Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2

Transcription

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Empagliflozin, Cardiovascular Outcomes,
and Mortality in Type 2 Diabetes
Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D.,
David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D.,
Michaela Mattheus, Dipl. Biomath., Theresa Devins, Dr.P.H.,
Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D.,
and Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators
A BS T R AC T
BACKGROUND
The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in
addition to standard care, on cardiovascular morbidity and mortality in patients
with type 2 diabetes at high cardiovascular risk are not known.
METHODS
We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or
placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the
pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.
RESULTS
A total of 7020 patients were treated (median observation time, 3.1 years). The
primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard
ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99;
P = 0.04 for superiority). There were no significant between-group differences in
the rates of myocardial infarction or stroke, but in the empagliflozin group there
were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9%
in the placebo group; 38% relative risk reduction), hospitalization for heart failure
(2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any
cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no
significant between-group difference in the key secondary outcome (P = 0.08 for
superiority). Among patients receiving empagliflozin, there was an increased rate
of genital infection but no increase in other adverse events.
From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
(B.Z.) and the Divisions of Endocrinology (B.Z.) and Cardiology (D.F.), University of Toronto — all in Toronto; the Department of Medicine, Division of
Nephrology, Würzburg University Clinic,
Würzburg (C.W.), Boehringer Ingelheim
Pharma, Biberach (E.B., S.H.), and Boehringer Ingelheim Pharma, Ingelheim
(M.M., H.J.W., U.C.B.) — all in Germany;
the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.);
Boehringer Ingelheim Pharmaceuticals,
Ridgefield, CT (T.D.); Boehringer Ingelheim Norway, Asker, Norway (O.E.J.);
and the Section of Endocrinology, Yale
University School of Medicine, New Haven, CT (S.E.I.). Address reprint requests
to Dr. Zinman at Mount Sinai Hospital,
60 Murray St., Suite L5-024, Box 17, Toronto, ONT M5T 3L9, Canada, or at
zinman@lunenfeld.ca.
This article was published on September
17, 2015, at NEJM.org.
DOI: 10.1056/NEJMoa1504720
Copyright © 2015 Massachusetts Medical Society.
CONCLUSIONS
Patients with type 2 diabetes at high risk for cardiovascular events who received
empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug
was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly;
EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)
n engl j med nejm.org
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Downloaded from nejm.org by RONALD SIGAL on September 17, 2015. For personal use only. No other uses without permission.
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1
The
T
ype 2 diabetes is a major risk factor
for cardiovascular disease,1,2 and the presence of both type 2 diabetes and cardiovascular disease increases the risk of death.3
Evidence that glucose lowering reduces the rates
of cardiovascular events and death has not been
convincingly shown,4-6 although a modest cardiovascular benefit may be observed after a prolonged
follow-up period.7 Furthermore, there is concern
that intensive glucose lowering or the use of specific glucose-lowering drugs may be associated
with adverse cardiovascular outcomes.8 Therefore, it is necessary to establish the cardiovascular safety benefits of glucose-lowering agents.9
Inhibitors of sodium–glucose cotransporter 2
reduce rates of hyperglycemia in patients with
type 2 diabetes by decreasing renal glucose reabsorption, thereby increasing urinary glucose
excretion.10 Empagliflozin is a selective inhibitor
of sodium glucose cotransporter 211 that has been
approved for type 2 diabetes.12 Given as either
monotherapy or as an add-on therapy, the drug
is reported to reduce glycated hemoglobin levels
in patients with type 2 diabetes, including those
with stage 2 or 3a chronic kidney disease.13-20
Furthermore, empagliflozin is associated with
weight loss and reductions in blood pressure without increases in heart rate.13-20 Empagliflozin
also has favorable effects on markers of arterial
stiffness and vascular resistance,21 visceral adiposity,22 albuminuria,20 and plasma urate.13-19
Empagliflozin has been associated with an increase in levels of both low-density lipoprotein
(LDL)14 and high-density lipoprotein (HDL) cholesterol.13-16 The most common side effects of
empagliflozin are urinary tract infection and genital infection.12
In the EMPA-REG OUTCOME trial, we examined the effects of empagliflozin, as compared
with placebo, on cardiovascular morbidity and
mortality in patients with type 2 diabetes at high
risk for cardiovascular events who were receiving standard care.
Me thods
Study Oversight
The trial was designed and overseen by a steering committee that included academic investigators and employees of Boehringer Ingelheim. The
role of Eli Lilly was limited to cofunding the trial.
Safety data were reviewed by an independent aca2
of
m e dic i n e
demic data monitoring committee every 90 days
or at the discretion of the committee. Cardiovascular outcome events and deaths were prospectively adjudicated by two clinical-events committees (one for cardiac events and the other for
neurologic events), as recommended by the Food
and Drug Administration (FDA) guidelines.9 A
list of investigators and committee members is
provided in Sections A and B, respectively, in the
Supplementary Appendix, which is available with
the full text of this article at NEJM.org.
The trial was conducted in accordance with
the principles of the Declaration of Helsinki and
the the International Conference on Harmonisation Good Clinical Practice guidelines and was
approved by local authorities. An independent
ethics committee or institutional review board
approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.
All the authors were involved in the study
design and had access to the data, which were
analyzed by one of the study sponsors, Boehringer Ingelheim. All the authors vouch for the
accuracy and completeness of the data analyses
and for the fidelity of the study to the protocol,
available at NEJM.org. Members of the University of Freiburg conducted an independent statistical analysis of cardiovascular outcomes (Section
B in the Supplementary Appendix). The manuscript was drafted by the first and last authors
and revised by all the authors. Medical writing
assistance, which was paid for by Boehringer
Ingelheim, was provided by Fleishman-Hillard
Group.
Study Design
As described previously,23 this was a randomized,
double-blind, placebo-controlled trial to assess
the effect of once-daily empagliflozin (at a dose
of either 10 mg or 25 mg) versus placebo on
cardiovascular events in adults with type 2 diabetes at high cardiovascular risk against a background of standard care. Patients were treated at
590 sites in 42 countries. The trial continued
until an adjudicated primary outcome event had
occurred in at least 691 patients.
Study Patients
Eligible patients with type 2 diabetes were adults
(≥18 years of age) with a body-mass index (the
weight in kilograms divided by the square of the
Empagliflozin in Type 2 Diabetes
height in meters) of 45 or less and an estimated
glomerular filtration rate (eGFR) of at least 30
ml per minute per 1.73 m2 of body-surface area,
according to the Modification of Diet in Renal
Disease criteria. All the patients had established
cardiovascular disease (as defined in Section C
in the Supplementary Appendix) and had received
no glucose-lowering agents for at least 12 weeks
before randomization and had a glycated hemoglobin level of at least 7.0% and no more than
9.0% or had received stable glucose-lowering
therapy for at least 12 weeks before randomization and had a glycated hemoglobin level of at
least 7.0% and no more than 10.0%. Other key
exclusion criteria are provided in Section D in
the Supplementary Appendix.
Study Procedures
Eligible patients underwent a 2-week, open-label,
placebo run-in period in which background glucose-lowering therapy was unchanged. Patients
meeting the inclusion criteria were then randomly assigned in a 1:1:1 ratio to receive either
10 mg or 25 mg of empagliflozin or placebo once
daily. Randomization was performed with the use
of a computer-generated random-sequence and
interactive voice- and Web-response system and
was stratified according to the glycated hemoglobin level at screening (<8.5% or ≥8.5%), bodymass index at randomization (<30 or ≥30), renal
function at screening (eGFR, 30 to 59 ml, 60 to
89 ml, or ≥90 ml per minute per 1.73 m2), and
geographic region (North America [plus Australia and New Zealand], Latin America, Europe,
Africa, or Asia).
Background glucose-lowering therapy was to
remain unchanged for the first 12 weeks after
randomization, although intensification was permitted if the patient had a confirmed fasting
glucose level of more than 240 mg per deciliter
(>13.3 mmol per liter). In cases of medical necessity, dose reduction or discontinuation of background medication could occur. After week 12,
investigators were encouraged to adjust glucoselowering therapy at their discretion to achieve
glycemic control according to local guidelines.
Throughout the trial, investigators were encouraged to treat other cardiovascular risk factors
(including dyslipidemia and hypertension) to
achieve the best available standard of care according to local guidelines. Patients were instructed
to attend the clinic at prespecified times, which
included a follow-up visit 30 days after the end
of treatment. Patients who prematurely discontinued a study drug were to be followed for ascertainment of cardiovascular outcomes, and
attempts were made to collect vital-status information for any patient who was lost to follow-up, as
allowed by local guidelines.
Study Outcomes
The primary outcome was a composite of death
from cardiovascular causes, nonfatal myocardial
infarction (excluding silent myocardial infarction), or nonfatal stroke. The key secondary outcome was a composite of the primary outcome
plus hospitalization for unstable angina. Definitions of the major clinical outcomes are provided in Section E in the Supplementary Appendix.
Safety was assessed on the basis of adverse
events that occurred during treatment or within
7 days after the last dose of a study drug and
were coded with the use of the Medical Dictionary
for Regulatory Activities, version 18.0. Adverse events
of special interest included confirmed hypoglycemic adverse events (plasma glucose level, ≤70 mg
per deciliter [3.9 mmol per liter] or an event requiring assistance), and adverse events reflecting
urinary tract infection, genital infection, volume
depletion, acute renal failure, bone fracture, diabetic ketoacidosis, and thromboembolic events.
Statistical Analysis
The primary hypothesis was noninferiority for
the primary outcome with empagliflozin (pooled
doses of 10 mg and 25 mg) versus placebo with
a margin of 1.3 for the hazard ratio.9 We used a
four-step hierarchical-testing strategy for the
pooled empagliflozin group versus the placebo
group in the following order: noninferiority for
the primary outcome, noninferiority for the key
secondary outcome, superiority for the primary
outcome, and superiority for the key secondary
outcome.
Since interim data from the trial were included
in a new-drug application submitted to the FDA,
under the Haybittle–Peto rule, a two-sided P value
of 0.0498 or less was considered to indicate statistical significance in the final analyses.23 For
the test of noninferiority for the primary outcome with a margin of 1.3 at a one-sided level of
0.0249, at least 691 events were required to provide a power of at least 90% on the assumption
of a true hazard ratio of 1.0. Noninferiority for
3
2821
1380
30
2359
1161
36
1534
741
42
370
166
48
4556
2243
4128
2012
3079
1503
30
2617
1281
36
1722
825
42
414
177
48
0
4687
2333
0
1
2
3
4
5
6
7
4556
2243
18
24
4128
2012
Month
4614
2271
6
4523
2226
12
4427
2173
18
3988
1932
Month
24
Hazard ratio, 0.65 (95% CI, 0.50–0.85)
P=0.002
4608
2280
12
2950
1424
30
3079
1503
30
2487
1202
36
2617
1281
36
Placebo
414
177
48
1634
775
42
395
168
48
Empagliflozin
1722
825
42
Empagliflozin
Figure 1. Cardiovascular Outcomes and Death from Any Cause.
Shown are the cumulative incidence of the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) (Panel A), cumulative incidence
of death from cardiovascular causes (Panel B), the Kaplan–Meier estimate for death from any cause (Panel C), and the cumulative incidence of hospitalization for heart failure
(Panel D) in the pooled empagliflozin group and the placebo group among patients who received at least one dose of a study drug. Hazard ratios are based on Cox regression
analyses.
4608
2280
24
Month
Empagliflozin
Placebo
4651
2303
18
No. at Risk
4687
2333
12
Empagliflozin
Placebo
6
Empagliflozin
Placebo
4651
2303
6
D Hospitalization for Heart Failure
4687
2333
0
Hazard ratio, 0.62 (95% CI, 0.49–0.77)
P<0.001
Placebo
of
No. at Risk
0
3851
1875
Hazard ratio, 0.68 (95% CI, 0.57–0.82)
P<0.001
4328
2112
24
Month
0
1
2
3
4
5
6
7
8
0
5
10
15
C Death from Any Cause
4455
2194
18
Empagliflozin
Placebo
4580
2256
12
No. at Risk
4687
2333
6
Empagliflozin
No. at Risk
0
Hazard ratio, 0.86 (95.02% CI, 0.74–0.99)
P=0.04 for superiority
Placebo
9
B Death from Cardiovascular Causes
Empagliflozin
Placebo
0
5
10
15
20
A Primary Outcome
Patients with Event (%)
4
The
m e dic i n e
the primary outcome was determined if the upper boundary of the two-sided 95.02% confidence
interval was less than 1.3. Analyses were based
on a Cox proportional-hazards model, with study
group, age, sex, baseline body-mass index, baseline glycated hemoglobin level, baseline eGFR,
and geographic region as factors. Estimates of
cumulative-incidence function were corrected
for death as a competing risk,24 except for death
from any cause, for which Kaplan–Meier estimates are presented. Because of the declining
numbers of patients at risk, cumulative-incidence plots have been truncated at 48 months.
We calculated the number of patients who would
need to be treated to prevent one death on the
basis of the exponential distribution.
We performed the primary analysis using a
modified intention-to-treat approach among patients who had received at least one dose of a
study drug. Data for patients who did not have
an event were censored on the last day they were
known to be free of the outcome. Secondary
Table 1. Primary and Secondary Cardiovascular Outcomes.
Placebo
(N = 2333)
Outcome
Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke: primary outcome*
Empagliflozin
(N = 4687)
no. (%)
rate/1000
patient-yr
no. (%)
rate/1000
patient-yr
282 (12.1)
43.9
490 (10.5)
37.4
Hazard Ratio
(95% CI)
P Value
0.86 (0.74–0.99)
Noninferiority
<0.001†
Superiority
0.04†
Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina: key secondary outcome*
333 (14.3)
52.5
599 (12.8)
46.4
0.89 (0.78–1.01)
Noninferiority
<0.001†
Superiority
0.08†
Death
From any cause
194 (8.3)
28.6
269 (5.7)
19.4
0.68 (0.57–0.82)
<0.001
From cardiovascular causes
137 (5.9)
20.2
172 (3.7)
12.4
0.62 (0.49–0.77)
<0.001
Fatal or nonfatal myocardial infarction excluding
silent myocardial infarction
126 (5.4)
19.3
223 (4.8)
16.8
0.87 (0.70–1.09)
0.23
Nonfatal myocardial infarction excluding silent
myocardial infarction
121 (5.2)
18.5
213 (4.5)
16.0
0.87 (0.70–1.09)
0.22
15 (1.2)
5.4
38 (1.6)
7.0
1.28 (0.70–2.33)
0.42
Silent myocardial infarction‡
Hospitalization for unstable angina
66 (2.8)
10.0
133 (2.8)
10.0
0.99 (0.74–1.34)
0.97
186 (8.0)
29.1
329 (7.0)
25.1
0.86 (0.72–1.04)
0.11
Fatal or nonfatal stroke
69 (3.0)
10.5
164 (3.5)
12.3
1.18 (0.89–1.56)
0.26
Nonfatal stroke
60 (2.6)
9.1
150 (3.2)
11.2
1.24 (0.92–1.67)
0.16
Transient ischemic attack
23 (1.0)
3.5
39 (0.8)
2.9
0.85 (0.51–1.42)
0.54
Coronary revascularization procedure
Hospitalization for heart failure
Hospitalization for heart failure or death from cardiovascular causes excluding fatal stroke
95 (4.1)
14.5
126 (2.7)
9.4
0.65 (0.50–0.85)
0.002
198 (8.5)
30.1
265 (5.7)
19.7
0.66 (0.55–0.79)
<0.001
*Data were analyzed with the use of a four-step hierarchical-testing strategy for the pooled empagliflozin group versus the placebo group in
the following order: noninferiority for the primary outcome, noninferiority for the key secondary outcome, superiority for the primary outcome, and superiority for the key secondary outcome. Each successive hypothesis could be tested, provided that those preceding it met the
designated level of significance. Data are based on Cox regression analyses in patients who received at least one dose of a study drug.
†One-sided P values are shown for tests of noninferiority, and two-sided P values are shown for tests of superiority.
‡Silent myocardial infarction was analyzed in 2378 patients in the empagliflozin group and 1211 patients in the placebo group.
5
The
of
m e dic i n e
Primary Outcome
Subgroup
Hazard Ratio
(95% CI)
Empagliflozin Placebo
Death from Cardiovascular Causes
P Value for
Interaction
Hazard Ratio
(95% CI)
P Value for
Interaction
no. in subgroup
All patients
Age
<65 yr
≥65 yr
Sex
Male
Female
Race
White
Asian
Black
Glycated hemoglobin
<8.5%
≥8.5%
Body-mass index
<30
≥30
Blood pressure control
SBP ≥140 mm Hg or DBP ≥90 mm Hg
SBP <140 mm Hg and DBP <90 mm Hg
Estimated glomerular filtration rate
≥90 ml/min/1.73 m2
60 to <90 ml/min/1.73 m2
<60 ml/min/1.73 m2
Urine albumin-to-creatinine ratio
<30 mg/g
≥30 to 300 mg/g
>300 mg/g
Cardiovascular risk
Only cerebrovascular disease
Only coronary artery disease
Only peripheral artery disease
2 or 3 high-risk categories
Insulin
No
Yes
Statins or ezetimibe
No
Yes
Antihypertensive therapy
No
Yes
ACE inhibitor or ARB
No
Yes
Beta-blocker
No
Yes
Diuretic
No
Yes
4687
2333
2596
2091
1297
1036
3336
1351
1680
653
3403
1006
237
1678
511
120
3212
1475
1607
726
2279
2408
1120
1213
1780
2907
934
1399
1050
2425
1212
488
1238
607
2789
1338
509
1382
675
260
635
2732
412
878
325
1340
191
451
2435
2252
1198
1135
1029
3658
551
1782
241
4446
112
2221
889
3798
465
1868
1631
3056
835
1498
2640
2047
1345
988
0.25
0.50
1.00
0.01
0.21
0.81
0.32
0.09
0.43
0.01
0.51
0.06
0.05
0.65
0.44
0.20
0.15
0.40
0.22
0.53
0.39
0.28
0.92
0.54
0.23
0.80
0.41
0.49
0.86
0.61
0.99
0.72
0.46
2.00
Favors Empagliflozin Favors Placebo
6
n engl j med
0.25
0.50
1.00
2.00
Favors Empagliflozin Favors Placebo
nejm.org
Figure 2 (facing page). Subgroup Analyses for the
Primary Outcome and Death from Cardiovascular
Causes.
Shown are the results of a prespecified Cox regression
analysis of data for subgroups of patients with respect
to the primary outcome. Subgroup analyses of death
from cardiovascular causes were conducted post hoc.
P values are for tests of homogeneity of betweengroup differences among subgroups with no adjustment for multiple testing. The size of the ovals is proportional to the number of patients in the subgroup.
ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, DBP diastolic blood pressure, and SBP systolic blood pressure.
analyses included comparisons of the 10-mg dose
of empagliflozin versus placebo and the 25-mg
dose versus placebo. Sensitivity analyses are described in the Section F in the Supplementary
Appendix. We analyzed the changes from baseline
in glycated hemoglobin level, weight, waist circumference, systolic and diastolic blood pressure, heart rate, LDL and HDL cholesterol, and
uric acid using a repeated-measures analysis as
a mixed model. Subgroup analyses are described
in Section F in the Supplementary Appendix.
R e sult s
Study Patients
A total of 7028 patients underwent randomization from September 2010 through April 2013.
Of these patients, 7020 were treated and included in the primary analysis (Fig. S1 in Section
G in the Supplementary Appendix). Reasons for
premature discontinuation are provided in Table
S1 in Section H in the Supplementary Appendix.
Overall, 97.0% of patients completed the study,
with 25.4% of patients prematurely discontinuing a study drug. Final vital status was available
for 99.2% of patients.
At baseline, demographic and clinical characteristics were well balanced between the placebo
group and the empagliflozin group (Table S2 in
Section I in the Supplementary Appendix). According to the inclusion criteria, more than 99%
of patients had established cardiovascular disease,
and patients were well treated with respect to the
use of lipid-lowering therapy and antihypertensive
medications at baseline. The median duration of
treatment was 2.6 years, and the median observation time was 3.1 years; both durations were
