Pharmacy powerpoint

With the attached powerpoint as the example, use the information from the attached journal and journal club and create a separate powerpoint that addresses the following questions:

What was the main purpose of the study?

The key findings?

What are the broader implications for the study’s findings?

The new england
journal of medicine

n engl j med 391;2 nejm.org July 11, 2024 10

established in 1812 July 11, 2024 vol. 391 no. 2

From the University of New South Wales,
Sydney (V.P.); the Division of Nephrolo-
gy, University of Washington School of
Medicine, Seattle, and Providence Medi-
cal Research Center, Providence Inland
Northwest Health, Spokane — both in
Washington (K.R.T.); Steno Diabetes Cen-
ter Copenhagen, Herlev (P.R.), the De-
partment of Clinical Medicine, University
of Copenhagen, Copenhagen (P.R.), and
Novo Nordisk, Søborg (F.M.M.B., T.I.,
H.B.-T., N.L.L.) — all in Denmark; Stan-
ford Center for Clinical Research, Depart-
ment of Medicine, Stanford School of
Medicine, Palo Alto, CA (K.W.M.); KfH
Kidney Center, Munich, and University
Hospital, Friedrich-Alexander University,
Erlangen — both in Germany (J.F.E.M.);
the Department of Medicine, American
Heart Association Comprehensive Hyper-
tension Center, University of Chicago Medi-
cine, Chicago (G.B.); and AdventHealth
Translational Research Institute, Orlando,
FL (R.P.). Dr. Perkovic can be contacted
at vlado . perkovic@ unsw . edu . au or at the
Chancellery, University of New South
Wales, Sydney, NSW 2052, Australia

*The FLOW Trial Committees and Inves-
tigators are listed in the Supplementary
Appendix, available at NEJM.org.

This article was published on May 24, 2024,
and updated on September 17, 2024, at
NEJM.org.

N Engl J Med 2024;391:109-21.
DOI: 10.1056/NEJMoa2403347
Copyright © 2024 Massachusetts Medical Society.

BACKGROUND
Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney
failure, cardiovascular events, and death. Whether treatment with semaglutide would
mitigate these risks is unknown.
METHODS
We randomly assigned patients with type 2 diabetes and chronic kidney disease
(defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute
per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albu-
min measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creati- nine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a compos- ite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary out- comes were tested hierarchically. RESULTS Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific com- ponents of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.)

a bs tr ac t

Effects of Semaglutide on Chronic Kidney Disease
in Patients with Type 2 Diabete

Vlado Perkovic, M.B., B.S., Ph.D., Katherine R. Tuttle, M.D., Peter Rossing, M.D., D.M.Sc.,
Kenneth W. Mahaffey, M.D., Johannes F.E. Mann, M.D., George Bakris, M.D., Florian M.M. Baeres, M.D.,

Thomas Idorn, M.D., Ph.D., Heidrun Bosch-Traberg, M.D., Nanna Leonora Lausvig, M.Sc., and
Richard Pratley, M.D., for the FLOW Trial Committees and Investigators*

CME

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org at Novo Nordisk–Bagsvaerd/Denmark on October 17, 2024. For personal use only.

http://clinicaltrials.gov/show/NCT03819153

n engl j med 391;2 nejm.org July 11, 20241

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

More than half a billion people
globally are affected by chronic kidney
disease and are at high risk for kidney

failure, cardiovascular events, and death.1 Type 2
diabetes is the most frequent cause of chronic
kidney disease in many countries. Renin–angio-
tensin system (RAS) inhibitors,2,3 sodium–glucose
cotransporter 2 (SGLT2) inhibitors, and finere-
none have been shown to protect the kidneys and
reduce the risk of adverse cardiovascular out-
comes4-8 and therefore are guideline-directed med-
ical therapies for chronic kidney disease in patients
with type 2 diabetes.9,10 Nevertheless, many pa-
tients continue to lose kidney function and go
on to have kidney failure or to die, most com-
monly from cardiovascular events. Thus, the ef-
fects of therapies such as glucagon-like peptide 1
(GLP-1) receptor agonists are of great interest.11

The FLOW (Evaluate Renal Function with
Semaglutide Once Weekly) trial assessed the ef-
ficacy and safety of subcutaneous semaglutide at
a dose of 1.0 mg once weekly for the prevention
of kidney failure, substantial loss of kidney func-
tion, and death from kidney-related or cardiovas-
cular causes in patients with type 2 diabetes and
chronic kidney disease.

Me thods

Trial Design and Oversight

We published the design of this international,
double-blind, randomized, placebo-controlled trial
previously.12 The trial was overseen by an academ-
ic-led steering committee (see the Supplementa-
ry Appendix, available with the full text of this
article at NEJM.org) in partnership with the trial
sponsor, Novo Nordisk, which also managed trial
operations. The trial steering committee provided
overall leadership; oversaw trial design, conduct,
and analysis; and was responsible for reporting
the results. Analyses were conducted by the spon-
sor and were independently verified with the use
of the original data by Statogen Consulting. The
first author wrote the first draft of the manu-
script, and all the authors contributed to subse-
quent revisions. Technical editorial assistance
was provided by OpenHealth and funded by the
sponsor. The authors had access to the full data
set, made the decision to submit the manuscript
for publication, and vouch for the accuracy and
completeness of the data and for the fidelity of
the trial to the protocol (available at NEJM.org).

Relevant approval from regulatory authorities
and institutional review boards was obtained. Each
participant provided written informed consent
before undergoing any trial-related procedures.

Participants

Adults with type 2 diabetes (glycated hemoglo-
bin level, ≤10%) were eligible for inclusion in the
trial if they had high-risk chronic kidney disease
and were receiving a stable maximal labeled dose
(or the maximal dose without unacceptable side
effects) of RAS inhibitors (angiotensin-convert-
ing–enzyme inhibitor or angiotensin-receptor
blocker). Kidney disease was defined by an esti-
mated glomerular filtration rate (eGFR) of 25 to
75 ml per minute per 1.73 m2 of body-surface
area (calculated with the serum creatinine level
and the Chronic Kidney Disease Epidemiology
Collaboration [CKD-EPI] 2009 formula,13 which
were used to calculate all reported eGFR values
unless otherwise indicated), with a urinary albu-
min-to-creatinine ratio (with albumin measured
in milligrams and creatinine measured in grams)
of greater than 300 and less than 5000 if the
eGFR was 50 ml per minute per 1.73 m2 or
higher or a urinary albumin-to-creatinine ratio
of greater than 100 and less than 5000 if the
eGFR was 25 to less than 50 ml per minute per
1.73 m2. Patients who were unable to receive RAS
inhibition because of side effects were eligible
for inclusion. A full list of inclusion and exclusion
criteria, including a range of specific kidney dis-
ease diagnoses, is provided in the Supplementary
Appendix.

Trial Procedures

Eligible participants were randomly assigned in
a 1:1 ratio to receive semaglutide or matching
placebo with the use of a central interactive Web-
based response system. The use of SGLT2 inhibi-
tors and mineralocorticoid-receptor antagonists
(MRAs) was permitted, and randomization was
stratified according to SGLT2 inhibitor use at
baseline. An 8-week dose-escalation regimen
was used, with dose escalation (as long as unac-
ceptable side effects did not occur) from 0.25 mg
per week for 4 weeks and 0.5 mg per week for
another 4 weeks, followed by a maintenance
dose of 1.0 mg per week throughout the remain-
der of the treatment period. If unacceptable ad-
verse effects occurred, dose-escalation intervals
could be extended, treatment could be paused,

A Quick Take
is available at

NEJM.org

n engl j med 391;2 nejm.org July 11, 2024 111

Effects of Semaglutide on Chronic Kidney Disease

or lower maintenance doses could be used. Labo-
ratory-based inclusion criteria were based on local
laboratory values recorded within 90 days before
the screening visit or central laboratory values
recorded at screening or at optional prescreen-
ing visits.

