Published in:
01-09-2018 | Letter to the Editor
Is the CANVAS of canaglifozin wide?
Published in: International Journal of Diabetes in Developing Countries | Issue 3/2018
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Dear Editor,-
The CANVAS Program has set a different precedence, as for the first time, data from two different studies (CANVAS and CANVAS-R) have been allowed to be pooled together to assess CV outcomes [1]. However, in the pooled analysis, the authors have not reported statistical similarity of the baseline characteristics between the canagliflozin and placebo arms. The baseline characteristics of participants in CANVAS Program reveal history of CVD in 64.8% participants in the canagliflozin arm and in 66.7% participants in the placebo arm. Statistical calculations show significantly more participants with history of CVD in the placebo arm (p = 0.046 and chi square = 3.967). The effect of this unequal distribution on the reported CV outcome data cannot be excluded.
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Participants in CANVAS were randomized to receive canagliflozin in different doses (100 and 300 mg), while in CANVAS-R, participants initially received 100 mg daily with an optional increase to 300 mg from week 13. However, in the CANVAS Program, the authors have not reported the effects of the two doses of canagliflozin separately. It is important from safety and efficacy point of view that the data of these two different doses of canagliflozin are examined.
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In sub-group analysis, effect of canagliflozin on the primary CV outcome appears to be better in patients receiving diuretics and beta-blockers, and not in participants not receiving these cardio-protective drugs. As SGLT-2 inhibitors have an osmotic diuretic effect due to glycosuria, the lack of benefit in participants not receiving diuretics is surprising. Further, canagliflozin was not found to be better in patients without history of CVD, without long-standing diabetes or with eGFR > 60 ml/min/1.73m2. Thus, the effect of canagliflozin may not be similar across varied patient profiles.
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The CANVAS study was unblinded due to an adverse effect on the LDL cholesterol [2]. This effect persisted even in the CANVAS Program. The LDL cholesterol elevation may have attenuated the positive effects on CV outcomes.
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Canagliflozin has been shown to lower both glycated hemoglobin levels and blood pressure. The investigators should have made efforts to achieve similar glycemic and blood-pressure control in the placebo group [3]; in the absence of which, the beneficial renoprotective effect cannot be attributed solely to canagliflozin.