Original Article
A BS T R AC T
BACKGROUND
Canagliflozin is a sodiumglucose cotransporter 2 inhibitor that reduces glycemia From the George Institute for Global
as well as blood pressure, body weight, and albuminuria in people with diabetes. Health, Faculty of Medicine, UNSW Syd-
ney (B.N., V.P.), the Charles Perkins Cen-
We report the effects of treatment with canagliflozin on cardiovascular, renal, and tre (B.N.), and the Royal North Shore
safety outcomes. Hospital (V.P., G.F.), University of Syd-
ney, and the Faculty of Medicine, Univer-
METHODS sity of New South Wales (B.N.) all in
Sydney; Imperial College London, Lon-
The CANVAS Program integrated data from two trials involving a total of 10,142 don (B.N.), and the Oxford Centre for Di-
participants with type 2 diabetes and high cardiovascular risk. Participants in each abetes, Endocrinology, and Metabolism
trial were randomly assigned to receive canagliflozin or placebo and were followed and Harris Manchester College, Univer-
sity of Oxford, Oxford (D.R.M.) both
for a mean of 188.2 weeks. The primary outcome was a composite of death from in the United Kingdom; the Stanford Cen-
cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ter for Clinical Research, Department of
Medicine, Stanford University School of
RESULTS Medicine, Stanford, CA (K.W.M.); the
The mean age of the participants was 63.3 years, 35.8% were women, the mean University Medical Center Groningen,
University of Groningen, Groningen, the
duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular Netherlands (D.Z.); and Janssen Research
disease. The rate of the primary outcome was lower with canagliflozin than with and Development, Raritan, NJ (N.E., W.S.,
placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ra- G.L., M.D.). Address reprint requests to
Dr. Neal at the George Institute for Glob-
tio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; al Health, UNSW Sydney, Level 5, 1 King
P=0.02 for superiority). Although on the basis of the prespecified hypothesis test- St., Newtown, NSW 2042, Australia, or at
ing sequence the renal outcomes are not viewed as statistically significant, the bneal@georgeinstitute.org.au.
results showed a possible benefit of canagliflozin with respect to the progression *A complete list of investigators in the
of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite out- Canagliflozin Cardiovascular Assessment
Study (CANVAS) Program is provided in
come of a sustained 40% reduction in the estimated glomerular filtration rate, the the Supplementary Appendix, available
need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; at NEJM.org.
95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously re- This article was published on June 12, 2017,
ported risks associated with canagliflozin except for an increased risk of amputa- at NEJM.org.
tion (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 DOI: 10.1056/NEJMoa1611925
to 2.75); amputations were primarily at the level of the toe or metatarsal. Copyright 2017 Massachusetts Medical Society.
CONCLUSIONS
In two trials involving patients with type 2 diabetes and an elevated risk of car-
diovascular disease, patients treated with canagliflozin had a lower risk of cardio-
vascular events than those who received placebo but a greater risk of amputation,
primarily at the level of the toe or metatarsal. (Funded by Janssen Research and
Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629
and NCT01989754, respectively.)
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The n e w e ng l a n d j o u r na l of m e dic i n e
T
ype 2 diabetes mellitus is associat- committee at each site and are available with the
ed with a substantial risk of cardiovascu- full text of this article at NEJM.org. All the par-
lar and renal disease.1,2 The use of inhibi- ticipants provided written informed consent. The
tors of sodiumglucose cotransporter 2 (SGLT2) trials were sponsored by Janssen Research and
results in favorable effects on biomarkers, includ- Development and were conducted as a collabora-
ing glycemia, blood pressure, weight,3 intrarenal tion between the sponsor, an academic steering
hemodynamics, and albuminuria,4 and may also committee, and an academic research organiza-
reduce the risk of serious cardiovascular compli- tion, George Clinical. Members of the commit-
cations, kidney disease, and death.5-7 The CANVAS tees are listed in the Supplementary Appendix,
Program, comprising two sister trials, was de- available at NEJM.org. Analyses were carried out
signed to assess the cardiovascular safety and independently by the sponsor and George Clini-
efficacy of canagliflozin and to evaluate the bal- cal. The first draft of the manuscript was written
ance between any potential benefits of the drug by the first author, with all coauthors participat-
and the risks associated with it, such as genito- ing in subsequent revisions. MedErgy provided
urinary infection, diabetic ketoacidosis, and frac- medical writing support, funded by the sponsor.