Trial Outcomes

The primary outcome was major kidney disease
events, a composite of onset of kidney failure (ini-
tiation of long-term dialysis, kidney transplanta-
tion, or a reduction in the eGFR to <15 ml per minute per 1.73 m2 sustained for ≥28 days), a sustained (for ≥28 days) 50% or greater reduc- tion in eGFR from baseline, or death from kid- ney-related or cardiovascular causes. Three key confirmatory secondary outcomes were defined and assessed with the use of a formal hierarchi- cal testing strategy: total eGFR slope (i.e., the annual rate of change in eGFR from randomiza- tion to the end of the trial); major cardiovascular events (a composite of nonfatal myocardial in- farction, nonfatal stroke, or death from cardio- vascular causes), assessed in a time-to-first-event analysis; and death from any cause. A range of additional supportive secondary, exploratory, and other outcomes were also prespecified and are listed in the Supplementary Appendix.

Safety was assessed by collecting data on all
serious adverse events, adverse events leading to
discontinuation of semaglutide or placebo, and
adverse events of special interest. Primary and sec-
ondary outcomes other than eGFR assessments
derived from the central laboratory were adjudi-
cated in a blinded fashion by an event adjudication
committee (see the Supplementary Appendix).

Statistical Analysis

This trial was event driven. We calculated that a
minimum of 854 primary-outcome events would
provide 90% power to detect a 20% lower relative
risk in the semaglutide group than in the placebo
group at an overall one-sided significance level of
2.5%. An interim analysis of efficacy was planned
for after two thirds of the total planned number
of primary-outcome events had occurred.

Efficacy analyses were based on the intention-
to-treat principle and included all unique partici-
pants who underwent randomization, irrespective
of adherence to semaglutide or placebo or chang-
es to background medications. Time-to-first-event
outcomes were analyzed with a stratified Cox

proportional-hazards model with randomization
assignment (semaglutide or placebo) as a fixed
factor and stratified according to SGLT2 inhibi-
tor use at baseline. P values were obtained from
a score test. For the primary outcome, the hazard
ratio, 95% confidence interval, and P value were
adjusted for the group sequential design with
the use of likelihood-ratio ordering. The eGFR
slope was analyzed with a linear mixed-effects
model with randomization assignment, SGLT2
inhibitor use at baseline, time, and the interac-
tion between randomization assignment and time
as fixed effects, participant as a random intercept,
and time as a random slope. Missing data were not
imputed.

If superiority was confirmed for the primary
outcome, testing of the confirmatory secondary
outcomes was performed in a prespecified hier-
archical order to ensure type I error control. To
account for the prespecified interim analysis, the
nominal significance level for the primary and
confirmatory secondary outcomes was calculated
with the Lan–DeMets alpha-spending function
and the actual observed number of primary-out-
come events available for the primary analysis. On
the basis of the available number of events, the
one-sided nominal significance level for the pri-
mary and confirmatory secondary outcomes was
updated to 0.0161 (equivalent to a two-sided level
of 0.0322, which is used in this report). Details
are provided in the Supplementary Appendix.

Continuous supportive secondary outcomes
were assessed by analysis of covariance with the
use of multiple imputation for missing values
under a missing-at-random assumption. Analyses
of supportive and exploratory outcomes were not
adjusted for multiplicity, and confidence intervals
for these outcomes should not be used in place
of hypothesis testing. All statistical analyses were
performed with SAS software, version 9.4 TS1M5
(SAS Institute).

R esult s

Trial Participants

The trial was conducted at 387 sites in 28 coun-
tries (see the Supplementary Appendix), with re-
cruitment occurring from June 2019 through May
2021. Among the 5581 screened candidates (Fig. S1
in the Supplementary Appendix), 3533 met the
entry criteria and were randomly assigned to the
semaglutide group (1767 participants) or the pla-

n engl j med 391;2 nejm.org July 11, 2024112

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Table 1. Characteristics of the Participants at Baseline.*

Characteristic
Semaglutide
(N = 1767)

Placebo
(N = 1766)

Total
(N = 3533)

Age — yr 66.6±9.0 66.7±9.0 66.6±9.0

Female sex — no. (%) 519 (29.4) 550 (31.1) 1069 (30.3)

Geographic region — no. (%)

Asia 478 (27.1) 434 (24.6) 912 (25.8)

Europe 472 (26.7) 491 (27.8) 963 (27.3)

North America 423 (23.9) 442 (25.0) 865 (24.5)

Other 394 (22.3) 399 (22.6) 793 (22.4)

Race or ethnic group — no. (%)†

White 1155 (65.4) 1168 (66.1) 2323 (65.8)

Asian 439 (24.8) 407 (23.0) 846 (23.9)

Black 78 (4.4) 82 (4.6) 160 (4.5)

Other 95 (5.4) 109 (6.2) 204 (5.8)

Hispanic or Latinx ethnic group — no. (%)†

Yes 273 (15.4) 283 (16.0) 556 (15.7)

No 1421 (80.4) 1411 (79.9) 2832 (80.2)

Not reported 73 (4.1) 72 (4.1) 145 (4.1)

Glycated hemoglobin level — % 7.8±1.3 7.8±1.3 7.8±1.3

Body-mass index‡ 31.9±6.1 32.0±6.5 32.0±6.3

Body weight — kg 89.5±19.8 89.8±21.2 89.6±20.

Systolic blood pressure — mm Hg 138.9±16.1 138.4±15.4 138.6±15.8

Diastolic blood pressure — mm Hg 76.8±10.0 76.1±10.0 76.4±10.0

Diabetes duration — no. (%)

<15 yr 774 (43.8) 753 (42.6) 1527 (43.2)

≥15 yr 992 (56.1) 1013 (57.4) 2005 (56.8)

Previous myocardial infarction or stroke — no. (%) 405 (22.9) 403 (22.8) 808 (22.9)

Chronic heart failure — no. (%) 342 (19.4) 336 (19.0) 678 (19.2)

Smoking status — no. (%)§

Current smoker 223 (12.6) 206 (11.7) 429 (12.1)

Previous smoker 661 (37.4) 696 (39.4) 1357 (38.4)

Never smoked 883 (50.0) 864 (48.9) 1747 (49.4)

eGFR — ml/min/1.73 m2¶ 46.9±15.6 47.1±14.7 47.0±15.2

eGFR distribution — no. (%)¶

≥60 ml/min/1.73 m2 366 (20.7) 353 (20.0) 719 (20.4)

≥45 to <60 ml/min/1.73 m2 515 (29.1) 540 (30.6) 1055 (29.9)

≥30 to <45 ml/min/1.73 m2 667 (37.7) 691 (39.1) 1358 (38.4)

<30 ml/min/1.73 m2 218 (12.3) 182 (10.3) 400 (11.3)

Median urinary albumin-to-creatinine ratio‖ 582.3 557.8 567.6

Category of albuminuria — no. (%)**

A1, normoalbuminuria 52 (2.9) 57 (3.2) 109 (3.1)

A2, microalbuminuria 509 (28.8) 495 (28.0) 1004 (28.4)

A3, macroalbuminuria 1205 (68.2) 1214 (68.7) 2419 (68.5)

n engl j med 391;2 nejm.org July 11, 2024 113

Effects of Semaglutide on Chronic Kidney Disease

cebo group (1766 participants) and included in
the analyses. Four participants underwent ran-
domization more than once, and only the first
randomization was included in analyses; one par-
ticipant was excluded from the analysis because of
a lack of adherence to Good Clinical Practice
guidelines at the relevant site.

