Integrated CANVAS: canagliflozin offers cardioprotection at amputation cost
medwireNews: The integrated results of the CANVAS and CANVAS-R studies show that canagliflozin reduces the risk for cardiovascular and renal events in patients with type 2 diabetes at high cardiovascular risk.
However, treatment with the sodium glucose co-transporter 2 inhibitor was also associated with an increased risk for amputation, the investigators reported at the American Diabetes Association scientific sessions in San Diego.
Medicine Matters editorial board member Carol Wysham (Rockwood Center for Diabetes and Endocrinology, Spokane, Washington, USA), who was a site investigator for CANVAS, said: “Clinically at this point, I’m not inclined to say that I need to be switching all my patients from canagliflozin to empagliflozin.
“I think the strong data that we have supports the class, particularly when we add that to the CVD-REAL study results, which are primarily primary prevention.”
The analysis involved 4330 patients from CANVAS and 5812 from CANVAS-R. The studies had identical main inclusion criteria, allowing a single analysis of all patients, who were either at least 30 years old with cardiovascular disease or at least 50 years old with two or more cardiovascular risk factors. The patients were 63.3 years old, on average, with an average diabetes duration of 13.5 years.
CANVAS used two doses of canagliflozin – 100 and 300 mg/day – whereas patients in CANVAS-R received the medication at a dose of 100 mg with the option to increase to 300 mg, as occurred in 71.4%.
During follow-up averaging 295.9 weeks in CANVAS and 108.0 weeks in CANVAS -R, the rate of the primary outcome (cardiovascular death, nonfatal myocardial, nonfatal stroke) per 1000 patient–years was 26.9 in the 5795 patients taking canagliflozin versus 31.5 in the 4347 taking placebo.
This met the criteria for noninferiority, and the 14% reduced rate with canagliflozin in fact made it statistically superior.
There were no differences for the primary endpoint outcomes considered individually, but canagliflozin had a marked effect on patients’ risk for being hospitalized for heart failure, reducing this risk by 33% (rates of 5.5 vs 8.7 per 1000 patient–years).
Canagliflozin also reduced the risk for renal outcomes, with progression of albuminuria occurring at a rate of 89.4 per 1000 patient–years in the canagliflozin group versus 128.7 per 1000 patient–years in the placebo group. There was a 40% reduction in the risk for the composite renal endpoint, which was a 40% reduction in estimated glomerular filtration rate, need for renal replacement therapy, or renal death.
Canagliflozin did not increase the risk for hypoglycemia, and serious adverse events were less common in the canagliflozin group than the placebo group. However, patients taking canagliflozin had an increased risk for amputation of toes, feet, or legs, with a rate per 1000 patient–years of 6.3 versus 3.4 in the placebo group.
Speaking to medwireNews, lead investigator Bruce Neal (George Institute for Global Health, Sydney, Australia) said that if 1000 people were treated with canagliflozin for 5 years, the medication would prevent 23 major cardiovascular events, 16 hospitalizations for heart failure, and 17 declines in kidney function. But it would also result in 15 amputations – two-thirds of toes or the fore-foot and a third above the ankle.
“Ultimately, it’s going to come down to clinicians making individualized decisions for patients,” he said.
“But it’s always going to be tough, because those people who have had a prior amputation – their risk of having a stroke or a heart attack is staggeringly high, so, as always, it’s not quite as simple as you’d like it to be.”
There was also an increased risk for fracture, with rates in the canagliflozin and placebo groups of 15.4 and 11.9 per 1000 patient–years, respectively. This increase was observed in CANVAS, but not in CANVAS-R.
The results were simultaneously published in The New England Journal of Medicine.
medwireNews is an independent medical news service provided by Springer Healthcare. © 2017 Springer Healthcare part of the Springer Nature group