ture. The Canagliflozin Cardiovascular Assessment The authors, who had full access to the data and
Study (CANVAS)8 was initiated in December 2009, made the final decisions about the content of
before the approval of canagliflozin by the Food the manuscript, vouch for the accuracy and com-
and Drug Administration (FDA), with the initial pleteness of the data and analyses and for the
goal of showing cardiovascular safety. The first fidelity of the trial to the protocol. The decision
approval of the compound by the FDA occurred to submit the manuscript for publication was
in March 2013, with interim data from CANVAS. made jointly by all the authors.
Owing to the inclusion of unmasked interim car-
diovascular outcome data in the regulatory filing Participants
documents, a planned expansion of the sample The main criteria for inclusion were identical in
size to enable a test of cardiovascular protection the two trials (Table S1 in the Supplementary
was not undertaken. Instead, CANVASRenal Appendix). Participants were men and women
(CANVAS-R)9 was designed as a second CANVAS- with type 2 diabetes (glycated hemoglobin level,
like, double-blind, randomized, placebo-controlled 7.0% and 10.5%) and were either 30 years of
trial to be analyzed jointly with CANVAS, to age or older with a history of symptomatic ath-
meet a post-approval cardiovascular safety com- erosclerotic cardiovascular disease or 50 years of
mitment to regulatory agencies. CANVAS-R, age or older with two or more of the following
which commenced in 2014, was also designed to risk factors for cardiovascular disease: duration
assess effects on albuminuria. The integrated of diabetes of at least 10 years, systolic blood
analysis of CANVAS and CANVAS-R as the pressure higher than 140 mm Hg while they were
CANVAS Program10 was undertaken to maximize receiving one or more antihypertensive agents,
statistical power to detect plausible effects of current smoking, microalbuminuria or macroal-
canagliflozin on cardiovascular, kidney, and safe- buminuria, or high-density lipoprotein (HDL) cho-
ty outcomes as suggested from evolving evidence lesterol level of less than 1 mmol per liter (38.7 mg
about SGLT2 inhibitors.6,7 per deciliter). Participants were required to have an
estimated glomerular filtration rate (eGFR) at
entry of more than 30 ml per minute per 1.73 m2
Me thods
of body-surface area and to meet a range of
Program Design and Oversight other criteria.
A total of 667 centers in 30 countries were in-
volved in the two trials. The trials were scheduled Randomization, Treatment, and Follow-up
for joint close-out and analysis when at least 688 All potential participants completed a 2-week,
cardiovascular events had been observed and the single-blind, placebo run-in period. Randomiza-
last participant who had undergone randomiza- tion was performed centrally through an interac-
tion had approximately 78 weeks of follow-up; tive Web-based response system with the use of
this occurred in February 2017. The protocols a computer-generated randomization schedule
for the two trials8,9 were approved by the ethics with randomly permuted blocks that was prepared
2 n engl j mednejm.org
by the trial sponsor. Participants in CANVAS were Exploratory cardiovascular outcomes prespec-
randomly assigned in a 1:1:1 ratio to receive cana- ified for evaluation were nonfatal myocardial in-
gliflozin at a dose of 300 mg, canagliflozin at a farction, nonfatal stroke, and hospitalization for
dose of 100 mg, or matching placebo, and partici- heart failure,10 and the key prespecified explor-
pants in CANVAS-R were randomly assigned in a atory renal outcomes were regression of albumin-
1:1 ratio to receive canagliflozin, administered uria (using criteria comparable to those defined
at an initial dose of 100 mg daily with an op- for category progression) and the renal compos-
tional increase to 300 mg starting from week 13, ite comprising a 40% reduction in eGFR sustained
or matching placebo. Participants and all trial for at least two consecutive measures, the need for
staff were unaware of the individual treatment renal-replacement therapy (dialysis or transplan-
assignments until completion of the trial. Use of tation), or death from renal causes (defined as
other background therapy for glycemic manage- death with a proximate renal cause). Evaluation
ment and other control of risk factors were guided of total hospitalizations was also prespecified.