The baseline characteristics of the participants
were well balanced between the groups (Table 1
and Table S1). The mean age was 66.6 years, and
1069 participants (30.3%) were women. The mean
eGFR was 47.0 ml per minute per 1.73 m2, and
the median urinary albumin-to-creatinine ratio
(with albumin measured in milligrams and cre-
atinine measured in grams) was 567.6. According
to the Kidney Disease: Improving Global Out-
comes risk calculators,14 68% of the participants
were at very high risk for kidney disease pro-
gression, kidney failure, cardiovascular events,
or death. The participants in the trial were
broadly representative of the relevant population

and consistent with those in previous trials,4,5,8
as described in Table S2.

A prespecified single interim analysis was
triggered in October 2023 after approximately
570 primary-outcome events had accrued. An in-
dependent data and safety monitoring committee
reviewed the data and recommended early com-
pletion of the trial for efficacy. This recommen-
dation was accepted, participants were recalled
for final visits, and the trial was completed with
the final participant visit occurring on January 9,
2024. At the time of completion of the trial, the
median participant follow-up was 3.4 years
(range, 0 to 4.5). The trial was closed early at
two sites in Russia that had been sanctioned by
the sponsor, and 14 participants at the affected
sites ended participation early. In total, 34 par-
ticipants withdrew consent, and vital status was
able to be confirmed at the end of trial for 3482
participants (98.6%). Semaglutide or placebo was
permanently discontinued by 26% of participants

Characteristic
Semaglutide
(N = 1767)

Placebo
(N = 1766)

Total
(N = 3533)

Medication use — no. (%)

SGLT2 inhibitor 277 (15.7) 273 (15.5) 550 (15.6)

ACE inhibitor 625 (35.4) 615 (34.8) 1240 (35.1)

ARB 1066 (60.3) 1061 (60.1) 2127 (60.2)

Lipid-lowering drug 1418 (80.2) 1416 (80.2) 2834 (80.2)

Diuretic agent 870 (49.2) 910 (51.5) 1780 (50.4)

Insulin 1083 (61.3) 1085 (61.4) 2168 (61.4)

* Plus–minus values are means ±SD. For all characteristics except the urinary albumin-to-creatinine ratio and estimated
glomerular filtration rate (eGFR), baseline was defined as the eligible assessment associated with the randomization
visit if it was performed before or at the date of first dose. If the assessment was missing or performed after the date
of first dose, the assessment from the screening visit was used. Percentages may not total 100 because of rounding.
ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and SGLT2 sodium–glucose cotrans-
porter 2.

† Race and ethnic group were reported by the participants. “Other” includes American Indian or Alaska Native, Native
Hawaiian or other Pacific Islander, and “not reported.”

‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Smoking was defined as smoking at least one cigarette or the equivalent daily.
¶ For eGFR, the baseline assessment is defined as the mean of the two assessments from the randomization visit and

the screening visit. If only one of the assessments was available, it was used as the baseline assessment. The mean
eGFR and the eGFR categories are based on the serum creatinine level and the Chronic Kidney Disease Epidemiology
Collaboration 2009 equation.

‖ The urinary albumin-to-creatinine ratio was calculated with albumin measured in milligrams and creatinine measured
in grams.

** Albuminuria categories are based on the urinary albumin-to-creatinine ratio, and the baseline assessment is defined
as the mean of the two assessments from the randomization visit. If only one of the assessments was available, it
was used as the baseline assessment. Normoalbuminuria is defined by a urinary albumin-to-creatinine ratio of less
than 30, microalbuminuria by a ratio of at least 30 and less than 300, and macroalbuminuria by a ratio of 300 or
greater.

Table 1. (Continued.)

n engl j med 391;2 nejm.org July 11, 2024114

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

6 12 18 24 42

Months since Randomization

A First Major Kidney Disease Event

Hazard ratio, 0.76 (95% CI, 0.66–0.88)
P=0.00

Placebo

Semaglutide

1766
1767

1682
1693

1605
16

1516
1572

>30

1408
1489

5
10

0
0 6 12 18 24 42 4830 36

1048
1131

354
392

Pe
rc

en
ta

ge
o

f P
ar

tic
ip

an
ts

100

0
0

Pe
rc

en
ta

ge
o

f P
ar

tic
ip

an
ts

100

0
0

Pe
rc

en
ta

ge
o

f P
ar

tic
ip

an
ts

100

0
0

No. at Risk

Pe
rc

en
ta

ge
o

f P
ar

tic
ip

an
ts

100

0
0

6 12 18 24 42 48

Months since Randomization

B First Kidney-Specific Component Event

Hazard ratio, 0.79 (95% CI, 0.66–0.94)

Difference in annual slope, 1.16 ml/min/1.73 m2/yr
(95% CI, 0.86–1.47)

P<0.0

Placebo
Semaglutide

1766
1767

1736
1738

1682
1693

1605
1640

1516
1572

1408
1489

0
0 6 12 18 24 42 4830 36

1048
1131

660
742

354
392

No. at Risk

6 12 18 24 42 48

Months since Randomization

C Death from Cardiovascular Causes

Hazard ratio, 0.71 (95% CI, 0.56–0.89)

1766
1767

1737
1739

1697
1703

1641
1665

1601
1627

1583

0
0 6 12 18 24 42 4830 36

1185
1234

772
838

437
460

e
G

FR
(m

l/
m

in
/1

.7
3

m
2 )

0
0 12 52 104 208

Weeks since Randomization

D Total eGFR Slope

Placebo
Semaglutide

1766
1766

1663
1665

1490
1521

1609
1606

1573
1590

1441
1468

1284
1345

876
952

156

609
651

199
218

No. at Risk

6 12 18 24 42 48

Months since Randomization

E First Major Cardiovascular Event

Hazard ratio, 0.82 (95% CI, 0.68–0.98)
P=0.029

1766
1767

1721
1725

1663
1672

1583
1622

1535
1575

1478
1515

0
0 6 12 18 24 42 4830 36

1133
1176

731
793

418
430

Pe
rc

en
ta

ge
o

f P
ar

tic
ip

an
ts

100

0
0 6 12 18 24 42 48

Months since Randomization

F Death from Any Cause

Hazard ratio, 0.80 (95% CI, 0.67–0.95)
P=0.01

Placebo
Semaglutide

1766
1767

1737
1739

1697
1703

1641
1665

1601
1627

1544
1583

0
0 6 12 18 24 42 4830 36

1185
1234

772
838

437
460

No. at Risk

Placebo
Semaglutide

No. at Risk

Placebo
Semaglutide

No. at Risk

Placebo

Semaglutide
Placebo

Semaglutide

Placebo

Semaglutide

Placebo

Semaglutide

Placebo

Semaglutide
Placebo

Semaglutide

n engl j med 391;2 nejm.org July 11, 2024 115

Effects of Semaglutide on Chronic Kidney Disease

during the trial, with adherence to the trial regi-
men averaging 89% of the planned time during
the trial period.

Primary Outcome

Primary-outcome events occurred less frequently
in the semaglutide group than in the placebo

group (331 first events [5.8 per 100 patient-years
of follow-up] vs. 410 first events [7.5 per 100 pa-
tient-years]), which resulted in a 24% lower rela-
tive risk of the primary outcome in the semaglu-
tide group (hazard ratio, 0.76; 95% confidence
interval [CI], 0.66 to 0.88; P = 0.0003) (Fig. 1 and
Table 2). The number of persons who would
need to be treated over 3 years to prevent one
primary-outcome event was 20 (95% CI, 14 to 40).
Lower risk with semaglutide was also observed
for a composite of the kidney-specific compo-
nents of the primary outcome (hazard ratio, 0.79;
95% CI, 0.66 to 0.94), as well as for death from
cardiovascular causes (hazard ratio, 0.71; 95% CI,
0.56 to 0.89) (Table 2). Results were consistent
across the range of prespecified sensitivity analy-
ses (Table S3) and were broadly consistent across
prespecified participant subgroups (Fig. 2).

