medwireNews: A comparison of CANVAS and CANVAS-R fails to detect any potential explanation for the increased fracture risk seen with canagliflozin versus placebo in the former trial.
Although canagliflozin use was associated with an increased risk for adverse events attributed to falls, and to volume depletion events, this was seen only in CANVAS and was not replicated in CANVAS-R. And there was no evidence for an effect of canagliflozin on hypoglycemia or retinopathy risk, which could explain an association with falls. There were also no consistent effects of canagliflozin on markers of bone metabolism.
Bruce Neal (The George Institute for Global Health, Sydney, New South Wales, Australia) and co-researchers suggest that the falls and volume depletion events may provide an explanation for the increased fracture rate with canagliflozin that was observed in CANVAS but not CANVAS-R.
They believe the absence of such an effect in CANVAS-R could have been due to more cautious uptitration of canagliflozin dose by “investigators sensitised to the risk of fracture.” However, they add that only serious adverse events were recorded in this trial, which may have hampered their ability to detect an association, because falls and volume depletion events “were frequently categorised as non-serious.”
But the team also notes in Diabetologia that there was no evidence of an increased fracture risk in CREDENCE, the recently published trial of canagliflozin in people with diabetes and chronic kidney disease, which “increases the likelihood of chance being the correct interpretation of the outlying CANVAS result.”
In CANVAS, the increased risk for fracture in canagliflozin users was evident immediately, whereas it never appeared in CANVAS-R, ruling out an effect of long-term exposure to the sodium-glucose cotransporter 2 inhibitor. There was also no evidence of a dose effect within CANVAS, which used two doses; there was no association between fracture type or location and the 100 and 300 mg doses.
Across all 10,142 CANVAS program participants, the risk for fracture seen with canagliflozin use was consistent regardless of variables such as age, sex, medical history, and medication use, with differences seen only for regional economic development.
The 4.9% of people who had a fracture were much more likely than other participants to be female (49.4 vs 35.1% male) and to have a history of fracture (33.9 vs 21.2% without), and they had multiple small differences in demographics, disease history, and other factors.
Of the 20 baseline characteristics significantly associated with overall fracture risk, 15 affected risk in the same manner in both CANVAS trials, whereas five factors, including history of hypertension, serum calcium, and the presence of albuminuria, were a risk factor in one trial while being protective in the other.
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