Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus
Open accessAbstract
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.
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The trial comparing saxagliptin with placebo showed an increased likelihood of hospitalization for congestive heart failure without an increase in mortality.
“The trial comparing saxagliptin with placebo showed an increased likelihood of hospitalization for CHF1045 without increase in mortality.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1045]
The Patients and study design and Incidence of fracture AEs sections describe canagliflozin trials and fracture outcomes, not a saxagliptin–placebo trial. Searches for saxagliptin, heart-failure hospitalization, and mortality found no passage addressing the attributed result. Page numbers were not available in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCardiovascular outcome trials of DPP-4 inhibitors achieved non-inferiority versus placebo for major adverse cardiovascular events.
“CVOTs with DPP-4 inhibitors achieved non-inferiority compared with placebo for the occurrence of MACE.1044–1046”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1045]
The Patients and study design section describes canagliflozin studies, including comparisons with sitagliptin, but reports no cardiovascular outcome results for DPP-4 inhibitors. Searches for DPP-4 inhibitor non-inferiority and MACE found no passage in our copy addressing the claimed result; page numbers were not available. (LLM, conf=0.76)
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- Authors
- Watts, N. B., Bilezikian, J. P., Usiskin, K., Edwards, R., Desai, M., Law, G., & Meininger, G.
- Affiliations
- Mercy Health (US)
- Corresponding author
- Watts, Nelson B.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-01
- Volume
- 101
- Issue
- 1
- Pages
- 157-166
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4701850
- OpenAlex
- W2179831365
- Cited by
- 454
- References
- 42
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 36 · 2023: 34 · 2022: 44 · 2021: 36 · 2020: 40 · 2019: 51 · 2018: 65 · 2017: 60 · 2016: 44 · 2015: 4
- FWCI
- 50.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (T32CA117846)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- canagliflozin, fracture risk, type 2 diabetes, SGLT2 inhibitors, falls, hypovolemia, CANVAS trial, adverse events
- MeSH terms
- Accidental Falls, Canagliflozin, Adult, Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diuretics, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Risk, Incidence, Fractures, Bone, Kaplan-Meier Estimate
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