Does Canagliflozin Increase Fracture Risk?

[Editor's note: please see edits below]

A new analysis of phase 3 randomized clinical trials (RCTs) has found an increased risk of fracture with canagliflozin therapy. Results were published in the January issue of the Journal of Clinical Endocrinology and Metabolism.¹

“[C]anagliflozin was associated with an increased risk of fractures, primarily in the upper and lower extremities, that was driven by a significantly higher fracture rate in patients with elevated CV disease risk,” wrote lead author Gary Meininger, MD, of Janssen Research & Development (Raritan, NJ), and colleagues.

Results from a single study, the CANagliflozin cardioVascular Assessment Study (CANVAS) contributed largely to the observed increased fracture risk associated with canagliflozin.² CANVAS has a high proportion of older patients with a past history or increased risk of cardiovascular disease (CVD), impaired renal function, and higher levels of diuretic use.

In the study, researchers looked at the incidence of fractures, fall-related adverse events, and volume-depletion related adverse events in 10,194 people who had received canagliflozin for one year or more while participating in nine placebo- and active-controlled phase 3 RCTs. They also did a separate analysis of interim results from the CANVAS trial. Finally, they did a pooled analysis of eight non-CANVAS studies (5867 participants).

Key Results:

• CANVAS:

♦ Significant increase in fractures with canagliflozin (4.0%) vs placebo (2.6%)

♦ Similar fracture incidence with canagliflozin 100 mg (3.9%) and 300 mg (4.0%)

♦ Higher fracture incidence in women vs men, and in patients with past fracture history vs none (nonsignificant results)

♦ The association between canagliflozin and increased fractures lost statistical significance in sensitivity analyses not excluding fractures associated with osteoporosis [edited from previous version]

• Pooled non-CANVAS studies:

♦ Similar fracture incidence with canagliflozin (1.7%) vs noncanagliflozin (1.5%)

♦ Similar fracture incidence for canagliflozin 100 mg (1.6%) and 300 mg (1.8%)

• Overall population:

♦ Higher fracture incidence with canagliflozin (2.7%) vs noncanagliflozin (1.9%)

♦ Same fracture incidence in canagliflozin 100 mg and 300 mg (2.7%)

♦ This risk was driven by the increase of fractures in CANVAS

• Fall-related adverse events: Low incidence

♦ CANVAS: 24% higher with canagliflozin 100 mg and over two times higher with canagliflozin 300 mg (HR 1.24, [0.71-2.17], and 2.12 [1.28-3.51], respectively)

♦ Pooled non-CANVAS studies: Not significantly different

♦ Overall population: Not significantly different

• Volume depletion adverse events

♦ CANVAS: Dose-related increase in incidence; 32% increased risk with canagliflozin 100 mg (though this risk was not statistically significant), 76% increased risk with canagliflozin 300 mg (a statistically significant increase) (HR 1.32 [0.94–1.87] and 1.76 [1.27–2.44], respectively) [edited from previous version]

♦ Pooled non-canvas studies: 13% increased risk with canagliflozin 100 mg; 45% increased risk with canagliflozin 300 mg (HR 1.13 [0.74–1.73] and 1.45 [0.98–2.13], respectively)

♦ None reported immediately before or within 30 days of a fracture

The authors noted that CANVAS results showed more fractures occurred at the beginning of treatment, after which the rate of increase remained continuous. Because CANVAS had an older population with high levels of diuretic use, CV and renal comorbidities, factors other than canagliflozin may account for these results.

Falls represent a prime candidate, according to the authors. Volume depletion related to osmotic diuresis caused by SGLT2 inhibition may increase the risk for falls, especially when combined with diuretics. Other factors common to patients with diabetes could predispose to falls, such as hypoglycemia, antihypertensive use, neuromuscular impairment, nephropathy, retinopathy, as well as peripheral and autonomic neuropathy and related orthostatic hypotension.

A recent phase 3 study, however, found that canagliflozin was associated with a small but significant decrease in bone mineral density (BMD) of the total hip over 104 weeks of treatment, as well as with increased bone turnover, resorption, and bone formation markers measured up to week 52.3 Other studies have linked canagliflozin to weight loss and decreased estradiol levels in women. Research evidence suggests that weight loss and low estradiol levels may be associated with increased bone turnover and decreased bone mineral density. If so, that may provide an explanation for the increased bone turnover and decreased bone mineral density observed with canagliflozin, according to background information in the article. [edited from previous version]

“Although the cause of the increased fracture risk with canagliflozin is unknown, the small, inconsistent changes in total hip BMD (but not femoral neck, lumbar spine, or distal forearm BMD) observed with canagliflozin over 104 weeks and the fact that an early increase in fractures was observed in only a subgroup of patients treated with canagliflozin suggest that extrinsic factors related to canagliflozin, possibly related to falls or other indirect effects of canagliflozin on bone strength, may be a more likely explanation for this observed imbalance,” the authors concluded.

More results from longer-term trials are needed to establish definitive conclusions.

Take-home Points

• An analysis of phase 3 RCTs has found an increased risk of fracture with canagliflozin, though results were driven by data from a single study (the CANVAS trial).

• Canagliflozin was also associated with increased risk of volume depletion-related and fall-related adverse events.

• Because CANVAS had an older population with high levels of diuretic use, CV and renal comorbidities, falls and indirect effects of canagliflozin on bone strength may explain the increased fracture risk.

• More, longer-term trials are needed to reach a definitive conclusion. 

The study was sponsored by Janssen Research & Development.

Keith Usiskin, Mehul Desai, Robert Edwards, Gordon Law, and Gary Mininger are current or former full-time employees of Janssen Research & Development, LLC. One or more authors has consulted for Janssen and/or Bristol-Myers Squibb. 

References:

1. Watts NB, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016 Jan;101(1):157-166.

2. Neal B, et al. Rationale, design, and baseline characteristics of the CANagliflozin cardioVascular Assessment Study (CANVAS)-a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.e11.

3. Bilezikian JP, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes mellitus treated with canagliflozin. J Clin Endocrinol Metab. 2016;157:44-45.