SGTL2 inhibitor shows CV risk reduction in outcome study, albeit with higher amputation riskNews - June 13, 2017
Results from the CANVAS Program showed that the SGLT2 inhibitor 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 (Renal endpoint) trials were published in the New England Journal of Medicine, and presented in a special symposium at the American Diabetes Association 77th Scientific 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. The CANVAS patients (n-4330) were randomized 1:1:1 to canagliflozin 300 mg or 100 mg or placebo and the CANVAS-R patients (n=5812) to 100 mg (with option to increase to 300 mg after week 13) or placebo.
Canagliflozin achieved a 14% reduction in the risk of the composite primary endpoint (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 of albuminuria 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 outcomes trial in patients with T2DM and kidney disease, is further evaluating the effects of canagliflozin on renal and CV outcomes.
An increased risk of amputation with canagliflozin was seen in both the completed CANVAS and CANVAS-R studies. 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.
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.
In the randomized, placebo-controlled Phase 3/4 studies of the CANVAS Program, a vast majority of patients were obese, with a history of hypertension, and 66% of patients had a history of CV disease (14% had a history of HF) and 34% of patients had at least two CV risk factors.
In the CANVAS study, the mean and median exposure to investigational product was approximately 4.3 and 5.8 years, respectively. The mean and median follow-up time was 5.7 and 6.1 years, respectively. In the CANVAS-R study, the mean and median exposure to investigational product was approximately 1.8 and 1.9 years, respectively. The mean and median follow-up time was 2.1 years.