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1
The authors' affiliations are listed in the
Appendix. Address reprint requests to
Dr. Bhatt at Brigham and Women’s Hos-
pital Heart and Vascular Center, Harvard
Medical School, 75 Francis St., Boston, MA
02115, or at dlbhattmd@ post . harvard . edu.
*A complete list of the SCORED trial inves-
tigators is provided in the Supplementary
Appendix, available at NEJM.org.
This article was published on November
16, 2020, at NEJM.org.
DOI: 10.1056/NEJMoa2030186
Copyright © 2020 Massachusetts Medical Society.
BACKGROUND
The efficacy and safety of sodium–glucose cotransporter 2 inhibitors such as so-
tagliflozin in preventing cardiovascular events in patients with diabetes with chronic
kidney disease with or without albuminuria have not been well studied.
METHODS
We conducted a multicenter, double-blind trial in which patients with type 2 dia-
betes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated
glomerular filtration rate, 25 to 60 ml per minute per 1.73 m
2
of body-surface
area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio
to receive sotagliflozin or placebo. The primary end point was changed during the
trial to the composite of the total number of deaths from cardiovascular causes,
hospitalizations for heart failure, and urgent visits for heart failure. The trial
ended early owing to loss of funding.
RESULTS
Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the
sotagliflozin group and 5292 assigned to the placebo group, and followed for a
median of 16 months. The rate of primary end-point events was 5.6 events per 100
patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the
placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88;
P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was
2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12;
P = 0.35). For the original coprimary end point of the first occurrence of death
from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the
hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point
of the first occurrence of death from cardiovascular causes or hospitalization for
heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital
mycotic infections, volume depletion, and diabetic ketoacidosis were more common
with sotagliflozin than with placebo.
CONCLUSIONS
In patients with diabetes and chronic kidney disease, with or without albuminuria,
sotagliflozin resulted in a lower risk of the composite of deaths from cardiovas-
cular causes, hospitalizations for heart failure, and urgent visits for heart failure
than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon
Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.)
ABSTR ACT
Sotagliflozin in Patients with Diabetes
and Chronic Kidney Disease
Deepak L. Bhatt, M.D., M.P.H., Michael Szarek, Ph.D., Bertram Pitt, M.D.,
Christopher P. Cannon, M.D., Lawrence A. Leiter, M.D.,
Darren K. McGuire, M.D., M.H.Sc., Julia B. Lewis, M.D., Matthew C. Riddle, M.D.,
Silvio E. Inzucchi, M.D., Mikhail N. Kosiborod, M.D., David Z.I. Cherney, M.D., Ph.D.,
Jamie P. Dwyer, M.D., Benjamin M. Scirica, M.D., M.P.H., Clifford J. Bailey, Ph.D.,
Rafael Díaz, M.D., Kausik K. Ray, M.D., Jacob A. Udell, M.D., M.P.H.,
Renato D. Lopes, M.D., Ph.D., Pablo Lapuerta, M.D., and P. Gabriel Steg, M.D.,
for the SCORED Investigators*
Original Article
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P
atients with diabetes mellitus are
at high risk for both heart failure and
ischemic events.
1-7
Sodium–glucose cotrans-
porter 2 (SGLT2) inhibitors have been shown to
be effective for the treatment of type 2 diabetes
mellitus
8-10
and to lower the risk of hospitaliza-
tion for heart failure among patients with or
without previous heart failure.
11-22
Their effect on
different types of ischemic events has been more
heterogeneous across drugs, trials, and popula-
tions. Coexisting chronic kidney disease in pa-
tients with diabetes mellitus further raises the
risk of heart failure and ischemic events.
23
Data
from randomized trials support the use of
SGLT2 inhibition in patients with chronic kidney
disease with or without diabetes.
12,19
These trials
have required the presence of macroalbuminuria
for inclusion, in addition to reduced estimated
glomerular filtration rate (eGFR).
These considerations led to the design of the
Effect of Sotagliflozin on Cardiovascular and Re-
nal Events in Patients with Type 2 Diabetes and
Moderate Renal Impairment Who Are at Cardio-
vascular Risk (SCORED) trial. Sotagliflozin is an
SGLT2 inhibitor that also inhibits gastrointesti-
nal SGLT1. Inhibition of SGLT2 increases urinary
glucose excretion, whereas inhibition of SGLT1
appears to delay glucose absorption and reduce
postprandial glucose.