by best practice instituted in line with local guide- All major cardiovascular events, renal out-
lines. comes, and deaths, plus selected safety outcomes,
After randomization, face-to-face follow-up was were adjudicated by end-point adjudication com-
scheduled in three visits during the first year and mittees. The members of the committees and the
at 6-month intervals thereafter, with telephone definitions that were used for the clinical events
follow-up between face-to-face assessments. Every are listed in the Supplementary Appendix. Inter-
follow-up included inquiry about primary and sec- mediate markers of cardiovascular risk and re-
ondary outcome events and serious adverse events. quirement for antihyperglycemic agents were as-
The urinary albumin-to-creatinine ratio was mea- sessed to help understand the observed effects
sured every 26 weeks in CANVAS-R and at week on cardiovascular and renal outcomes. Analyses
12 and then annually in CANVAS. Measurement of safety included adverse events coded with the
of serum creatinine with eGFR was performed at use of the latest version of the Medical Dictionary
least every 26 weeks in both trials. Participants for Regulatory Activities (MedDRA). For bone frac-
who prematurely discontinued the trial regimen ture, the primary prespecified analysis was for
continued scheduled follow-up whenever possible; low-trauma fracture events, but secondary analysis
extensive efforts were made to obtain full outcome of all fractures was also performed. Amputations
data for all participants during the final follow-up were assessed overall, but the numbers of cases
window that spanned November 2016 to Febru- above and below the ankle were also reported.
ary 2017.
Statistical Analysis
Outcomes The primary hypothesis test was a test of nonin-
The primary outcome was a composite of death feriority, with the use of a margin of 1.3 for the
from cardiovascular causes, nonfatal myocardial hazard ratio for the primary outcome with cana-
infarction, or nonfatal stroke. Secondary outcomes gliflozin as compared with placebo in the full,
planned for sequential conditional hypothesis integrated data set (i.e., all available follow-up
testing were death from any cause, death from data from all participants who underwent ran-
cardiovascular causes, progression of albumin- domization) and with the intention-to-treat ap-
uria, and the composite of death from cardiovas- proach. We calculated that with 688 cardiovascu-
cular causes and hospitalization for heart failure lar safety events recorded across the trials, there
(Fig. S1 in the Supplementary Appendix). Pro- would be at least 90% power, at an alpha level of
gression of albuminuria was defined as more 0.05, to exclude an upper margin of the 95%
than a 30% increase in albuminuria and a change confidence interval for the hazard ratio of 1.3.
from either normoalbuminuria to microalbumin- Cardiovascular safety was to be shown if the up-
uria or macroalbuminuria or from microalbumin- per boundary of the 95% confidence interval of
uria to macroalbuminuria. If sequential testing the hazard ratio with canagliflozin as compared
was not significant for all the outcomes speci- with placebo was less than 1.3, and superiority
fied, the remaining outcomes were scheduled for was to be shown if the upper boundary was less
assessment as exploratory variables in the inte- than 1.0. Hypothesis testing was scheduled to
grated data set. proceed sequentially, conditional on the primary
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* Plusminus values are means SD. The CANVAS Program comprised two trials: the Canagliflozin Cardiovascular
Assessment Study (CANVAS) and CANVASRenal (CANVAS-R).
One participant underwent randomization at two different sites; only the first randomization is included in the inten-
tion-to-treat analysis set.
Race was determined by investigator inquiry of the participant. Other includes American Indian or Alaska Native,
Native Hawaiian or other Pacific Islander, multiple races, other race, and unknown.
Some participants had more than one type of atherosclerotic disease.
A history of cardiovascular disease was defined as a history of symptomatic atherosclerotic vascular disease (coro-
nary, cerebrovascular, or peripheral).
The body-mass index is the weight in kilograms divided by the square of the height in meters.
** Values for estimated glomerular filtration rate (eGFR) were calculated with data from 5794 participants in the cana-
gliflozin group, 4346 in the placebo group, and 10,140 in the total population.
The albumin-to-creatinine ratio was measured in milligrams of albumin and grams of creatinine.
