Dr. Ruth Ezinne Chibueze MD, Ph.D
June 12, 2017- Based on a multicenter, randomized controlled study, the Diabetes Drug Canagliflozin reduced the incidence of deaths in type 2 diabetes patients, who were at an increased risk of cardiovascular disease.
Dr. Bruce Neal M.B., CH.B., Ph.D., MD with the George Institute for Global Health, Faculty of Medicine, University of New South Wales, Australia and other investigators on the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS-Renal studies, reported their findings in the June 12 online issue of the New England Journal of Medicine (NEJM).
Canagliflozin is a sodium-glucose transport inhibitor used in the treatment of type 2 diabetes patients. It lowers blood glucose accumulation by inducing renal glucose excretion in urine. To date, there are uncertainties concerning the safety and efficacy of the drug in diabetes treatment.
To assess these concerns, the benefits, and the associated risks, the authors conducted two multicenter, randomized controlled trials, CANVAS, and CANVAS-R.
Both studies included a total of 10,142 patients with type 2 diabetes from 30 countries, and 9734 (96%) patients completed the study. For the CANVAS trial (4330 patients), patients were randomized in a 1:1:1 ratio to receive canagliflozin at 100 mg, 300 mg or a placebo-matched dose.
For the CANVAS-R trial (5812 patients), a random 1:1 ratio was applied and canagliflozin administered at 100 mg and then an elective increase of 300 mg from week 13 onwards or a matched placebo dose. A longer follow-up period was recorded for CANVAS (295.5 weeks) than that of the CANVAS-R trial (108 weeks).
Effects of canagliflozin on patient outcomes were assessed using composite outcomes. These included the incidence of deaths (from cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke), as the primary endpoint and deaths from any cause (cardiovascular events, renal disorders (albuminuria, creatinuria), bone fractures and amputations) as secondary endpoints.
The incidence of deaths (as a composite of cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke) were significantly lower in the treated group compared to placebo (26.9 vs 31.5 participants with an event per 1000 patient years (hazard ratio, 0.86; 95% CI, 0.75 to 0.97; P=0.001 for noninferiority; P=0.02 for superiority). This incidence remained across subgroups, excluding those who had a history of diuretic use.
A similar reduction in the number of deaths from renal causes was reported in the canagliflozin treated group compared to placebo (5.5 vs. 9.0 participants with the outcome per 1000 patient-years; hazard ratio, 0.60; 95% CI, 0.47 to 0.77).
No difference was observed for the incidence of deaths from any cause (hazard ratio, 0.87; 95% CI, 0.74 to 1.01, and from cardiovascular causes (hazard ratio, 0.87; 95% CI, 0.72 to 1.06).
The progression (89.4 vs. 128.7 participants with an event per 1000 patient-years; hazard ratio 0.73 (95% CI, 0.67 to 0.79)) and regression (293.4 vs. 187.5 participants with regression per 1000 patient-years; hazard ratio 1.70 (95% CI, 1.51 to 1.91)) of albuminuria was lower in canagliflozin-treated group compared to placebo. A greater effect on albuminuria progression was observed in patients in the CANVAS- R trial (hazard ratio, 0.64; 95% CI, 0.57 to 0.73) compared to those in the CANVAS trial (hazard ratio, 0.80; 95% CI, 0.72 to 0.90), (P=0.02 for homogeneity)).
The risk of amputation of parts of the lower extremities were higher in the treated group (6.3 vs. 3.4 participants with amputation per 1000 patient years (hazard ratio, 1.97; 95% CI, 1.41 to 2.75). The risk of adverse events was increased due to genital infections, volume depletion, and diuresis. The incidence of all fractures (15.4 vs. 11.9 participants with fracture per 1000 patient-years; hazard ratio, 1.26; 95% CI, 1.04 to 1.52) and low-trauma fracture (11.6 vs. 9.2 participants with fracture per 1000 patient-years; hazard ratio, 1.23; 95% CI, 0.99 to 1.52) were higher in the treated group.
Dr. Bruce and his colleagues suggest a kidney-protective effect for canagliflozin and other SGLT-2 inhibitors of the same class. Also, they conclude that canagliflozin-treated patients with type 2 diabetes and an increased risk of cardiovascular disease, “had a significantly lower risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than those who received placebo, but a greater risk of amputation.”
The mechanism of amputation-related incidents from the drug is unclear, the low frequency of events for specified outcomes further limits generalization, even to at-risk populations. Thus, caution is advised for canagliflozin treatment in patients at risk of amputation.
Janssen Research & Development, LLC supported this study. The authors report financial relationships or are employees of a host of pharmaceutical companies including Janssen Research & Development, LLC. A full list of disclosures is provided in the journal article. CANVAS and CANVAS-R ClinicalTrials.gov number, NCT01032629 and NCT01989754.
N Engl J Med. Published on June 12, 2017.
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