetic association analysis showed that both the weighted genetic risk scores constructed from the six and two SNPs were not causally associated with heel BMD, osteoporosis, and fracture (all p ≥ 0.387). Therefore, this study does not support an effect of genetically proxied SGLT2 inhibition on fracture risk. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

Dai

Zheng

Zhu

et al. 2023

Journal of Bone and Mineral Research

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“…“That's good news for our patients,” she said. Overall, SGLT2 inhibitors do not increase risk of major osteoporotic fracture unless the cumulative dose is high 17 …”

Section: Management Of Osteoporosis In Diabetesmentioning

confidence: 98%

“…Overall, SGLT2 inhibitors do not increase risk of major osteoporotic fracture unless the cumulative dose is high. 17 Does diabetes affect fracture risk assessment? "Bone turnover markers work well for healthy controls, but not for people with diabetes," Professor Langdahl said.…”

Section: Do Diabetes Medications Increase Fracture Risk?mentioning

confidence: 99%

Highlights from the Diabetes UK Professional Conference 2023

Bishop

2023

Prescriber

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Sodium-Glucose Cotransporter 2 Inhibitors vs Incretin-Based Drugs and Risk of Fractures for Type 2 Diabetes

Ko,

Bea,

Jeong

et al. 2023

JAMA Netw Open

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ImportancePostmenopausal individuals with type 2 diabetes are susceptible to fractures due to the interaction of elevated blood glucose levels and a deficiency of the hormone estrogen. Despite continued concerns of fracture risks associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), existing evidence in this high-risk population is lacking.ObjectiveTo assess the risk of fractures associated with SGLT2i vs incretin-based drugs of dipeptidyl-peptidase 4 inhibitors (DPP4i) and glucagon-like peptide 1 receptor agonists (GLP1RA), separately, in postmenopausal individuals with type 2 diabetes.Design, Setting, and ParticipantsThis active-comparator, new-user cohort study used nationwide claims data of Korea and took place from January 1, 2013, to December 31, 2020. Postmenopausal individuals (aged ≥45 years) with type 2 diabetes were included.ExposuresNew users of SGLT2i or comparator drugs.Main Outcomes and MeasuresThe primary outcome was overall fractures, comprising vertebral, hip, humerus, and distal radius fractures. Patients were followed up from the day after drug initiation until the earliest of outcome occurrence, drug discontinuation (90-day grace period) or switch, death, or end of the study period. After propensity score fine stratification, hazard ratios (HRs) with 95% CIs were estimated using weighted Cox models.ResultsAmong 37 530 (mean [SD] age, 60.6 [9.7] years) and 332 004 (mean [SD] age, 60.6 [9.9] years) new users of SGLT2i and DPP4i, respectively, a lower rate of incident overall fractures was presented with SGLT2i vs DPP4i (weighted HR, 0.78; 95% CI, 0.72-0.84). Among 111 835 (mean [SD] age, 61.4 [9.8] years) and 8177 (mean [SD] age, 61.1 [10.3] years) new users of SGLT2i and GLP1RA, respectively, no association with an increased risk of overall fractures was presented with SGLT2i vs GLP1RA (weighted HR, 0.92; 95% CI, 0.68-1.24). Results from several subgroup and sensitivity analyses presented consistent results from main analysis.Conclusions and relevanceThis population-based cohort study suggests that SGLT2i was not associated with an increased rate of incident fractures compared with DPP4i and GLP1RA, separately, among postmenopausal individuals with type 2 diabetes.

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Use of sodium-glucose co-transporter 2 inhibitors, changes in body mass index and risk of fracture: A population-based cohort study

Cited by 9 publications

References 32 publications

Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

Highlights from the Diabetes UK Professional Conference 2023

Sodium-Glucose Cotransporter 2 Inhibitors vs Incretin-Based Drugs and Risk of Fractures for Type 2 Diabetes

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