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An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.
This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.
A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.
There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.
ClinicalTrials.gov NCT01032629, NCT01989754.
Shanbhogue VV, Hansen S, Frost M, Brixen K, Hermann AP (2017) Bone disease in diabetes: another manifestation of microvascular disease? Lancet Diabetes Endocrinol 5(10):827–838. https://doi.org/10.1016/S2213-8587(17)30134-1 CrossRefPubMed
Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123. https://doi.org/10.1016/j.bone.2014.08.010 CrossRefPubMed
Meier C, Schwartz AV, Egger A, Lecka-Czernik B (2016) Effects of diabetes drugs on the skeleton. Bone 82:93–100. https://doi.org/10.1016/j.bone.2015.04.026 CrossRefPubMed
Neal B, Perkovic V, de Zeeuw D et al (2013) Rationale, design, and baseline characteristics of the CANagliflozin cardioVascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J 166(2):217–223. https://doi.org/10.1016/j.ahj.2013.05.007
Neal B, Perkovic V, Matthews DR et al (2017) Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 19(3):387–393. https://doi.org/10.1111/dom.12829 CrossRefPubMedPubMedCentral
Bilezikian JP, Watts NB, Usiskin K et al (2016) Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor. J Clin Endocrinol Metab 101(1):44–51. https://doi.org/10.1210/jc.2015-1860 CrossRefPubMed
Bristol-Myers Squibb (2014) Highlights of prescribing information. Available from www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s003lbl.pdf. Accessed 11 Dec 2018
Radholm K, Wu JH, Wong MG et al (2018) Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes - a systematic review. Diabetes Res Clin Pract 140:118–128. https://doi.org/10.1016/j.diabres.2018.03.027 CrossRefPubMed
Fralick M, Kim SC, Schneeweiss S, Kim D, Redelmeier DA, Patorno E (2019) Fracture risk after initiation of use of canagliflozin: a cohort study. Ann Intern Med 170(3):155–163. https://doi.org/10.7326/M18-0567
de Waard EA, van Geel TA, Savelberg HH, Koster A, Geusens PP, van den Bergh JP (2014) Increased fracture risk in patients with type 2 diabetes mellitus: an overview of the underlying mechanisms and the usefulness of imaging modalities and fracture risk assessment tools. Maturitas 79(3):265–274. https://doi.org/10.1016/j.maturitas.2014.08.003 CrossRefPubMed
Alba M, Xie J, Fung A, Desai M (2016) The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin 32(8):1375–1385. https://doi.org/10.1080/03007995.2016.1174841
Weir MR, Kline I, Xie J, Edwards R, Usiskin K (2014) Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin 30(9):1759–1768. https://doi.org/10.1185/03007995.2014.919907 CrossRefPubMed
- Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program
David R. Matthews
Kenneth W. Mahaffey
Dick de Zeeuw
Nelson B. Watts
- Springer Berlin Heidelberg
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