Effects of GLP-1 Receptor Agonists on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus: A 52-Week Clinical Study

Ting-Ting Cai, Hui-Qin Li, Lan-Lan Jiang, Hui-Ying Wang, Meng-Hui Luo, Xiao-Fei Su, Jian-Hua Ma, Ting-Ting Cai, Hui-Qin Li, Lan-Lan Jiang, Hui-Ying Wang, Meng-Hui Luo, Xiao-Fei Su, Jian-Hua Ma

Abstract

Introduction: Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM.

Methods: In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n = 19), dulaglutide group (n = 19), insulin glargine group (n = 10), and placebo (n = 17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry.

Results: Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11 ± 0.24% vs. 7.40 ± 0.16%, P = 0.007), dulaglutide (8.77 ± 0.37% vs. 7.06 ± 0.28%, P < 0.001), and insulin glargine (8.57 ± 0.24% vs. 7.23 ± 0.25%, P < 0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P = 0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P < 0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P < 0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P < 0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P = 0.001).

Conclusions: Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

Conflict of interest statement

The authors declare no conflict of interest.

Copyright © 2021 Ting-ting Cai et al.

References

    1. Napoli N., Chandran M., Pierroz D. D., Abrahamsen B., Schwartz A. V., Ferrari S. L. Mechanisms of diabetes mellitus-induced bone fragility. Nature Reviews. Endocrinology. 2017;13(4):208–219. doi: 10.1038/nrendo.2016.153.
    1. Valderrábano R. J., Linares M. I. Diabetes mellitus and bone health: epidemiology, etiology and implications for fracture risk stratification. Clinical diabetes and endocrinology. 2018;4(1) doi: 10.1186/s40842-018-0060-9.
    1. Dede A. D., Tournis S., Dontas I., Trovas G. Type 2 diabetes mellitus and fracture risk. Metabolism: clinical and experimental. 2014;63(12):1480–1490. doi: 10.1016/j.metabol.2014.09.002.
    1. Golden S. H., Lazo M., Carnethon M., et al. Examining a bidirectional association between depressive symptoms and diabetes. JAMA. 2008;299(23):2751–2759. doi: 10.1001/jama.299.23.2751.
    1. Jackson K., Moseley K. F. Diabetes and bone fragility: SGLT2 inhibitor use in the context of renal and cardiovascular benefits. Current Osteoporosis Reports. 2020;18(5):439–448. doi: 10.1007/s11914-020-00609-z.
    1. Li Z., Li S., Wang N., Xue P., Li Y. Liraglutide, a glucagon-like peptide-1 receptor agonist, suppresses osteoclastogenesis through the inhibition of NF-κB and MAPK pathways via GLP-1R. Biomedicine & pharmacotherapy = Biomédecine & pharmacothérapie. 2020;130:p. 110523. doi: 10.1016/j.biopha.2020.110523.
    1. Zhang L., Li P., Tang Z., Dou Q., Feng B. Effects of GLP-1 receptor analogue liraglutide and DPP-4 inhibitor vildagliptin on the bone metabolism in ApoE-/- mice. Annals of translational medicine. 2019;7(16)
    1. Pereira M., Jeyabalan J., Jørgensen C. S., et al. Chronic administration of glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice. Bone. 2015;81:459–467. doi: 10.1016/j.bone.2015.08.006.
    1. Mabilleau G., Mieczkowska A., Chappard D. Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. Journal of Diabetes. 2014;6(3):260–266.
    1. Driessen J. H., Henry R. M., van Onzenoort H. A., et al. Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis. Calcified Tissue International. 2015;97(2):104–112. doi: 10.1007/s00223-015-9993-5.
    1. Mohsin S., Kaimala S., Sunny J. J., Adeghate E., Brown E. M. Type 2 diabetes mellitus increases the risk to hip fracture in postmenopausal osteoporosis by deteriorating the trabecular bone microarchitecture and bone mass. Journal of Diabetes Research. 2019;2019:10. doi: 10.1155/2019/3876957.3876957
    1. Moon H. U., Lee N., Chung Y. S., Choi Y. J. Reduction of visceral fat could be related to the improvement of TBS in diabetes mellitus. Journal of Bone and Mineral Metabolism. 2020;38(5):702–709. doi: 10.1007/s00774-020-01107-z.