similar in the pooled empagliflozin group and
the placebo group (Table S3 in Section J in the
Supplementary Appendix).
Cardiovascular Outcomes
The primary outcome occurred in a significantly
lower percentage of patients in the empagliflozin
group (490 of 4687 [10.5%]) than in the placebo
group (282 of 2333 [12.1%]) (hazard ratio in the
empagliflozin group, 0.86; 95.02% confidence
interval [CI], 0.74 to 0.99; P<0.001 for noninferiority and P = 0.04 for superiority) (Fig. 1A). The
key secondary outcome occurred in 599 of 4687
patients (12.8%) in the empagliflozin group and
333 of 2333 patients (14.3%) in the placebo group
(hazard ratio, 0.89; 95% CI, 0.78 to 1.01; P<0.001
for noninferiority and P = 0.08 for superiority).
As compared with placebo, empagliflozin resulted in a significantly lower risk of death from
cardiovascular causes (hazard ratio, 0.62; 95% CI,
0.49 to 0.77; P<0.001) (Fig. 1B), death from any
cause (hazard ratio, 0.68; 95% CI, 0.57 to 0.82,
P<0.001; Fig. 1C), and hospitalization for heart
failure (hazard ratio, 0.65; 95% CI, 0.50 to 0.85;
P = 0.002) (Fig. 1D). Hazard ratios for cardiovascular outcomes with empagliflozin versus placebo are shown in Table 1. Absolute reductions in
incidence rates for cardiovascular outcomes are
provided in Table S4 in Section K in the Supplementary Appendix. All categories of death from
cardiovascular causes contributed to the reduction
in cardiovascular death in the empagliflozin group
(Table S5 in Section L in the Supplementary Appendix). There were no significant between-group
differences in the occurrence of myocardial infarction or stroke (Table 1). Myocardial infarction was reported in 4.8% of patients in the
empagliflozin group and 5.4% of those in the
placebo group, and stroke in 3.5% and 3.0% of
patients, respectively.
For the primary and key secondary outcomes,
hazard ratios for the comparison between the
10-mg dose of empagliflozin versus placebo and
the 25-mg dose versus placebo were virtually identical to those in the pooled analysis, but the individual dose effects were not significant, owing
to the smaller numbers of outcome events in the
individual groups (Table S6 and Fig. S2 in Sec-
7
The
Adjusted Mean Glycated Hemoglobin (%)
9.0
Placebo
of
m e dic i n e
Empagliflozin 10 mg
Empagliflozin 25 mg
8.5
8.0
7.5
7.0
6.5
6.0
0
12
164
178
192
206
2188 2133 2113 2063 2008 1967 1741 1456 1241 1109 962
2218 2150 2155 2108 2072 2058 1805 1520 1297 1164 1006
2212 2152 2150 2115 2080 2044 1842 1540 1327 1190 1043
705
749
795
420
488
498
151
170
195
28
40
52
66
80
94
108
122
136
150
Week
No. at Risk
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2294 2272
2296 2272
2296 2280
Figure 3. Glycated Hemoglobin Levels.
Shown are mean (±SE) glycated hemoglobin levels in the three study groups, as calculated with the use of a repeated-measures analysis as a mixed model of all data for patients who received at least one dose of a study drug and
had a baseline measurement. The model included baseline glycated hemoglobin as a linear covariate, with baseline
estimated glomerular filtration rate, geographic region, body-mass index, the last week a patient could have had a
glycated hemoglobin measurement, study group, visit, visit according to treatment interaction, and baseline glycated hemoglobin according to visit interaction as fixed effects.
tion M in the Supplementary Appendix). The hazard ratios for the primary outcome were 0.85
(95% CI, 0.72 to 1.01; P = 0.07) for the 10-mg dose
of empagliflozin versus placebo and 0.86 (95% CI,
0.73 to 1.02; P = 0.09) for the 25-mg dose versus
placebo.
In subgroup analyses, there was some heterogeneity for the primary outcome. In contrast,
there was a consistent benefit of empagliflozin
versus placebo on death from cardiovascular
causes across all subgroups (Fig. 2, and Tables
S7 and S8 in Section N in the Supplementary
Appendix).
In prespecified sensitivity analyses based on
events that occurred within 30 days after last
dose of a study drug, results for the primary
outcome, cardiovascular death, myocardial infarction, and stroke were consistent with the
primary analyses, and the point estimate for the
hazard ratio for stroke was closer to 1.00 (Tables
S9 and S10 in Section O in the Supplementary
Appendix). A sensitivity analysis of death from
any cause in which it was assumed that all pa8
tients who were lost to follow-up in the empagliflozin group died and all patients who were
lost to follow-up in the placebo group were alive
showed a significant benefit of empagliflozin
versus placebo (hazard ratio, 0.77; 95% CI, 0.65
to 0.93; P = 0.005).
Glycemic Control
After 12 weeks, during which glucose-lowering
therapy was to remain unchanged, the adjusted
mean differences in the glycated hemoglobin level
between patients receiving empagliflozin and
those receiving placebo were −0.54 percentage
points (95% CI, −0.58 to −0.49) in the 10-mg
group and −0.60 percentage points (95% CI,
−0.64 to −0.55) in the 25-mg group (Fig. 3). At
week 94, the adjusted mean differences in the
glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were −0.42 percentage points (95% CI, −0.48
to −0.36) and −0.47 percentage points (95% CI,
−0.54 to −0.41), respectively; at week 206, the differences were −0.24 percentage points (95% CI,
Table 2. Adverse Events.*
Event
Placebo
(N = 2333)
Empagliflozin,
10 mg
(N = 2345)
Empagliflozin,
25 mg
(N = 2342)
Pooled
Empagliflozin
(N = 4687)
number of patients (percent)
Any adverse event
2139 (91.7)
2112 (90.1)
2118 (90.4)
4230 (90.2)†
592 (25.4)
536 (22.9)
564 (24.1)
1100 (23.5)‡
Any
988 (42.3)
876 (37.4)
913 (39.0)
1789 (38.2)†
Death
119 (5.1)
97 (4.1)
79 (3.4)
176 (3.8)§
453 (19.4)
416 (17.7)
397 (17.0)
813 (17.3)§
650 (27.9)
656 (28.0)
647 (27.6)
1303 (27.8)
36 (1.5)
33 (1.4)
30 (1.3)
63 (1.3)
423 (18.1)
426 (18.2)
416 (17.8)
842 (18.0)
Male patients
158 (9.4)
180 (10.9)
170 (10.1)
350 (10.5)
Female patients
265 (40.6)
246 (35.5)
246 (37.3)
492 (36.4)‡
Complicated urinary tract infection**
41 (1.8)
34 (1.4)
48 (2.0)
82 (1.7)
Event consistent with genital infection††
42 (1.8)
153 (6.5)
148 (6.3)
301 (6.4)†
Male patients
25 (1.5)
89 (5.4)
77 (4.6)
166 (5.0)†
Female patients
17 (2.6)
64 (9.2)
71 (10.8)
135 (10.0)†
Event consistent with volume depletion‡‡
115 (4.9)
115 (4.9)
124 (5.3)
239 (5.1)
Acute renal failure§§
155 (6.6)
121 (5.2)
125 (5.3)
246 (5.2)§
Acute kidney injury
37 (1.6)
26 (1.1)
19 (0.8)
45 (1.0)‡
Severe adverse event
Serious adverse event
Adverse event leading to discontinuation of a
study drug
Confirmed hypoglycemic
adverse event¶
Any
Requiring assistance
Event consistent with urinary tract infection‖
Diabetic ketoacidosis¶¶
1 (<0.1)
3 (0.1)
1 (<0.1)
4 (0.1)
Thromboembolic event§§
20 (0.9)
9 (0.4)
21 (0.9)
30 (0.6)
Bone fracture‖‖
91 (3.9)
92 (3.9)
87 (3.7)
179 (3.8)
*Data are for patients who had one or more event and who had received at least one dose of a study drug. All events occurred within
7 days after the last receipt of the study drug.
†P<0.001 for the comparison with placebo.
‡P<0.05 for the comparison with placebo.
§P<0.01 for the comparison with placebo.
¶A confirmed hypoglycemic adverse event was a plasma glucose level of less than 70 mg per deciliter (3.9 mmol per liter) or an event requiring assistance.
‖The definition of urinary tract infection was based on 79 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA).
Percentages were calculated as the proportions of all men and all women with the event.
**Complicated urinary tract infection was defined as pyelonephritis, urosepsis, or a serious adverse event consistent with urinary tract infection. A breakdown of such events according to MedDRA preferred terms is provided in Table S13 in Section R in the Supplementary
Appendix.
††The definition of genital infection was based on 88 MedDRA preferred terms. Percentages were calculated as the proportions of all men
and all women with the event.
‡‡The definition of volume depletion was based on 8 MedDRA preferred terms.
§§The definitions of acute renal failure and thromboembolic event were based on 1 standardized MedDRA query for each.
¶¶The definition of ketoacidosis was based on 4 MedDRA preferred terms.
‖‖The definition of bone fracture was based on 62 MedDRA preferred terms.
9
The
of
m e dic i n e
−0.40 to −0.08) and −0.36 percentage points gliflozin had a lower rate of the primary com(95% CI, −0.51 to −0.20).
posite outcome of death from cardiovascular
causes, nonfatal myocardial infarction, or nonfatal
Cardiovascular Risk Factors
stroke than did patients receiving placebo. The
Over the course of the study, empagliflozin, as difference between empagliflozin and placebo
compared with placebo, was associated with was driven by a significant reduction in death
small reductions in weight, waist circumference, from cardiovascular causes, with no significant
uric acid level, and systolic and diastolic blood between-group difference in the risk of myocarpressure with no increase in heart rate and small dial infarction or stroke. Since the two groups
increases in both LDL and HDL cholesterol (Fig. had similar rates of hospitalization for unstable
S3 in Section P in the Supplementary Appendix). angina, there was no significant difference in
A higher percentage of patients in the placebo the key secondary outcome, which included the
group received additional glucose-lowering med- risk of hospitalization for unstable angina. Patients
ications (including sulfonylurea and insulin), in the empagliflozin group had significantly lower
antihypertensive medications (including diuret- risks of death from any cause and for hospitalics), and anticoagulants during the trial, with no ization for heart failure than did those in the
between-group difference in the receipt of lipid- placebo group.
lowering drugs (Tables S11 and S12 in Section Q
Although a small dose–response effect for
in the Supplementary Appendix).
the 10-mg dose of empagliflozin versus placebo
and the 25-mg dose versus placebo has been docuSafety and Adverse Events
mented for metabolic responses, in our study the
The proportions of patients who had adverse two dose groups had similar hazard ratios for
events, serious adverse events, and adverse events cardiovascular outcomes. Thus, in clinical pracleading to the discontinuation of a study drug tice, the choice of the empagliflozin dose will
were similar in the empagliflozin group and the probably depend primarily on the achievement
placebo group (Table 2). Genital infection was of metabolic targets and the occurrence of adreported in a higher percentage of patients in verse events.
the pooled empagliflozin group. The proportions
These benefits were observed in a population
of patients with confirmed hypoglycemic adverse with established cardiovascular disease in whom
events, acute renal failure, diabetic ketoacidosis, cardiovascular risk factors, including blood
thromboembolic events, bone fracture, and events pressure and dyslipidemia, were well treated
consistent with volume depletion were similar in with the use of renin–angiotensin–aldosterone
the two study groups. Urosepsis was reported in system inhibitors, statins, and acetylsalicylic
0.4% of patients in the empagliflozin group and acid. The reductions in the risk of cardiovascular
0.1% of those in the placebo group, but there was death in the empagliflozin group were consisno imbalance in overall rates of urinary tract infec- tent across subgroups according to baseline
tion, complicated urinary tract infection, or pyelo- characteristics.
nephritis (Table S13 in Section R in the SuppleNotably, reductions in the risks of death from
mentary Appendix). Clinical laboratory data are cardiovascular causes and from any cause ocprovided in Table S14 in Section S in the Supple- curred early in the trial, and these benefits conmentary Appendix. There were no relevant chang- tinued throughout the study. The relative reduces in electrolytes in the two study groups. Hema- tion of 32% in the risk of death from any cause
tocrit values were higher in the empagliflozin in the pooled empagliflozin group means that
groups than in the placebo group (mean [±SD] 39 patients (41 in the 10-mg group and 38 in the
changes from baseline, 4.8±5.5% in the group 25-mg group) would need to be treated during a
receiving 10 mg of empagliflozin, 5.0±5.3% in 3-year period to prevent one death, but these
the group receiving 25 mg of empagliflozin, and numbers cannot be extrapolated to patient pop0.9±4.7% in the placebo group).
ulations with other clinical characteristics.
Even though investigators were encouraged to
adjust
glucose-lowering therapy according to loDiscussion
cal guidelines, many patients did not reach their
Among patients with type 2 diabetes at high risk glycemic targets, with an adjusted mean glycatfor cardiovascular events, those receiving empa- ed hemoglobin level at week 206 of 7.81% in the
10
pooled empagliflozin group and 8.16% in the
placebo group. Our trial was designed to assess
the specific effects of empagliflozin on clinical
outcomes, and the mechanisms behind the observed benefits are speculative. As such, we infer
that the mechanisms behind the cardiovascular
benefits of empagliflozin are multidimensional25 and possibly involve changes in arterial stiffness,26,27 cardiac function, and cardiac oxygen
demand (in the absence of sympathetic-nerve
activation),26 as well as cardiorenal effects,21,26,28,29
reduction in albuminuria,20,30 reduction in uric
acid,13-20 and established effects on hyperglycemia, weight, visceral adiposity, and blood pressure.13-20
Our trial provides data to support the longterm use of empagliflozin, as well as strong evidence for a reduction in cardiovascular risk. As
observed in previous trials, genital infection was
more common in patients treated with empagliflozin. Urosepsis was infrequent but reported
in more patients treated with empagliflozin, although there was no increase in the overall rate
of urinary tract infection, complicated urinary
tract infection, or pyelonephritis. The proporReferences
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Supported by Boehringer Ingelheim and Eli Lilly.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the patients who participated in this trial and Elizabeth Ng and Wendy Morris of Fleishman-Hillard Group for
their assistance in medical writing.
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Copyright © 2015 Massachusetts Medical Society.
Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in
type 2 diabetes. N Engl J Med. DOI: 10.1056/NEJMoa1504720
SUPPLEMENTARY APPENDIX
Supplement to: Zinman B, Wanner C, Lachin J, et al. Empagliflozin, Cardiovascular Outcomes
and Mortality in Type 2 Diabetes. N Engl J Med.
Table of Contents
Section A. List of investigators ................................................................................................... 2
Section B. Trial committees and independent statistical center .................................................14
Section C. Definition of high risk of cardiovascular events ........................................................16
Section D. Exclusion criteria......................................................................................................17
Section E. Definitions of major clinical outcomes ......................................................................19
Section F. Sensitivity analyses and subgroup analyses (methodology) .....................................32
Section G. Patient disposition ...................................................................................................33
Section H. Reasons for premature discontinuation from study medication ................................34
Section I. Baseline characteristics .............................................................................................35
Section J. Treatment and observation times .............................................................................38
Section K. Absolute reductions in incidence rates for cardiovascular outcomes. .......................39
Section L. Categories of cardiovascular death ..........................................................................40
Section M. Cardiovascular outcomes with empagliflozin 10 mg and 25 mg ...............................41
Section N. Subgroup analyses for the primary outcome and for cardiovascular death ..............46
Section O. Sensitivity analyses .................................................................................................51
Section P. Weight, waist circumference, blood pressure, heart rate, low density and high density
lipoprotein cholesterol, and uric acid over time. .........................................................................55
Section Q. Glucose-lowering and cardiovascular medications introduced post-baseline ...........62
Section R. Complicated urinary tract infections .........................................................................64
Section S. Clinical laboratory data.............................................................................................65
Section A. List of investigators
Argentina: D. Aizenberg, Centro Médico Viamonte, Capital Federal, BS AS; M. Ulla, ILAIMCEOM, Córdoba, CBA; J. Waitman, Centro Diabetologico Dr Waitman, Córdoba, CBA; L. De
Loredo, Hospital Privado - Centro Médico de Córdoba S.A., Parque Velez Sarfield, CBA; J.
Farías, H. Fideleff, Sanatorio Güemes, Capital Federal, BS AS; M. Lagrutta, Instituto de
Investigaciones Clinicas, Rosario, STA FE; N. Maldonado, Centro Medico de Alta Complejidad,
Rosario, STA FE; H. Colombo, Clinica Privada Colombo, Cordoba, CO; F. Ferre Pacora, Centro
Médico Colon, Cordoba, CO; A. Wasserman, Fepreva, Buenos Aires, BA; L. Maffei,
Consultorios Asociados de Endocrinología e Invest Clínica, Capital Federal, BS AS; Australia:
R. Lehman, Adelaide Medical Research, Ashford, SA; J. Selvanayagam, Heart and Vascular
Institute, Fullarton, SA; M. d’Emden, Royal Brisbane and Womens Hospital; Herston, QLD;
Austria: P. Fasching, Wilhelminenspital Wien, Wien; B. Paulweber, LKH Salzburg - St.
Johanns-Spital, Salzburg; H. Toplak, Medical University Graz, Graz; A. Luger, Univ.-Klinik für
Innere Medizin III, Wien; H. Drexel, Landeskrankenhaus Feldkirch, Feldkirch; R. Prager,
Krankenhaus Hietzing mit NZR, Wien; C. Schnack, G. Schernthaner, Krankenanstalt
Rudolfstiftung inkl. Semmelweis Frauenklinik, Wien; G. Schernthaner, Univ. Klinik für Innere
Medizin II, Wien; E. Fliesser-Görzer, Ordination Dr. Fliesser-Görzer, St. Stefan; S. Kaser,
Universitätsklinik Innsbruck, Innsbruck; Belgium: A. Scheen, Centre Hospitalier Universitaire de
Liège, Liège; L. Van Gaal, UZA, Edegem; G. Hollanders, Dr. Geert Hollanders, De Pinte; Y.
Kockaerts, Ziekenhuis Oost Limburg, Genk; L. Capiau, Dr. Luc Capiau, Massemen-Wetteren; A.
Chachati, CHR Huy, Huy; A. Persu, M. Hermans, Cliniques Universitaires Saint-Luc, Bruxelles ;
D. Vantroyen, Huisartsenpraktijk Hygeia, Hasselt; C. Vercammen, Imelda ZH Bonheiden,
Bonheiden; P.Van de Borne, Hôpital universitaire Erasme, Bruxelles; K. Benhalima, C. Mathieu,
UZ Gasthuisberg, Leuven; F. Lienart, CHU de Tivoli, La Louvière; J. Mortelmans, Private
Practice, Oostham; M. Strivay, CHR de la Citadelle - Site Citadelle, Liège; G. Vereecken, Dr
Guy Vereecken, Halen; B. Keymeulen, F. Lamkanfi, UZ Brussel, Brussel; Brazil: A. Chacra,
Hospital São Paulo UNIFESP, Villa Clementino, SP; F. Eliaschewitz, Centro de Pesquisas
Clínicas Ltda, Higienópolis, SP; M. Zanella, Hospital do Rim e Hipertensão, Vila Clementino,
SP; A. Faludi, M. Bertolami, Instituto Dante Pazzanese De Cardiologia, São Paulo, Brasil; C.
Hayashida, Blumenau Serviços Médicos S/C Ltda, Vila Leopoldina, SP; J. Nunes Salles, O.
Monte, Salles, Irmandade da Santa Casa de Misericórdia de São Paulo, Vila Albuquerque, SP;
M. Dinato, Centro de Pesquisas Clinicas do Hospital Guilherme Álvaro, Boqueirão, ST; E.
Manenti, Hospital Mãe de Deus, Porto Alegre, RS; N. Rassi, Hospital Geral de Goiânia,
Goiânia, Brasil; A. Halpern, Hospital das Clinicas de Sao Paulo – FMUSP, São Paulo, Brasil; M.
Lima Filho, Hospital Electro Bonini Universidade de Ribeirão Preto, Ribeirão Preto, BR; J.
Ayoub, Instituto de Molestias Cardiovasculares – IMC, São José do Rio Preto, BR; J. Felicio,
Hospital Universitário João de Barros Barreto, Belém, PA; J. Borges, Centro de Pesquisa
Clínica do Brasil, Brasília, BR; J. Gross, Centro de Pesquisas em Diabetes, Porto Alegre, RS; J.
Sgarbi, Hospital de Clinicas da Faculdade de Medicina de Marilia, Marilia, BR; R. Betti, Instituto
do Coração, São Paulo, Brasil; A. Tiburcio, S. Purisch, Santa Casa de Misericordia de Belo
Horizonte, Belo Horizonte, BR; H. Schmid, Irmandade Santa Casa de Misericordia de Porto
Alegre, Porto Algre, BR; M. Takahashi, Universidade Estadual de Maringá, Maringá, BR; M.
Castro, Instituto de Pesquisa Clínica e Medicina Avançada, São Paulo, BR; R. Rea,
Universidade Federal do Paraná, Curitiba, BR; M. Hissa, Centro de Pesquisas em Diabetes e
Doenças, Fortaleza, Brasil; B. Geloneze Neto, Ced Centro de Endocrinologia e Diabetes,