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The n e w e ng l a n d j o u r na l of m e dic i n e
for all comparisons) (Fig.1). The use of other 128.7 participants with an event per 1000 patient-
antihyperglycemic agents during follow-up was years), corresponding to a hazard ratio of 0.73
9.3% lower (95% CI, 11.0 to 7.6) in the cana- (95% CI, 0.67 to 0.79) (Figs. 3 and 5); the effects
gliflozin group than in the placebo group. The were greater in CANVAS-R (hazard ratio, 0.64;
level of HDL cholesterol was higher in the cana- 95% CI, 0.57 to 0.73) than in CANVAS (hazard
gliflozin group than in the placebo group (by ratio, 0.80; 95% CI, 0.72 to 0.90) (P=0.02 for
2.05 mg per deciliter; 95% CI, 1.77 to 2.33 [0.05 homogeneity) (Table S7 in the Supplementary Ap-
mmol per liter; 95% CI, 0.05 to 0.06]), as was the pendix). Regression of albuminuria also occurred
level of low-density lipoprotein (LDL) cholesterol more frequently among those assigned to cana-
(by 4.68 mg per deciliter; 95% CI, 3.64 to 5.73 gliflozin than among those assigned to placebo
[0.12 mmol per liter; 95% CI, 0.09 to 0.15]); the (293.4 vs. 187.5 participants with regression per
ratio of LDL cholesterol to HDL cholesterol was 1000 patient-years; hazard ratio, 1.70; 95% CI,
unchanged (Fig. S4 in the Supplementary Ap- 1.51 to 1.91). The composite outcome of sustained
pendix). 40% reduction in eGFR, the need for renal-replace-
ment therapy, or death from renal causes occurred
Cardiovascular Outcomes, Death, less frequently among participants in the cana-
and Hospitalizations gliflozin group than among those in the placebo
Significantly fewer participants in the canagliflozin group (5.5 vs. 9.0 participants with the outcome
group than in the placebo group had a primary per 1000 patient-years, corresponding to a haz-
outcome event (the composite of death from car- ard ratio of 0.60; 95% CI, 0.47 to 0.77) (Figs. 3
diovascular causes, nonfatal myocardial infarction, and 5); no significant difference in this outcome
or nonfatal stroke): 26.9 vs. 31.5 participants with was seen between CANVAS and CANVAS-R (Ta-
an event per 1000 patient-years (hazard ratio, ble S7 in the Supplementary Appendix).
0.86; 95% CI, 0.75 to 0.97; P<0.001 for noninfe-
riority; P=0.02 for superiority) (Figs. 2 and 3). Safety Outcomes
The effects on the primary outcome were nearly Serious adverse events were less common among
the same when imputation for missing events was participants assigned to canagliflozin than among
performed (hazard ratio, 0.85; 95% CI, 0.75 to those assigned to placebo (104.3 vs. 120.0 par-
0.97). There were broadly consistent effects acrossticipants with an event per 1000 patient-years;
a wide range of prespecified subgroups (Fig.4), hazard ratio, 0.93; 95% CI, 0.87 to 1.00). Adverse
except for subgroups defined according to base- events leading to discontinuation did not differ
line use of diuretics (P<0.001 for homogeneity). significantly between groups (35.5 vs. 32.8 par-
Superiority was not shown for the first second- ticipants with an event per 1000 patient-years;
ary outcome in the testing sequence (death from hazard ratio, 1.13; 95% CI, 0.99 to 1.28) (Ta-
any cause; P=0.24), and hypothesis testing was ble2). There was a higher risk of amputation of
discontinued. Therefore, estimates for the fatal toes, feet, or legs with canagliflozin than with
secondary outcomes, including death from any placebo (6.3 vs. 3.4 participants with amputation
cause (hazard ratio, 0.87; 95% CI, 0.74 to 1.01) per 1000 patient-years, corresponding to a haz-
and death from cardiovascular causes (hazard ard ratio of 1.97; 95% CI, 1.41 to 2.75), with 71%
ratio, 0.87; 95% CI, 0.72 to 1.06), are not consid-of the affected participants having their highest
ered to be significant (Figs. 2, 3, and 5). Effect amputation at the level of the toe or metatarsal
estimates for exploratory cardiovascular outcomes (Fig. S5 in the Supplementary Appendix). The high-
are shown in Figures 2, 3, and 5. There was no est absolute risk of amputation occurred among
evidence of differences in effects between the patients who had a history of amputation or pe-
CANVAS and CANVAS-R trials for the primary, ripheral vascular disease, but the relative risk of
fatal, or exploratory cardiovascular outcomes amputation with canagliflozin as compared with
(Table S6 in the Supplementary Appendix). placebo was similar across these subgroups (Table
S8 in the Supplementary Appendix).
