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Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in real-world use: systematic review and meta-analysis of observational studies

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Abstract

Summary

In the present meta-analysis based on real-world data, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1ra), or sodium-glucose cotransporter-2 inhibitors (SGLT2i) was not associated with the risk of fracture.

Introduction

Cumulative evidence from randomized control trials (RCTs) with limited fracture events showed that the use of DPP-4i, GLP-1ra, or SGLT2i may not affect the risk of fracture. However, additional insights from large population-based studies with routinely collected data on fracture events and an adequate amount of fracture events are necessary to draw firm conclusions. To refine and complement the results from RCTs, a systematic review and meta-analysis of observational studies were performed to investigate the association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture in real-world settings.

Methods

The PubMed and Web of Science databases were searched to identify relevant observational studies. A random-effect model was used to estimate the summary relative risks (RRs).

Results

The use of DPP-4i (RR 0.83, 95% CI [confidence interval] 0.60, 1.14; n = 11), GLP-1ra (RR 0.65, 95% CI 0.24, 1.74; n = 4), or SGLT2i (RR 1.02, 95% CI 0.91, 1.16; n = 4) was not associated with the risk of fracture. In general, there was a consistent lack of association between the use of DPP-4i or GLP-1ra and the risk of fracture across nearly all subgroups, except for a significantly reduced risk of hip fracture with the use of GLP-1ra (RR 0.21, 95% CI 0.04, 0.98).

Conclusions

Cumulative real-world evidence does not support an association between the use of DPP-4i, GLP-1ra, or SGLT2i and the risk of fracture. Our findings, together with the cumulative evidence from RCTs, should reassure policy makers and medical practitioners that the use of these medications is unlikely to increase the risk of fracture among type 2 diabetes mellitus patients in general. Further studies need to investigate the long-term impact of these drugs on the fracture risk, particularly in high-risk populations.

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References

  1. NCD Risk Factor Collaboration (NCD-RisC) (2016) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387:1513–1530

    Article  Google Scholar 

  2. Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (2014) Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol 2:634–647

    Article  Google Scholar 

  3. Bommer C, Heesemann E, Sagalova V, Manne-Goehler J, Atun R, Bärnighausen T, Vollmer S (2017) The global economic burden of diabetes in adults aged 20-79 years: a cost-of-illness study. Lancet Diabetes Endocrinol 5:423–430

    Article  PubMed  Google Scholar 

  4. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14:88–98

    Article  PubMed  Google Scholar 

  5. Napoli N, Chandran M, Pierroz DD et al (2017) Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13:208–219

    Article  CAS  PubMed  Google Scholar 

  6. Wang H, Ba Y, Xing Q, Du JL (2019) Diabetes mellitus and the risk of fractures at specific sites: a meta-analysis. BMJ Open 9:e024067

    Article  PubMed  PubMed Central  Google Scholar 

  7. Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505

    Article  PubMed  Google Scholar 

  8. Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123

    Article  CAS  PubMed  Google Scholar 

  9. Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180:32–39

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schwartz AV (2017) Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia 60:1170–1179

    Article  CAS  PubMed  Google Scholar 

  11. Adil M, Khan RA, Kalam A, Venkata SK, Kandhare AD, Ghosh P, Sharma M (2017) Effect of anti-diabetic drugs on bone metabolism: evidence from preclinical and clinical studies. Pharmacol Rep 69:1328–1340

    Article  CAS  PubMed  Google Scholar 

  12. Kalaitzoglou E, Fowlkes JL, Popescu I, Thrailkill KM (2018) Diabetes pharmacotherapy and effects on the musculoskeletal system. Diabetes Metab Res Rev 35:e3100

    Article  PubMed  PubMed Central  Google Scholar 

  13. Blau JE, Bauman V, Conway EM, Piaggi P, Walter MF, Wright EC, Bernstein S, Courville AB, Collins MT, Rother KI, Taylor SI (2018) Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight 3:e99123

