PMID- 26580237 OWN - NLM STAT- MEDLINE DCOM- 20160509 LR - 20220309 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 101 IP - 1 DP - 2016 Jan TI - Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. PG - 157-66 LID - 10.1210/jc.2015-3167 [doi] AB - CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of this study was to describe the effects of canagliflozin on bone fracture risk. DESIGN AND SETTING: This was a randomized phase 3 study in patients with T2DM. PATIENTS AND INTERVENTIONS: Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867). OUTCOME MEASURES: The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed. RESULTS: The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. CONCLUSIONS: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown. FAU - Watts, Nelson B AU - Watts NB AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Bilezikian, John P AU - Bilezikian JP AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Usiskin, Keith AU - Usiskin K AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Edwards, Robert AU - Edwards R AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Desai, Mehul AU - Desai M AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Law, Gordon AU - Law G AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. FAU - Meininger, Gary AU - Meininger G AD - Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869. LA - eng SI - ClinicalTrials.gov/NCT00968812 SI - ClinicalTrials.gov/NCT01032629 SI - ClinicalTrials.gov/NCT01064414 SI - ClinicalTrials.gov/NCT01081834 SI - ClinicalTrials.gov/NCT01106625 SI - ClinicalTrials.gov/NCT01106651 SI - ClinicalTrials.gov/NCT01106677 SI - ClinicalTrials.gov/NCT01106690 SI - ClinicalTrials.gov/NCT01137812 GR - T32 CA117846/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20151118 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Diuretics) RN - 0 (Hypoglycemic Agents) RN - 0SAC974Z85 (Canagliflozin) SB - IM CIN - J Clin Endocrinol Metab. 101:44. MH - Accidental Falls MH - Adult MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Canagliflozin/*adverse effects/therapeutic use MH - Cardiovascular Diseases/complications MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Diuretics/adverse effects MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Fractures, Bone/*epidemiology MH - Humans MH - Hypoglycemic Agents/*adverse effects/therapeutic use MH - Incidence MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Risk PMC - PMC4701850 EDAT- 2015/11/19 06:00 MHDA- 2016/05/10 06:00 PMCR- 2015/11/18 CRDT- 2015/11/19 06:00 PHST- 2015/11/19 06:00 [entrez] PHST- 2015/11/19 06:00 [pubmed] PHST- 2016/05/10 06:00 [medline] PHST- 2015/11/18 00:00 [pmc-release] AID - 15-3167 [pii] AID - 10.1210/jc.2015-3167 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2016 Jan;101(1):157-66. doi: 10.1210/jc.2015-3167. Epub 2015 Nov 18.