LAUSR

The much waited presentation at this year’s ADA meeting was the integrated analysis of the CANVAS and CANVAS-R trials which formed the landmark CANVAS Program. The trial, funded by Jansen Pharmaceuticals, showed that canagliflozin (Invokana) significantly reduced the combined risk of cardiovascular (CV) death, myocardial infarction (MI), and nonfatal stroke, versus placebo in patients with type 2 diabetes at risk for or with a history of CV disease. While this was reassuring and largely reflected the findings from the Empa-Reg study with Empagliflozin, there remains ongoing debate about the small observed increase risk of lower limb amputation with Canagliflozin compared with placebo. Specifically, what is the mechanism for this? Was this a chance finding (given the small event rate), was it a class effect or specific to the canagliflozin molecule? Importantly, how would this translate to clinical practice and treatment guidelines? In this study, the efficacy, safety, and durability of canagliflozin was investigated in more than 10 000 patients with type 2 diabetes, who had either a prior history of CV disease, or at least 2 CV risk factors. It is composed of 2, nearly-identical large outcomes studies: CANVAS (CANagliflozin CardioVascular Assessment Study) and CANVAS-R (Study of the nd rEffects of Canagliflozin on Renal Endpoints). The results showed that canagliflozin reduced the overall risk of cardiovascular disease by 1% and reduced the risk of heart failure hospitalization by 33%. The drug also demonstrated significant renal protective effects. However, the CANVAS data also revealed a significant doubling in the risk for amputations, primarily of the toe or metatarsal (6.3 vs 3.4 cases per 1000 patient-years; hazard ratio, 1.97) – i.e 15 more patients per 1000 over 5 years. Whether the amputation risk is a class effect is still an open question. Amputation data were not reported in Empa-Reg, although a post hoc analysis has not detected a signal with empagliflozin compared with placebo. Further analysis suggests that those patients who undergo lower limb amputation during the CANVAS trial, either had previous amputation or has peripheral vascular disease at baseline. Thus, it seems reasonable to be selective when determining which patients are suitable for canagliflozin therapy. In addition, cardiovascular death was not significantly reduced in CANVAS, as it was in both EMPA-REG and the LEADER trial of the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk). Crucially, unlike participants from the Empa-Reg and LEADER where all patients have established cardiovascular disease, about a third of the patients in CANVAS did not have established cardiovascular disease. Thus, any discordant in the cardiovascular outcomes observed in CANVAS compared with Empa-Reg or LEADER maybe explained by the differences in study participants. The study was simultaneously published in the New England Journal of Medicine.