Renal Outcomes Previously reported risks of adverse events of
Progression of albuminuria occurred less frequent- interest attributable to infections of male or female
ly among participants assigned to canagliflozin genitalia, volume depletion, and diuresis were ob-
than among those assigned to placebo (89.4 vs. served. We detected no higher risks of hypogly-
6 n engl j mednejm.org
n engl j mednejm.org
137
Placebo 78
136
135 77 Placebo
132 75
131
(mm Hg)
(mm Hg)
74 Canagliflozin
130
Canagliflozin
73
128
127 72
0 0
Base- 26 52 78 104 130 156 182 208 234 260 286 312 338 Base- 26 52 78 104 130 156 182 208 234 260 286 312 338
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line line
12/13 Weeks since Randomization 12/13 Weeks since Randomization
No. of Patients No. of Patients
Placebo 4247 4032 3945 3707 2979 1629 1038 939 922 836 828 763 713 252 Placebo 4247 4032 3945 3707 2979 1629 1038 939 922 836 828 763 713 252
Canagliflozin 5652 5355 5293 5049 4338 2883 2255 2049 2092 1908 1936 1782 1675 567 Canagliflozin 5652 5355 5293 5049 4338 2883 2255 2049 2092 1908 1936 1782 1675 567
Figure 1. Effects of Canagliflozin on Glycated Hemoglobin Level, Body Weight, and Systolic and Diastolic Blood Pressure in the Integrated CANVAS Program.
A total of 10,142 participants were included in the CANVAS Program, which comprised two trials: the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS
Renal (CANVAS-R).
7
8
A Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, or Nonfatal Stroke B Death from Cardiovascular Causes
100 20 100 12
Hazard ratio, 0.86 (95% CI, 0.750.97) Hazard ratio, 0.87 (95% CI, 0.721.06)
90 18 P<0.001 for noninferiority Placebo 90
16 10
P=0.02 for superiority
80 14 80 Placebo
8
70 12 Canagliflozin 70
10 6
60 8 60 Canagliflozin
6 4
50 50
4 2
40 40
2
30 0 30 0
0 26 52 78 104 130 156 182 208 234 260 286 312 338 0 26 52 78 104 130 156 182 208 234 260 286 312 338
20 20
Placebo 4347 4239 4153 4061 2942 1626 1240 1217 1187 1156 1120 1095 789 216 Placebo 4347 4316 4279 4236 3119 1759 1356 1344 1328 1310 1292 1280 924 258
Canagliflozin 5795 5672 5566 5447 4343 2984 2555 2513 2460 2419 2363 2311 1661 448 Canagliflozin 5795 5768 5723 5679 4576 3182 2761 2736 2710 2687 2651 2615 1904 532
40 0 40 0
30 30
20 20
10 10
0 0
0 26 52 78 104 130 156 182 208 234 260 286 312 338 0 26 52 78 104 130 156 182 208 234 260 286 312 338
Downloaded from nejm.org on June 28, 2017. For personal use only. No other uses without permission.
Figure 2. Cardiovascular Outcomes in the Integrated CANVAS Program.
The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The hazard ratios and 95% confidence intervals for
the primary outcome and the components of the outcome were estimated with the use of Cox regression models with stratification according to trial and history of cardiovascular
disease for all canagliflozin groups combined versus placebo. Analyses are based upon the full, integrated data set comprising all participants who underwent randomization. The
inset in each panel shows the same data on an enlarged y axis.
Canagliflozin and Cardiovascular Events in Type 2 Diabetes
Canagliflozin Placebo
Outcome (N=5795) (N=4347) Hazard Ratio (95% CI)
no. of participants per 1000 patient-yr
Death from cardiovascular causes, 26.9 31.5 0.86 (0.750.97)
nonfatal myocardial infarction,
or nonfatal stroke
Death from cardiovascular causes 11.6 12.8 0.87 (0.721.06)
Nonfatal myocardial infarction 9.7 11.6 0.85 (0.691.05)
Nonfatal stroke 7.1 8.4 0.90 (0.711.15)
Fatal or nonfatal myocardial infarction 11.2 12.6 0.89 (0.731.09)
Fatal or nonfatal stroke 7.9 9.6 0.87 (0.691.09)
Hospitalization for any cause 118.7 131.1 0.94 (0.881.00)
Hospitalization for heart failure 5.5 8.7 0.67 (0.520.87)
Death from cardiovascular causes 16.3 20.8 0.78 (0.670.91)
or hospitalization for heart failure
Death from any cause 17.3 19.5 0.87 (0.741.01)
Progression of albuminuria 89.4 128.7 0.73 (0.670.79)
40% reduction in eGFR, renal-replacement 5.5 9.0 0.60 (0.470.77)
therapy, or renal death
0.5 1.0 2.0
Figure 3. Effects of Canagliflozin on Cardiovascular, Renal, Hospitalization, and Death Events in the Integrated
CANVAS Program.
Hazard ratios and 95% confidence intervals were estimated with the use of Cox regression models, with stratifica-
tion according to trial and history of cardiovascular disease for all canagliflozin groups combined versus placebo.
For the primary outcome (the composite of death from cardiovascular causes, nonfatal myocardial infarction, or
nonfatal stroke), P<0.001 for noninferiority and P=0.02 for superiority. Progression of albuminuria was evaluated
with data from the 9015 participants with normoalbuminuria or microalbuminuria at baseline. The composite renal
outcome was a 40% reduction in the estimated glomerular filtration rate (eGFR), the need for renal-replacement
therapy, or death from renal causes. The 40% reduction in eGFR was required to be sustained, which was defined
as being present on at least two consecutive measurements more than 30 days apart, and adjudicated by an expert
committee. The need for renal-replacement therapy owing to end-stage kidney disease was defined as a need for
dialysis for at least 30 days or transplantation and was required to be adjudicated by an expert committee. Death
from renal causes was defined as death for which the proximate cause was renal as defined by the end-point adju-
dication committee. There were three deaths from renal causes, all in the placebo group.
cemia, hyperkalemia, acute kidney injury, pancre- were observed with canagliflozin and placebo (0.6
atitis, malignancies, or venous thromboembolism vs. 0.3 participants with an event per 1000 patient-
with canagliflozin than with placebo. The rate of years; hazard ratio, 2.33; 95% CI, 0.76 to 7.17).
all fractures was higher with canagliflozin than
with placebo (15.4 vs. 11.9 participants with frac- Discussion
ture per 1000 patient-years; hazard ratio, 1.26;
95% CI, 1.04 to 1.52), and there was a similar Patients with type 2 diabetes and established car-
trend with respect to low-trauma fracture events diovascular disease or at high risk for cardiovas-
(11.6 vs. 9.2 participants with fracture per 1000 cular events who were treated with canagliflozin
patient-years; hazard ratio, 1.23; 95% CI, 0.99 to had significantly lower rates of the primary car-
1.52). There was evidence of heterogeneity in the diovascular outcome than patients assigned to
bone-fracture findings between CANVAS and placebo. All three components of the primary
CANVAS-R with respect to both low-trauma frac- outcome death from cardiovascular causes,
ture and all fracture (both P0.005), with risks nonfatal myocardial infarction, and nonfatal
higher in the canagliflozin group than in the stroke showed point estimates of effect that
placebo group in CANVAS but not in CANVAS-R suggested benefit, although the individual effects
(Table S9 in the Supplementary Appendix). Only did not reach significance. The results also showed
a small number of events of diabetic ketoacidosis that patients treated with canagliflozin had a
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Figure 4 (facing page). Effects of Canagliflozin on the data are required to confirm the effects on kidney
Primary Cardiovascular Outcome in Subgroups. failure. Definitive evidence about the effects of
A total of 10,142 participants were included in the canagliflozin on clinical kidney outcomes are
analysis. Hazard ratios and 95% confidence intervals likely to be provided by the ongoing Canagliflozin
were estimated with the use of Cox regression models. and Renal Endpoints in Diabetes with Established
P values for homogeneity were obtained by fitting in-
Nephropathy Clinical Evaluation trial (CREDENCE;
teraction terms. The body-mass index (BMI) is the
weight in kilograms divided by the square of the ClinicalTrials.gov number, NCT02065791).