Campinas, Brasil; J. Saraiva, Hospital e Maternidade Celso Peirro – PUCCAMP, Campinas,
Brasil; Canada: S. Henein, SKDS Research Incorporated, Newmarket, ON; H. Lochnan,
Ottawa, ON; S.A. Imran, D. Clayton, QEII Health Sciences Centre, Centre for Clinical Research,
Halifax, NS; K. Bayly, Mount Royal Family Physicians, Saskatoon, SK; J. Berlingieri, Burlington,
ON; P. Boucher, Longueuil, QC; Y. Chan, Niagara Falls, ON; M. Gupta, Brampton, ON; R.
Chehayeb, A. Ouellett, ViaCar Recherche Clinique Inc, Longueuil, QC; E. Ur, Vancouver, BC;
V. Woo, Winnipeg, MB; B. Zinman, Toronto, ON; E. St. Amour, Q&T Research Outaouais,
Gatineau, QC; Colombia: M. Terront Lozano, UNIENDO Unidad Integral de Endocrinologia,
Bogotá, Colombia; H. Yupanqui Lozno, Dexa-Diab IPS, Bogotá, CO; M. Urina, Fundación del
Caribe para la Investigación Biomédica, Barranquilla, Atlantico; P. Lopez Jaramillo, Fundación
Oftalmologica de Santander, Floridablanca, CO; N. Jaramillo, CEMDE, Medellín, CO; G.
Sanchez, CEQUIN, Armenia, CO; G. Pérez, Cardiolab Ltda., Bogotá, CO; Croatia: S. Tusek,
Specialized Hospital for Medical Rehabilitation, Krapinske Toplice; G. Mirosevic, V. Goldoni ,
University Hospital Centre 'Sestre Milosrdnice', Zagreb; D. Jurisic-Erzen, University Hospital
Centre Rijeka, Rijeka; A. Balasko, S. Balic, General Hospital Sveti Duh, Zagreb; E. DrvodelicSunic, General Hospital Karlovac, Karlovac; S. Canecki Varzic, Clinical Hospital Centre Osijek,
Osijek; Czech Republic: M. Machkova, CCBR Czech Prague s.r.o., Praha 3; P. Weiner,
Diabetology Out Patient Clinic of Hospital Jindrichuv Hradec, Jindrichuv Hradec; J. Lastuvka,
Masaryk Hospital, Usti nad Labem; J. Olsovsky, St. Anna Hospital, Brno; Denmark: T. Krarup,
Bispebjerg Hospital, København NV; M. Ridderstråle, L. Tarnow, T. Welløv Boesgaard, Steno
Diabetes Center, Gentofte; A. Sætre Lihn, Regionshospitalet Randers, Randers NØ; P.
Christensen, H. Juhl, Slagelse Sygehus, Slagelse; S. Urhammer, Frederiksberg Hospital,
Frederiksberg; P. Lund, Forskningscentret Nordsjællands Hospital, Helsingør; Estonia: B.
Adojaan, Tartu Endocrinology Centre, Tartu; Ü. Jakovlev, East Tallinn Central Hospital, Tallin;
R. Lanno, Merelahe Family Doctors Centre, Tallinn; M. Lubi, T. Marandi, Tartu University
Hospital, Tartu; T. Marandi, North Estonia Medical Centre Foundation, Tallin; France: D. Gouet,
HOP Saint Louis, La Rochelle Cedex 1; J. Courrèges, CH Narbonne, Narbonne Cedex; P.
Zaoui, Chu de Grenoble, Grenoble; G. Choukroun, Chu Sud, Amiens; C. Petit, Centre
Hospitalier Général Sud Francilien, Corbeil Essonnes; L. Formagne, Cabinet Médical, Derval; B.
Estour, Hôpital Nord, Saint Priez en Jarez; P. Mabire, Cabinet Médical, Fleury sur Orne; C.
Daugenet, Cabinet Médical, Equeurdreville Haineville; B. Lemarie, Cabinet Médical, Bourg des
cptes; S. Clavel, Hôpital Hôtel Dieu, Le Creusot; P. Aure, Cabinet Médical, Angers; P. Remaud,
Cabinet Médical, Angers; J. Halimi, CHU de Tours, Tours; S. Hadjadj, Hôpital de Poitiers,
Poitiers; T. Couffinhal, Hôpital Cardiologique du Haut Levèque, Pessac; Georgia: S. Glonti,
Unimed Ajara LLC, Batumi; D. Metreveli, David Metreveli Medical Centre Ltd., Tbilisi; Z.
Lominadze, L&J Clinic, Kutaisi; E. Giorgadze, National Institute of Endocrinology Ltd., Tbilisi; T.
Burtchuladze, L. Javashvili, Chemotherapy & Immunotherapy Clinic "Medulla", Tbilisi; G.
Kurashvili, R. Kurashvili, National Center for Diabetes Research Ltd., Tbilisi; D. Virsaladze,
Medical Centre Medelite Ltd., Tbilisi; L. Nadareishvili, A. Khomasuridze, Zhordania Institute of
Human Reproduction, Tbilisi; United Kingdom: T. Cahill, The Research Unit, Frome, Somerset;
F. Green, NHS Dumfries & Galloway, Dumfries; S. MacRury, Highland Diabetes Institute,
Inverness; M. Waldron, A. Middleton, Fowey River Practice, Fowey; J. McKnight, Western
General Hospital, Edinburgh; E. Pearson, NHS Tayside, Dundee; M. Butler, Waterloo Medical
Centre, Blackpool; M. Choksi, I. Caldwell, Swan Lane Medical Centre, Bolton; I. Farmer,
Stanwell Road Surgery, Ashford; N. Wyatt, J. Patrick, The Health Centre, Bradford on Avon; I.
O'Brien, NHS Lanarkshire, Wishaw; M. Devers, NHS Lanarkshire, Airdrie, Lanarks; Greece: S.
Bousboulas, S. Pappas, General Hospital of Nikaia, Nikaia; G. Piaditis, General Hospital of
Athens "G. Gennimatas", Athens; A. Vryonidou, "Korgialenio-Benakio", Hellenic Red Cross
Hospital, Athens; N. Tentolouris, General Hospital of Athens "Laiko", Athens; K. Karamitsos,
General Hospital of Larissa, Larissa; C. Manes, General Hospital "Papageorgiou", Thessaloniki;
M. Benroubi, General Hospital of Athens "Polikliniki", Athens; I. Avramidis, General Hospital of
Thessaloniki "G. Papanikolaou", Thessaloniki; Hong Kong: R. Ozaki, Prince of Wales Hospital,
Hong Kong; K. Tan, Queen Mary Hospital, Hong Kong; S. Siu, T. Ip, Tung Wah Eastern
Hospital, Hong Kong; C. Tsang, Alice Ho Miu Ling Nethersole Hospital, Hong Kong; Hungary:
M. Dudas, Bekes County Pandy Kalman Hospital, Gyula; K. Nagy, Synexus Hungary Ltd.,
Budapest; C. Salamon, Clinfan SMO Ltd., Szekszard; L. Gerö, Semmelweis University,
Budapest; J. Patkay, Szent Pantaleon Hospital, Dunaujvaros; A. Tabak, G. Tamas,
Semmelweis University, Budapest; F. Juhasz, CEE Research Kft., Kisvarda; I. Szentpeteri,
CRU Hungary Kft., Szikszo; India: N. Ghaisas, Shatabbdi Superspeciality Hopsital, Nashik,
Maharashtra; G. Bantwal, St. Johns Medical College and Hospital, Bangalore; V. Mohan, Dr
Mohan's Diabetes Specialities, Chennai; J. Gupta, S. R. Kalla Gastroentoroly & General
Hospital, Jaipur; N. Sadhu, Shree Krishna Hospital and Heart Care Centre, Ahmedabad,
Ahmedabad; A. Kulkarni, Deendayal Memorial Hospital, Pune, Pune; N. Garg, Tagore Hospital
and Heart Care Centre, Jalandhar; S. Reddy, Sumana Hospital, Hyderabad; N. Deshpande,
Spandan Heart Institute and Research Centre, Nagpur; K. Gutlapalli, Dr. Ramesh Cardiac and
Multispecialty Hospital Ltd, Vijaywada; M. Pillai, Lakshmi Hospital, Cochin; R. Premchand,
Krishna Institute of Medical Sciences, Secunderabad; M. Badgandi, Manipal Hospital,
Bangalore, Karnataka; S. Jain, TOTAL Diabetes Hormone Institute, Indore, Madhya Pra; S.
Aravind, DIACON Hospital & Research Center, Bangalore, NA; P. Shamanna, Bangalore
Clinisearch, Bangalore; A. Pandey, Heritage Hospital Ltd., Varanasi, UP; S. Gupta, Diabetes
Care n Research Centre, Nagpur; Indonesia: B. Pramono, Sardjito Hospital, Yogyakarta; H.
Dante Saksono, Cipto Mangunkusumo Hospital, Jakarta; P. Agung, Soetomo Hospital,
Surabaya; S. Djoko Wahono, Saiful Anwar Hospital, Malang; K. Suastika, Sanglah Hospital,
Denpasar, Bali; Y. Tanggo, Rumah Sakit FK UKI, Jakarta; Y. Juwana, Cinere Hospital, Depok;
B. Siswanto, Harapan Kita National Cardiovascular Center, Jakarta; Israel: F. Adawi, ZIV
Medical Center, Safed; S. Efrati, Assaf Harofeh Medical Center, Zerifin; E. Mazen, Haemek
Medical Centre, Afula; A. Bashkin, T. Herskovits, Western Galilee Hospital, Nahariya; A. Jaffe,
Hillel Yaffe Medical Center, Hadera; E. Schiff, Bnai Zion Medical Center, Haifa; J. Wainstein,
The E. Wolfson Medical Center, Holon; Italy: S. Taddei, Dipartimento Medicina Interna, Pisa, IT;
A. Aiello, U.O.C. Endocrinologia, Diabetologia e Malattie Metaboliche, Campobasso, IT; M.
Arca, Dipartimento di Clinica e Terapia Medica, Roma, IT; P. Calabro, U.O.C. di Cardiologia,
Napoli, IT; M. Cignarelli, Dipartimento di Scienze Mediche, Foggia, IT; P. Fioretto, Azienda
Ospedaliera di Padova, Padova, IT; G. Marchesini Reggiani, Policlinico "S. Orsola-Malpighi",
Bologna, IT; A. Gnasso, A:o. "Mater Domini" , Catanzaro, IT; N. Marchionni, A. Marsilii, A.O.
"Careggi", Firenze, IT; M. Bucci, A. Mezzetti, Fondazione Università "G. D'Annunzio", Chieti, IT;
P. Pozzilli, Area Endocrinologia, Roma, IT; F. Colivicchi, M. Santini, Divisione di Cardiologia,
Roma, IT; E. Moro, A. Semplicini, U.O. di Mediicna Interna, Venezia, IT; V. Toscano, U.O.C.
Endocrinologia, Roma, IT; A. Fucili, Centro per lo Scompenso Cardiaco, Ferrara, I; Japan: S.
Monno, Chibanishi General Hospital, Matsudoshi, Chiba; K. Furui, Hanyu General Hospital,
Hanyushi, Saitama; S. Higashiue, N. Hiramatsu, Kishiwada Tokushukai Hospital, Kishiwadashi.
Osaka; K. Kawamitsu, Okinawa Tokushukai medical corporation, Shimajiri-gun,Okinawa; T.
Takenaka, National Hospital Organization Hokkaido Medical Center, Nishi-ku, Sapporoshi,
Hokkaido; H. Takahashi, Iryouhouijneiwakai Minamiakatsuka clinic, Mitoshi, Ibaraki; F. Hojo,
Kobari General Hospital, Nodashi, Chiba; Y. Onishi, The Institute for Adult Diseases, Chuo-ku,
Tokyo; K. Izumino, Fujikoshi Hospital, Toyamashi, Toyama; M. Okubo, Gifu Heart Center,
Gifushi, Gifu; Y. Wakida, Daishinkai Medical Corporation Ookuma Hospital, Kita-ku, Nagoyashi,
Aichi; Y. Kondo, Clinic Horikawa, Kamigyo-ku, Kyotoshi, Kyoto; K. Hieshima, H. Jinnouchi,
Jinnouchi Diabetes Center, Kumamoto-shi, Kumamoto; A. Suzuki, M. Ito, Fujita Health
University Hospital, Toyoakeshi, Aichi; Republic of Korea: S. Park, Severance Hospital, Seoul,
NA; Y. Kim, Asan Medical Center, Seoul; T. Hong, Pusan National University Hospital, Pusan;
H. Park, Kyungpook National University Hospital, Daegu; H. Gwon, Samsung Medical Center,
Seoul; H. Kim, Seoul National University Hospital, Seoul; K. Kang, S. Lee, Eulji University
Hospital, Daejeon; M. Jeong, Chonnam National University Hospital, Gwangju; K. Seung, The
Catholic University of Korea, Seoul; D. Lim, Korea University Anam Hospital, Seoul; S. Rha,
Korea University Guro Hospital, Seoul; S. Tahk, Ajou University Hospital, Suwon; J. Yang,
National Health Insurance Service Ilsan Hospital, Goyang; J. Yoon, Wonju Severance Christian
Hospital, Wonju; M. Shin, Gachon University Gil Medical center, Incheon; D. Kim, Inje University
Haeundae Paik Hospital, Busan; J. Jeong, Chungnam National University Hospital, Daejoen;
Malaysia: N. Nik Ahmad, Hospital Tengku Ampuan Afzan, Pahang; N. Mustafa, Pusat
Perubatan University, Kuala Lumpur; W. Wan Mohamed, Hospital Universiti Sains Malaysia,
Kelantan; Y. Fung, Queen Elizabeth Hospital, Kota Kinabalu; R. Abdul Ghani, A. Chandramouli,
Universiti Teknologi Mara, Selangor; K. Chee, University Malaya Medical Centre, Kuala Lumpur;
K. Abdul Kadir, Monash University (Sunway Campus), Selangor Darul Ehsan; K. Ling, Hospital
Sultanah Aminah, Johor Bahru; M. Abu Hassan, Hospital Sultanah Bahiyah, Kedah; S. Foo,
Hospital Selayang, Selangor; Mexico: P. Garcia Hernandez, Hospital Universitario de Nuevo
Leon, Monterrey, Nl; C. Aguilar-Salinas, Instituto Nacional de Ciencias Médicas y Nutrición,
Distrito Federal, Mex; M. Vidrio Velazquez, Unidad de Investigacion Clinica Cardiometabolica,
Colonia Americana, Gua; F. Flores, Hospital Dr. Angel Leaño, Los Robles, Mex; M. Alpizar
Salazar, Centro Especializado de Diabetes, Reforma Social, Mex; D. Micher Escalante, M.
Garcia Soria, Clinical Research Institute, San Lucas tepetlcalco, Mex; E. Cardona Muñoz, ICLE
SC, Ladron de Guevara, MEx; Netherlands: G. Storms, St. Antonius Ziekenhuis, Utrecht; N.
Schaper, Maastricht UMC+ (UM en azM werken samen onder de naam Maastricht UMC+),
Maastricht; A. Kooy, Bethesda Ziekenhuis, Hoogeveen; M. Krekels, Orbis Medisch Centrum,
Geleen; T. Bemmel van, R. Verhoeven, Gelre Ziekenhuizen Apeldoorn, Apeldoorn; H. Mulder,
Rotterdam Research Institute, Rotterdam; P. Oldenburg-Ligtenberg, Meander Medisch
Centrum, locatie Amersfoort Lichtenberg, Amersfoort; F. Gonkel, Ropcke-Zweers Ziekenhuis,
Hardenberg; A. Jong de, Huisartsenpraktijk De Hooge Boom, Hoogwoud; J. Soest van,
Huisartsenmaatschap LSV, Nijverdal; P. Viergever, Gemini Ziekenhuis, Den Helder; H.
Mevissen, Huisartsenpraktijk Wildervank, Wildervank; G. Lochorn, Medisch Centrum Gorecht,
Hoogezand; G. Zwiers, Vlietland Ziekenhuis, Schiedam; P. Hoogslag, Diaconessenhuis Meppel,
Meppel; E. Ronner, Reinier de Graaf Gasthuis, Delft; P. Nierop, Sint Franciscus Gasthuis,
Rotterdam; N. Al – Windy, Gelre Ziekenhuizen locatie Zutphen, Zutphen; J. Kragten, Atrium
Medisch Centrum, locatie Heerlen, Heerlen; P. Dekelver, Huisartsenpraktijk Dekelver, Baarle Nassau; New Zealand: J. Benatar, Auckland City Hospital, Grafton / Auckland; J. Krebs,
Wellington Hospital, Wellington; R. Scott, Christchurch Hospital Campus, Christchurch;
Norway: E. Heggen, Oslo Universitetssykehus HF, Oslo; A. Berz, Medisinsk Senter Fornebu ,
Fornebu; C. Fossum, Sykehuset Innlandet HF, Gjøvik; U. Hurtig, Sykehuset Innlandet HF, Avd.
Tynset, Tynset; G. Langslet, Oslo Universitetssykehus HF, Oslo; M. Baranowski, Intern Medic,
Trondheim; J. Sparby, Sykehuset Innlandet HF, Kongsvinger, Kongvinger; T. Karlsson, Dr.
Thomas Karlsson, Kløfta; Peru: C. Delgado Torres, Instituto Delgado de Investigacion Medica,
Arequipa, PE; A. Rodriguez Escudero, Hospital Alberto Sabogal Sologuren, Bellavista, PE; R.
Lisson, Hospital Nacional Edgardo Rebagliati Martins, Jesus Maria, Lima; A. Allemant
Maldonado, Hospital Nacional Hipólito Unanue, El Agustino, PE; W. Gallardo Rojas, Instituto
Medico Miraflores, Miraflores, PE; L. Gonzales Bravo, Clinica Medica San Martin, Ica, PE; J.
Lema Osores, Hospital Nacional Arzobispo Loayza, Lima, PE; J. Farfan, Instituto
Endocrinologico Farfan, Arequipa, PE; L. Zapata, Casa de Diabetes & Nutrición, Lima, PE; J.
Godoy Junchaya, Hospital Nacional Daniel Alcides Carrión, Lima, PE; Y. Roldan Concha, J.
Urquiaga Calderon, Centro de Investigación Heart Help, Lima, LI; Philippines: R. Sy, Cardinal
Santos Medical Center, Manila; G. Tan, Cebu Doctors University Hospital, Cebu; G. Aquitania,
Philippine Nikkei Jin Kai Polyclinic and Diagnostic Center, Davao; G. De Los Santos,
Metropolitan Medical Center, Manila; A. Panelo, UERM-Institute for Studies on Diabetes
Foundation,Inc, Marikina City; O. Roderos, De La Salle University Medical Center, Cavite City;
R. Rosales, Metropolitan Medical Center, Manila; R. Toledo, Señor Santo Niño Hospital, Tarlac;
A. Liwag, West Visayas State University Medical Center, Jaro Iloilo City; H. Ramoncito, Amang
Rodriguez Medical Centre, Marikina City; Poland: E. Skokowska, NZOZ Przychodnia
Specjalistyczna "Medica", Lublin; E. Krzyzagorska, Private Practice Dr. Ewa Krzyzagorska,
Poznan; M. Ogorek, NZOZ All-Med Medical Centre, Lodz; L Wojnowski, Citomed Sp. Z.o.o.,
Torun; J. Spyra, Specialized Practice Dr. Janusz Spyra, Ruda Slaska; M. Konieczny,
Specialized Physician's Office Ko-Med, Pulawy; W. Piesiewicz, Medical Centre Hospital Swietej
Rodziny, Lodz; W. Kus, Individual Specialized Practice, Lodz; A. Ocicka-Kozakiewicz, NonPublic HealthCare Center "Nasz Lekarz", Torun; E. Orlowska-Kunikowska, University Clinical
Center, Gdansk; W. Zmuda, Oswiecimskie Centrum Badan Klinicznych Medicome Sp. z o.o.,
Oswiecim; Portugal: S. Duarte, Centro Hospitalar Lisboa Ocidental, Lisboa; A. Leitão, Centro
Hospitalar Lisboa Central, Lisboa; P. Monteiro, Hospitais da Universidade de Coimbra,
Coimbra; H. Rita, Unidade de Saúde do Litoral Alentejano, EPE, Santiago do Cacém; V.
Salgado, Hospital Fernando Fonseca, Amadora; L. Pinto, Centro Hospitalar de Leiria-Pombal,
EPE, Leiria; J. Queirós, Hospital de São João, Porto; J. Teixeira, Unidade Local de Saúde do
Alto Minho, Viana do Castelo; C. Rogado, R. Duarte, APDP-Associação Protectora dos
Diabéticos de Portugal, Lisboa; F. Sobral do Rosário, Hospital da Luz, Lisboa; A. Silva, Centro
Hospitalar do Algarve, EPE, Faro; L. Andrade, Centro Hospitalar de Vila Nova de Gaia/Espinho,
Vila Nova de Gaia; M. Velez, Centro Hospitalar Médio Tejo, EPE, Torres Novas; M. Brazão,
Serviço Região Autónoma da Madeira, EPE, Funchal, Madeira; Romania: O. Istratoaie, SC
Cardiocenter Dr. Istratoaie SRL, Craiova; R. Lichiardopol, Institute of Diabetes Nutrition and
Metabolic Diseases, Bucharest; D. Catrinoiu, County Clinical Hospital, Constanta; C. Militaru,
S.C. Cardiomed S.R.L, Craiova; C. Zetu, Institute of Diabetes Nutrition and Metabolic Diseases,
Bucharest; D. Barbonta, SC Diana Barbonta SRL, Alba Iulia; D. Cosma, Pelican Impex SRL,
Cabinet Nr. 15, Oradea; C. Crisan, RAI Medicals SRL, Mediab SRL, Targu-Mures; L. Pop,
Cabinet Med. Individual Diabet, Nutritie, Boli Metabolice Private Practice Dr. Lavinia Pop, Baia
Mare Maramures; Russia: V. Esip, Saint Petersburg State Healthcare Institution, St.
Petersburg, F. Khetagurova, A. Petrov, Vsevolozhsk Central Regional Hospital, Vsevolozhsk; G.
Arutyunov, City Clinical Hospital No. 4, Moscow; M. Boyarkin, City Alexander Hospital St.
Petersburg, St. Petersburg; A. Agafyina, Saint-Petersburg GUZ "City Clinical Hospital #40, Saint
Petersburg; N. Vorokhobina, St. Petersburg GUZ City Clinical Hospital of Saint Elizabeth, St.
Petersburg; N. Petunina, City Clinical Hospital No. 67, Moscow; I. Libov, Moscow GUZ City
Clinical Hospital named after S.P. Botkin, Moscow; A. Zalevskaya, Autonomous nonprofit
organization, St. Petersburg; K. Nikolaev, City Clinical Hospital No. 19, Novosibirsk; O.
Barbarash, Heart & Vessels Diseases complex problems, Kemerovo; V. Potemkin, Moscow
GUZ City Clinical Hospital No. 68, Moscow; A. Bystrova, E. Krasilnikova, St. Petersburg State
Medical Univ. n.a. I Pavlov Roszdrava, St. Petersburg; V. Barbarich, City Clinical Hospital No.
1, Novosibirsk; G. Chumakova, Altai State Medical University, Barnaul; N. Tarasov, Medicosanitary Unit of Main Dept. of Internal Affairs, Kemerovo; T. Meleshkevich, Central Clinical
Hospital No. 2, Moscow; D. Zateyshchikov, City Hospital No. 17, Moscow; O. Lantseva, StPetersburg State Healthcare Institution, St. Petersburg; D. Belenkiy, MUZ Novosibirsk Municipal
Clinical Hospital of Emergency No. 2, Novosibirsk; A. Obrezan, LLC International Medical
Center SOGAZ, Saint Petersburg; L. Rossolko, City Polyclinic No. 120, Saint Petersburg; E.
Fillipova, LLC Medinet, Saint Petersburg; P. Yakhontova, Novosibirsk Regional Clinical,
Novosibirsk; A. Khokhlov, MUZ Clinical Hospital #2, Yaroslavl; Singapore: R. Tan, National
Heart Center, Singapore; C. Sum, Khoo Teck Puat Hospital, Singapore; H. Chang, Singapore
General Hospital, Singapore; South Africa: L. Distiller, Centre For Diabetes and Endocrinology,
Houghton; M. Pretorius, Tiervlei Trial Centre, Bellville; H. Nortje, Dr H. Nortje, Goodwood; E.
Mitha, Newtown Clinical Research Centre, Newtown; L. Burgess, Tread Research, Parow; S.
Blignaut, Paarl Research Centre, Paarl; T. Venter, Cardiology Clinical Research, Alberton; R.
Moodley, Dr. Moodley and Dr. Sarvan, Tongaat; J. Lombaard, Josha Research Centre,
Bloemfontein; U. Govind, Dr U. Govind, Sydenham; V. Naidoo, Durban, KZN; M. Mookadam,
Langeberg Clinical Trials, Cape town, WC; J. Engelbrecht, Vergelegen Medi-Clinic, Somerset
West; M. Omar, Centre for Diabetes and Endocrinology, Durban; J. Jurgens, DJW Navorsing,
Krugersdorp; G. Podgorski, Greenacres Hospital, Port Elizabeth; H. Vawda, D. Naidoo,
Cardiology Research Clinic, Durban, KZN; S. Emanuel, Synopsis Research, Cape Town, WC;
A. Roodt, Clinresco Centre (Pty) Ltd, Kempton Park, GAU; A. Amod, Medical Centre,
Chatsworth Unit 10, KZN; L. Van zyl, Clinical Projects Research, Worcester, WC; Spain: J.
Segura, Hospital 12 de Octubre, Madrid; M. Brito, Hospital Universitario Puerta de Hierro,
Mahadahonda (Madrid); A. Fernandez-Cruz, Hospital Clínico Universitario San Carlos, Madrid;
S. Artola, Centro de Salud Maria Jesus Hereza, Leganes (Madrid); R. Iglesias, Centro de Salud
Pedro Lain Entralgo, Alcorcon (Madrid); E. Toural, Centro de Salud Lavapies, Madrid; L. GarciaOrtiz, Centro de Salud La Alamedilla, Salamanca; J. Saban, Hospital Universitario Ramon y
Cajal, Madrid; J. Mesa, Hospital Vall d´Hebron, Barcelona; J. Vidal, Hospital Clinic i Provincial
de Barcelona, Barcelona; J. Linares, Clinica Inmaculada Concepcion, Granada; F. del Cañizo,
Hospital Infanta Leonor, Madrid; M. Rigla, Corporacio Sanitaria Parc Tauli, Sabadell
(Barcelona); C. Suarez, Hospital Universitario La Princesa, Madrid; I. Llorente, Hospital Nuestra
Señora de la Candelaria, Santa Cruz de Tenerife; B. Moreno, Hospital General universitario,
Madrid; A. Antoli, F. Gomez Peralta, Hospital Nuestra Señora de Sonsoles, Avila; M. Iglesias,
CAP Badía del Vallès, Badía del Vallès – Barcelona; F. Gomez-Peralta, Hospital General de
Segovia, Segovia; V Pereg, Hospital Son Espases, Palma de Mallorca; L. de Teresa, Instituto
de Ciencias Médicas, Alicante; M. Camafort, Hospital Clinic i Provincial de Barcelona,
Barcelona; C. Trescoli, Hospital de la Ribera, Alzira, Valencia; Sri Lanka: R. Satarasinghe, Sri
Jayewardenepura General Hospital & PGMI, Nugegoda; N. Somasundaram, National Hospital,
Colombo; S. Siyambalapitiya, Colombo North Teaching Hospital, Ragama; C. Antonypillai,
Diabetes and Endocrine Unit, Kandy; D. Bulugahapitiya, Diabetes Clinic, Kalubowila; U.
Medagama, Teaching Hospital Peradeniya, Kandy; Taiwan: C. Huang, Chung Shan Medical
University Hospital, Taichung; Y. Lu, E-Da Hospital, Kaohsiung; J. Hwang, National Taiwan
University Hospital, Taipei; C. Chiang, Taipei Veterans General Hospital, Taipei; M. Wen,
Chang Gung Memorial Hospital,Linkou, Taoyuan; J. Chen, National Cheng Kung University
Hospital, Tainan; W. Lai, Kaohsiung Medical University Hospital, Kaohsiung; K. Chang, China
Medical University Hospital, Taichung; J. Wang, Buddhist Tzu Chi General Hospital, Hualien; H.
Yeh, Mackay Memorial Hospital, Tamsui, Taipei County; Thailand: P. Kriangsak, Udonthani