24-29
We conducted this trial
to determine whether sotagliflozin was noninfe-
rior to placebo with respect to ischemic events
and whether it was superior with respect to heart
failure events. On the basis of emerging data
about SGLT2 inhibitors, we aimed to examine
whether sotagliflozin would reduce the total
number of deaths from cardiovascular causes,
hospitalizations for heart failure, and urgent
visits for heart failure in patients with diabetes
mellitus and chronic kidney disease, regardless
of the degree of albuminuria.
Methods
Trial Design
This was a phase 3, randomized, double-blind,
placebo-controlled trial that compared sota-
gliflozin (200 mg once daily, with an increase to
400 mg once daily if unacceptable side effects
did not occur) with placebo in patients with type
2 diabetes mellitus, chronic kidney disease, and
additional cardiovascular risk; all the patients
also received standard-of-care treatments. Ran-
domization was stratified according to criteria
for heart failure (ejection fraction of ≤40% docu-
mented within the past year or hospitalization
for heart failure during the previous 2 years) and
geographic region (North America, Latin Amer-
ica, western Europe, eastern Europe, or rest of the
world). The original plan was for approximately
10,500 patients to undergo randomization, and
this plan was accomplished. Final trial visits
were initiated in March 2020 before the target
number of events had occurred because of loss
of funding from the sponsor.
30
This led to a revi-
sion of end points, as indicated in the end-points
section below and in the original and revised
protocols, available with the full text of this ar-
ticle at NEJM.org. Details of the trial design are
provided in Figure S1 in the Supplementary Ap-
pendix, available at NEJM.org. Patients were en-
rolled at 750 sites in 44 countries. The first pa-
tient underwent randomization on December 8,
2017, and the last on January 20, 2020.
The original sponsor was Sanofi. Sponsorship
was transferred to Lexicon Pharmaceuticals as
of January 30, 2020. The executive and steering
committees, consisting of academic physicians,
and representatives from the sponsors developed
the protocol and statistical analysis plan (avail-
able with the protocol at NEJM.org) and were
responsible for the conduct and oversight of the
trial, as well as the interpretation of data. The
sponsors provided sotagliflozin and placebo and
were responsible for the collection and handling
of the data and funded the statistical analysis
performed by an independent academic statisti-
cian (the second author). The protocol was ap-
proved by the relevant health authority, institu-
tional review board, or ethics committee at each
trial site. The authors vouch for the complete-
ness and accuracy of the data, for the accurate
and full reporting of adverse events, and for the
fidelity of the trial to the protocol and statistical
analysis plan. An independent data and safety
monitoring board oversaw the trial. There were
confidentiality agreements between the sponsors
and the authors. The sponsor had the right to
review and comment on the manuscript, with no
obligation of the authors to incorporate any com-
ments, and the authors were not restricted from
publishing the results of the trial.
Patients
Persons 18 years of age or older with type 2 dia-
betes mellitus with a glycated hemoglobin level of
7% or higher, chronic kidney disease (eGFR, 25 to
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Sotagliflozin in Diabetes and Chronic Kidney Disease
60 ml per minute per 1.73 m
2
of body-surface
area), and additional cardiovascular risk factors
were enrolled. The risk factors consisted of at
least one major cardiovascular risk factor in those
18 years of age or older or at least two minor
cardiovascular risk factors in those 55 years of
age or older. An exclusion criterion was any plan
to start an SGLT2 inhibitor during the trial. In-
clusion criteria (including definitions of major
and minor cardiovascular risk factors) and ex-
clusion criteria are listed in the Supplementary
Appendix. Written informed consent was obtained
from all the patients.
End Points
The original coprimary end points, assessed in
time-to-event analyses, were the first occurrence
of a major adverse cardiovascular event (MACE,
defined as death from cardiovascular causes, non-
fatal myocardial infarction, or nonfatal stroke) and
the first occurrence of death from cardiovascu-
lar causes or hospitalization for heart failure.
Because of the early closing of the trial and the
fewer than planned number of events, with the
investigators and sponsor unaware of the trial-
group assignments and without end-point infor-
mation from an interim analysis, the primary end
point was changed on August 21, 2020, to the total
number of deaths from cardiovascular causes,
hospitalizations for heart failure, and urgent
visits for heart failure.