    Article  PubMed Central  Google Scholar 

  14. Yang J, Huang C, Wu S, Xu Y, Cai T, Chai S, Yang Z, Sun F, Zhan S (2017) 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 12:e0187537

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Fu J, Zhu J, Hao Y, Guo C, Zhou Z (2016) Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci Rep 6:29104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mamza J, Marlin C, Wang C, Chokkalingam K, Idris I (2016) DPP-4 inhibitor therapy and bone fractures in people with type 2 diabetes - a systematic review and meta-analysis. Diabetes Res Clin Pract 116:288–298

    Article  CAS  PubMed  Google Scholar 

  17. Monami M, Dicembrini I, Antenore A, Mannucci E (2011) Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 34:2474–2476

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mosenzon O, Wei C, Davidson J, Scirica BM, Yanuv I, Rozenberg A, Hirshberg B, Cahn A, Stahre C, Strojek K, Bhatt DL, Raz I (2015) Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 trial. Diabetes Care 38:2142–2150

    Article  PubMed  Google Scholar 

  19. Josse RG, Majumdar SR, Zheng Y, Adler A, Bethel MA, Buse JB, Green JB, Kaufman KD, Rodbard HW, Tankova T, Westerhout CM, Peterson ED, Holman RR, Armstrong PW, on behalf of the TECOS Study Group (2017) Sitagliptin and risk of fractures in type 2 diabetes: results from the TECOS trial. Diabetes Obes Metab 19:78–86

    Article  CAS  PubMed  Google Scholar 

  20. Zhang YS, Weng WY, Xie BC, Meng Y, Hao YH, Liang YM, Zhou ZK (2018) Glucagon-like peptide-1 receptor agonists and fracture risk: a network meta-analysis of randomized clinical trials. Osteoporos Int 29:2639–2644

    Article  CAS  PubMed  Google Scholar 

  21. Su B, Sheng H, Zhang M, Bu L, Yang P, Li L, Li F, Sheng C, Han Y, Qu S, Wang J (2015) Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists' treatment: a meta-analysis of randomized controlled trials. Endocrine 48:107–115

    Article  CAS  PubMed  Google Scholar 

  22. Mabilleau G, Mieczkowska A, Chappard D (2014) Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 6:260–266

    Article  CAS  PubMed  Google Scholar 

  23. Azharuddin M, Adil M, Ghosh P, Sharma M (2018) Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a systematic literature review and Bayesian network meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 146:180–190

    Article  CAS  PubMed  Google Scholar 

  24. Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T (2017) Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev 33 https://doi.org/10.1002/dmrr.2903

    Article  CAS  Google Scholar 

  25. Tang HL, Li DD, Zhang JJ, Hsu YH, Wang TS, Zhai SD, Song YQ (2016) Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 18:1199–1206

    Article  CAS  PubMed  Google Scholar 

  26. Neal B, Perkovic V, Matthews DR (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:2099

    Article  PubMed  Google Scholar 

  27. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, Meininger G (2016) Effects of Canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 101:157–166

    Article  CAS  PubMed  Google Scholar 

  28. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283:2008–2012

    Article  CAS  PubMed  Google Scholar 

  29. Wells GA, Shea B, O’connell D et al (2000) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed on Feb 2019

  30. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  31. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  32. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56:455–463

    Article  CAS  PubMed  Google Scholar 

  34. Bunck MC, Poelma M, Eekhoff EM et al (2012) Effects of vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled type 2 diabetes patients. J Diabetes 4:181–185

    Article  CAS  PubMed  Google Scholar 

  35. Vianna AGD, de Lacerda CS, Pechmann LM (2017) Vildagliptin has the same safety profile as a sulfonylurea on bone metabolism and bone mineral density in post-menopausal women with type 2 diabetes: a randomized controlled trial. Diabetol Metab Syndr 9:35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bunck MC, Eliasson B, Cornér A, Heine RJ, Shaginian RM, Taskinen MR, Yki-Järvinen H, Smith U, Diamant M (2011) Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 13:374–347

