INVOKANA reduces the risk of CV, MI and stroke

Results from the landmark CANVAS Program showed INVOKANA (canagliflozin) significantly reduced the combined risk of cardiovascular (CV) death, myocardial infarction (MI), and nonfatal stroke, versus placebo in patients with type 2 diabetes mellitus (T2DM) at risk for or with a history of CV disease. The results also showed canagliflozin treatment was associated with a reduced risk for hospitalization for heart failure (HHF) and demonstrated potential renal protective effects. These data from the integrated analysis of the CANVAS and CANVAS-R trials were published in the New England Journal of Medicine, and presented in a special symposium at the American Diabetes Association 77^thScientific Sessions on Monday, June 12, in San Diego. 

Canagliflozin was studied in the longest, largest and broadest completed CV outcomes program of any sodium glucose cotransporter-2 (SGLT2) inhibitor. The CANVAS Program is the first program to assess the efficacy, safety, and durability of canagliflozin in more than 10,000 patients with T2DM, who had either a prior history of CV disease, or at least two CV risk factors.

Canagliflozin achieved a 14% reduction in the risk of the composite primary endpoint of CV mortality, nonfatal MI or nonfatal stroke (HR: 0.86; 95% CI: 0.75 to 0.97), and demonstrated the CV safety of canagliflozin (p<0.0001 for non-inferiority) and superiority compared to placebo (p=0.0158). Each component evenly contributed to this risk reduction, including nonfatal MI by 15% (HR: 0.85; 95% CI: 0.69 to 1.05), CV death by 13% (HR: 0.87; 95% CI: 0.72 to 1.06), and nonfatal stroke by 10% (HR: 0.90; 95% CI: 0.71 to 1.15). These outcomes were broadly consistent across various patient subgroups and across the individual components of the primary endpoint.

Additional analysis further revealed canagliflozin lowered the risk of HHF by 33% (HR: 0.67; 95% CI: 0.52 to 0.87) and provided sustained positive effects on glycemic and blood pressure control, as well as weight reduction, demonstrating wide-ranging durability.

In addition, canagliflozin showed potential renal protective effects, delaying progression ofalbuminuria and reducing the risk of clinically important renal composite outcomes (such as renal death, renal replacement therapy, and 40% reduction of eGFR) by 40% (HR: 0.60; 95% CI: 0.47 to 0.77). The ongoing, fully enrolled CREDENCE study, the first dedicated SGLT2 inhibitor renal outcome trial in patients with T2DM and kidney disease, is further evaluating the effects of canagliflozin on renal and CV outcomes.

"The CANVAS results are important because they show clear benefit of canagliflozin over current standard-of-care treatments," said Bruce Neal, M.B., Ch.B., Ph.D., principal investigator of the CANVAS and CANVAS-R trials, Professor of Medicine, University of New South Wales Sydney, and Senior Director, The George Institute for Global Health. "Furthermore, the CANVAS Program showed consistent reductions across all components of the primary study outcome – CV death, MI and stroke – indicating efficacy of canagliflozin for all the main CV risks likely to affect patients with diabetes."

"Patients with diabetes are two to four times more likely to suffer from associated comorbidities, such as heart failure and kidney disease, and the CANVAS results demonstrate the potential of canagliflozin in reducing the risk for such conditions in high-risk type 2 diabetes patients," said David Matthews, CANVAS Steering Committee co-chair, and Professor of Diabetic Medicine andHonorary Consultant Physician, University of Oxford. "These data are promising as they suggest canagliflozin may offer potential benefits for patients with type 2 diabetes, who are also facing complications from, or are at risk for, hospitalization for heart failure or kidney disease."

"With the CANVAS Program results, we are excited to show the positive benefit-risk profile for cardiovascular and renal endpoints," said James F. List, M.D., Ph.D., Global Therapeutic Head, Cardiovascular & Metabolism, Janssen. "The success of this Program is especially encouraging for our ongoing and future studies exploring the potential of canagliflozin in additional patient populations."

Overall adverse events seen in the CANVAS Program were consistent with previous findings. An increased risk of amputation with canagliflozin was seen in both the completed CANVAS study and CANVAS-R studies. This is consistent with the observation made by the study’s Independent Data Monitoring Committee (IDMC) in 2016, and the data shared with Health Authorities and Health Care Professionals. There was an increased risk of amputation (6.3 vs. 3.4/1000 patient-years) corresponding to a hazard ratio (HR) of 1.97. The highest absolute risk of amputation occurred in patients with a prior history of amputation or peripheral vascular disease, but the relative risk for amputation with canagliflozin was comparable across these subgroups. These findings have been shared by the U.S. FDA and will be reflected in the U.S. Prescribing Information for canagliflozin. The risk has been included in the canagliflozin European Union Summary of Product Characteristics (SmPC).

Separately, while an increased risk of adjudicated low trauma fracture was identified in the CANVAS study, no increase was observed in the CANVAS-R study. A full assessment is ongoing to provide a complete safety review of these results.