Michael Fralick, MD, SM; Seoyoung C. Kim, MD, ScD, MSCE; Sebastian Schneeweiss, MD, ScD; Dae Kim, MD, ScD; Donald A. Redelmeier, MD, MSc; Elisabetta Patorno, MD, DrPH
Note: Drs. Fralick and Patorno affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Financial Support: By the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. Dr. Fralick receives funding from the Eliot Phillipson Clinician-Scientist Training Program at the University of Toronto, the Clinician Investigator Program at the University of Toronto, the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program, and the Detweiler Travelling Fellowship funded by the Royal College of Physicians and Surgeons of Canada. Dr. Dae Kim is supported by the Paul B. Beeson Clinical Scientist Development Award in Aging (K08AG051187) from the National Institute on Aging, the American Federation for Aging Research, the John A. Hartford Foundation, and the Atlantic Philanthropies. Dr. Redelmeier has received funding from a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, and the BrightFocus Foundation. Dr. Patorno is supported by a career development grant (K08AG055670) from the National Institute on Aging.
Disclosures: Dr. Seoyoung Kim reports grants from Pfizer, Bristol-Myers Squibb, and Roche outside the submitted work. Dr. Schneeweiss reports grants from Genentech, Boehringer Ingelheim, the U.S. Food and Drug Administration, the Patient-Centered Outcomes Research Institute, and Bayer; personal fees from WHISCON and Aetion; and other support from Aetion outside the submitted work. Dr. Dae Kim reports grants from the National Institute on Aging during the conduct of the study. Dr. Patorno reports grants from the National Institute on Aging, GlaxoSmithKline, and Boehringer Ingelheim outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-0567.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See Appendix Tables and . Statistical code: Available from Dr. Fralick (e-mail, email@example.com). Data set: Available from data vendors under a data use agreement.
Corresponding Author: Michael Fralick, MD, SM, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA 02120; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Fralick, Seoyoung Kim, Schneeweiss, Dae Kim, and Patorno: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA 02120.
Dr. Redelmeier: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room G1 5, Toronto, Ontario M4N 3M5, Canada.
Author Contributions: Conception and design: M. Fralick, S.C. Kim, S. Schneeweiss, D.A. Redelmeier, E. Patorno.
Analysis and interpretation of the data: M. Fralick, S.C. Kim, S. Schneeweiss, D. Kim, D.A. Redelmeier, E. Patorno.
Drafting of the article: M. Fralick.
Critical revision of the article for important intellectual content: M. Fralick, S.C. Kim, S. Schneeweiss, D. Kim, D.A. Redelmeier, E. Patorno.
Final approval of the article: M. Fralick, S.C. Kim, S. Schneeweiss, D. Kim, D.A. Redelmeier, E. Patorno.
Provision of study materials or patients: M. Fralick, S. Schneeweiss.
Statistical expertise: M. Fralick, S.C. Kim, S. Schneeweiss, D.A. Redelmeier.
Obtaining of funding: S. Schneeweiss.
Administrative, technical, or logistic support: M. Fralick, S. Schneeweiss, D.A. Redelmeier.
Collection and assembly of data: M. Fralick, S.C. Kim, S. Schneeweiss.
Sodium–glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture.
To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist.
Population-based new-user cohort study.
Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015.
Persons with type 2 diabetes who initiated use of canagliflozin were propensity score–matched in a 1:1 ratio to those initiating use of a GLP-1 agonist.
The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR).
79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]).
Unmeasured confounding, measurement error, and low fracture rate.
In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists.
Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.
Fralick M, Kim SC, Schneeweiss S, Kim D, Redelmeier DA, Patorno E. Fracture Risk After Initiation of Use of Canagliflozin: A Cohort Study. Ann Intern Med. [Epub ahead of print ]:. doi: 10.7326/M18-0567
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Published: Ann Intern Med. 2019.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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