In patients with type 2 diabetes mellitus who have cardiovascular disease (or are at high risk for cardiovascular disease), what is the effect of canagliflozin on health outcomes?

Using canagliflozin to treat patients with type 2 diabetes mellitus (T2DM) who have vascular disease (or are at high risk for it) has some benefits and some harms. There are small, probably real, reductions in cardiovascular (CV) death, acute myocardial infarction, and nonfatal stroke, as well as fewer adverse renal outcomes, but also increases in the risk of amputation, genital infections, and osmotic diuresis. The benefits are likely to be smaller in average-risk diabetics, while the harms are likely to be similar, which should give us pause about using these drugs in anyone but T2DM patients at the highest risk. Also, the average retail price is $527 per month in the United States (www.goodrx.com on 9/1/17). (LOE = 1b)

Neal B, Perkovic V, Mahaffey KW, et al, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644-657.  [PMID:28605608]

Randomized controlled trial (double-blinded)

Industry

Concealed

Outpatient (any)

Canagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor that has been shown to reduce blood sugar by increasing renal excretion, and also cause modest reductions in blood pressure and body mass index. The current report is the combined analysis of 2 very similar randomized controlled trials that compared canagliflozin (100 mg or 300 mg) with placebo. The participants all had T2DM and either known vascular disease or a high risk of vascular disease based on the presence of multiple risk factors. The mean age of participants was 63 years, 36% were women, and 22% were non-white. Overall, 71% had a history of coronary, cerebrovascular, and/or peripheral vascular disease, and their mean baseline hemoglobin A1c was 8.2%. Allocation was appropriately concealed, and analysis was by intention to treat. The trial was designed as a noninferiority trial to assess CV safety as required by the FDA, but the authors report superiority data. The 10,142 participants were seen every 6 months and had a mean follow-up of 3.6 years and a median follow-up of 2.4 years. The drug did what it was supposed to do: It reduced body mass index by approximately 2 kg/m2; blood pressure by approximately 4/2 mm Hg; and hemoglobin A1c by 0.7% initially, but only by 0.2% after 5 years of follow-up. The composite of CV death, nonfatal myocardial infarction, and nonfatal stroke was significantly reduced (26.9 vs 31.5 episodes per 1000 person-years; number needed to treat [NNT] = 22 over 10 years). However, there was no statistically significant reduction in CV death, nonfatal myocardial infarction, or nonfatal stroke as individual outcomes. The absolute (nonsignificant) differences for each of these outcomes were small. Reported as episodes per 1000 person-years, if we think about it as 100 persons followed for 10 years, the NNT was 83 for CV death, 53 for nonfatal myocardial infarction, and 77 for nonfatal stroke over 10 years. The reduction in all-cause mortality was not statistically significant (17.3 vs 19.5 per 1000 person-years; hazard ratio = 0.87; 95% CI 0.74 - 1.01). The likelilhood of having an adverse renal outcome (renal death, need for renal replacement therapy, or a 40% reduction in glomerular filtration rate) was statistically significant but modest in absolute terms: 3.5 fewer such episodes per 1000 person-years (number needed to treat to harm [NNTH] = 29 over 10 years). Use of the drug was also not without other harms: more amputations (NNTH = 35 over 10 years), more genital infections (NNTH = 41 for men, NNTH = 19 for women over 10 years), and an increase in episodes of osmotic diuresis (NNTH = 47).