Confirmatory Secondary Outcomes

Benefits were observed for the three confirma-
tory secondary outcomes tested in a hierarchical
fashion, all of which had two-sided P values be-
low the prespecified interim analysis threshold of
0.0322 (Table 2). The mean annual slope of the
eGFR was significantly less steep (indicating a
slower decrease) in the semaglutide group than
in the placebo group (−2.19 vs. −3.36 ml per
minute per 1.73 m2 per year; between-group dif-
ference, 1.16; 95% CI, 0.86 to 1.47; P<0.001) (Fig. 1D).

The risk of major cardiovascular events was
18% lower in the semaglutide group than in the
placebo group (212 vs. 254 events; hazard ratio,
0.82; 95% CI, 0.68 to 0.98; P = 0.029) (Fig. 1E).
Effects on the individual components of this com-
posite outcome are shown in Table 2; findings for
myocardial infarction and death from cardiovascu-
lar causes were consistent with those in the pri-
mary analysis, but the findings for stroke showed
a numerical imbalance in favor of placebo.

The risk of death from any cause was 20%
lower in the semaglutide group than in the pla-
cebo group (227 vs. 279 events; hazard ratio,
0.80; 95% CI, 0.67 to 0.95, P = 0.01) (Fig. 1F).
Over 3 years, 45 persons (95% CI, 23 to 623)
would need to be treated to prevent one major
cardiovascular event, and 39 (95% CI, 21 to 238)
would need to be treated to prevent one death
from any cause.

Figure 1 (facing page). Primary and Confirmatory
Secondary Outcomes.

Shown are cumulative incidence plots of the primary
outcome, major kidney disease events (a composite of
the onset of kidney failure [dialysis, transplantation, or
an estimated glomerular filtration rate {eGFR} of
<15 ml per minute per 1.73 m2 of body-surface area], ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes) and several confirmatory secondary outcomes: kidney-specific components of the primary outcome (persistent ≥50% reduction in eGFR, persistent eGFR of <15 ml per minute per 1.73 m2, initiation of long-term renal- replacement therapy, or death from kidney-related causes), death from cardiovascular causes, total eGFR slope, major cardiovascular events (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes), and death from any cause. Cumulative incidence estimates are based on the time from randomization to the first event, with death not included in the outcome modeled as a competing risk with the use of the Aalen–Johansen es- timator. Data from participants without events of in- terest were censored at the end of each participant’s in-trial observation period. Estimates are based on a Cox proportional-hazards model with treatment as a categorical fixed factor and stratified according to so- dium–glucose cotransporter 2 (SGLT2) inhibitor use at baseline. The eGFR data are least-squares means from a mixed model for repeated measures with treat- ment as a fixed factor; I bars indicate the standard er- ror. The annual rate of change in eGFR was analyzed with a linear random-effects model with randomiza- tion assignment, SGLT2 inhibitor use at baseline, time (as a continuous variable), and the interaction of ran- domization with time as fixed effects and including the participant effect as a random intercept and time as a random slope. On the basis of the available num- ber of primary-outcome events, the nominal signifi- cance level was updated to 0.0322 with the use of the Lan–DeMets alpha-spending function. Events that are not related to eGFR were confirmed by the event adju- dication committee. The eGFR was calculated with the serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formu- la.13 The P value cutoff for significance was 0.032 in Panels A, D, E, and F. Insets show the same data on an expanded y axis.

n engl j med 391;2 nejm.org July 11, 2024116

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Ta
bl

e
2.

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—

n engl j med 391;2 nejm.org July 11, 2024 117

Effects of Semaglutide on Chronic Kidney Disease

Other Efficacy Outcomes

The results for additional efficacy outcomes are
shown in Figure S2. At 104 weeks, the urinary
albumin-to-creatinine ratio was reduced by 12%
in the placebo group, as compared with 40% in
the semaglutide group; the ratio of the value at
week 104 to the value at baseline was 32% lower
(95% CI, 25 to 38) in the semaglutide group
than in the placebo group. Loss of kidney func-
tion, as indicated by the cystatin C–based eGFR,
was lower by 3.39 ml per minute per 1.73 m2
(95% CI, 2.63 to 4.15) in the semaglutide group
than in the placebo group at week 104. A post
hoc analysis of the change in creatinine-based
eGFR from baseline to week 104 showed an al-
most identical difference of 3.30 ml per minute
per 1.73 m2 (95% CI, 2.43 to 4.17).

At week 104, the mean reduction in body
weight was 4.10 kg greater (95% CI, 3.65 to 4.56)
in the semaglutide group than in the placebo
group, the mean reduction in the glycated hemo-
globin level was 0.81 percentage points greater
(95% CI, 0.72 to 0.90), and the mean reduction
in systolic blood pressure was 2.23 mm Hg greater
(95% CI, 1.13 to 3.33). However, the mean reduc-
tion in diastolic blood pressure was 0.78 mm Hg
greater (95% CI, 0.16 to 1.41) with placebo than
with semaglutide.

Safety Outcomes

Serious adverse events (Table 3 and Tables S4
and S5) were reported in fewer participants in
the semaglutide group than in the placebo group
(877 [49.6%] vs. 950 [53.8%]), primarily because
fewer participants in the semaglutide group were
reported to have serious infections or infestations
(317 [17.9%] vs. 376 [21.3%]) or serious cardio-
vascular disorders (273 [15.4%] vs. 319 [18.1%]).
Eye disorders reported as serious adverse events
were more common among participants who re-
ceived semaglutide than among those who re-
ceived placebo (53 [3.0%] vs. 30 [1.7%]), whereas
the numbers of systematically recorded diabetic
retinopathy events were similar in the two groups
(504 events among 402 participants [22.8%] in
the semaglutide group and 483 events among
398 participants [22.5%] in the placebo group).
Adverse events leading to permanent discon-
tinuation of semaglutide or placebo were more
common in the semaglutide group than in the
placebo group (233 [13.2%] vs. 211 [11.9%]); this
finding was driven mainly by discontinuation O

ut
co

m
e

Se
m

ag
lu

tid
e

=
1

76
7)

Pl
ac

eb
o

=
1

76
6)

H
az

ar
d

R
at

(
95

%
C

I)
Es

tim
at

ed
D

iff
er

en
ce

(

95
%

C
I)

P
V

al
ue

M
aj

or
a

dv
er

se
li

m
b

ev
en

t i
n

a
tim

e-
to

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rs

t-
ev

en
t a

na
ly

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s

—
n

of
e

ve
nt

s
16

28
0.

56
(

0.
30

to
1

.0
2)

—
—

N
o.

o
f s

ev
er

e
hy

po
gl

yc
em

ic
e

pi
so

de
s

47
46

1.
02

(
0.

62
to

1
.6

7)
‡

—
—

Su
pp

le
m

en
ta

ry
a

na
ly

si
s:

d
ea

th
fr

om
n

on
ca

rd
io

va
sc

ul
ar

a
nd

n
on

–k
id

–
ne

y-
re

la
te

d
ca

us
es

in
a

ti
m

e-
to

-fi
rs

t-
ev

en
t a

na
ly

si
s

—
n

of
e

ve
nt

99
10

5
0.