height in meters. The analysis according to the history The adverse effects observed in this program
of heart failure was not prespecified. RAAS denotes of two integrated trials are generally consistent
reninangiotensinaldosterone system. with the known safety profile of canagliflozin
and other SGLT2 inhibitors.5 The increased rate
of amputation is a new finding for which the
lower risk of hospitalization for heart failure, mechanism is unknown, and care is warranted
progression of albuminuria, and substantive loss in the use of canagliflozin in patients at risk for
of kidney function than patients who received amputation. An increase in bone fractures has
placebo, although on the basis of the prespecified been described previously with canagliflozin,24
hypothesis testing sequence these findings are but the excess in bone fracture seen in CANVAS
not considered statistically significant. was not observed in CANVAS-R. There is no clear
Several established effects of SGLT2 inhibi- explanation for the difference in fracture risk be-
tors on intermediate outcomes may contribute to tween the two trials, which included directly com-
cardiovascular and renal protection. Although parable patient groups and assessed the same
pleiotropic effects have been inferred, improved intervention.
glycemic control, lowering of blood pressure, de- The trial program has certain strengths. It
crease in intraglomerular pressure, reduction in benefits from the large size of the combined tri-
albuminuria, and amelioration of volume over- als, the long duration of the trials, the random-
load are all plausible protective mechanisms.4,13-23 ized design, the breadth of included participants,
The effects on cardiovascular and renal out- and the high standard to which the conduct of
comes observed within this program of two inte- the trials was held. The inclusion of participants
grated trials are similar to those observed with and those without established cardiovascu-
previously with this drug class.5,6 The favorable lar disease extends the population for which data
direction of effect with respect to stroke ob- are available.
served in this trial program differs from a previ- The trial program has certain limitations, the
ously reported possible adverse effect on stroke major one being the moderate number of events
risk.5,6 Apparent differences in the effect sizes for for many important outcomes in particular,
other secondary and exploratory outcomes may the paucity of events of end-stage kidney disease.
be attributable to chance, since precision in the The relatively small proportion of participants with
effect estimates of each is limited. Although it is established kidney disease also limits general-
also possible that variation in effect sizes could ization to that population. The large number of
reflect features of trial design or actual differences analyses and relatively few events increases the
between the agents, additional data will be re- risk of false positive findings, though the broad
quired to clarify the differing results. internal and external consistency of the data
The possible benefit of canagliflozin use with strengthens the conclusions. Discontinuation of
respect to renal outcomes is supported by the randomized therapy and greater use of other glu-
magnitude of the effects observed, the consistency cose-lowering agents in the placebo group dur-
of the observation across renal outcomes, and the ing the trial program is the likely explanation
consistency of the findings with other recently for the convergence of glycated hemoglobin levels
reported data.12 Prespecification, confirmation, over time and may have resulted in underestima-
and adjudication of the renal outcomes in this tion of any benefits and risks associated with
trial program add support to the possibility that canagliflozin.