    1. Alberti K. G., Zimmet P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic medicine: a journal of the British Diabetic Association. 1998;15(7):539–553. doi: 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>;2-S.
    1. Paschou S. A., Dede A. D., Anagnostis P. G., Vryonidou A., Morganstein D., Goulis D. G. Type 2 diabetes and osteoporosis: a guide to optimal management. The Journal of Clinical Endocrinology and Metabolism. 2017;102(10):3621–3634. doi: 10.1210/jc.2017-00042.
    1. Montagnani A., Gonnelli S., Alessandri M., Nuti R. Osteoporosis and risk of fracture in patients with diabetes: an update. Aging Clinical and Experimental Research. 2011;23(2):84–90. doi: 10.1007/BF03351073.
    1. Gruntmanis U., Fordan S., Ghayee H. K., et al. The peroxisome proliferator-activated Receptor-γ agonist rosiglitazone increases bone resorption in women with type 2 diabetes: a randomized, controlled trial. Calcified Tissue International. 2010;86(5):343–349. doi: 10.1007/s00223-010-9352-5.
    1. Borges J. L., Bilezikian J. P., Jones-Leone A. R., et al. A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Diabetes, Obesity & Metabolism. 2011;13(11):1036–1046.
    1. Gilbert M. P., Marre M., Holst J. J., et al. Comparison of the long-term effects of liraglutide and glimepiride monotherapy on bone mineral density in patients with type 2 diabetes. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016;22(4):406–411.
    1. Monami M., Dicembrini I., Antenore A., Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: Figure 1. Diabetes Care. 2011;34(11):2474–2476. doi: 10.2337/dc11-1099.
    1. Khazai N. B., Beck G. R., Jr., Umpierrez G. E. Diabetes and fractures: an overshadowed association. Current Opinion in Endocrinology, Diabetes, and Obesity. 2009;16(6):435–445.
    1. Jensen L. B., Kollerup G., Quaade F., Sørensen O. H. Bone minerals changes in obese women during a moderate weight loss with and without calcium supplementation. Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research. 2001;16(1):141–147.
    1. Mabilleau G., Mieczkowska A., Irwin N., Flatt P. R., Chappard D. Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. The Journal of Endocrinology. 2013;219(1):59–68.
    1. Eminov E., Hortu I., Akman L., Erbas O., Yavasoglu A., Cirpan T. Exenatide preserves trabecular bone microarchitecture in experimental ovariectomized rat model. Archives of Gynecology and Obstetrics. 2018;297(6):1587–1593.
    1. Iepsen E. W., Lundgren J. R., Hartmann B., et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. The Journal of Clinical Endocrinology and Metabolism. 2015;100(8):2909–2917.
    1. Cheng L., Hu Y., Li Y. Y., et al. Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes/metabolism research and reviews. 2019;35(7)
    1. Meng J., Ma X., Wang N., et al. Activation of GLP-1 receptor promotes bone marrow stromal cell osteogenic differentiation through β-catenin. Stem Cell Reports. 2016;6(4):579–591. doi: 10.1016/j.stemcr.2016.02.002.
    1. Gao L., Li S. L., Li Y. K. Liraglutide promotes the osteogenic differentiation in MC3T3-E1 cells via regulating the expression of Smad2/3 through PI3K/Akt and Wnt/β-catenin pathways. DNA and Cell Biology. 2018;37(12):1031–1043.
    1. Luo G., Liu H., Lu H. Glucagon-like peptide-1(GLP-1) receptor agonists: potential to reduce fracture risk in diabetic patients. British Journal of Clinical Pharmacology. 2016;81(1):78–88.
    1. Shen W. R., Kimura K., Ishida M., et al. The glucagon-like peptide-1 receptor agonist exendin-4 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption via inhibition of TNF-α expression in macrophages. Journal of Immunology Research. 2018;2018:10. doi: 10.1155/2018/5783639.5783639

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa