Evaluation of the risk of fracture in type 2 diabetes mellitus patients with incretins: an updated meta-analysis
Abstract
Introduction: The effect of incretins including dipeptidyl peptidase 4 inhibitors (DPP4-Is) and glucagon-like peptide1 receptor agonists (GLP1-ras) in the treatment of type 2 diabetes increasing the risk of fracture remains controversial. No meta-analysis has been written to discuss this from the prospective interventional studies.
The objective was to evaluate the association between the use of incretins and fracture risk.
Material and methods: Multiple databases were searched for original articles that investigated the relationship between the use of incretin agents and fracture risk, up to December 2019. Trials using the Mantel-Haenszel method to calculate OR and 95% CI were pooled. The multiple sensitivity, heterogeneity, publication bias, and quality were analysed among the studies to evaluate the robustness of results.
Results: The fixed-effects model was used on account of the I2 test for heterogeneity (I2 = 0.0%). Incretins were not associated with fracture risk [0.97 (95% CI: 0.88–1.08)]. But in the subgroup analysis, when sitagliptin 100 mg per day (OR 0.495, 95% CI: 0.304–0.806) or liraglutide 1.8 mg per day was administered (OR 0.621, 95% CI: 0.413–0.933), it reduced fracture risk. The sensitivity analysis and publication bias prompted the robustness of results.
Conclusions: This meta-analysis suggested that the current use of incretins not only is safe for fracture in type 2 diabetes patients from RCT studies, but also, when sitagliptin 100 mg or liraglutide 1.8 mg per day was administered, it may exhibit protective effects on bone metabolism.
Keywords: incretinsGLP-1DPP-4fracturemeta-analysisRCT
References
- Braithwaite RS, Col NF, Wong JB. Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc. 2003; 51(3): 364–370.
- Moayeri A, Mohamadpour M, Mousavi SF, et al. Fracture risk in patients with type 2 diabetes mellitus and possible risk factors: a systematic review and meta-analysis. Ther Clin Risk Manag. 2017; 13: 455–468.
- Wolverton D, Blair MM. Fracture risk associated with common medications used in treating type 2 diabetes mellitus. Am J Health Syst Pharm. 2017; 74(15): 1143–1151.
- Schwartz AV, Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 2017; 60(7): 1163–1169.
- Schwartz AV, Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 2017; 60(7): 1163–1169.
- Schott G, Martinez YV, Ediriweera de Silva RE, et al. Effectiveness and safety of dipeptidyl peptidase 4 inhibitors in the management of type 2 diabetes in older adults: a systematic review and development of recommendations to reduce inappropriate prescribing. BMC Geriatr. 2017; 17(Suppl 1): 226.
- Tasyurek HM, Altunbas HA, Balci MK, et al. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev. 2014; 30(5): 354–371.
- Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018; 20 Suppl 1: 5–21.
- Monami M, Dicembrini I, Antenore A, et al. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care. 2011; 34(11): 2474–2476.
- Mabilleau G, Mieczkowska A, Chappard D. Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes. 2014; 6(3): 260–266.
- Su B, Sheng H, Zhang M, et al. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists' treatment: a meta-analysis of randomized controlled trials. Endocrine. 2015; 48(1): 107–115.
- Fu J, Zhu J, Hao Y, et al. Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci Rep. 2016; 6: 29104.
- Dombrowski S, Kostev K, Jacob L. Use of dipeptidyl peptidase-4 inhibitors and risk of bone fracture in patients with type 2 diabetes in Germany-A retrospective analysis of real-world data. Osteoporos Int. 2017; 28(8): 2421–2428.
- Yang J, Huang C, Wu S, et al. The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. PLoS One. 2017; 12(12): e0187537.
- Driessen JHM, de Vries F, van Onzenoort H, et al. The use of incretins and fractures — a meta-analysis on population-based real life data. Br J Clin Pharmacol. 2017; 83(4): 923–926.
- Knobloch K, Yoon U, Vogt PM. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg. 2011; 39(2): 91–92.
- Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414): 557–560.
- Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17(1): 1–12.
- Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019; 10: ED000142.
- Begg C, Mazumdar M. Operating Characteristics of a Rank Correlation Test for Publication Bias. Biometrics. 1994; 50(4): 1088.
- Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629–634.
- Gilbert MP, Marre M, Holst JJ, et al. Comparison of the Long-Term Effects of Liraglutide and Glimepiride Monotherapy on Bone Mineral Density in Patients with Type 2 Diabetes. Endocr Pract. 2016; 22(4): 406–411.
- Wen B, Zhao Lu, Zhao H, et al. Liraglutide exerts a bone-protective effect in ovariectomized rats with streptozotocin-induced diabetes by inhibiting osteoclastogenesis. Exp Ther Med. 2018; 15(6): 5077–5083.
- Mabilleau G, Pereira M, Chenu C. Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists. J Endocrinol. 2018; 236(1): R29–R42.
- Zhang L, Yang M, Ren H, et al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013; 33(5): 794–804.
- Vilsboll T. Liraglutide: a new treatment for type 2 diabetes. Drugs Today (Barc). 2009; 45(2): 101–113.
- Cusick T, Mu J, Pennypacker BL, et al. Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione. Diabetes Obes Metab. 2013; 15(10): 954–957.
- Hegazy SK. Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab. 2015; 33(2): 207–212.
- Mabilleau G, Mieczkowska A, Irwin N, et al. Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol. 2013; 219(1): 59–68.
- Montagnani A, Gonnelli S, Alessandri M, et al. Osteoporosis and risk of fracture in patients with diabetes: an update. Aging Clin Exp Res. 2011; 23(2): 84–90.
- Mabilleau G, Gobron B, Bouvard B, et al. Incretin-based therapy for the treatment of bone fragility in diabetes mellitus. Peptides. 2018; 100: 108–113.
- Scheen AJ. The safety of gliptins : updated data in 2018. Expert Opin Drug Saf. 2018; 17(4): 387–405.
- Josse RG, Majumdar SR, Zheng Y, et al. TECOS Study Group. Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial. Diabetes Obes Metab. 2017; 19(1): 78–86.
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