93
(

0.
70

to
1

.2
2)

—
—

*
D

at
a

ar
e

fo
r

th
e

fu
ll

an
al

ys
is

p
op

ul
at

io
n

fr
om

t
he

in
-t

ri
al

p
er

io
d

(f
ro

m
r

an
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m
iz

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t
he

e
nd

o
f t

ri
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p
ar

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ip

at
io

n)
. C

om
po

si
te

k
id

ne
y

di
se

as
e

ev
en

ts
a

nd
c

om
po

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te

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aj

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va

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ul

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al

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ed

in
a

t
im

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to

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t-
ev

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t

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al

ys
is

w
ith

t
he

u
se

o
f a

C
ox

p
ro

po
rt

io
na

l-h
az

ar
ds

m
od

el
w

ith
t

re
at

m
en

t
as

a
c

at
eg

or
ic

al
fi

xe
d

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ct

or
a

nd
s

tr
at

ifi
ed

a
cc

or
di

ng
t

o
SG

LT
2

in
hi

bi
to

r
us

e
at

b
as

el
in

e.
D

at
a

fr
om

p
ar

tic
ip

an
ts

w
ith

ou
t

ev
en

ts
o

f i
nt

er
es

t
w

er
e

ce
ns

or
ed

a
t

th
e

en
d

of
t

he
ir

in
-t

ri
al

p
er

io
d.

T
he

n
om

in
al

s
ig

ni
fic

an
ce

le
ve

w
as

u
pd

at
ed

t
o

0.
03

w
ith

t
he

u
se

o
f t

he
L

an
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eM
et

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al

ph
a-

sp
en

di
ng

fu
nc

tio
n.

T
he

e
G

FR
w

as
c

al
cu

la
te

d
w

ith
s

er
um

c
re

at
in

in
e

le
ve

l a
nd

t
he

C
hr

on
ic

K
id

ne
y

D
is

ea
se

E
pi

de
m

io
lo

gy
C

ol
la

bo
ra

tio
n

fo
rm

ul
a.

en
ts

n
ot

r
el

at
ed

t
o

th
e

eG
FR

w
er

e
co

nf
ir

m
ed

b
y

th
e

ev
en

t
ad

ju
di

ca
tio

n
co

m
m

itt
ee

. “
Pe

rs
is

te
nt

”
w

as
d

ef
in

ed
a

s
tw

o
co

ns
ec

ut
iv

e
m

ea
su

re
m

en
ts

a
t

le
as

t
4

w
ee

ks
a

pa
rt

fu
lfi

lli
ng

t
he

ite
ri

a.
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ea
th

fr
om

c
ar

di
ov

as
cu

la
r

ca
us

es
, a

s
co

nf
ir

m
ed

b
y

th
e

ev
en

t
ad

ju
di

ca
tio

n
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m
m

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ee

, i
nc

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de

s
bo

th
d

ea
th

fr
om

c
ar

di
ov

as
cu

la
r

ca
us

es
a

nd
d

ea
th

fr
om

u
nd

et
er

m
in

ed
c

au
se

s
ad

ju
di

ca
te

d
by

t
ha

t
co

m
m

itt
ee

.
†

T
he

p
ri

m
ar

y
ou

tc
om

e
w

as
m

aj
or

k
id

ne
y

di
se

as
e

ev
en

ts
, a

c
om

po
si

te
o

f t
he

o
ns

et
o

f k
id

ne
y

fa
ilu

re
(

di
al

ys
is

, t
ra

ns
pl

an
ta

tio
n,

o
r

an
e

G
FR

o
f <

15
m

l p
er

m
in

ut
e

pe
r

1.
73

m
2 )

, a
t

le
as

t
a

50
%

r
ed

uc
tio

n
in

e
G

FR
fr

om
b

as
el

in
e,

o
r

de
at

h
fr

om
k

id
ne

y-
re

la
te

c
ar

di
ov

as
cu

la
r

ca
us

es
. A

dj
us

tm
en

t
fo

r
th

e
gr

ou
p

se
qu

en
tia

l d
es

ig
n

w
as

p
er

fo
rm

ed
w

ith
t

he
u

se
o

f l
ik

el
ih

oo
d-

ra
tio

de
ri

ng
.

‡
V

al
ue

is
t

he
r

at
io

o
f t

he
v

al
ue

in
t

he
s

em
ag

lu
tid

e
gr

ou
p

to
t

he
v

al
ue

in
t

he
p

la
ce

bo
g

ro
up

n engl j med 391;2 nejm.org July 11, 2024118

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

0.50 1.00 2.00

Placebo BetterSemaglutide Better

Primary analysis, all patients

Sex

Female

Male

Age

<65 yr

≥65 to <75 yr

≥75 yr

Body-mass index

≤30

>30

Duration of diabetes

<15 yr

≥15 yr

Glycated hemoglobin

≤8.0%

>8.0%

≤7.0%

>7.0%

Geographic region

North America

Europe

Asia

Other

Race or ethnic group

Asian

Black

White

Other

Hispanic or Latinx ethnic group

Yes

Estimated GFR

≥60 ml/min/1.73 m2

≥45 to <60 ml/min/1.73 m2

≥30 to <45 ml/min/1.73 m2

<30 ml/min/1.73 m2

Urinary albumin‐to‐creatinine ratio

<300

≥300

Cardiovascular disease

No previous myocardial infarction or stroke

Previous myocardial infarction of stroke

Chronic heart failure

Yes

Insulin use

Yes

Metformin use

Yes

SGLT2 inhibitor use

Yes

Semaglutide Hazard Ratio (95% CI)PlaceboSubgroup
no. of participants with event/no. of participants in analysis

0.25

98/423 102/442 0.98 (0.74–1.30)

98/478 98/434 0.85 (0.65–1.13)

331/1767 410/1766 0.76 (0.66–0.88)

88/519 127/550 0.70 (0.53–0.92)

243/1248 283/1216 0.79 (0.66–0.94)

131/633 175/652 0.71 (0.57–0.90)

160/816 170/773 0.85 (0.69–1.06)

40/318 65/341 0.63 (0.42–0.93)

142/734 164/733 0.82 (0.65–1.03)

189/1031 244/1029 0.73 (0.61–0.89)

148/774 153/753 0.90 (0.72–1.13)
183/992 257/1013 0.68 (0.56–0.82)

200/1106 251/1093 0.75 (0.62–0.90)

131/659 159/672 0.79 (0.63–1.00)

104/536 147/571 0.69 (0.54–0.89)

227/1229 263/1194 0.80 (0.67–0.96)

65/472 104/491 0.61 (0.45–0.83)

70/394 106/399 0.62 (0.46–0.84)

95/439 95/407 0.86 (0.64–1.14)

20/78 24/82 0.81 (0.44–1.46)

197/1155 260/1168 0.73 (0.61–0.88)

11/56 21/69 0.63 (0.29–1.28)

57/273 89/283 0.61 (0.43–0.85)

261/1421 298/1411 0.83 (0.70–0.98)

41/366 59/353 0.64 (0.43–0.96)

80/515 103/540 0.78 (0.58–1.04)

137/667 181/691 0.74 (0.59–0.92)

73/218 67/182 0.81 (0.58–1.13)

55/561 62/552 0.86 (0.60–1.23)

276/1205 348/1214 0.74 (0.63–0.87)

240/1345 308/1343 0.73 (0.62–0.87)

87/405 93/403 0.91 (0.68–1.22)

264/1424 322/1430 0.79 (0.67–0.93)

67/342 88/336 0.67 (0.49–0.93)

114/684 129/681 0.85 (0.66–1.09)

217/1083 281/1085 0.72 (0.61–0.86)

193/859 219/842 0.80 (0.66–0.97)

138/908 191/924 0.71 (0.57–0.88)

290/1490 372/1493 0.73 (0.63–0.85)

41/277 38/273 1.07 (0.69–1.67)

n engl j med 391;2 nejm.org July 11, 2024 119

Effects of Semaglutide on Chronic Kidney Disease

because of gastrointestinal disorders (79 [4.5%]
vs. 20 [1.1%]).

Discussion

In our trial involving patients with type 2 diabe-
tes and chronic kidney disease, semaglutide at a
dose of 1.0 mg once weekly significantly reduced
the risk of major kidney disease events (the pri-
mary outcome), by 24%. Semaglutide also reduced
the risk of major cardiovascular events and death
from any cause while slowing the annual loss of
kidney function by a mean of 1.16 ml per minute
per 1.73 m2. These benefits reflect important
clinical effects on kidney, cardiovascular, and sur-
vival outcomes among high-risk patients, particu-
larly given the reassuring safety findings, and
support a therapeutic role for semaglutide in
this population.

