SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
Dr. Bruce Neal
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.