Hospital, Muang District; C. Deerochanawong, Rajavithi Hospital, Bangkok; S. Suwanwalaikorn,
King Chulalongkorn Memorial Hospital, Bangkok; A. Mangklabruks, Maharaj Nakorn Chiangmai
Hospital, Chiang Mai; P. Kaewsuwanna, Maharat Nakhon Ratchasima Hospital,
Nakhonratchasima; D. Piyayotai, Thammasat University Hospital, Pathum Tani; Ukraine: M.
Iabluchanskyi, Clinical Hospital No. 5, Kharkov; O. Samoylov, Scientific Center of Radiation,
Kiev; O. Godlevska, City Clinical Hospital of Emergency Care, Kharkov; O. Kovalyova, Kharkiv
City Hospital No. 3, Kharkiv; O. Voloshyna, Odessa State Medical University, Odessa; V.
Tseluyko, City Clinical Hospital No. 8, Kharkiv; S. Zotov, I. Vykhovanyuk, Clinic for Cardiology
"Sertse i sudyny" LTD, Kiev; United States of America: A. Dulgeroff, High Desert Medical
Group, Lancaster, CA; R. Mayfield, Mountain View Clinical Research, Greer, SC; M. ZaniewskiSingh, Michelle Zaniewski, M.D., PA, Houston, TX; J. Ullal, J. Aloi, The Strelitz Diabetes Center,
Norfolk, VA; R. De La Rosa, Four Rivers Clinical Research, Paducah, KY; J. Mosely, B.
Wittmer, Commonwealth Biomedical Research LLC, Madisonville, KY; S. Aronoff, Research
Institute of Dallas, Dallas, TX; J. Rosenfeld, M. Seidner, Green and Seidner Family Practice,
Lansdale, PA; M. Warren, Physicians East, PA, Greenville, NC; N. Fishman, Diabetes and
Endocrine Specialists Inc, Chesterfield, MO; R. Weiss, Maine Research Associates, Auburn,
ME; A. Arif, Apex Medical Research, Flint, MI; M. Sandberg, Westcott Medical Center,
Flemington, NJ; D. Lewis, Arkansas Primary Care Clinics, Little Rock, AK; E. Ball, Walla Walla
Clinic, Walla Walla, WA; R. Graf, MultiCare Specialties Research, Tacoma, WA; C. Breton,
International Research Associates, LLC, Miami, FL; R. Tamayo, Genesis Research
International, Longwood, FL; R. Richards, W. Cefalu, G. Uwaifo, Louisiana State University,
New Orleans, LA; D. Zayour, J. Hoffman, Via Christi Clinic, PA, Wichita, KS; D. Fitz-Patrick,
East-West Medical Research, Honolulu, HI; B. Khan, Atlanta Clinical Research Center, Atlanta,
GA; K. Blaze, South Broward Research, Pembroke Pines, FL; P. Bressler, North Texas
Endocrine Center, Dallas, TX; S. Halpern, D. Chappell, Radiant Research, Inc, Santa Rosa, CA;
R. Bergenstal, R. Cuddihy, G. Matfin, International Diabetes Center, Minneapolis, MN; Z.
Freedman, Endocrine-Diabetes Care and Resource Center, Rochester, NY; J. GonzalezCampoy, Minnesota Center for Obesity, Metabolism, & Edocrinology, PA, Eagan, MN; S.
Lerman, The Center for Diabetes and Endocrine Care, Ft. Lauderdale, FL; M. Rendell,
Creighton University School of Medicine Diabetes Center, Omaha, NE; S. Sitar, Orange County
Research Institute, Anaheim, CA; M. Reeves, Michael L. Reeves, MD, Chattanooga, TN; T.
Howard, Medical Affiliated Research Center, Inc, Huntsville, AL; J. Soufer, Chase Medical
Research, LLC, Waterbury, CT; B. Miranda-Palma, University of Miami/ Diabetes Research
Institute, Miami, FL; A. Laliotis, Integrated Research Center, San Diego, CA; M. Shomali, Union
Memorial Hospital Diabetes and Endocrine Center, Baltimore, MD; M. Teltser, A & R Research
Group, LLC, Pembroke Pines, FL; D. Hurley, Medical Research South, LLC, Charleston, SC; E.
Morawski, Holston Medical Group, Kingsport, TN; R. Cherlin, Richard Cherlin, MD, Los Gatos,
CA; V. Houchin, Harrisburg Family Medical Center, Harrisburg, AR; M. Welch, D. Goytia-Leos,
Consano Clinical Research, San Antonio, TX; M. Syed, Ilumina Clinical Associates, Indiana, PA;
E. Kowaloff, L. Weinrauch, Atlantic Clinical Trials, LLC, Watertown, MA; J. Peniston, Avington
Memorial Hospital, Feasterville Trevose, PA; A. Brockmyre, Holston Medical Group, Bristol, TN;
B. First, Ritchken & First MD's, San Diegeo, CA; L. Feld, Horizon Clinical Research Associates,
Gilbert, AZ; D. Huffman, University Diabetes & Endocrine Consultants, Inc, Chattanooga, TN; O.
Nassim, Clinical Research, Inc, Huntington Park, CA; G. Gottschlich, New Horizons Clinical
Research, Cincinnati, OH; A. Patel, C. Knopke, Integrated Research Group, Inc, Riverside, CA;
M. Hernandez, Berma Research Group, Hialeah, FL; J. Diaz, The Community Research of
South Florida, Hialeah, FL; G. Giugliano, J. Nicasio, Baystate Medical Center, Springfield, MA;
D. Eagerton, Carolina Health Specialists, Myrtle Beach, SC; R. Huntley, Norwalk Medical,
Norwalk, CT; J. Reed, III, Endocrine Research Solutions, Inc, Roswell, GA; M. Magee, MedStar
Health Research Institute, Washington, DC; R. Hippert, Integrated Medical Group PC,
Fleetwood, PA; C. Sofley, Jr., Internal Medicine Associates of Anderson, PA, Anderson, SC; O.
Alzohaili, Alzohaili Medical Consultants, Dearborn, MI; P. Levins, R. Anspach, Clinical Research
Advantage, Inc, Phoenix, AZ; S. Shah, St. Joseph's Medical Associates, Stockton, CA; O.
Brusco, Osvaldo Brusco, MD, Corpus Christi, TX; J. Naidu, Naidu Clinic, Odessa, TX; J.
Lindenbaum, Jeffry Lindenbaum DO, PC, Yardley, PA; R. Jacks, Hill County Medical
Associates, New Braunfels, TX; G. Hammond, Dormir Clinical Trials, Inc, Midvale, UT; C.
Arena, Utah Clinical Trials, LLC, Salt Lake City, UT; K. Saxman, Oregon Medical Group Adult
Medicine Clinic, Eugene, OR; M. Mach, Valley Endocrine & Diabetes Consultants, Inc, Valencia,
CA; H. Kerstein, Howard Kerstein, MD, Denver, CO; D. Kereiakes, The Carl and Edyth Linder
Center For Research and Education, Cincinnati, OH; J. Wahlen, Advanced Research Institute,
South Ogden, UT; K. Wehmeier, UF Endocrinology & Diabetes, Jacksonville, FL; L. Chaykin,
Meriden Research, Bradenton, FL; J. Rothman, University Physicians Group, Staten Island, NY;
L. Fogelfeld, John H. Stroger Jr, Hospital of Cook County, Chicago, IL; N. Bittar, Gemini
Scientific, LLC, Madison, WI; J. Rosenstock, Dallas Diabetes and Endocrine Center, Dallas, TX;
D. Kayne, Medical Group of Encino, Encino, CA; J. Navarro, Genesis Clinical Research,
Tampa, FL; H. Colfer, Nisus Research, Petoskey, MI; S. Mokshagundam, Robley Rex VA
Medical Center, Louisville, KY; L. Shandilya, Ettrick Health Center, PA, South Chesterfield, VA;
L. Connery, Lion Research, Norman, OK; C. Wysham, Rockwood Diabetes and Metabolic
Health Center, Spokane, WA; A. Dela Llana, MediSphere Medical Research Center, LLC,
Evansville, IN; M. Jardula, Desert Oasis Healthcare, Palm Springs, CA; M. MacAdams, Lubbock
Diagnostic Clinic, Lubbock, TX; G. Flippo, Alabama Clinical Therapeutics, LLC, Birmingham,
AL; E. Heurich, C. Curtis, Compass Research, Orlando, FL; D. Sanders, R. Rawls, Horizan
Research Group, Inc, Mobile, AL; F. Velazquez, Pioneer Research Solutions, Inc, Houston, TX;
E. Osea, Innovative Clinical Research, Inc, Harbor City, CA; K. Mahood, Family Medicine of
Sayebrook, Myrtle Beach, SC; G. Feldman, South Carolina Pharmaceutical Research,
Spartanburg, SC; F. Eder, United Medical Associates, Binghamton, NY; E. Riley, IV, W. Fowler,
Tower Pointe Research Center, Hodges, SC; M. Jain, Southwest Clinical Research Centers,
LLC, Pearland, TX; M. Shepard, Medstar Research Institute, Hyattsville, MD; M. Schear, Dayton
Clinical Research, Dayton, OH; B. Barker, Delaware Research, Delaware, OH; C. Strout,
Coastal Carolina Research Center, Mt. Pleasant, SC; O. Obiekwe, Ropheka Medical Center,
Riverdale, GA; M. Shanik, Endocrine Associates of Long Island, PC, Smithtown, NY; C. Green,
E. Blakney, The Green Clinic PC, Memphis, TN; K. Roberson, Delta Waves, Inc., Colorado
Springs, CO; E. Bretton, Albuquerque Clinical Trials, Albuquerque, NM; R. Pish, Pish Medical
Associates, Uniontown, PA; K. Kaveh, Coastal Nephrology Associates Research Center, LLC,
Port Charlotte, FL; B. Maynard, W. Barager, R. Soldyshev, Great Falls Clinic, LLP, Great Falls,
MT; B. Austin, Preferred Primary Care Physicians, Inc, Pittsburgh, PA; P. Parmar, R. Simpson,
The Lynn Institute, Denver, CO; A. Chauhan, Prime Medicial Group, Clairton, PA; J. Kasper, R.
Burr, Focus Clinical Research, Draper, UT; N. Patel, Wells Institute for Health Awareness,
Kettering, OH; H. Mariano, Research Center of Fresno, Inc, Fresno, CA; T. Pluto, Fay West
Family Practice, Scottdale, PA; C. Bratcher, Diabetes America at Plano, Plano, TX; M. Juarez,
Panacea Clinical Research, San Antonio, TX; L. Levinson, Tipton Medical & Diagnostic Center,
Tipton, PA; A. Awad, Clinical Research Consultants, LLC, Kansas City, MO; K. Longshaw,
Leading Edge Research, PA, Dallas, TX; K. Hoffman, TRY Research, Maitland, FL; R.
Richwine, Texas Health Physicians Group, Fort Worth, TX; D. Molter, North Myrtle Beach
Family Practice, North Myrtle Beach, SC; J. Boscia, III, CU Pharmaceutical Research, Union,
SC; S. Kowalyk, Endocrinolgy Associates, Greensburg, PA; P. Lemis, Jefferson Cardiology
Association, Clairton, PA; J. Liss, Medical Research & Health Education Foundation Inc,
Columbus, GA; R. Orr, Phoenix Medical Group, PC, Peoria, AZ; J. Riser, Riser Medical
Research, Picayune, MS; J. Wood, Leading Edge Research, PA/INOVA, Richardson, TX; A.
Ubani, Windsor Medical Clinic, Tampa, FL; W. Paine, F. Hassani, Mileground Family Practice,
Morgantown, WV; F. Miranda, Dr. Francisco Miranda, Miami, FL; V. Hansen, Val R. Hansen,
MD, Bountiful, UT; N. Farris, The Research Group of Lexington, LLC, Lexington, KY; R.
Bowden, Charleston Internal Medicine Research Institute, Charleston, Charleston, WV; D. Ajani,
Southwest Clinical Trial, Houston, TX; K. Maw, J. Andersen, Meridien Research, Brooksville,
FL; B. Bergman, Benefis Health Group, Great Falls, MT; S. Dunmyer, Pharmacotherapy
Research Associates, Inc, Zanesville, OH; D. Brandon, California Research Foundation, San
Diego, CA; M. Anderson, Kernodle Clinic, Burlington, NC; P. Bononi, Partners in Nephrology &
Endocrinology, Pittsburgh, PA; J. Prawer, Joel Prawer, MD, Saint Petersburg, FL; B. Seidman,
Seidman Clinical Trials, Delray Beach, FL; H. Cruz, Florida Institute for Clinical Research,
Orlando, FL; K. Wilks, Kerri Wilks, MD; Hallandale Beach, FL; L. DiSanto, Lisa DiSanto, DO,
Saint Petersburg, FL; R. Buynak, Buynak Clinical Research, Valparaiso, IN; T. Christensen,
Calabash Medical Center, Calabash, NC; P. Denker, Gulfcoast Endocrine and Diabetes Center,
Clearwater, FL; W. Koppel, Walter Koppel, MD, Towson, MD; M. Stedman, Stedman Clinical
Trials, Tampa, FL; L. Lewy-Alterbaum, All Medical Research LLC, Cooper City, FL; S. Karim, J.
Shapiro, Philadelphia Health Associates, Philadelphia, PA; T. Gardner, T. Oskin, Northside
Internal Medicine, Spokane, WA; N. Gabra, J. Malano, Burke Internal Medicine & Research,
Burke, VA.
Section B. Trial committees and independent statistical center
Steering Committee
Bernard Zinman, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of
Toronto, Toronto, Canada; Christoph Wanner, Würzburg University Clinic, Würzburg, Germany;
John M. Lachin, The George Washington University, Rockville, MD, USA; David Fitchett,
University of Toronto, Toronto, Canada; Erich Bluhmki, Boehringer Ingelheim Pharma GmbH &
Co. KG, Biberach, Germany; Odd Erik Johansen, Boehringer Ingelheim KS, Asker, Norway;
Hans J. Woerle, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Uli C.
Broedl, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Silvio E. Inzucchi,
Yale University School of Medicine, CT, USA.
Data Monitoring Committee
Francine K. Welty (Chair), Beth Israel Deaconess Medical Center, Boston, USA; Klaus G.
Parhofer, University of Munich, Munich, Germany; Terje R. Pedersen, Oslo University Hospital,
Oslo, Norway; Kennedy R Lees, University of Glasgow, Glasgow, UK; Tim Clayton, London
School of Hygiene and Tropical Medicine, London, UK; Stuart Pocock (ad hoc), London School
of Hygiene and Tropical Medicine, London, UK; Mike Palmer (Independent Statistician), N Zero
1 Ltd, Wilmslow, UK.
Clinical Event Committee: Cardiology
Peter Clemmensen, Peer Grande, Steen Pehrson, Heart Center of ‘Rigshospitalet’, the
Copenhagen University Hospital, Copenhagen, Denmark; James Januzzi Jr and Malissa J.
Wood, Massachusetts General Hospital, Boston, USA; Mark Petrie, Golden Jubilee National
Hospital, Glasgow, UK.
Clinical Event Committee: Neurology
Tiina Sairanen, Turgut Tatlisumak, Lauri Soinne, Helsinki University Central Hospital, Helsinki,
Finland; Carlos Kase, Boston University Medical Center, Boston, USA; Tanya Turan, Medical
University of South Carolina (MUSC) Stroke Program, Charleston, USA.
Adjudication Committee: Hepatic
Paul Watkins, Hamner-UNC Institute for Drug Safety Sciences, Research Triangle Part, North
Carolina, USA; James Lewis, Georgetown University School of Medicine, Georgetown
University Hospital, Washington, USA; James Freston, Division of Gastroenterology and
Hepatology, University of Connecticut Health Center, Farmington, USA; Steven Schenker,
University of Texas Health Science Center, San Antonio, USA.
Adjudication Committee: Oncology
Rebecca Heist, Massachusetts General Hospital and Harvard Medical School, Boston, USA;
Richard J Lee, Massachusetts General Hospital Cancer Center and Harvard Medical School,
Boston, USA; Ronald B Natale, Cedars-Sinai Outpatient Cancer Center, Los Angeles, USA;
Ryan J Sullivan, Massachusetts General Hospital Cancer Center, Harvard Medical School,
Boston, USA; Elizabeth I Buchbinder, Division of Oncology, Dana Farber Cancer Institute,
Boston, USA; Gerald Chodak, Midwest Prostate and Urology Health Center, Weiss Memorial
Hospital, Chicago, USA
Independent Statistical Center
Martin Schumacher1, Claudia Schmoor2, Stefanie Hieke1,2, Kristin Ohneberg1, Clinical Trials
Unit1 and Institute for Medical Biometry2 of Medical Center, University of Freiburg, Freiburg,
Germany
Section C. Definition of high risk of cardiovascular events
High risk of cardiovascular events was defined as the presence of ≥1 of the following:
•
History of myocardial infarction >2 months prior to informed consent
•
Evidence of multi-vessel coronary artery disease i.e. in ≥2 major coronary arteries or the
left main coronary artery, documented by any of the following:
–
Presence of significant stenosis: ≥50% luminal narrowing during angiography
(coronary or multi-slice computed tomography)
–
Previous revascularization (percutaneous transluminal coronary angioplasty ±
stent or coronary artery bypass graft >2 months prior to consent
–
The combination of revascularization in one major coronary artery and significant
stenosis (≥50% luminal narrowing) in another major coronary artery
•
Evidence of single-vessel coronary artery disease, ≥50% luminal narrowing during
angiography (coronary or multi-slice computed tomography) not subsequently
successfully revascularized, with at least 1 of the following:
•
–
A positive non-invasive stress test for ischemia
–
Hospital discharge for unstable angina ≤12 months prior to consent
Unstable angina >2 months prior to consent with evidence of single- or multi-vessel
coronary artery disease
•
History of stroke (ischemic or hemorrhagic) >2 months prior to consent
•
Occlusive peripheral artery disease documented by any of the following:
–
Limb angioplasty, stenting, or bypass surgery
–
Limb or foot amputation due to circulatory insufficiency
–
Evidence of significant peripheral artery stenosis (>50% on angiography, or
>50% or hemodynamically significant via non-invasive methods ) in 1 limb
–
Ankle brachial index <0.9 in ≥1 ankle
Section D. Exclusion criteria
•
Uncontrolled hyperglycemia with glucose >240 mg/dL after an overnight fast during
placebo run-in and confirmed by a second measurement (not on the same day)
•
Indication of liver disease, defined by serum levels of alanine amininotransferase,
aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal
during screening or run-in phase
•
Planned cardiac surgery or angioplasty within 3 months
•
Estimated glomerular filtration rate <30 ml/min/1.73 m2 (according to the Modification of
Diet in Renal Disease equation) at screening or during run-in phase
•
Bariatric surgery within the past two years and other gastrointestinal surgeries that
induce chronic malabsorption
•
Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells
•
Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer
within the last 5 years
•
Contraindications to background therapy according to the local label
•
Treatment with anti-obesity drugs 3 months prior to informed consent or any other
treatment at time of screening leading to unstable body weight
•
Treatment with systemic steroids at time of informed consent or change in dosage of
thyroid hormones within 6 weeks prior to informed consent
•
Any uncontrolled endocrine disorder except type 2 diabetes
•
Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who were
nursing, pregnant, or of child-bearing potential and were not practicing an acceptable
method of birth control, or did not plan to continue using this method throughout the
study, or did not agree to submit to periodic pregnancy testing during the trial
–
Acceptable methods of birth control include tubal ligation, transdermal patch,
intrauterine devices/systems, oral, implantable or injectable contraceptives, sexual
abstinence, double barrier method, vasectomy of partner
•
Alcohol or drug abuse within 3 months of informed consent that would interfere with trial
participation or any ongoing condition leading to decreased compliance with study
procedures or study drug intake
•
Intake of an investigational drug in another trial within 30 days prior to intake of study
medication in this trial or participating in another trial involving an investigational drug
and/or follow-up
•
Any clinical condition that would jeopardize patient safety while participating in this
clinical trial (in Canada, this included current genito-urinal infection or genito-urinal
infection within 2 weeks prior to informed consent)
•
Acute coronary syndrome, stroke, or transient ischemic attack within 2 months prior to
informed consent
•
In South Africa: blood pressure >160/100 mmHg at screening
Section E. Definitions of major clinical outcomes
Cardiovascular death
The cause of death was determined by the principal condition that caused the death, not the
immediate mode of death. Clinical Events Committee (CEC) members reviewed all available
information and used their clinical expertise to adjudicate the cause of death. All deaths not
attributed to the categories of CV death and not attributed to a non-CV cause were presumed
CV deaths. Death certificates or summary, if possible, were provided for all patients who died,
including date and details surrounding death. However, if a death certificate was the only
information available for review besides the patient profile in the clinical trial database, the CEC
may have decided not to use this information as cause of death if another etiology appeared
more plausible. The following definitions were used for the adjudication of fatal cases:
Sudden cardiac death
Death that occurs unexpectedly in a previously stable patient and includes the following deaths:
•
Witnessed and instantaneous without new or worsening symptoms
•
Witnessed within 60 minutes of the onset of new or worsening cardiac symptoms
•
Witnessed and attributed to an identified arrhythmia (e.g., captured on ECG recording or
witnessed on a monitor by either a medic or paramedic)
•
Subjects unsuccessfully resuscitated from cardiac arrest or successfully resuscitated
from cardiac arrest but who die within 24 hours without identification of a non-cardiac
etiology
•
Unwitnessed death and there is no conclusive evidence of another, non-CV, cause of
death (i.e. presumed CV death)
Sudden death due to acute MI (MI type 3)
Sudden death occurring up to 14 days after a documented acute MI (verified either by the
diagnostic criteria outlined for acute MI or by autopsy findings showing recent MI or recent
coronary thrombus) and where there is no conclusive evidence of another cause of death. If
death occurs before biochemical confirmation of myocardial necrosis can be obtained,
adjudication should be based on clinical presentation and ECG evidence.
Death due to heart failure or cardiogenic shock
Death occurring in the context of clinically worsening symptoms and/or signs of congestive heart
failure (CHF) without evidence of another cause of death.
New or worsening signs and/or symptoms of CHF include any of the following:
•
New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an
increase in, treatment directed at heart failure or occurring in a patient already receiving
maximal therapy for heart failure
•
Heart failure symptoms or signs requiring continuous intravenous therapy or oxygen
administration
•
Confinement to bed predominantly due to heart failure symptoms
•
Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context
of an acute myocardial infarction or as the consequence of an arrhythmia occurring in
the absence of worsening heart failure
•
Cardiogenic shock not occurring in the context of an acute MI or as the consequence of
an arrhythmia occurring in the absence of worsening heart failure
–
Cardiogenic shock is defined as SBP <90 mmHg for more than 1 hour, not
responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary
to cardiac dysfunction and associated with at least one of the following signs of
hypoperfusion:

Cool, clammy skin

Oliguria (urine output < 30 mL/hour)
–

Altered sensorium

Cardiac index < 2.2 L/min/m2
Cardiogenic shock can also be defined in the presence of SBP ≥90 mmHg or for a
time period <1 hour if the blood pressure measurement or the time period is
influenced by the presence of positive inotropic or vasopressor agents alone and/or
with mechanical support <1 hour. The outcome of cardiogenic shock will be based
on CEC assessment and must occur after randomization. Episodes of cardiogenic
shock occurring before and continuing after randomization will not be part of the
study outcome. This category will include sudden death occurring during an
admission for worsening heart failure
Death due to stroke, cerebrovascular event
Death occurring up to 30 days after a stroke that is either due to the stroke or caused by
complication of the stroke.
Death due to other CV causes
Death must be due to a fully documented CV cause not included in the above categories (e.g.
dysrythmia, pulmonary embolism, or CV intervention). Death due to a MI that occurs as a direct
consequence of a CV investigation/procedure/ operation will be classified as death due to other
CV cause.
Non-CV death
Non-CV death is defined as any death not covered by cardiac death or vascular death. The
CEC will be asked to indicate the most likely cause of non-CV death. Examples of non-CV
death are: pulmonary causes, renal causes, gastrointestinal causes, infection (including sepsis),
non-infectious (e.g., systemic inflammatory response syndrome (SIRS)), malignancy (i.e., new
malignancy, worsening of prior malignancy), hemorrhage (not intracranial), accidental/trauma,
suicide, non-CV organ failure (e.g., hepatic failure) or non-CV surgery.
Myocardial infarction (MI) (non-fatal)
The term MI should be used when there is evidence of myocardial necrosis in a clinical setting
consistent with myocardial ischemia. Under these conditions, any one of the following criteria A
to C meets the diagnosis for myocardial infarction.
Criteria A: Spontaneous MI (type 1)
To identify a type 1 MI, patients should demonstrate spontaneous symptoms of myocardial
ischemia unprovoked by supply/demand inequity, together with ≥1 of the following criteria:
•
Cardiac biomarker elevation: Troponin is the preferred marker for use to adjudicate the
presence of acute myocardial infarction. At least one value should show a rise and/or fall
above the lowest cut-point providing 10% imprecision (typically the upper reference limit
for the troponin run per standard of clinical care). Creatine kinase-MB is a secondary
choice to troponin; a rise of CK-MB above the local upper reference limit would be
consistent with myocardial injury
•
ECG changes consistent with new ischemic changes
–
ECG changes indicative of new ischemia (new ST-T changes or new left bundle
branch block [LBBB]) or ECG manifestations of acute myocardial ischemia (in
absence of left ventricular hypertrophy [LVH] and LBBB):
–
Development of pathological Q waves in the ECG

Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads V2
and V3

Q-wave ≥ 0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II,
aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I,
aVL, V6; V4-V6; II, III, and aVF)
–
ST elevation: New ST elevation at the J-point in two contiguous leads with the
cut-off points: ≥0.2 mV in men or ≥ 0.15 mV in women in leads V2-V3 and/or ≥0.1
mV in other leads
–
ST depression and T-wave changes: New horizontal or down-sloping ST
depression ≥0.05 mV in two contiguous leads; and/or T inversion ≥0.1 mV in two
contiguous leads with prominent R-wave or R/S ratio >1
•
Imaging evidence of new non-viable myocardium or new wall motion abnormality
Criteria B: “Demand” related (type 2) MI
•
Patients with type 2 MI should be considered with similar diagnostic criteria as a type 1 MI,
however type 2 MI should be considered present when myocardial ischemia and infarction
are consequent to supply/demand inequity, rather than a spontaneous plaque rupture and
coronary thrombosis.
Criteria C: Percutaneous Coronary Intervention (PCI)-related MI (type 4a/4b)
•
For PCI in patients with normal baseline troponin values, elevations of cardiac biomarkers
above the 99th percentile URL within 24 hours of the procedure are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers >3 x 99th percentile
URL (troponin or CK-MB >3 x 99th percentile URL) are consistent with PCI-related MI.
•
If the cardiac biomarker is elevated prior to PCI, a ≥20% increase of the value in the second
cardiac biomarker sample within 24 hours of PCI and documentation that cardiac biomarker
values were decreasing (two samples ≥6 hours apart) prior to the suspected recurrent MI is
consistent with PCI-related MI.
•
Symptoms of cardiac ischemia are not required.
Criteria D: Coronary Artery Bypass Grafting (CABG)-related MI (type 5)
•
For CABG in patients with normal baseline troponin values, elevation of cardiac biomarkers
above the 99th percentile URL within 72 hours of the procedure is indicative of periprocedural myocardial necrosis. By convention, an increase of biomarkers >5 x 99th
percentile URL (troponin or CK-MB >5 x 99th percentile URL) plus at least one of the
following
–
New pathological Q waves in at least 2 contiguous leads on the electrocardiogram
that persist through 30 days or new LBBB
–
Angiographically documented new graft or native coronary artery occlusion
–
Imaging evidence of new loss of viable myocardium is consistent with CABG-related
MI
•
If the cardiac biomarker is elevated prior to CABG, a ≥20% increase of the value in the
second cardiac biomarker sample within 72 hours of CABG and documentation that cardiac
biomarker values were decreasing (two samples ≥6 hours apart) prior to the suspected
recurrent MI plus new pathological Q waves in ≥2 contiguous leads on the
electrocardiogram or new LBBB, angiographically documented new graft or native coronary
artery occlusion, or imaging evidence of new loss of viable myocardium is consistent with a
periprocedural MI after CABG. Symptoms of cardiac ischemia are not required.
Clinical classification of acute MI
For every MI identified by the CEC, one of the following will be assigned:
•
Type 1: Spontaneous MI related to ischemia due to a primary coronary event such as
plaque erosion and/or rupture, fissuring, or dissection
•
Type 2: MI secondary to ischemia due to either increased oxygen demand or decreased
supply, e.g. coronary artery spasm, coronary embolism, anemia, arrhythmias, hypertension,
or hypotension
•
Type 3: Sudden unexpected cardiac death, including cardiac arrest, often with symptoms
suggestive of myocardial ischemia, accompanied by presumably new ST elevation, or new
LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy,
but death occurring before blood samples could be obtained, or at a time before the
appearance of cardiac biomarkers in the blood
•
Type 4a: MI associated with PCI
•
Type 4b: MI associated with stent thrombosis as documented by angiography or at autopsy
•
Type 5: MI associated with CABG
The date of this event is the day of hospitalization of the patient including any overnight stay at
an emergency room or chest pain unit. Unstable angina requiring hospitalization is defined as all
of the following:
•
No elevation in cardiac biomarkers (cardiac biomarkers are negative for myocardial
necrosis) according to conventional assays or contemporary sensitive assays
•
Clinical presentation: Cardiac symptoms lasting ≥10 minutes and considered to be
myocardial ischemia on final diagnosis with one of the following:
–
Rest angina
–
New-onset (<2 months) severe angina (Canadian Cardiovascular Society [CCS]
Grading Scale, or CCS classification system, classification severity ≥III)
–
Increasing angina (in intensity, duration, and/or frequency) with an increase in
severity of >1 CCS class to CCS class >III
•
Requiring an unscheduled visit to a healthcare facility and overnight admission
•
At least one of the following:
–
New or worsening ST or T wave changes on ECG. ECG changes should satisfy the
following criteria for acute myocardial ischemia in the absence of LVH and LBBB:

ST elevation: New transient (known to be <20 minutes) ST elevation at the Jpoint in two contiguous leads with the cut-off points - ≥0.2 mV in men or
≥0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads

ST depression and T-wave changes: New horizontal or down-sloping ST
depression ≥ 0.05 mV in two contiguous leads; and/or T inversion ≥0.1 mV in
two contiguous leads with prominent R-wave or R/S ratio >1
–
Evidence of ischemia on stress testing with cardiac imaging
–
Evidence of ischemia on stress testing with angiographic evidence of ≥70% lesion
and/or thrombus in an epicardial coronary artery or initiation/increased dosing of
antianginal therapy
–
Angiographic evidence of ≥70% lesion and/or thrombus in an epicardial coronary
artery
Stent thrombosis
Timing
Class
Description of stage
Class I
“Ordinary physical activity does not cause . . . angina,” such as walking or
climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at
work or recreation
Class II
“Slight limitation of ordinary activity.” Angina occurs on walking or climbing stairs
rapidly; walking uphill; walking or stair climbing after meals; in cold, in wind, or
under emotional stress; or only during the few hours after awakening. Angina
occurs on walking more than 2 blocks on the level and climbing more than 1 flight
of ordinary stairs at a normal pace and under normal conditions
Class III
“Marked limitations of ordinary physical activity.” Angina occurs on walking 1 to 2
blocks on the level and climbing 1 flight of stairs under normal conditions and at a
normal pace
Class IV
“Inability to carry on any physical activity without discomfort—anginal symptoms
may be present at rest”
Type
Timing
Early stent
Acute stent thrombosis
0 to 24 hours after stent implantation
thrombosis
Subacute stent
>24 hours to 30 days after stent implantation
thrombosis
Late stent thrombosis*
>30 days to 1 year after stent implantation
Very late stent thrombosis*
>1 year after stent implantation
Stent thrombosis should be reported as a cumulative value over time and at the various
individual time points specified above. Time 0 is defined as the time point after the guiding
catheter has been removed and the patient has left the catheterization laboratory
*Includes primary as well as secondary late stent thrombosis; secondary late stent thrombosis is
a stent thrombosis after a target lesion revascularization
Definitions of definite, probable, and possible stent thrombosis
Definite stent thrombosis is considered to have occurred by either angiographic or pathological
confirmation:
•
Angiographic confirmation of stent thrombosis: The presence of an intracoronary thrombus
that originates in the stent or in the segment 5 mm proximal or distal to the stent and
presence of ≥1 of the following criteria within a 48-hour time window:
–
Acute onset of ischemic symptoms at rest
–
New ischemic ECG changes that suggest acute ischemia
–
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI:
troponin or CK-MB >99th percentile of URL, according to conventional assays or
contemporary sensitive assays)
–
Non-occlusive thrombus Intracoronary thrombus is defined as a (spheric, ovoid, or
irregular) noncalcified filling defect or lucency surrounded by contrast material (on 3
sides or within a coronary stenosis) seen in multiple projections, or persistence of
contrast material within the lumen, or a visible embolization of intraluminal material
downstream
–
Occlusive thrombus TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most
adjacent proximal side branch or main branch (if originates from the side branch)
NOTE: The incidental angiographic documentation of stent occlusion in the absence of clinical
signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion)
•
Pathological confirmation of stent thrombosis Evidence of recent thrombus within the stent
determined at autopsy or via examination of tissue retrieved following thrombectomy
Probable Stent Thrombosis is considered to have occurred after intracoronary stenting in the
following cases:
•
Any unexplained death within the first 30 days
–
In ST-elevation MI population, one may consider the exclusion of unexplained death
within 30 days as evidence of probable stent thrombosis
•
Irrespective of the time after the index procedure, any MI that is related to documented
acute ischemia in the territory of the implanted stent without angiographic confirmation of
stent thrombosis and in the absence of any other obvious cause
Possible Stent Thrombosis is considered to have occurred with any unexplained death from 30
days after intracoronary stenting until end of trial follow-up.
Heart Failure (HF) requiring hospitalization
The date of this event is the day of hospitalization of the patient including any overnight stay at
an emergency room or chest pain unit. HF requiring hospitalization is defined as an event that
meets all of the following criteria:
•
Requires hospitalization defined as an admission to an inpatient unit or a visit to an
emergency department that results in at least a 12-hour stay (or a date change if the time of
admission/discharge is not available)
•
Clinical manifestations of heart failure (new or worsening) including at least one of the
following:
•
–
Dyspnea
–
Orthopnea
–
Paroxysmal nocturnal dyspnea
–
Edema
–
Pulmonary basilar crackles
–
Jugular venous distension
–
Third heart sound or gallop rhythm
–
Radiological evidence of worsening heart failure
Additional/increased therapy: at least one of the following:
–
Initiation of oral diuretic, intravenous diuretic, inotrope, or vasodilator therapy
–
Uptitration of oral diuretic or intravenous therapy, if already on therapy
–
Initiation of mechanical or surgical intervention (mechanical circulatory support, heart
transplantation or ventricular pacing to improve cardiac function), or the use of
ultrafiltration, hemofiltration, or dialysis that is specifically directed at treatment of
heart failure
Changes in biomarker (e.g., brain natriuretic peptide) consistent with CHF will support this
diagnosis.
Either CABG or PCI (e.g., angioplasty, coronary stenting).
•
CABG: the successful placement of ≥1 conduit with either a proximal and distal anastomosis
or a distal anastomosis only
•
PCI: Successful balloon inflation with or without stenting and the achievement of a residual
stenosis <50%. The balloon inflation and/or stenting could have been preceded by device
activation (e.g., angiojet, directional coronary atherectomy, or rotational atherectomy)
In cases where the procedure leads to a MI (type 4a, 4b or 5) the event will be adjudicated as
an MI.
Transient Ischemic Attack (TIA)
TIA: a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal
ischemia, without acute infarction.
Stroke
Stroke: the rapid onset of a new persistent neurologic deficit attributed to an obstruction in
cerebral blood flow and/or cerebral hemorrhage with no apparent non-vascular cause (e.g.,
trauma, tumor, or infection). Available neuroimaging studies are considered to support the
clinical impression and to determine if there is a demonstrable lesion compatible with an acute
stroke. Strokes are classified as ischemic, hemorrhagic, or unknown.
Diagnosis of stroke.
For the diagnosis of stroke, the following 4 criteria should be fulfilled:
•
Rapid onset of a focal/global neurological deficit with at least one of the following:
–
Change in level of consciousness
–
Hemiplegia
–
Hemiparesis
–
Numbness or sensory loss affecting one side of the body
–
Dysphasia/aphasia
–
Hemianopia (loss of half of the field of vision of one or both eyes)
–
Other new neurological sign(s)/symptom(s) consistent with stroke
NOTE: If the mode of onset is uncertain, a diagnosis of stroke may be made provided that there
is no plausible non-stroke cause for the clinical presentation
•
Duration of a focal/global neurological deficit ≥24 hours OR < 24 hours if this is because of
at least one of the following therapeutic interventions:
–
Pharmacologic (i.e., thrombolytic drug administration)
–
Non-pharmacologic (i.e., neurointerventional procedure [e.g. intracranial
angioplasty])
OR
–
Available brain imaging clearly documents a new hemorrhage or infarct
–
The neurological deficit results in death
OR
•
No other readily identifiable non-stroke cause for the clinical presentation (e.g., brain tumor,
trauma, infection, hypoglycemia, peripheral lesion)
•
Confirmation of the diagnosis by at least one of the following:*
–
Neurology or neurosurgical specialist
–
–
Brain imaging procedure (at least one of the following):