The use of GLP-1 receptor agonists in broader
populations with type 2 diabetes has previously
been shown to improve glycemic control, de-
crease body weight, and reduce cardiovascular
events.11,15,16 However, previous dedicated trials
addressing clinically important kidney outcomes,
such as kidney failure or a substantial decline in
the eGFR, have been lacking. The effects on sec-
ondary and post hoc kidney outcomes in clinical
trials of GLP-1 receptor agonists for cardiovas-
cular outcomes and glycemic control have sug-
gested benefits.15 The magnitude of the benefits
observed in our trial provides confidence that
the use of semaglutide in patients with type 2

diabetes and chronic kidney disease will reduce
the risk of kidney failure and slow the decline in
the eGFR, as well as reduce the risk of cardio-
vascular events and death.

Few previous trials of GLP-1 receptor agonists
have recruited substantial numbers of partici-
pants with considerably reduced kidney func-
tion. The cardiovascular and survival benefits of
semaglutide in such patients are particularly im-
portant, since they are among the populations at
highest risk for cardiovascular disease and death.

Because three other guideline-directed medi-
cal therapies have been shown to have benefits
in patients with type 2 diabetes and chronic kid-
ney disease (RAS inhibition, SGLT2 inhibition,
and mineralocorticoid-receptor antagonism with
finerenone),17 clinicians and patients will need
to consider the order and priority of use for
semaglutide (and, once studied, other GLP-1 re-
ceptor agonists). Although studies of SGLT2 in-
hibitors in patients with chronic kidney disease
have clearly identified important benefits with
respect to kidney outcomes,4-6 the findings re-
garding effects on major cardiovascular events
and death from any cause in this population
have been mixed. In the context of the favorable
safety profile, the benefits for these outcomes
shown in the present trial provide a rationale for
consideration of the use of semaglutide along
with these other proven therapies as part of the
initial therapeutic options in this patient popula-
tion. Combination therapy is likely to be impor-
tant in the future, and we found no clear hetero-
geneity of effect among patients receiving SGLT2
inhibitors at baseline as compared with those
who were not, although the statistical power of
this analysis was limited. Further analyses of these
data are planned, and studies assessing approach-
es to combination therapy should be a priority.

The mechanisms of kidney protection with
semaglutide are likely to be multifactorial. Al-
though a reduction in kidney and cardiovascular
risk factors may contribute, a previous mediation
analysis showed that these factors only modestly
mediated effects on kidney outcomes.11 In addi-
tion, the effect of semaglutide was unrelated to
changes in body weight regardless of whether
the eGFR was computed with serum creatinine,
cystatin C, or both,18,19 and consistent effects on
creatinine-based and cystatin C–based eGFR were
identified in this trial. On the basis of experi-
mental models and biomarker data, the direct

Figure 2 (facing page). Subgroup Analysis of the Primary
Outcome.

For the primary analysis, the hazard ratio and confi-
dence interval were adjusted for the group sequential
design with the use of likelihood-ratio ordering. For
the subgroup analyses, estimated hazard ratios and
corresponding confidence intervals were calculated in
a stratified Cox proportional-hazards model with the
interaction between randomly assigned group and the
relevant subgroup as a fixed factor. The model is
stratified according to SGLT2 inhibitor use at baseline.
Gray shading highlights the 95% confidence interval
for the result in the overall population. The body-mass
index is the weight in kilograms divided by the square
of the height in meters. Race and ethnic group were
reported by the participants; “other” includes Ameri-
can Indian or Alaska Native, Native Hawaiian or other
Pacific Islander, and “not reported.” For the urinary
albumin-to-creatinine ratio, albumin was measured in
milligrams and creatinine in grams.

n engl j med 391;2 nejm.org July 11, 2024120

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

effects of GLP-1 receptor agonists on the kidney
may include decreases in inflammation, oxidative
stress, and fibrosis. Intrinsic kidney and immune
cells contain the GLP-1 receptor, and GLP-1 recep-
tor agonists reduce cellular expression of proin-
flammatory and profibrotic mediators.20-23

Our trial has important strengths. This trial
of a GLP-1 receptor agonist in a population of
patients with chronic kidney disease and type 2
diabetes assessed clinically important outcomes,
and significant benefits were shown for kidney
and cardiovascular outcomes and death from any
cause. The trial was large and rigorous and pro-
vides clear conclusions about benefits and risks.
It also has some important limitations. Because
SGLT2 inhibitors and nonsteroidal MRAs had
not been approved for kidney protection at the
time the trial was initiated, the number of partici-

pants who were receiving these agents at base-
line was modest, which limited our ability to
assess the effects of combination therapy. The
trial was also not powered to detect differences
within and between important subgroups, and
most participants identified their race as White,
whereas kidney disease disproportionately affects
marginalized populations, especially Black and
Indigenous persons. The effects on kidney func-
tion may not be generalizable to other popula-
tions, such as those at lower risk, and the trial
was not powered to separately detect effects on
kidney failure. Finally, it is possible that modest
weight loss could slightly lower serum creatinine
levels, but the almost identical effects on the
cystatin C–based and creatinine-based eGFR in-
dicate that this is unlikely to meaningfully influ-
ence the trial results.

Table 3. Safety Outcomes.

Adverse Event
Semaglutide
(N = 1767)

Placebo
(N = 1766)

no. of participants (%)

Serious adverse event 877 (49.6) 950 (53.8)

Adverse event leading to permanent discontinuation of semaglutide
or placebo

233 (13.2) 211 (11.9)

Prespecified adverse events of special interest

Diabetic retinopathy* 402 (22.8) 398 (22.5)

Covid-19–related disorder 358 (20.3) 404 (22.9)

Serious adverse event: cardiovascular disorder 273 (15.4) 319 (18.1)

Heart failure* 133 (7.5) 175 (9.9)

Acute kidney failure* 172 (9.7) 182 (10.3)

Malignant tumor* 120 (6.8) 104 (5.9)

Serious adverse event: gastrointestinal disorder 95 (5.4) 94 (5.3)

Serious adverse event: rare event 48 (2.7) 57 (3.2)

Acute gallbladder disease* 32 (1.8) 39 (2.2)

Severe hypoglycemia* 37 (2.1) 37 (2.1)

Medication error* 15 (0.8) 13 (0.7)

Serious adverse event: hepatic disorder 18 (1.0) 20 (1.1)

Acute pancreatitis* 10 (0.6) 7 (0.4)

Serious adverse event: allergic reaction 6 (0.3) 9 (0.5)

Serious adverse event: abuse and misuse 1 (0.1) 4 (0.2)

Serious adverse event: suspected transmission of infectious
agent through semaglutide or placebo

0 1 (0.1)

* Data were from an additional data-collection form; data for all other prespecified events of special interest were col-
lected by means of a Medical Dictionary for Regulatory Activities search.

n engl j med 391;2 nejm.org July 11, 2024 121

Effects of Semaglutide on Chronic Kidney Disease

In this trial, semaglutide reduced the risk of
clinically important kidney outcomes, major car-
diovascular events, and death from any cause in
participants with type 2 diabetes and chronic kid-
ney disease.

Supported by Novo Nordisk.

Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.

We thank all the patients who participated in this trial, as
well as the site investigators and staff; and Isabella Goldsbrough
Alves, Ph.D., of Apollo, OPEN Health Communications, for edi-
torial assistance with earlier versions of the figures.

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Copyright © 2024 Massachusetts Medical Society.

