Practice Update: Diabetes

EDITOR’S PICKS 5

Canagliflozin May Reduce Cardiovascular Events in Type 2 Diabetes The New England Journal of Medicine Take-home message • Patients with type 2 diabetes and at high cardiovascular (CV) risk were randomized to receive the SGLT2 inhibitor canagliflozin or placebo to evaluate the effect of canagliflozin on safety outcomes, particularly CV disease. The combined rate of death from CV causes, nonfatal myocardial infarction, and nonfatal stroke was significantly lower in the canagliflozin group than the placebo group (26.9 vs 31.5 participants per 1000 patient-years; P = .02 for superiority). Canagliflozin provided some renal protection by reducing the progression of albuminuria, the eGFR, the need for renal replacement therapy, and death due to renal causes; however, this did not reach statistical significance. Canagliflozin was associated with an increased risk of amputation, primarily at the level of the toe or metatarsal, but otherwise adverse effects were consistent with those reported in previous studies. • Patients with type 2 diabetes and at high CV risk may achieve a reduction in CV risk with canagliflozin, but with a higher risk of toe or metatarsal amputation.

Abstract BACKGROUND Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on car- diovascular, renal, and safety outcomes. METHODS The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high car- diovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS The mean age of the participants was 63.3 years, 35.8% were women, the mean dura- tion of diabetes was 13.5 years, and 65.6% had COMMENT By Silvio E Inzucchi MD T he final report from the CANVAS program (CANVAS and CANVAS-R trials) was recently published and presented simultaneously at the ADA meeting in San Diego. It showed, once again, that a member of the SGLT2 inhib- itor class (here, canagliflozin) reduced the primary CV outcome (3-point MACE) by a modest degree (14% RRR). In contrast to the well-known EMPA-REG OUTCOME study from 2015 (which tested empagli- flozin), the effect on CV mortality was not significant (HR, 0.87; 95% CI, 0.72–1.06). In EMPA-REG, the risk of this important out- come was reduced by 38%, which led to a 32% reduction in the all-cause mortal- ity risk. Consistent with the empagliflozin data, canagliflozin in CANVAS was asso- ciated with a significant 40% reduction in the composite renal outcome comprised

a history of cardiovascular disease. The rate of the primary outcome was lower with canagli- flozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the pre- specified hypothesis testing sequence the renal outcomes are not viewed as statistically signif- icant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular fil- tration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported of development of macroalbuminuria, 40% reduction in GFR, need for renal replacement therapy, and renal death. A similar composite was reduced by 30% in EMPA-REG. Also, the drug reduced hos- pitalization for heart failure (HHF) by 33%, similar to the 35% reduction with empag- liflozin. Finally, two adverse effects of canagliflozin were identified: an increase in amputations and an increase in fracture rates, neither seen in the EMPA-REG trial. So, CANVAS convinces me of two things – some of the dramatic results from EMPA-REG are, in part, “class effects” – particularly those on MACE, CKD, and HHF outcomes. However, not all mem- bers of the class seem to reduce mortality to the same degree. It is unclear if this is due to intrinsic differences between the drugs or merely a reflection of study

risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 partici- pants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. CONCLUSIONS In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 Jun 12;[EPub Ahead of Print], B Neal, V Perkovic, KW Mahaffey, et al.

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methodology. For example, in CANVAS, about one-third of the participants had no known CVD (primary prevention cohort). Importantly, these patients experienced no difference in MACE (HR, 0.98). As for the new adverse effects, they are con- cerning, especially the amputation data. We should consider the totality of any drug’s effects when prescribing, particu- larly those used chronically.

Dr Inzucchi is Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut, where he serves as the Clinical Chief of the Section of Endocrinology, Program Director of the

Endocrinology and Metabolism Fellowship, and Director of the Yale Diabetes Center.

VOL. 1 • NO. 2 • 2017