    Article  CAS  PubMed  Google Scholar 

  37. Li R, Xu W, Luo S, Xu H, Tong G, Zeng L, Zhu D, Weng J (2015) Effect of exenatide, insulin and pioglitazone on bone metabolism in patients with newly diagnosed type 2 diabetes. Acta Diabetol 52:1083–1091

    Article  CAS  PubMed  Google Scholar 

  38. Gilbert MP, Marre M, Holst JJ, Garber A, Baeres FMM, Thomsen H, Pratley RE (2016) Comparison of the long-term effects of liraglutide and glimepiride monotherapy on bone mineral density in patients with type 2 diabetes. Endocr Pract 22:406–411

    Article  PubMed  Google Scholar 

  39. Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD, Sugg J, Parikh S (2012) Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 14:990–999

    Article  CAS  PubMed  Google Scholar 

  40. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, Sugg J, Parikh S (2014) Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16:159–169

    Article  CAS  PubMed  Google Scholar 

  41. Bode B, Stenlöf K, Harris S, Sullivan D, Fung A, Usiskin K, Meininger G (2015) Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes Metab 17:294–303

    Article  CAS  PubMed  Google Scholar 

  42. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, Rosenthal N (2016) Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with Canagliflozin. J Clin Endocrinol Metab 101:44–51

    Article  CAS  PubMed  Google Scholar 

  43. Rosenstock J, Frias J, Páll D, Charbonnel B, Pascu R, Saur D, Darekar A, Huyck S, Shi H, Lauring B, Terra SG (2018) Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab 20:520–529

    Article  CAS  PubMed  Google Scholar 

  44. Losada-Grande E, Hawley S, Soldevila B (2017) Insulin use and excess fracture risk in patients with type 2 diabetes: a propensity-matched cohort analysis. Sci Rep 7:3781

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Driessen JH, van Onzenoort HA, Henry RM et al (2014) Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture. Bone 68:124–130

    Article  CAS  PubMed  Google Scholar 

  46. Driessen JH, van Onzenoort HA, Starup-Linde J et al (2015) Use of dipeptidyl peptidase 4 inhibitors and fracture risk compared to use of other anti-hyperglycemic drugs. Pharmacoepidemiol Drug Saf 24:1017–1025

    Article  CAS  PubMed  Google Scholar 

  47. Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS (2016) Risk of fractures and diabetes medications: a nationwide cohort study. Osteoporos Int 27:2709–2715

    Article  CAS  PubMed  Google Scholar 

  48. Majumdar SR, Josse RG, Lin M, Eurich DT (2016) Does Sitagliptin affect the rate of osteoporotic fractures in type 2 diabetes? Population-based cohort study. J Clin Endocrinol Metab 101:1963–1969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dombrowski S, Kostev K, Jacob L (2017) 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 28:2421–2428

    Article  CAS  PubMed  Google Scholar 

  50. Driessen JH, van den Bergh JP, van Onzenoort HA (2017) Long-term use of dipeptidyl peptidase-4 inhibitors and risk of fracture: a retrospective population-based cohort study. Diabetes Obes Metab 19:421–428

    Article  CAS  PubMed  Google Scholar 

  51. Starup-Linde J, Gregersen S, Frost M, Vestergaard P (2017) Use of glucose-lowering drugs and risk of fracture in patients with type 2 diabetes. Bone 95:136–142

    Article  CAS  PubMed  Google Scholar 

  52. Wallander M, Axelsson KF, Nilsson AG, Lundh D, Lorentzon M (2017) Type 2 diabetes and risk of hip fractures and non-skeletal fall injuries in the elderly: a study from the fractures and fall injuries in the elderly cohort (FRAILCO). J Bone Miner Res 32:449–460

    Article  CAS  PubMed  Google Scholar 

  53. Gamble JM, Donnan JR, Chibrikov E, Twells LK, Midodzi WK, Majumdar SR (2018) The risk of fragility fractures in new users of dipeptidyl peptidase-4 inhibitors compared to sulfonylureas and other anti-diabetic drugs: a cohort study. Diabetes Res Clin Pract 136:159–167