Effects of Semaglutide on Chronic Kidney Disease in Patients with Type

Diabetes: Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial

Valerie Nguyen

General Study Overview
Citation for this article	Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. Published online May 24, 2024. doi:10.1056/NEJMoa2403347
Background
Title	· Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes · New England Journal of Medicine · Published May 24, 2024
Background	· Over time, uncontrolled type 2 diabetes mellitus (T2DM) can cause chronic kidney disease (CKD) and affects over half a billion people worldwide. As fibrosis continues, proteinuria will cause further damage. · Although there are drugs that have shown to be renal protective and decrease the risk of cardiovascular disease, such as RAS inhibitors and SGLT2 inhibitors, many people continue to lose kidney function. · This study was conducted to find the efficacy and safety of using a glucagon-like peptide 1 (GLP-1) receptor agonist, semaglutide 1.0 mg SUBQ once weekly, to prevent kidney failure and damage to those with T2DM and CKD.
Previous Trials	· LEADER (2016): multicenter, double blind, placebo-controlled trial to show the impact of liraglutide on death from CV events, nonfatal MI, or nonfatal stroke. Prespecified outcomes included composite renal microvascular outcomes (nephropathy, the need for continuous renal replacement therapy, or death from renal disease). The incidence was lower in the liraglutide group than in the placebo group with: · Hazard ratio: 0.78; 95% CI: 0.67 to 0.92; P=0.003 · SUSTAIN-6 (2016): randomized, double blind, placebo controlled, parallel group trial to show the impact of semaglutide on death from CV events, nonfatal MI, or nonfatal stroke. Prespecified secondary outcomes included new or worsening nephropathy occurred in 3.8% in the semaglutide group vs 6.1% in the placebo group. · Hazard ratio: 0.64; 95% CI: 0.46 to 0.88; P=0.005
Funding	· Sponsored, managed trial operations, and analysis by Novo Nordisk
Objective
Study Objective	· To evaluate if semaglutide 1.0 mg SUBQ once weekly will delay the progression of renal damage compared to placebo in patients with T2DM and CKD.
Methods
Study Design	· International, double blinded, randomized, placebo controlled · Intention to treat protocol
Enrollment	· N = 3533, with a 1:1 randomization to receive semaglutide (N=1767) or placebo (N=1766) · Performed at 387 sites in 28 countries (recruitment from June 2019-May 2021)
Inclusion Criteria	· Informed consent obtained · Age ≥18 years · Diagnosed with T2DM · HbA1c ≤ 10% · Serum creatinine based eGFR between 50-75 mL/min/1.73 m2 using 2009 CKD-EPI and UACR between 300–5000 mg/g or serum creatinine based eGFR between 25 – 50 mL/min/1.73 m2 using 2009 CKD-EPI and UACR between 100 – 5000 mg/g · Treated with maximum tolerated dose of RAAS inhibitor (ACE inhibitor or ARB), unless contraindicated, for ≥4 weeks before lab assessments measured for inclusion criteria and kept stable until screening
Exclusion Criteria	· Congenital or hereditary kidney disease · Use of GLP-1 receptor agonist within 30 days before screening · MI, stroke, hospitalization for unstable angina pectoris or TIA within 60 days before screening · NYHA Class IV heart failure · Planned coronary, carotid, or peripheral artery revascularization · Current or within 90 days of chronic or intermittent hemodialysis or peritoneal dialysis · Uncontrolled and unstable diabetic retinopathy or maculopathy
Interventions	· Two arms: semaglutide at an 8 week dose-escalation regimen given that unacceptable side effects did not occur from 0.25 mg SUBQ weekly x 4 weeks, then 0.5 mg SUBQ weekly x 4 weeks, then 1.0 mg SUBQ weekly for the remaining treatment period · The trial ended with a final participant visit on January 9, 2024
Primary endpoint	· Major kidney disease events · Initiation of long-term dialysis · Kidney transplant · eGFR reduction to <15 ml/min/1.73m2 for ≥28 days · ≥50% reduction in eGFR compared to baseline · Renal or CV death · Calculated a minimum of 854 primary events needed to provide 90% power to detect a 20% relative risk in the semaglutide group than placebo at an overall one-sided significance level of 2.5%
Secondary endpoints	· Annual rate of eGFR change using CKD-EPI · Time to first occurrence of major CV events (non-fatal MI, non-fatal stroke, CV death) · Time to occurrence of all cause death
Other efficacy endpoints	· UACR · Body weight
Safety endpoints	· CV, eye, or GI disorders · Infections or infestations
Key definitions	· Kidney disease – eGFR 50-75 ml/min/1.73m2 using 2009 CKD-EPI equation with UACR 300-5000 mg/g or eGFR 25-50 ml/min/1.73m2 with UACR 100-5000mg/g · Type 2 diabetes – glycated hemoglobin level ≤ 10%
Statistics	· The trial was event driven, with time-to-first-event outcomes analyzed using a stratified Cox proportional hazards model with randomization as a fixed factor and grouped according to SGLT2 inhibitor use at baseline · P values obtained using a score test · Pre-specified subgroups for primary endpoint analysis included baseline eGFR, UACR, and SGLT2 inhibitor use · Secondary outcomes analyzed with two sided CI’s and an alpha value of < 0.05 considered significant
Results
Baseline Characteristics See Table 1, pages 4-5 in article	· Mean age of 66.6 years with ~30% women · Mean eGFR was 47 ml/min/1.73m2 with mean UACR being 567.6 mg/g · 68% of participants at high risk for kidney disease progression, kidney failure, CV events, or death · Patient demographic characteristics were matched with no significant difference between the treatment and placebo group
Primary endpoint results See Table 2, pages 8-9 in article	· 331 first events(18.7%) in semaglutide arm vs. 410 first events (23.2%) in placebo arm · Hazard ratio 0.76; 95% confidence interval [CI] 0.66 to 0.88; P=0.0003 · NTT over 3 years to prevent one primary outcome event was 20 (95% CI 14-40) · Results were consistent across range of prespecified sensitivity analysis and participant subgroups
Secondary endpoint results See Table 2, pages 8-9 in article	· Mean annual slope of eGFR was less steep in semaglutide vs placebo · Risk of major CV events was lower in semaglutide vs placebo (individual components of MI and death from CV events were consistent with primary analysis but fewer stroke in placebo vs semaglutide) · Risk of death from any cause was lower in semaglutide vs placebo · NNT = 45 persons over 3 years to prevent one major CV event · NNT = 39 persons over 3 years to prevent once death from any cause
Author’s Conclusions
Author’s Conclusions	”Semaglutide at a dose of 1.0 mg once weekly significantly reduced the risk of major kidney disease events (the primary outcome), by 24%. Semaglutide also reduced the risk of major cardiovascular events and death from any cause while slowing the annual loss of kidney function by a mean of 1.16 ml/minute/1.73 m2”
Discussion
Strengths	· Large, international, multicenter population · double blinded, randomized, placebo-controlled trial Patient demographic characteristics were matched with no significant difference between the treatment and placebo group
Limitations	· Did not assess effects of combination therapy of SGLT2 inhibitors or nonsteroidal MRAs · No generalizable to marginalized populations such as Black and Indigenous persons or persons with lower risk of kidney disease progression · Novo Nordisk sponsored, maintained the clinical database, conducted statistical analysis, and reviewed the manuscript to provide suggested revisions
Overall Assessment
Although the FLOW trial has limitations, it has showed statistically and clinically significant results in reducing the risk of major kidney disease compared to placebo for those with T2DM and CKD. Future studies need to be done to access combination therapy, especially since SGLT2 inhibitors and nonsteroidal MRAs have been approved for kidney protection and affect more patients.

