A different diabetes medication also has been shown to reduce cardiovascular (CV) events, but with some risks. Canagliflozin is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that promotes glycosuria, reducing glycemia. SGLT-2 inhibitors also reduce blood pressure, body weight, and albuminuria. The authors of the CANVAS Program examined canagliflozin regarding CV, renal, and safety outcomes in two trials that contained more than 10,000 type 2 diabetics who were at high CV risk. Participants were randomized to canagliflozin or placebo for about 3.5 years. The primary outcome (composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) was lower with canagliflozin than placebo (26.9 vs. 31.5 participants per 1,000 patient-years; HR, 0.86; 95% CI, 0.75-0.97; P < 0.001 for noninferiority; P = 0.02 for superiority). Renal benefits were not statistically significant, although there was a possible benefit regarding albuminuria, sustained 40% reduction in glomerular filtration rate, and need for renal replacement therapy or death from renal causes (HR, 0.60; 95% CI, 0.47-0.77). However, the risk for amputation was nearly doubled with canagliflozin (6.3 vs. 3.4 per 1,000 patient-years; HR, 1.97; 95% CI, 1.41-2.75), mostly at the toe and metatarsal level. The authors suggested that canagliflozin resulted in a lower risk of CV disease in type 2 diabetics who were at high CV risk. However, there was a higher risk of amputation, which is a new finding; the mechanism is unknown. The authors recommended care in use of the drug in patients at risk for amputation. (N Engl J Med 2017;377:644-657)