    Article  CAS  PubMed  Google Scholar 

  54. Hou WH, Chang KC, Li CY, Ou HT (2018) Dipeptidyl peptidase-4 inhibitor use is associated with decreased risk of fracture in patients with type 2 diabetes: a population-based cohort study. Br J Clin Pharmacol 84:2029–2039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lin SY, Hsu WH, Lin CC, Lin CL, Tsai CH, Yeh HC, Hsu CY, Kao CH (2018) Sitagliptin and fractures in type 2 diabetes: a Nationwide population-based propensity-matching study. Front Pharmacol 9:677

    Article  PubMed  PubMed Central  Google Scholar 

  56. Losada E, Soldevila B, Ali MS, Martínez-Laguna D, Nogués X, Puig-Domingo M, Díez-Pérez A, Mauricio D, Prieto-Alhambra D (2018) Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case-control study. Osteoporos Int 29:2079–2086

    Article  CAS  PubMed  Google Scholar 

  57. Driessen JH, Henry RM, van Onzenoort HA et al (2015) Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis. Calcif Tissue Int 97:104–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Driessen JH, van Onzenoort HA, Starup-Linde J et al (2015) Use of glucagon-like-peptide 1 receptor agonists and risk of fracture as compared to use of other anti-hyperglycemic drugs. Calcif Tissue Int 97:506–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schmedt N, Andersohn F, Walker J, Garbe E (2019) Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower limbs in patients with type 2 diabetes: a nested case-control study. Diabetes Obes Metab 21:52–60

    Article  CAS  PubMed  Google Scholar 

  60. Toulis KA, Bilezikian JP, Thomas GN, Hanif W, Kotsa K, Thayakaran R, Keerthy D, Tahrani AA, Nirantharakumar K (2018) Initiation of dapagliflozin and treatment-emergent fractures. Diabetes Obes Metab 20:1070–1074

    Article  CAS  PubMed  Google Scholar 

  61. Ueda P, Svanström H, Melbye M (2018) Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 363:k4365

    Article  PubMed  PubMed Central  Google Scholar 

  62. Fralick M, Kim SC, Schneeweiss S et al (2019) Fracture risk after initiation of use of Canagliflozin: A Cohort Study. Ann Intern Med. https://doi.org/10.7326/M18-0567. (ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  63. Driessen JH, de Vries F, van Onzenoort H (2017) The use of incretins and fractures - a meta-analysis on population-based real life data. Br J Clin Pharmacol 83:923–926

    Article  CAS  PubMed  Google Scholar 

  64. Driessen JHM, Knapen LM, Geusens PPMM, van den Bergh JPW (2017) Fracture risk reduction with use of dipeptidyl peptidase-4 inhibitors: is there immortal time bias? Osteoporos Int 28:2429–2430

    Article  CAS  PubMed  Google Scholar 

  65. Kostev K, Dombrowski S (2017) Fracture risk reduction with use of dipeptidyl peptidase-4 inhibitors: response to Driessen et al. Osteoporos Int 28:2431

    Article  CAS  PubMed  Google Scholar 

  66. Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167:492–499

    Article  PubMed  Google Scholar 

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Funding

The study was supported by grants from Suzhou Science and Technology Bureau (No. SYS201741).

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  1. K. Hidayat and X. Du contributed equally to this work.

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  1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, 215006, China

    K. Hidayat, X. Du & B.-M. Shi

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Contributions

K.H. designed the research. K.H. and X.D. performed the literature search, data extraction, and quality assessment. K.H. performed the data analyses and wrote the paper. B.-M.S. took primary responsibility for the final content. All authors read and approved the final manuscript.

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Correspondence to K. Hidayat or B.-M. Shi.

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Khemayanto Hidayat, Xuan Du, and Bi-Min Shi declare that they have no conflicts of interest.

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Hidayat, K., Du, X. & Shi, BM. Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in real-world use: systematic review and meta-analysis of observational studies. Osteoporos Int 30, 1923–1940 (2019). https://doi.org/10.1007/s00198-019-04968-x

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