References:

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.
N Engl J Med. Published online May 24, 2024. doi:10.1056/NEJMoa2403347

Tommerdahl KL, Kendrick J, Bjornstad P. The Role of Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists in the Prevention and Treatment of Diabetic Kidney Disease: Insights from the AMPLITUDE-O Trial.
Clin J Am Soc Nephrol. 2022;17(6):905-907. doi:10.2215/CJN.00020122

Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141

Yu JH, Park SY, Lee DY, Kim NH, Seo JA. GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions.
Kidney Res Clin Pract. 2022;41(2):136-149. doi:10.23876/j.krcp.22.001

Effects of Semaglutide on Chronic Kidney Disease in Patients with Type

Diabetes

RxKnowledge PLLC

trial is designed to assess whether treatment with once-weekly subcutaneous semaglutide delays the progression of kidney disease and lowers the risk of kidney failure, as well as kidney and CV disease mortality, compared with placebo in people with CKD and T2D

Introduction

Semaglutide part of the incretinmimetics is a glucagon-like peptide-1 receptor agonist commonly used for type 2 diabetes and obesity
Currently it is amongst the first line treatment in diabetes especially in patients with ASCVD
A few questions for discussion: have providers had any insight reggarding semaglutide use in their patients with diabetic retinopathy? Are they reluctant to use semaglutide?
Have providers changed their strategy with t2dm in using tirzepatide over semaglutide or what is the usual question if any when it comes to semaglutide vs tirzepatide
Have providers changed their standard of care with CKD/DM patients

GLP-1 RA: Semaglutide

FDA Approved for Type 2 DM

Phase 3 Trial: FLOW

Methods

Participants were required to be on RAAS blockade unless treatment was contraindicated or not tolerated; overall, 95.3% were receiving RAAS inhibitors at baseline
Many participants had comorbidities such as neuropathy and retinopathy (43.0% and 44.9%, respectively) at baseline.
A medical history of CVD was also common (52.0%) and 19.1% of participants had previous heart failure.
The most frequently used glucose-lowering medications at baseline were insulin (61.5%) and metformin (51.6%), and 15.5% of participants were receiving SGLT2is

Study Design

Phase 3b study

Randomized, double blind, parallel group, multinational

Study Population

3534 enrolled patients; average age of 66.6 years

Average hemoglobin A1c of 7.8%

Average duration of diabetes 17.4 years

Treatment Protocol

Dose escalation regimen

Expected duration of approximately 5 years

Funding

Novo Nordisk

Median follow up of 3.4 years

Methods

kidney outcomes trial to assess semaglutide, a once-weekly GLP-1RA, in a population with CKD and T2D at high risk of kidney disease progression.
FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial
randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with dose escalation (as tolerated) from 0.25 mg/week for 4 weeks to 0.5 mg for 4 weeks, followed by a maintenance dose of 1.0 mg/week throughout the remainder of the treatment period.
The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested as well and them being total eGFR slope, major CV event or death from CV causes and death from any cause 4 Results The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group confidence interval [CI], 0.66 to 0.88; Pvalue=0.0003 meaning a very clinically significance In the chart we see the eGFR rate and the slope was less steep indicating a slower decrease 5 Results This slide continues to show the primary and secondary endpoints in the semagltuide and placebo groups The risk of major cardiovascular events was 18% lower in the semaglutide group than in the placebo The risk of death from any cause was 20% lower in the semaglutide group than in the placebo group At 104 weeks, the urinary albumin-to-creatinine ratio was reduced by 12% in the placebo group, as compared with 40% in the semaglutide group Even the mean reduction in body weight was 4kg ggreater in the semaglutide group than placebo so we can see clinical significance with semaglutide use in these patients wtih a range of benefits 6 Safety Look at the safety profile, we see that serious adverse events were reported in fewer patients in the semaglutide group than in the placebo group (about 50% vs 54%). Althouggh this is a small incremental change, we can still say it is clinically significant. Also, less patients in the semaglutide group were reported to have serious infections or infestations (about 18% vs 21%) or serious CV disorders (15.4% vs 18.1%) which is something to keep in mind. The most significant and most common serious event were eye disorders, which was more common in the semaglutide group than placebo (52 patients vs 30 patients), but both groups reported similar diabetic retinopathy events 8 Strengths and Weaknesses of the FLOW trial Strengths Large Sample Size; Rigorous Study Long Follow-Up Period Target Population Comprehensive Outcome Measures Weaknesses/Limitations Specific to Type 2 Diabetes Short-Term Renal Outcomes Lack of Racial Diversity Limited Use of SGLT2 Inhibitors and MRAs The trial included a large population, with well-conducted procedures which strengthens the reliability of the conclusions drawn about the benefits and risks of semaglutide. And also it being a randomized, double-blind, placebo-controlled trial, it is considered a gold standard in clinical trial design, minimizing bias and enhancing the reliability of results. The trial’s follow-up duration (~5 years) ensures long-term data on both efficacy and safety, providing a better understanding of semaglutide’s impact on CKD progression The inclusion of patients with CKD, a high-risk and often underrepresented population in clinical trials, addresses a significant unmet medical need, as many diabetes treatments are not suitable for these patients. The trial assessed key outcomes like kidney and cardiovascular function, as well as overall mortality, offering significant clinical insights. And the conclusions are clear on the benefits and risks again showing significant benefits in reducing kidney and CV issues, all cause mortality and adding treatment decisions for CKD in type 2 DM patients he trial focuses on patients with type 2 diabetes and CKD, so the results may not be applicable to those with CKD but without diabetes, limiting generalizability to the broader CKD population. The trial does include long term follow up but some kidney improvement functions may take longer to manifest and the some of the putcomes may not fully capture the long term renal protective effects of semalgutide beyond the study duration Most participants identified as White, whereas CKD disproportionately affects marginalized populations like Black and Indigenous people. This limits the generalizability of the findings across different racial groups. At the beginning of the trial SGGLT2i and MRAs were not widely used for kidney protection, leading to smaller sample soze of participants on these agents which limits the assessment of combination therapies 9 Conclusion Clinical Impact: Semaglutide shows to reduce risk of clinically important kidney outcomes and death from cardiovascular events in patients with type 2 diabetes and chronic kidney disease Provides a new potential option for kidney and cardiovascular protection in patients with CKD and type 2 diabetes. Primary Endpoint: the study achieved notable reduction in loss of kidney function Secondary Endpoints: demonstrated promising results in reducing the decrease in eGFR, major cardiovascular events and risk of death from any cause Because three other therapies have been shown to have benefits in patients with type 2 diabetes and CKD (renin-angiotensin system inhibition, SGLT2 inhibition, and mineralocorticoid with finerenone), clinicians will need to consider the order and priority of use for semaglutide and will need to individualize therapy with a possible role for combination of these agents Future Research Needed: Further studies should explore combination therapies, diverse populations, and longer-term outcomes to enhance generalizability. If I were to approach the FLOW trial differently: first I would Increase Diversity in the Study Population, prioritzing more racially diverse cohort especially populations disproportionately affected by CKD such as black and indigenous groups Incorporate SGLT2 Inhibitors and MRAs Early: given the role SGLT2i and MRAs play in kidney protection, I would design the study to include higher proportion of participants on these agents to get a more comprehensive assessment of the effects of combo therapy with semaglutidse I also would power the study for subgroup analysis to detect more meaningful differences within and between important subgroups like patients with different stages of CKD, or different racial/ethnic groups I would also consider including kidney failure as a primary endpoint to provide more targeted data on the progression of CKD in relation to semaglutide treatment 10 References Perkovic V, Perkovic V, Perkovic V, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England journal of medicine/�The �New England journal of medicine. Published online May 24, 2024. doi:https://doi.org/10.1056/nejmoa2403347 Rossing P, Baeres FMM, Bakris G, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrology Dialysis Transplantation. Published online January 18, 2023. doi:https://doi.org/10.1093/ndt/gfad009 de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022;45:3075-3090.‌ ‌Mann JFE, Buse JB, Idorn T, et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab 2021;23:2058-2066. image1 image2 image3 image4 image5

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