Fewer CV events but higher risk of amputation with SGLT2 inhibitor in T2DM patients
Canagliflozin and Cardiovascular and Renal Events in Type 2 DiabetesNeal B, Perkovic V, Mahaffey KW, et al, for the CANVAS Program Collaborative Group - NEJM 2017; published online ahead of print
SGLT2 inhibitors have favorable effects on glycemia, blood pressure, body weight, intrarenal hemodynamics, and albuminuria, and they may also reduce the risk of serious CV complications, kidney disease, and death [1-3].
The CANVAS program consisted of 2 studies: The Canagliflozin Cardiovascular Assessment Study (CANVAS) was set up to evaluate CV safety, including kidney and other safety outcomes, such as genitourinary infection, diabetic ketoacidosis, and fracture. CANVAS–Renal (CANVAS-R) was designed as a second CANVAS-like trial with similar design to CANVAS, to be analyzed jointly with CANVAS, to meet a post-approval CV safety commitment to regulatory agencies. CANVAS-R therefore also assessed effects on albuminuria.
This is an integrated analysis of CANVAS (n=4330) and CANVAS-R (n=5812) on data of T2DM patients with elevated CV risk, randomized to canagliflozin (300 or 100 mg in CANVAS, 100 mg in CANVAS-R) or placebo, in addition to background therapy [4-6]. Patients were followed for a mean of 295.9 weeks in CANVAS and 108.0 weeks in CANVAS-R.
- Compared with placebo, canagliflozin was associated with significantly fewer primary outcome events (CV death, non-fatal MI, or non-fatal stroke): 26.9 vs. 31.5 participants with an event per 1000 person-years (PY) (HR: 0.86; 95%CI: 0.75-0.97; P<0.001 for non-inferiority; P = 0.02 for superiority).
- As no superiority was shown for the first secondary outcome in the testing sequence (all-cause death), estimates for these outcomes, including death from any cause (HR: 0.87; 95%CI: 0.74-1.01) and CV death (HR: 0.87; 95%CI: 0.72-1.06), are not considered significant.
- Progression of albuminuria occurred less frequently in the canagliflozin group compared with the placebo group (89.4 vs. 128.7 participants per 1000 PY; HR: 0.73; 95%CI: 0.67-0.79). Regression of albuminuria occurred more frequently in the canagliflozin group compared with the placebo group (293.4 vs. 187.5 participants per 1000 PY; HR: 1.70; 95%CI: 1.51-1.91).
- The composite outcome of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes, occurred less frequently in the canagliflozin group compared with the placebo group (5.5 vs. 9.0 participants per 1000 PY; HR: 0.60; 95%CI: 0.47-0.77).
- Serious adverse events were less common in the canagliflozin group compared with the placebo group (104.3 vs. 120.0 participants per 1000 PY; HR: 0.93; 95%CI: 0.87-1.00).
- There was a higher risk of amputation of toes, feet, or legs with canagliflozin than with placebo (6.3 vs. 3.4 participants per 1000 PY; HR: 1.97; 95%CI: 1.41-2.75), with 71% of the affected participants having their highest amputation at the level of the toe or metatarsal.
- The rate of all fractures was higher with canagliflozin compared with placebo (15.4 vs. 11.9 participants per 1000 PY; HR: 1.26; 95%CI: 1.04-1.52).
In the CANVAS trial program, diabetic patients with elevated CV risk treated with canagliflozin had a significantly lower risk of CV death, non-fatal MI, or non-fatal stroke compared with those who received placebo, but a higher risk of amputation and fractures.