SGLT2 inhibition may have an important kidney- In summary, the trial program showed that
protective effect in type 2 diabetes. Since most among patients with type 2 diabetes who had an
renal events were based on changes in eGFR, more increased risk of cardiovascular disease, patients
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12
A Hospitalization for Heart Failure B Death from Any Cause
100 8 100 20
Hazard ratio, 0.67 (95% CI, 0.520.87) Hazard ratio, 0.87 (95% CI, 0.741.01)
90 7 90 18
16
80 6 80
Placebo 14
5 12 Placebo
70 70
4 10
60 60 8
3 Canagliflozin
50 50 6
2 Canagliflozin 4
40 1 40
2
30 0 30 0
0 26 52 78 104 130 156 182 208 234 260 286 312 338 0 26 52 78 104 130 156 182 208 234 260 286 312 338
20 20
Placebo 4347 4267 4198 4123 3011 1667 1274 1256 1236 1210 1180 1158 829 233 Placebo 4347 4316 4279 4236 3119 1759 1356 1344 1328 1310 1292 1280 924 258
Canagliflozin 5795 5732 5653 5564 4437 3059 2643 2610 2572 2540 2498 2451 1782 490 Canagliflozin 5795 5768 5723 5679 4576 3182 2761 2736 2710 2687 2651 2615 1904 532
C Progression of Albuminuria D Composite of 40% Reduction in eGFR, Requirement for Renal-Replacement Therapy,
or Death from Renal Causes
100 100 10
Hazard ratio, 0.73 (95% CI, 0.670.79) 9 Hazard ratio, 0.60 (95% CI, 0.470.77)
90 90 8
7
80 80 6 Placebo
70 70 5
4
60 60 3
2
50 Placebo 50 1 Canagliflozin
n e w e ng l a n d j o u r na l
0
40 40
30 30
Canagliflozin
20 20
10 10
0 0
0 26 52 78 104 130 156 182 208 234 260 286 312 338 0 26 52 78 104 130 156 182 208 234 260 286 312 338
Weeks since Randomization Weeks since Randomization
No. at Risk No. at Risk
Placebo 3819 3473 3096 2700 1690 877 724 652 626 565 548 485 303 67 Placebo 4347 4287 4227 4151 3029 1674 1274 1253 1229 1202 1173 1148 819 229
Canagliflozin 5196 4791 4475 4027 2968 1951 1730 1593 1528 1408 1354 1213 775 185 Canagliflozin 5795 5737 5664 5578 4454 3071 2654 2623 2576 2542 2495 2450 1781 493
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Figure 5. Rates of Hospitalization for Heart Failure, Death from Any Cause, and Renal Outcomes in the Integrated CANVAS Program.
The hazard ratios and 95% confidence intervals were estimated with the use of Cox regression models with stratification according to trial and history of cardiovascular disease for
all canagliflozin groups combined versus placebo. Analyses are based upon the full, integrated data set comprising all participants who underwent randomization. The insets in
Panels A, B, and D show the same data on enlarged y axes.
Canagliflozin and Cardiovascular Events in Type 2 Diabetes
* Analyses were performed on data from the on-treatment data set (patients who had a safety outcome while they were
receiving canagliflozin or placebo or within 30 days after discontinuation of the drug or placebo), except for fracture,
amputation, cancer, and diabetic ketoacidosis outcomes, which included all events at any time point in all patients who
underwent randomization and received at least one dose of canagliflozin or placebo.
P values were estimated from Cox regression models.
Low-trauma fracture was the prespecified primary fracture outcome, and all fracture was a secondary outcome.
Infection of male genitalia included balanitis, phimosis, and events leading to circumcision.
For these adverse events, the annualized incidence rates are reported with data from CANVAS alone through January 7,
2014, because after this time, only serious adverse events or adverse events leading to discontinuation were collected.
In CANVAS-R, only serious adverse events or adverse events leading to discontinuation were collected. Owing to the
differences between the two trials in methods of collection of the data, an integrated analysis of these adverse events is
not possible.
treated with canagliflozin had a significantly Supported by Janssen Research and Development.
lower risk of death from cardiovascular causes, Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
nonfatal myocardial infarction, or nonfatal stroke We thank all investigators, trial teams, and patients for par-
than those who received placebo but a greater ticipating in these trials and the following people for their con-
risk of amputation. tributions to the statistical monitoring and analyses and the
n engl j mednejm.org 13
The New England Journal of Medicine
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
protocol development, safety monitoring, and operational im- Connell, Michele Wells, Jacqueline Yee, Dainius Balis, Frank Ver-
plementation over the duration of the two trials: Lyndal Hones, cruysse, Elisa Fabbrini, Richard Oh, Nicole Meyers, Gary
Lucy Perry, Sharon Dunkley, Tao Sun, Hsiaowei Deng, George Meininger, and Norm Rosenthal. Medical writing support was
Capuano, Qiang Li, Severine Bompoint, Laurent Billot, Mary provided by Kimberly Dittmar, Ph.D., of MedErgy, and was fund-
Lee, Joan Lind, Roger Simpson, Mary Kavalam, Terry Barrett, Ed ed by Janssen Global Services.
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