CT scan

MRI scan

Cerebral vessel angiography
Lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial hemorrhage)
If a stroke is reported but evidence of confirmation of the diagnosis by the methods outlined
above is absent, the event will be discussed at a full CEC meeting. In such cases, the event
may be adjudicated as a stroke on the basis of the clinical presentation alone, but full CEC
consensus is mandatory.
If the acute focal signs represent a worsening of a previous deficit, these signs must have either
•
Persisted for more than one week
OR
•
Persisted for more than 24 hours and were accompanied by an appropriate new CT or MRI
finding
Classification of stroke
Strokes are sub-classified as follows:
•
Ischemic (non-hemorrhagic): A stroke caused by an arterial obstruction due to a thrombotic
(e.g., large vessel disease/atherosclerotic or small vessel disease/lacunar) or embolic
etiology. This category includes ischemic strokes with hemorrhagic transformation (i.e. no
evidence of hemorrhage on an initial imaging study but appearance on a subsequent scan)
•
Hemorrhagic: A stroke due to a hemorrhage in the brain as documented by neuroimaging or
autopsy. This category includes strokes due to primary intracerebral hemorrhage
(intraparenchymal or intraventricular) and primary subarachnoid hemorrhage
•
Not assessable: The stroke type could not be determined by imaging or other means (e.g.,
lumbar puncture, neurosurgery, or autopsy) or no imaging was performed
Section F. Sensitivity analyses and subgroup analyses (methodology)
Sensitivity analyses were conducted in patients who received ≥1 dose of study drug including
only events observed ≤30 days after a patient’s last intake of trial medication, in patients who
received study drug for ≥30 days (cumulative) including only events that occurred ≤30 days after
a patient’s last intake of trial medication (on treatment set), and in patients treated with ≥1 dose
of study drug who did not have important protocol violations (per-protocol set; for primary
outcome only).
Subgroup analyses were performed in subgroups by baseline age, sex, race, ethnicity, region,
glycated hemoglobin, body mass index, blood pressure control, estimated glomerular filtration
rate according to the Modification of Diet in Renal Disease equation, urine albumin-to-creatinine
ratio, cardiovascular risk factors, use of glucose-lowering medication, use of statins/ezetimibe,
use of anti-hypertensive therapy, and use of acetylsalicylic acid.
Section G. Patient disposition
Figure S1. Patient disposition.
Section H. Reasons for premature discontinuation from study medication
Table S1. Reasons for premature discontinuation from study medication
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
Pooled empagliflozin
no. (%)
Treated
2333 (100.0)
2345 (100.0)
2342 (100.0)
4687 (100.0)
683 (29.3)
555 (23.7)
542 (23.1)
1097 (23.4)
Adverse event
303 (13.0)
267 (11.4)
273 (11.7)
540 (11.5)
Refusal to continue, not due to adverse event
172 (7.4)
118 (5.0)
122 (5.2)
240 (5.1)
Non-compliant with protocol
15 (0.6)
15 (0.6)
12 (0.5)
27 (0.6)
Lost to follow up
15 (0.6)
9 (0.4)
6 (0.3)
15 (0.3)
Lack of efficacy*
11 (0.5)
1 (<0.1)
0
1 (<0.1)
Other
162 (6.9)
142 (6.1)
125 (5.3)
267 (5.7)
5 (0.2)
3 (0.1)
4 (0.2)
7 (0.1)
Prematurely discontinued from trial medication
Missing
*Hyperglycemia above the protocol-defined level despite intensification or addition of glucose-lowering therapy.
Section I. Baseline characteristics
Table S2. Baseline characteristics
Characteristic*
Age – years
Male – no. (%)
Race – no. (%)
White
Asian
Black/African-American
Other/Missing
Ethnicity – no. (%)
Not Hispanic or Latino
Hispanic or Latino
Missing
Region – no. (%)
Europe
North America (plus Australia and New Zealand)
Asia
Latin America
Africa
Weight – kg
2†
Body mass index – kg/m
CV risk factor – no. (%)
Coronary artery disease
Multi-vessel coronary artery disease
History of myocardial infarction
Coronary artery bypass graft
‡
History of stroke
Peripheral artery disease
‡
Single vessel coronary artery disease
§
Cardiac failure
¶
Glycated hemoglobin – %
Time since diagnosis of type 2 diabetes – no. (%)
Placebo
(N = 2333)
63.2 ± 8.8
1680 (72.0)
Empagliflozin 10 mg
(N = 2345)
63.0 ± 8.6)
1653 (70.5)
Empagliflozin 25 mg
(N = 2342)
63.2 ± 8.6)
1683 (71.9)
(N = 4687)
63.1 ± 8.6
3336 (71.2)
1678 (71.9)
511 (21.9)
120 (5.1)
24 (1.0)
1707 (72.8)
505 (21.5)
119 (5.1)
14 (0.6)
1696 (72.4)
501 (21.4)
118 (5.0)
27 (1.2)
3403 (72.6)
1006 (21.5)
237 (5.1)
41 (0.9)
1912 (82.0)
418 (17.9)
3 (0.1)
1909 (81.4)
432 (18.4)
4 (0.2)
1926 (82.2)
415 (17.7)
1 (<0.1)
3835 (81.8)
847 (18.1)
5 (0.1)
959 (41.1)
462 (19.8)
450 (19.3)
360 (15.4)
102 (4.4)
86.6 ± 19.1
30.7 ± 5.2
2307 (98.9)
1763 (75.6)
1100 (47.1)
1083 (46.4)
563 (24.1)
553 (23.7)
479 (20.5)
238 (10.2)
244 (10.5)
8.08 ± 0.84
966 (41.2)
466 (19.9)
447 (19.1)
359 (15.3)
107 (4.6)
85.9 ± 18.8
30.6 ± 5.2
2333 (99.5)
1782 (76.0)
1078 (46.0)
1107 (47.2)
594 (25.3)
535 (22.8)
465 (19.8)
258 (11.0)
240 (10.2)
8.07 ± 0.86
960 (41.0)
466 (19.9)
450 (19.2)
362 (15.5)
104 (4.4)
86.5 ± 19.0
30.6 ± 5.3
2324 (99.2)
1763 (75.3)
1101 (47.0)
1083 (46.2)
581 (24.8)
549 (23.4)
517 (22.1)
240 (10.2)
222 (9.5)
8.06 ± 0.84
1926 (41.1)
932 (19.9)
897 (19.1)
721 (15.4)
211 (4.5)
86.2 ± 18.9
30.6 ± 5.3
4657 (99.4)
3545 (75.6)
2179 (46.5)
2190 (46.7)
1175 (25.1)
1084 (23.1)
982 (21.0)
498 (10.6)
462 (9.9)
8.07 ± 0.85
≤1 years
>1 to 5 years
>5 to 10 years
52 (2.2)
371 (15.9)
571 (24.5)
68 (2.9)
338 (14.4)
585 (24.9)
60 (2.6)
374 (16.0)
590 (25.2)
128 (2.7)
712 (15.2)
1175 (25.1)
>10 years
Glucose-lowering therapy – no. (%)
Medication taken alone or in combination
Metformin
Insulin
‖
Median daily dose – IU
1339 (57.4)
1354 (57.7)
1318 (56.3)
2672 (57.0)
1734 (74.3)
1135 (48.6)
52.0
1729 (73.7)
1132 (48.3)
52.5
1730 (73.9)
1120 (47.8)
54.0
3459 (73.8)
2252 (48.0)
54.0
Sulfonylurea
Dipeptidyl peptidase-4 inhibitor
Thiazolidinedione
Glucagon-like peptide-1 agonist
Monotherapy
Dual therapy
Anti-hypertensive therapy – no. (%)
Angiotensin-converting enzyme
inhibitors/angiotensin receptor blockers
Beta-blockers
Diuretics
Calcium channel blockers
Mineralocorticoid receptor antagonists
Renin inhibitors
Other
Lipid-lowering therapy – no. (%)
Statins
Fibrates
Ezetimibe
Niacin
Other
Anti-coagulants – no. (%)
Acetylsalicylic acid
992 (42.5)
267 (11.4)
101 (4.3)
70 (3.0)
691 (29.6)
1148 (49.2)
985 (42.0)
282 (12.0)
96 (4.1)
68 (2.9)
704 (30.0)
1110 (47.3)
1029 (43.9)
247 (10.5)
102 (4.4)
58 (2.5)
676 (28.9)
1149 (49.1)
2014 (43.0)
529 (11.3)
198 (4.2)
126 (2.7)
1380 (29.4)
2259 (48.2)
2221 (95.2)
1868 (80.1)
2227 (95.0)
1896 (80.9)
2219 (94.7)
1902 (81.2)
4446 (94.9)
3798 (81.0)
1498 (64.2)
988 (42.3)
788 (33.8)
136 (5.8)
19 (0.8)
191 (8.2)
1864 (79.9)
1773 (76.0)
199 (8.5)
81 (3.5)
35 (1.5)
175 (7.5)
2090 (89.6)
1927 (82.6)
1530 (65.2)
1036 (44.2)
781 (33.3)
157 (6.7)
16 (0.7)
193 (8.2)
1926 (82.1)
1827 (77.9)
214 (9.1)
95 (4.1)
56 (2.4)
172 (7.3)
2098 (89.5)
1939 (82.7)
1526 (65.2)
1011 (43.2)
748 (31.9)
148 (6.3)
11 (0.5)
190 (8.1)
1894 (80.9)
1803 (77.0)
217 (9.3)
94 (4.0)
35 (1.5)
193 (8.2)
2064 (88.1)
1937 (82.7)
3056 (65.2)
2047 (43.7)
1529 (32.6)
305 (6.5)
27 (0.6)
383 (8.2)
3820 (81.5)
3630 (77.4)
431 (9.2)
189 (4.0)
91 (1.9)
365 (7.8)
4162 (88.8)
3876 (82.7)
Clopidogrel
249 (10.7)
253 (10.8)
241 (10.3)
494 (10.5)
Vitamin K antagonists
156 (6.7)
141 (6.0)
125 (5.3)
266 (5.7)
Systolic blood pressure – mmHg
135.8 ± 17.2
134.9 ± 16.8
135.6 ± 17.0
135.3 ± 16.9
Diastolic blood pressure – mmHg
76.8 ± 10.1
76.6 ± 9.8
76.6 ± 9.7
76.6 ± 9.7
Total cholesterol – mg/dL**
161.9 ± 43.1
163.7 ± 45.2
163.3 ± 43.2
163.5 ± 44.2
††
Low density lipoprotein cholesterol – mg/dL
84.9 ± 35.3
86.3 ± 36.7
85.5 ± 35.2
85.9 ± 36.0
High density lipoprotein cholesterol – mg/dL**
44.0 ± 11.3
44.7 ± 12.0
44.5 ± 11.8
44.6 ± 11.9
Triglycerides – mg/dL**
170.7 ± 121.2
168.4 ± 127.3
172.6 ± 132.0
170.5 ± 129.7
2‡‡
Estimated glomerular filtration rate – mL/min/1.73m
73.8 ± 21.1
74.3 ± 21.8
74.0 ± 21.4
74.2 ± 21.6
‡‡
Estimated glomerular filtration rate – no. (%)
2
≥90 mL/min/1.73m
488 (20.9)
519 (22.1)
531 (22.7)
1050 (22.4)
2
60 to <90 mL/min/1.73m
1238 (53.1)
1221 (52.1)
1202 (51.3)
2423 (51.7)
2
<60 mL/min/1.73m
607 (26.0)
605 (25.8)
607 (25.9)
1212 (25.9)
§§
Urine albumin-to-creatinine ratio – no. (%)
<30 mg/g
1382 (59.2)
1405 (59.9)
1384 (59.1)
2789 (59.5)
30 to 300 mg/g
675 (28.9)
645 (27.5)
693 (29.6)
1338 (28.5)
>300 mg/g
260 (11.1)
261 (11.1)
248 (10.6)
509 (10.9)
* Plus–minus values are means ± SD.
† Body mass index is the weight in kilograms divided by the square of the height in meters.
‡ Information was not available for one patient in the placebo group.
§ Based on the narrow standard MedDRA query ‘cardiac failure’.
¶ Data were available for 2333 patients in the placebo group, 2344 patients in the empagliflozin 10 mg group, 2341 patients in the empagliflozin
25 mg group.
‖ Data were not available for 18 patients in the placebo group, 10 patients in the empagliflozin 10 mg group and 14 patients in the empagliflozin
25 mg group.
** Data were available for 2309 patients in the placebo group, 2318 patients in the empagliflozin 10 mg group, 2308 patients in the empagliflozin
25 mg group. Conversion factor: 1 mg/dL = 0.02586 mmol/L for cholesterol and 1 mg/dL = 0.01129 mmol/L for triglycerides.
†† Data were available for 2309 patients in the placebo group, 2317 patients in the empagliflozin 10 mg group, 2306 patients in the empagliflozin
25 mg group. 1 mg/dL = 0.02586 mmol/L.
‡‡ Data were not available for 2 patients in the empagliflozin 25 mg group. The estimated glomerular filtration rate was calculated using the
Modification of Diet in Renal Disease formula.
§§ Data were not available for 16 patients in the placebo group, 34 patients in the empagliflozin 10 mg group, 17 patients in the empagliflozin 25
mg group.
There were no significant differences (p<0.05) between pooled empagliflozin and placebo based on Chi-square test for binary/categorical
variables, t-test for continuous variables, and Wilcoxon rank sum test for insulin dose.
Section J. Treatment and observation times
Table S3. Treatment and observation times
Treatment – years
Median (interquartile range)
Mean
Observation – years
Median (interquartile range)
Mean
Placebo
(N = 2333)
(N = 4687)
2.6 (1.8–3.4)
2.5
2.6 (2.0–3.4)
2.6
3.1 (2.2–3.5)
2.9
3.2 (2.2–3.6)
3.0
Section K. Absolute reductions in incidence rates for cardiovascular outcomes.
Table S4. Absolute reductions in incidence rates for 3-point MACE, all-cause mortality,
cardiovascular death, hospitalization for heart failure and heart failure hospitalization or
cardiovascular death.
Placebo
Empagliflozin
(N = 2333)
(N = 4687)
Rate difference
Rate/1000
Rate/1000
(95% CI)
patient-years
patient-years
43.9
37.4
-6.5 (-12.6, -0.4)
0.04
All-cause mortality
28.6
19.4
-9.1 (-13.8, -4.5)
<0.001
20.2
12.4
-7.7 (-11.6, -3.9)
<0.001
14.5
9.4
-5.1 (-8.4, -1.8)
0.003
Heart failure hospitalization or
30.1
19.7
-10.5 (-15.3, -5.6)
<0.001
Cardiovascular death, non-fatal
p-value
myocardial infarction, or non-fatal
stroke (3-point MACE): primary
outcome
cardiovascular death (excluding
fatal stroke)
Section L. Categories of cardiovascular death
Table S5. Categories of cardiovascular death.
Placebo
Empagliflozin
Empagliflozin
Pooled
(N = 2333)
10 mg
25 mg
empagliflozin
(N = 2345)
(N = 2342)
(N = 4687)
no. (%)
Patients with cardiovascular
137 (5.9)
90 (3.8)
82 (3.5)
172 (3.7)
Sudden death
38 (1.6)
30 (1.3)
23 (1.0)
53 (1.1)
Worsening of heart failure
19 (0.8)
7 (0.3)
4 (0.2)
11 (0.2)
Acute myocardial infarction
11 (0.5)
6 (0.3)
9 (0.4)
15 (0.3)
Stroke
11 (0.5)
9 (0.4)
7 (0.3)
16 (0.3)
Cardiogenic shock
3 (0.1)
1 (<0.1)
2 (0.1)
3 (0.1)
Other cardiovascular death
55 (2.4)
37 (1.6)
37 (1.6)
74 (1.6)
death
Section M. Cardiovascular outcomes with empagliflozin 10 mg and 25 mg
Figure S2. Time to first occurrence of cardiovascular outcomes and all-cause mortality.
Cumulative incidence function for the primary outcome (Panel A), cumulative incidence
function for cardiovascular death (Panel B), Kaplan-Meier estimate for all-cause
mortality (Panel C) and cumulative incidence function for hospitalization for heart failure
(Panel D) in the empagliflozin and placebo groups based on patients treated with ≥1
dose of study drug. Hazard ratios are based on Cox regression analyses.
A. Primary outcome (3-point MACE)
B. Cardiovascular death
C. All-cause mortality
D. Hospitalization for heart failure
Table S6. Cardiovascular outcomes with empagliflozin 10 mg and empagliflozin 25 mg
Placebo
(N = 2333)
Empagliflozin 10 mg Empagliflozin 25 mg
(N = 2345)
(N = 2342)
no. (%)
Cardiovascular death, non-fatal myocardial
282 (12.1)
243 (10.4)
247 (10.5)
0.85 (0.72, 1.01)
0.86 (0.73, 1.02)
0.07
0.09
300 (12.8)
299 (12.8)
0.89 (0.76, 1.04)
0.88 (0.76, 1.03)
0.15
0.12
90 (3.8)
82 (3.5)
0.65 (0.50, 0.85)
0.59 (0.45, 0.77)
0.002
<0.001
137 (5.8)
132 (5.6)
0.70 (0.56, 0.87)
0.67 (0.54, 0.83)
0.001
<0.001
101 (4.3)
122 (5.2)
0.79 (0.61, 1.03)
0.95 (0.74, 1.22)
0.09
0.71
19 (1.6)
19 (1.6)
1.32 (0.67, 2.60)
1.24 (0.63, 2.45)
0.42
0.53
96 (4.1)
117 (5.0)
0.79 (0.60,1.03)
0.95 (0.74,1.23)
0.08
0.71
69 (2.9)
64 (2.7)
1.03 (0.74, 1.45)
0.96 (0.68, 1.35)
0.85
0.80
154 (6.6)
175 (7.5)
infarction, or non-fatal stroke (3-point MACE):
primary outcome
Hazard ratio (95% CI)
p-value
Cardiovascular death, non-fatal myocardial
333 (14.3)
infarction, non-fatal stroke, or hospitalization
for unstable angina (4-point MACE): key
secondary outcome
p-value
137 (5.9)
p-value
All-cause mortality
194 (8.3)
p-value
Fatal and non-fatal myocardial infarction
126 (5.4)
(excluding silent myocardial infarction)
p-value
Silent myocardial infarction*
15 (1.2)
p-value
Non-fatal myocardial infarction
121 (5.2)
p-value
66 (2.8)
p-value
186 (8.0)
p-value
Fatal and non-fatal stroke
69 (3.0)
p-value
Non-fatal stroke
60 (2.6)
p-value
Transient ischemic attack
23 (1.0)
p-value
95 (4.1)
p-value
Heart failure hospitalization or cardiovascular
198 (8.5)
0.81 (0.65, 1.00)
0.92 (0.75, 1.13)
0.05
0.42
85 (3.6)
79 (3.4)
1.22 (0.89, 1.68)
1.13 (0.82, 1.56)
0.21
0.46
77 (3.3)
73 (3.1)
1.27 (0.91, 1.79)
1.20 (0.85, 1.69)
0.16
0.30
19 (0.8)
20 (0.9)
0.83 (0.45, 1.53)
0.87 (0.48, 1.58)
0.56
0.64
60 (2.6)
66 (2.8)
0.62 (0.45, 0.86)
0.68 (0.50, 0.93)
0.004
0.02
133 (5.7)
132 (5.6)
0.66 (0.53, 0.83)
0.65 (0.52, 0.81)
<0.001
<0.001
death (excluding fatal stroke)
p-value
Based on Cox regression analyses in patients treated with ≥1 dose of study drug.
* Analyzed in 1211 patients in the placebo group, 1174 patients in the empagliflozin 10 mg group and
1204 patients in the empagliflozin 25 mg group.
Section N. Subgroup analyses for the primary outcome and for cardiovascular
death
Table S7. Hazard ratios for the primary outcome in subgroups.
