Practice Update: Diabetes

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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
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
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.
COMMENT
By Silvio E Inzucchi MD
The 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
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
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.
EDITOR’S PICKS 5
VOL. 1 • NO. 2 • 2017