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Cited by 117Diabetes Treatment and ManagementBone health and osteoporosis researchPharmaceutical Practices and Patient Outcomes

Effects of anti-diabetic drugs on fracture risk: a systematic review and network meta-analysis

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Zhang, Yu-Sheng, Zheng, Yan-Dan, Yuan, Yan, Chen, Shi-Chun, Xie, Bao-Cheng·2021·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.735824PMC PMC8553257
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Abstract

Purpose: Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of anti-diabetic drugs on fracture risk in type 2 diabetes mellitus (T2DM) patients. Methods: Embase, Medline, ClinicalTrials.gov, and Cochrane CENTRAL were searched for relevant trials. All data analyses were performed with STATA (12.0) and R language (3.6.0). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining data for the fracture effects of anti-diabetic drugs, including sodium–glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, meglitinides, α-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, and sulfonylureas. Results: One hundred seventeen eligible randomized controlled trials (RCTs) with 221,364 participants were included in this study. Compared with placebo, trelagliptin (RR 3.51; 1.58–13.70) increased the risk of fracture, whereas albiglutide (RR 0.29; 0.04–0.93) and voglibose (RR 0.03; 0–0.11) decreased the risk of fracture. Other medications were comparable in terms of their effects on fracture risk, and no statistical significance was observed. In terms of fractures, voglibose (0.01%) may be the safest option, and trelagliptin (13.64%) may be the worst. Sensitivity analysis results were consistent with those of the main analysis. No statistically significant differences were observed in the regression coefficients of age (1.03; 0.32–2.1), follow-up duration (0.79; 0.27–1.64), and sex distribution (0.63; 0.15–1.56). Conclusions: We found varied results on the association between the use of anti-diabetic drugs and fracture risk. Specifically, trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefit with statistical difference. Other drugs were comparable in terms of their effects on fracture risk. Some drugs (omarigliptin, sitagliptin, vildagliptin, saxagliptin, empagliflozin, ertugliflozin, rosiglitazone, pioglitazone, and nateglinide) may increase the risk of fracture, while others (such as dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide, linagliptin, alogliptin, canagliflozin, dapagliflozin, glipizide, gliclazide, glibenclamide, glimepiride, metformin, and insulin) may show benefits. The risk of fracture was independent of age, sex distribution, and the duration of exposure to anti-diabetic drugs. When developing individualized treatment strategies, the clinical efficacy of anti-diabetic drugs must be weighed against their benefits and risks brought about by individual differences of patients. Systematic Review Registration: This Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).

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  • Meglitinides (repaglinide and nateglinide) increase the risk of hypoglycemia and fracture risk.

    “meglitinides (repaglinide and nateglinide) increase the risk of hypoglycemia and fracture risk”

    From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [123]

    The Results (‘Others’; page unavailable) report a higher fracture-risk estimate for nateglinide versus placebo (RR 1.35), but its confidence interval (0.24–7.55) includes no increase; the Conclusions accordingly say it may increase risk. The copy does not establish increased fracture risk for repaglinide or increased hypoglycemia risk for either meglitinide. The Discussion’s reference to hypoglycemic episodes concerns sulfonylureas, not meglitinides. (LLM, conf=0.88)

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Authors
Zhang, Y.-S., Zheng, Y.-D., Yuan, Y., Chen, S.-C., & Xie, B.-C.
Affiliations
First People's Hospital of Foshan (CN)
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2021-10-14
Volume
12
Pages
735824-735824
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2021.735824
PMC
PMC8553257
OpenAlex
W3206235521
Cited by
117
References
46
Citations by year
2026: 18 · 2025: 29 · 2024: 28 · 2023: 21 · 2022: 20 · 2021: 1
FWCI
2.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82000842)
  • Natural Science Foundation of Guangdong Province (2021A1515010151)
  • Traditional Chinese Medicine Bureau of Guangdong Province (20211403)
  • Guangdong Medical Research Foundation (B2020086)
  • Dongguan Science and Technology Bureau (202050715001197)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
Keywords
antidiabetic drugs, fracture risk, type 2 diabetes, SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, sulfonylureas, trelagliptin, albiglutide, voglibose
MeSH terms
Network Meta-Analysis, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Risk Factors, Fractures, Bone

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