Abstract
PurposeAvailable 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.MethodsEmbase, 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.ResultsOne 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).ConclusionsWe 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 RegistrationThis Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).
Highlights
Diabetes is a major global health problem
The risk of fracture was independent of age (RC 1.03; 0.32–2.1), duration of treatment (RC 0.79; 0.27–1.64), and sex distribution (RC 0.63; 0.15–1.56), but fracture risk had no clear associations with plasma glucose, level, and drug doses in patients treated with anti-diabetic drugs
Trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefits with statistically significant differences
Summary
Diabetes is a major global health problem. It affects nearly half a billion patients worldwide. T2DM patients with an increased bone mineral density (BMD) may suffer more from bone fractures. Many studies have suggested that a deteriorated bone quality, rather than a decreased BMD, may be the key factor influencing bone fragility in T2DM patients. From the perspective of clinical diagnosis, T2DMrelated complications (for instance, neuropathy, macroangiopathy, and retinopathy) can be regarded as predictors of bone fractures, and drug therapies may have negative effects on bone quality [5]. It is still not entirely clear why diabetes complications can lead to fragility fractures [6]. The developed antidiabetic treatment strategies should at least not increase the risk of bone fractures in the vulnerable population [10, 11]
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