The original secondary end points were the
first occurrence, in patients with a baseline eGFR
of at least 30 ml per minute per 1.73 m
2
, of a
sustained decrease of at least 50% in the eGFR
from baseline for at least 30 days, long-term
dialysis, renal transplantation, or a sustained
eGFR of less than 15 ml per minute per 1.73 m
2
for at least 30 days; the first occurrence, in pa-
tients with a baseline eGFR of at least 30 ml per
minute per 1.73 m
2
and a baseline urinary albu-
min-to-creatinine ratio (with albumin measured
in milligrams and creatinine measured in grams)
of at least 300, of the above composite end point;
the first occurrence of death from cardiovascular
causes, hospitalization for heart failure, or an
urgent visit for heart failure; deaths from cardio-
vascular causes; and deaths from any cause. The
revised secondary end points were the total
number of hospitalizations for heart failure and
urgent visits for heart failure; deaths from car-
diovascular causes; the total number of deaths
from cardiovascular causes, hospitalizations for
heart failure, nonfatal myocardial infarctions, and
nonfatal strokes; the total number of deaths from
cardiovascular causes, hospitalizations for heart
failure, urgent visits for heart failure, and events
of heart failure during hospitalization; the first
occurrence of the composite of a sustained de-
crease of at least 50% in the eGFR from baseline
for at least 30 days, long-term dialysis, renal trans-
plantation, or a sustained eGFR of less than 15 ml
per minute per 1.73 m
2
for at least 30 days; deaths
from any cause; and the total number of deaths
from cardiovascular causes, nonfatal myocardial
infarctions, and nonfatal strokes. The use of total
events allowed for a single patient to have more
than one event contributing to the analysis. Sub-
group analyses were prespecified. Because of loss
of funding, planned adjudication of end-point
events was not completed and investigator-report-
ed events were used for end-point analyses.
Statistical Analysis
The original design of the trial intended to estab-
lish the noninferiority of sotagliflozin to placebo
with respect to the first occurrence of a MACE
and the superiority of sotagliflozin over placebo
with respect to the first occurrence of death from
cardiovascular causes or hospitalization for heart
failure. We estimated that for 10,500 randomly
assigned patients, 1189 events would be needed
to test for noninferiority with respect to the first
occurrence of a MACE, on the basis of the upper
boundary of a two-sided 95% confidence inter-
val for the hazard ratio being less than 1.3, and
844 events would be needed to test for superior-
ity with respect to the first occurrence of death
from cardiovascular causes or hospitalization for
heart failure. In a hierarchical fashion, the copri-
mary end points and prespecified secondary end
points were to be tested with a prespecified pro-
cedure to control for type I error. No formal power
calculation was performed for the revised primary
end point.
All efficacy analyses followed the intention-
to-treat principle. To allow for analyses of total
events, competing-risk marginal models for re-
current events that were stratified according to
heart-failure criteria and geographic region, with
deaths not included in a given end point treated
as competing terminal events, were applied to
generate hazard ratios with Wald 95% confidence
intervals and P values.
31
Proportionality was con-
firmed by interaction terms between trial-group
assignment and the logarithm of time. Event rates
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Table 1. Baseline Characteristics of the Patients.*
Characteristic
Sotagliflozin
(N = 5292)
Placebo
(N = 5292)
Median age (IQR) — yr 69 (63–74) 69 (63–74)
Female sex — no. (%) 2347 (44.3) 2407 (45.5)
Race or ethnic group — no. (%)†
White 4402 (83.2) 4347 (82.1)
Black 176 (3.3) 188 (3.6)
Asian 317 (6.0) 365 (6.9)
American Indian or Alaska Native 206 (3.9) 216 (4.1)
Native Hawaiian or other Pacific Islander 25 (0.5) 15 (0.3)
Multiple 109 (2.1) 95 (1.8)
Unknown 57 (1.1) 66 (1.2)
Median glycated hemoglobin (IQR) — % 8.3 (7.6–9.3) 8.3 (7.6–9.4)
Median body-mass index (IQR) 31.9 (28.1–36.2) 31.7 (28.0–36.1)
Estimated glomerular filtration rate
Median (IQR) — ml/min/1.73 m
2
44.4 (37.0–51.3) 44.7 (37.0–51.5)
Distribution — no. (%)
<30 ml/min/1.73 m
2
419 (7.9) 394 (7.4)
30 to <45 ml/min/1.73 m
2
2347 (44.3) 2308 (43.6)
≥45 ml/min/1.73 m
2
2526 (47.7) 2590 (48.9)
Geographic region — no. (%)
Eastern Europe 1613 (30.5) 1613 (30.5)
Western Europe 711 (13.4) 709 (13.4)
Latin America 1586 (30.0) 1586 (30.0)
North America 746 (14.1) 747 (14.1)
Rest of the world 636 (12.0) 637 (12.0)
Ejection fraction of ≤40% within past year or hospitalization for
heart failure during previous 2 years — no. (%)
1054 (19.9) 1054 (19.9)
History of heart failure — no. (%)‡ 1640 (31.0) 1643 (31.0)
Ejection fraction of <40% 505 (9.5) 528 (10.0)
Ejection fraction of 40 to <50% 290 (5.5) 291 (5.5)
Ejection fraction of ≥50% 843 (15.9) 824 (15.6)
Ejection fraction unknown 2 (<0.1) 0
Cardiovascular risk factors — no. (%)
At least one major 4682 (88.5) 4699 (88.8)
No major, at least two minor 405 (7.7) 413 (7.8)
No major and less than two minor 205 (3.9) 180 (3.4)
Previous myocardial infarction — no. (%) 1051 (19.9) 1057 (20.0)
Previous coronary revascularization — no. (%) 1208 (22.8) 1167 (22.1)
Previous stroke — no. (%) 472 (8.9) 474 (9.0)
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Sotagliflozin in Diabetes and Chronic Kidney Disease
were summarized by the number of events per
100 patient-years of follow-up,
32
and accrual of
events over time was summarized by cumulative
incidence functions. For subgroup analyses, 95%
confidence intervals are reported without adjust-
ment for multiple comparisons, and no conclu-
sions can be drawn from these data.