Patients with event/
patients analyzed
All patients
Age
<65 years
≥65 years
Sex
Male
Female
Race
White
Asian
Ethnicity
Hispanic/Latino
Not Hispanic/Latino
Region
Europe
North America
Latin America
Africa
Asia
Glycated hemoglobin
<8.5%
≥8.5%
Body mass index
2
<30 kg/m
2
≥30 kg/m
SBP ≥140 mmHg and/or
DBP ≥90 mmHg
SBP <140 mmHg and
DBP <90 mmHg
Estimated glomerular
filtration rate
2
≥90 mL/min/1.73m
2
60 to <90 mL/min/1.73m
2
<60 mL/min/1.73m
Urine albumin-tocreatinine ratio
<30 mg/g
30 to 300 mg/g
>300 mg/g
Cardiovascular risk
Only cerebrovascular
disease
Hazard
ratio
(95% CI)
Empagliflozin
Placebo
490/4687
282/2333
0.86
(0.74, 0.99)
251/2596
239/2091
121/1297
161/1036
1.04
0.71
(0.84, 1.29)
(0.59, 0.87)
367/3336
123/1351
212/1680
70/653
0.87
0.83
(0.73, 1.02)
(0.62, 1.11)
366/3403
79/1006
39/237
205/1678
58/511
14/120
0.88
0.68
1.48
(0.74, 1.04)
(0.48, 0.95)
(0.80, 2.72)
70/847
420/3835
52/418
230/1912
0.63
0.91
(0.44, 0.90)
(0.77, 1.07)
226/1926
114/932
53/721
26/211
71/897
112/959
63/462
43/360
14/102
50/450
1.02
0.89
0.58
0.86
0.70
(0.81, 1.28)
(0.65, 1.21)
(0.39, 0.86)
(0.45, 1.65)
(0.49, 1.01)
322/3212
168/1475
209/1607
73/726
0.76
1.14
(0.64, 0.90)
(0.86, 1.50)
225/2279
265/2408
148/1120
134/1213
0.74
0.98
(0.60, 0.91)
(0.80, 1.21)
214/1780
131/934
0.83
(0.66, 1.03)
276/2907
151/1399
0.89
(0.73, 1.08)
p-value for
interaction
0.01
0.81
0.09
0.07
0.13
0.01
0.06
0.65
0.20
102/1050
212/2425
176/1212
44/488
139/1238
99/607
1.10
0.76
0.88
(0.77, 1.57)
(0.61, 0.94)
(0.69, 1.13)
0.40
241/2789
158/1338
86/509
134/1382
90/675
58/260
0.89
0.89
0.69
(0.72, 1.10)
(0.69, 1.16)
(0.49, 0.96)
65/635
29/325
1.15
(0.74, 1.78)
0.53
Only coronary artery
disease
Only peripheral artery
disease
2 or 3 high
cardiovascular risk
categories
Metformin
No
Yes
Sulfonylurea
No
Yes
Insulin
No
Yes
Thiazolidinediones
No
Yes
DPP-4 inhibitor
No
Yes
Statins/ezetimibe
No
Yes
Antihypertensives
No
Yes
Angiotensin-converting
enzyme inhibitors/
angiotensin receptor
blockers
No
Yes
Calcium channel
blockers
No
Yes
Beta blockers
No
Yes
Diuretics
No
Yes
No
Yes
261/2732
152/1340
0.83
(0.68, 1.02)
25/412
12/191
0.94
(0.47, 1.88)
137/878
87/451
0.79
(0.61, 1.04)
0.14
146/1228
344/3459
93/599
189/1734
0.72
0.92
(0.56, 0.94)
(0.77, 1.10)
0.83
295/2673
195/2014
173/1341
109/992
0.85
0.87
(0.70, 1.02)
(0.69, 1.11)
225/2435
265/2252
140/1198
142/1135
0.79
0.93
(0.64, 0.97)
(0.75, 1.13)
0.28
0.44
467/4489
23/198
271/2232
11/101
0.85
1.13
(0.73, 0.98)
(0.55, 2.31)
423/4158
67/529
254/2066
28/267
0.81
1.27
(0.70, 0.95)
(0.82, 1.98)
0.06
0.22
106/1029
384/3658
71/551
211/1782
0.79
0.88
(0.59, 1.07)
(0.74, 1.04)
21/241
469/4446
11/112
271/2221
0.94
0.85
(0.45, 1.95)
(0.73, 0.99)
0.80
0.49
91/889
399/3798
61/465
221/1868
0.77
0.88
(0.56, 1.07)
(0.75, 1.04)
0.71
321/3158
169/1529
179/1545
103/788
0.87
0.83
(0.73, 1.05)
(0.65, 1.06)
0.61
159/1631
331/3056
90/835
192/1498
0.90
0.83
(0.70, 1.17)
(0.70, 1.00)
228/2640
262/2047
138/1345
144/988
0.83
0.88
(0.67, 1.02)
(0.71, 1.07)
0.72
0.66
88/811
402/3876
53/406
229/1927
0.80
0.87
(0.57, 1.12)
(0.74, 1.02)
Cox regression analysis in patients treated with ≥1 dose of study drug. Subgroup factors were prespecified for the primary outcome.
p-value is for test of homogeneity of the treatment group difference among subgroups (test for group by
covariate interaction) with no adjustment for multiple tests.
Table S8. Hazard ratios for cardiovascular death in subgroups.
All patients
Age
<65 years
≥65 years
Sex
Male
Female
Race
White
Asian
Ethnicity
Hispanic/Latino
Not Hispanic/Latino
Region
Europe
North America plus
Australia and New
Zealand
Latin America
Africa
Asia
Glycated hemoglobin
<8.5%
≥8.5%
Body mass index
2
<30 kg/m
2
≥30 kg/m
SBP ≥140 mmHg and/or
DBP ≥90 mmHg
SBP <140 mmHg and
DBP <90 mmHg
Estimated glomerular
filtration rate
2
≥90 mL/min/1.73m
2
60 to <90 mL/min/1.73m
2
<60 mL/min/1.73m
Urine albumin-tocreatinine ratio
<30 mg/g
≥30 to 300 mg/g
>300 mg/g
Cardiovascular risk
Only cerebrovascular
disease
Only coronary artery
disease
Only peripheral artery
Patients with event/
patients analyzed
Empagliflozin
Placebo
172/4687
137/2333
Hazard
ratio
(95% CI)
0.62
(0.49, 0.77)
p-value for
interaction
0.21
85/2596
87/2091
59/1297
78/1036
0.72
0.54
(0.52, 1.01)
(0.40, 0.73)
125/3336
47/1351
107/1680
30/653
0.58
0.76
(0.45, 0.75)
(0.48, 1.20)
134/3403
22/1006
13/237
102/1678
25/511
9/120
0.64
0.44
0.77
(0.50, 0.83)
(0.25, 0.78)
(0.33, 1.79)
31/847
141/3835
28/418
109/1912
0.53
0.64
(0.32, 0.88)
(0.50, 0.83)
80/1926
40/932
56/959
25/462
0.72
0.81
(0.51, 1.01)
(0.49, 1.33)
22/721
12/211
18/897
24/360
7/102
25/450
0.43
0.80
0.35
(0.24, 0.77)
(0.31, 2.03)
(0.19, 0.65)
114/3212
58/1475
96/1607
41/726
0.59
0.69
(0.45, 0.77)
(0.46, 1.03)
80/2279
92/2408
78/1120
59/1213
0.50
0.78
(0.37, 0.68)
(0.56, 1.08)
72/1780
65/934
0.56
(0.40, 0.79)
100/2907
72/1399
0.67
(0.50, 0.91)
0.32
0.43
0.49
0.15
0.51
0.05
0.44
0.15
28/1050
69/2425
75/1212
19/488
70/1238
48/607
0.70
0.49
0.78
(0.39, 1.25)
(0.35, 0.68)
(0.54, 1.12)
0.22
81/2789
48/1338
42/509
52/1382
49/675
36/260
0.77
0.49
0.55
(0.55, 1.10)
(0.33, 0.74)
(0.35, 0.86)
21/635
15/325
0.72
(0.37, 1.39)
90/2732
63/1340
0.69
(0.50, 0.95)
13/412
7/191
0.85
(0.34, 2.13)
0.39
disease
2 or 3 high
cardiovascular risk
categories
Metformin
No
Yes
Sulfonylurea
No
Yes
Insulin
No
Yes
Thiazolidinediones*
No
Yes
DPP-4 inhibitor
No
Yes
46/878
50/451
0.47
(0.31, 0.70)
54/1228
118/3459
53/599
84/1734
0.46
0.71
(0.32, 0.68)
(0.54, 0.94)
105/2673
67/2014
86/1341
51/992
0.61
0.64
(0.46, 0.81)
(0.44, 0.92)
79/2435
93/2252
63/1198
74/1135
0.61
0.63
(0.44, 0.85)
(0.46, 0.85)
165/4489
7/198
131/2232
6/101
NC
NC
NC
NC
–
–
156/4158
16/529
130/2066
7/267
0.59
1.23
(0.46, 0.74)
(0.51, 2.99)
0.11
0.07
0.85
0.92
Statins/ezetimibe
0.23
No
41/1029
43/551
0.50
(0.32, 0.76)
Yes
131/3658
94/1782
0.68
(0.52, 0.88)
Antihypertensives
0.41
No
10/241
5/112
0.97
(0.33, 2.83)
Yes
162/4446
132/2221
0.61
(0.48, 0.76)
Angiotensin-converting
0.86
enzyme inhibitors/
angiotensin receptor
blockers
No
35/889
28/465
0.65
(0.39, 1.06)
Yes
137/3798
109/1868
0.61
(0.48, 0.79)
Calcium channel
0.29
blockers
No
120/3158
87/1545
0.67
(0.51, 0.89)
Yes
52/1529
50/788
0.52
(0.35, 0.77)
Beta blockers
0.99
No
61/1631
49/835
0.62
(0.43, 0.90)
Yes
111/3056
88/1498
0.62
(0.47, 0.82)
Diuretics
0.46
No
76/2640
57/1345
0.68
(0.48, 0.95)
Yes
96/2047
80/988
0.57
(0.42, 0.77)
0.99
No
40/811
31/406
0.62
(0.39, 0.99)
Yes
132/3876
106/1927
0.62
(0.48, 0.80)
Cox regression analysis in patients treated with ≥1 dose of study drug. Subgroup analyses of
cardiovascular death were conducted post-hoc.
*Hazard ratio and 95% CI were not analyzed as the total number of patients with an event was <14 in one
subgroup.
p-value is for homogeneity of the treatment group difference among subgroups (test for group by
covariate interaction) with no adjustment for multiple tests. p=0.054 for body mass index.
Section O. Sensitivity analyses
Table S9. Sensitivity analyses of the primary outcome
Placebo
Empagliflozin
Cardiovascular death, non-fatal myocardial infarction (excluding silent myocardial infarction), or
non-fatal stroke (3-point MACE): primary outcome
Patients who received ≥1 dose of study drug including only events observed ≤30 days after a
patient’s last intake of trial medication
N
Patients with events – no. (%)
Rate/1000 patient-years
2333
4687
229 (9.8)
412 (8.8)
39.8
34.4
0.87 (0.74, 1.02)
p-value
0.09
Patients who received study drug for ≥30 days (cumulative) including only events that occurred
≤30 days after a patient’s last intake of trial medication (on treatment set)
N
2308
4607
227 (9.8)
407 (8.8)
39.5
34.1
0.87 (0.74, 1.02)
p-value
0.08
Patients treated with ≥1 dose of study drug who did not have important protocol violations (perprotocol set)
N
p-value
Cox regression analysis.
2316
4654
278 (12.0)
487 (10.5)
43.4
37.4
0.86 (0.75, 1.00)
0.05
Table S10. Sensitivity analyses of cardiovascular death, myocardial infarction and
stroke
Placebo
Empagliflozin
patient’s last intake of trial medication*
N
2333
4687
92 (3.9)
114 (2.4)
15.5
9.2
0.59 (0.45, 0.78)
p-value
<0.001
N
2308
4607
90 (3.9)
112 (2.4)
15.2
9.1
0.60 (0.45, 0.79)
p-value
<0.001
Non-fatal myocardial infarction
N
2333
4687
103 (4.4)
193 (4.1)
17.7
15.9
0.90 (0.71, 1.15)
p-value
0.40
N
p-value
2308
4607
102 (4.4)
192 (4.2)
17.5
15.9
0.91 (0.71, 1.15)
0.43
Fatal and non-fatal myocardial infarction
N
2333
4687
108 (4.6)
202 (4.3)
18.6
16.7
0.90 (0.71, 1.14)
p-value
0.39
N
2308
4607
107 (4.6)
200 (4.3)
18.4
16.5
0.90 (0.71, 1.14)
p-value
0.39
Non-fatal stroke
N
2333
4687
58 (2.5)
133 (2.8)
9.9
10.9
1.12 (0.82, 1.52)
p-value
0.48
N
2308
4607
58 (2.5)
131 (2.8)
9.9
10.8
1.10 (0.81, 1.50)
p-value
0.54
Fatal and non-fatal stroke
N
p-value
2333
4687
66 (2.8)
143 (3.1)
11.3
11.7
1.06 (0.79, 1.41)
0.71
N
p-value
Cox regression analysis. *Post-hoc analyses.
2308
4607
66 (2.9)
141 (3.1)
11.3
11.6
1.04 (0.78, 1.40)
0.78
Section P. Weight, waist circumference, blood pressure, heart rate, low density
and high density lipoprotein cholesterol, and uric acid over time.
Figure S3. Weight (A), waist circumference (B), blood pressure (C and D), heart rate
(E), low density and high density lipoprotein cholesterol (F and G), uric acid (H) over
time.
Mixed model repeated measures analysis using all data up to individual trial completion
in treated patients who had a baseline and post-baseline measurement for the
respective outcome. The model included baseline glycated hemoglobin and baseline of
the outcome in question as linear covariates and baseline eGFR, region, body mass
index, the last week a patient could have had a measurement of the outcome in
question, treatment, visit, visit by treatment interaction, baseline glycated hemoglobin by
visit interaction and baseline of the outcome in question by visit interaction as fixed
effects.
A. Weight
B. Waist circumference.
C. Systolic blood pressure
D. Diastolic blood pressure
E. Heart rate
F. Low density lipoprotein cholesterol
Conversion factor: 1 mg/dL = 0.02586 mmol/L
G. High density lipoprotein cholesterol
Conversion factor: 1 mg/dL = 0.02586 mmol/L
H. Uric acid
Conversion factor: 1 mg/dL = 59.485 µmol/L
Section Q. Glucose-lowering and cardiovascular medications introduced post-baseline
Table S11. Glucose-lowering medications introduced post-baseline
Placebo (N = 2333)
Empagliflozin (N = 4687)
no. (%)
Any glucose-lowering therapy
Insulin
Dipeptidyl peptidase-4 inhibitor
Sulfonylurea
Metformin
Thiazolidinedione
Glucagon-like peptide-1 agonist
Data are from patients treated with ≥1 dose of study drug.
736 (31.5)
268 (11.5)
193 (8.3)
164 (7.0)
112 (4.8)
68 (2.9)
914 (19.5)
273 (5.8)
263 (5.6)
176 (3.8)
172 (3.7)
56 (1.2)
57 (2.4)
65 (1.4)
Table S12. Cardiovascular medications introduced post-baseline
Placebo (N = 2333)
Empagliflozin (N = 4687)
no. (%)
Anti-hypertensive therapy
Angiotensin-converting enzyme inhibitors/angiotensin
receptor blockers
Diuretics
Beta blockers
1106 (47.4)
640 (27.4)
1903 (40.6)
1108 (23.6)
530 (22.7)
420 (18.0)
760 (16.2)
745 (15.9)
Calcium channel blockers
Mineralocorticoid receptor antagonists
Renin inhibitors
Other
Lipid-lowering drugs
Statins
427 (18.3)
110 (4.7)
6 (0.3)
138 (5.9)
643 (27.6)
529 (22.7)
592 (12.6)
135 (2.9)
8 (0.2)
234 (5.0)
1245 (26.6)
1040 (22.2)
Fibrates
Ezetimibe
Niacin
Other
Anticoagulants
118 (5.1)
44 (1.9)
12 (0.5)
64 (2.7)
623 (26.7)
402 (17.2)
188 (4.0)
87 (1.9)
23 (0.5)
92 (2.0)
1179 (25.2)
736 (15.7)
112 (4.8)
89 (3.8)
224 (4.8)
136 (2.9)
Clopidogrel
Vitamin K antagonists
Data are from patients treated with ≥1 dose of study drug.
Section R. Complicated urinary tract infections
Table S13. Breakdown of complicated urinary tract infections by MedDRA preferred term
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
(N = 2333)
(N = 2345)
(N = 2342)
(N = 4687)
no. (%) with one or more event
Complicated urinary tract infection
41 (1.8)
34 (1.4)
48 (2.0)
82 (1.7)
Urinary tract infection
16 (0.7)
13 (0.6)
16 (0.7)
29 (0.6)
Urosepsis
3 (0.1)
6 (0.3)
11 (0.5)
17 (0.4)
Pyelonephritis
4 (0.2)
3 (0.1)
10 (0.4)
13 (0.3)
Pyelonephritis chronic
10 (0.4)
4 (0.2)
6 (0.3)
10 (0.2)
Pyelonephritis acute
6 (0.3)
7 (0.3)
1 (<0.1)
8 (0.2)
Cystitis
2 (0.1)
0
0
0
Kidney infection
2 (0.1)
1 (<0.1)
3 (0.1)
4 (0.1)
0
0
3 (0.1)
3 (0.1)
Cystitis bacterial
1 (<0.1)
0
0
0
Escherichia urinary tract infection
1 (<0.1)
0
0
0
0
0
1 (<0.1)
1 (<0.1)
0
0
1 (<0.1)
1 (<0.1)
1 (<0.1)
0
0
0
0
1 (<0.1)
0
1 (<0.1)
Urinary tract infection fungal
Urinary tract infection
pseudomonal
Cystitis glandularis
Cystitis hemorrhagic
Nephritis
Data are from patients treated with ≥1 dose of study drug based on events that occurred on treatment or ≤7 days after the last intake of study
medication. Complicated urinary tract infection defined as pyelonephritis, urosepsis or serious adverse event consistent with urinary tract infection.
There were no significant differences (p<0.05) between pooled empagliflozin and placebo.
Section S. Clinical laboratory data.
Table S14. Changes in clinical laboratory parameters.
Placebo
Change from
baseline
41.1 ± 5.7
0.9 ± 4.7
13.4 ± 1.5
-0.1 ± 1.2
Baseline
Hematocrit, %
Hemoglobin, g/dL
Empagliflozin 10 mg
Baseline
Change from
baseline
41.2 ± 5.6
4.8 ± 5.5
13.4 ± 1.5
0.8 ± 1.3
Empagliflozin 25 mg
Baseline
Change from
baseline
41.3 ± 5.7
5.0 ± 5.3
13.5 ± 1.5
0.8 ± 1.3
Serum creatinine, mg/dL
1.03 ± 0.29
0.03 ± 0.22
1.02 ± 0.28
0.04 ± 0.18
1.03 ± 0.30
0.05 ± 0.18
Estimated glomerular filtration rate,
74.0 ± 21.1
-2.0 ± 11.5
74.4 ± 21.8
-2.3 ± 12.1
74.3 ± 21.1
-2.9 ± 11.8
2
mL/min/1.73m
Aspartate aminotransferase, U/L
14 ± 12
0 ± 24
13 ± 10
0 ± 15
14 ± 11
0 ± 26
Alanine aminotransferase, U/L
18 ± 14
0 ± 32
17 ± 11
-1 ± 17
18 ± 12
-2 ± 22
Alkaline phosphatase, U/L
64 ±32
5 ± 33
65 ± 32
3 ± 33
64 ± 33
3 ± 26
Electrolytes
Sodium, mEq/L
141 ± 2
0±2
141 ± 2
0±2
141 ± 2
0±2
Potassium, mEq/L
4.3 ± 0.4
0.0 ± 0.4
4.3 ± 0.4
0.0 ± 0.4
4.3 ± 0.4
0.0 ± 0.4
Calcium, mg/dL
9.7 ± 0.5
0.0 ± 0.5
9.7 ± 0.4
0.0 ± 0.5
9.7 ± 0.4
0.0 ± 0.5
Magnesium, mEq/L
1.7 ±0.2
0.0 ± 0.2
1.7 ± 0.2
0.1 ± 0.2
1.7 ± 0.2
0.1 ± 0.2
Chloride, mEq/L
102 ± 2
-1 ± 2
102 ± 2
-1 ± 2
102 ± 2
-1 ± 2
Phosphate, mg/dL
3.7 ± 0.3
0.0 ± 0.3
3.7 ± 0.3
0.1 ± 0.3
3.7 ± 0.3
0.1 ± 0.3
Plus-minus values are means ± SD and data are normalized to a standard reference range. Changes from baseline are the last measurement ≤3
days after the last intake of study medication. Data are from patients treated with ≥1 dose of study drug with a baseline and on-treatment
measurement.
Conversion factors: serum creatinine: 1 mg/dL = 88.4 µmol/L; sodium, potassium, chloride and phosphate: 1 mEq/L = 1 mmol/L; calcium: 1 mg/dL
= 0.25 mmol/L; magnesium: 1 mEq/L = 0.5 mmol/L

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2

Transcription

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