Total events of myocardial infarction and to-
tal events of stroke were evaluated post hoc.
Testing for differences between the two groups in
adverse events was performed post hoc; P values
were obtained from Pearson chi-square tests.
Change in the eGFR, glycated hemoglobin level,
systolic blood pressure, diastolic blood pressure,
and weight over time was analyzed post hoc by
means of repeated-measures mixed-effects mod-
els with absolute change from baseline as the
outcome, a random effect for intercept, and fixed
effects for trial-group assignment, baseline val-
ue, and time. Changes in these outcomes were
also jointly modeled with death from any cause
to account for competing risk. Data for patients
Characteristic
Sotagliflozin
(N = 5292)
Placebo
(N = 5292)
Urinary albumin-to-creatinine ratio§
Median (IQR) 74 (18–486) 75 (17–477)
Distribution — no. (%)
<30 1864 (35.2) 1845 (34.9)
30 to <300 1770 (33.4) 1819 (34.4)
≥300 1658 (31.3) 1628 (30.8)
Median left ventricular ejection fraction (IQR) — %‡ 60 (51–64) 60 (51–65)
Median NT-proBNP (IQR) — pg/ml 196.0 (75.1–564.6) 198.1 (74.6–560.7)
Median systolic blood pressure (IQR) — mm Hg 138 (127–149) 139 (127–149)
Median diastolic blood pressure (IQR) — mm Hg 78 (70–85) 78 (70–85)
Any RAAS inhibitor — no. (%)¶ 4705 (88.9) 4660 (88.1)
ACE inhibitor 2009 (38.0) 2039 (38.5)
Angiotensin-receptor blocker 2619 (49.5) 2562 (48.4)
Angiotensin receptor–neprilysin inhibitor 66 (1.2) 65 (1.2)
Mineralocorticoid-receptor antagonist 810 (15.3) 776 (14.7)
Beta-blocker — no. (%) 3310 (62.5) 3306 (62.5)
Calcium-channel blocker — no. (%) 2228 (42.1) 2202 (41.6)
Loop diuretic — no. (%) 1869 (35.3) 1867 (35.3)
Other diuretic — no. (%) 1568 (29.6) 1605 (30.3)
Any glucose-lowering medication — no. (%) 5111 (96.6) 5136 (97.1)
Metformin 2907 (54.9) 2955 (55.8)
Sulfonylurea 1400 (26.5) 1486 (28.1)
DPP-4 inhibitor 1041 (19.7) 1044 (19.7)
Insulin 3389 (64.0) 3333 (63.0)
GLP-1 receptor agonist 310 (5.9) 323 (6.1)
* Percentages may not total 100 because of rounding. ACE denotes angiotensin-converting enzyme, DPP-4 dipeptidyl
peptidase 4, GLP-1 glucagon-like peptide 1, IQR interquartile range, and NT-proBNP N-terminal pro–brain natriuretic
peptide.
† Race and ethnic group were reported by the investigators.
‡ Ejection fraction was measured within 1 year before screening or during the screening period.
§ The ratio was calculated with albumin measured in milligrams and creatinine measured in grams.
¶ Some patients were taking more than one renin–angiotensin–aldosterone system (RAAS) inhibitor.
Table 1. (Continued.)
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