new england

The
journal of medicine
established in 1812 July 11, 2024 vol. 391 no. 2

Effects of Semaglutide on Chronic Kidney Disease

in Patients with Type 2 Diabetes
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*​​
a bs t r ac t
BACKGROUND
Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney From the University of New South Wales,
failure, cardiovascular events, and death. Whether treatment with semaglutide would Sydney (V.P.); the Division of Nephrolo-
gy, University of Washington School of
mitigate these risks is unknown. Medicine, Seattle, and Providence Medi-
METHODS cal Research Center, Providence Inland
Northwest Health, Spokane — both in
We randomly assigned patients with type 2 diabetes and chronic kidney disease Washington (K.R.T.); Steno Diabetes Cen-
(defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute ter Copenhagen, Herlev (P.R.), the De-
per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albu- partment of Clinical Medicine, University
of Copenhagen, Copenhagen (P.R.), and
min measured in milligrams and creatinine measured in grams] of >300 and <5000 Novo Nordisk, Søborg (F.M.M.B., T.I.,
or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creati- H.B.-T., N.L.L.) — all in Denmark; Stan-
nine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg ford Center for Clinical Research, Depart-
ment of Medicine, Stanford School of
weekly or placebo. The primary outcome was major kidney disease events, a compos- Medicine, Palo Alto, CA (K.W.M.); KfH
ite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per Kidney Center, Munich, and University
minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from Hospital, Friedrich-Alexander University,
Erlangen — both in Germany (J.F.E.M.);
kidney-related or cardiovascular causes. Prespecified confirmatory secondary out- the Department of Medicine, American
comes were tested hierarchically. Heart Association Comprehensive Hyper-
RESULTS tension Center, University of Chicago Medi-
cine, Chicago (G.B.); and AdventHealth
Among the 3533 participants who underwent randomization (1767 in the semaglutide Translational Research Institute, Orlando,
group and 1766 in the placebo group), median follow-up was 3.4 years, after early FL (R.P.). Dr. Perkovic can be contacted
trial cessation was recommended at a prespecified interim analysis. The risk of a at ­vlado​.­perkovic@​­unsw​.­edu​.­au or at the
Chancellery, University of New South
primary-outcome event was 24% lower in the semaglutide group than in the placebo Wales, Sydney, NSW 2052, Australia.
group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66
*The FLOW Trial Committees and Inves-
to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific com- tigators are listed in the Supplementary
ponents of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for Appendix, available at NEJM.org.
death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results This article was published on May 24, 2024,
for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR and updated on September 17, 2024, at
slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 NEJM.org.

in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower N Engl J Med 2024;391:109-21.
(hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any DOI: 10.1056/NEJMoa2403347
Copyright © 2024 Massachusetts Medical Society.
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 CME
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.)
n engl j med 391;2 nejm.org July 11, 2024 109
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 The n e w e ng l a n d j o u r na l of m e dic i n e

M
ore than half a billion people Relevant approval from regulatory authorities
globally are affected by chronic kidney and institutional review boards was obtained. Each
disease and are at high risk for kidney participant provided written informed consent
failure, cardiovascular events, and death.1 Type 2 before undergoing any trial-related procedures.
diabetes is the most frequent cause of chronic
kidney disease in many countries. Renin–angio- Participants
A Quick Take
is available at tensin system (RAS) inhibitors,2,3 sodium–glucose Adults with type 2 diabetes (glycated hemoglo-
NEJM.org cotransporter 2 (SGLT2) inhibitors, and finere- bin level, ≤10%) were eligible for inclusion in the
none have been shown to protect the kidneys and trial if they had high-risk chronic kidney disease
reduce the risk of adverse cardiovascular out- and were receiving a stable maximal labeled dose
comes4-8 and therefore are guideline-directed med- (or the maximal dose without unacceptable side
ical therapies for chronic kidney disease in patients effects) of RAS inhibitors (angiotensin-convert-
with type 2 diabetes.9,10 Nevertheless, many pa- ing–enzyme inhibitor or angiotensin-receptor
tients continue to lose kidney function and go blocker). Kidney disease was defined by an esti-
on to have kidney failure or to die, most com- mated glomerular filtration rate (eGFR) of 25 to
monly from cardiovascular events. Thus, the ef- 75 ml per minute per 1.73 m2 of body-surface
fects of therapies such as glucagon-like peptide 1 area (calculated with the serum creatinine level
(GLP-1) receptor agonists are of great interest.11 and the Chronic Kidney Disease Epidemiology
The FLOW (Evaluate Renal Function with Collaboration [CKD-EPI] 2009 formula,13 which
Semaglutide Once Weekly) trial assessed the ef- were used to calculate all reported eGFR values
ficacy and safety of subcutaneous semaglutide at unless otherwise indicated), with a urinary albu-
a dose of 1.0 mg once weekly for the prevention min-to-creatinine ratio (with albumin measured
of kidney failure, substantial loss of kidney func- in milligrams and creatinine measured in grams)
tion, and death from kidney-related or cardiovas- of greater than 300 and less than 5000 if the
cular causes in patients with type 2 diabetes and eGFR was 50 ml per minute per 1.73 m2 or
chronic kidney disease. 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
Me thods
1.73 m2. Patients who were unable to receive RAS
Trial Design and Oversight inhibition because of side effects were eligible
We published the design of this international, for inclusion. A full list of inclusion and exclusion
double-blind, randomized, placebo-controlled trial criteria, including a range of specific kidney dis-
previously.12 The trial was overseen by an academ- ease diagnoses, is provided in the Supplementary
ic-led steering committee (see the Supplementa- Appendix.
ry Appendix, available with the full text of this
article at NEJM.org) in partnership with the trial Trial Procedures
sponsor, Novo Nordisk, which also managed trial Eligible participants were randomly assigned in
operations. The trial steering committee provided a 1:1 ratio to receive semaglutide or matching
overall leadership; oversaw trial design, conduct, placebo with the use of a central interactive Web-
and analysis; and was responsible for reporting based response system. The use of SGLT2 inhibi-
the results. Analyses were conducted by the spon- tors and mineralocorticoid-receptor antagonists
sor and were independently verified with the use (MRAs) was permitted, and randomization was
of the original data by Statogen Consulting. The stratified according to SGLT2 inhibitor use at
first author wrote the first draft of the manu- baseline. An 8-week dose-escalation regimen
script, and all the authors contributed to subse- was used, with dose escalation (as long as unac-
quent revisions. Technical editorial assistance ceptable side effects did not occur) from 0.25 mg
was provided by OpenHealth and funded by the per week for 4 weeks and 0.5 mg per week for
sponsor. The authors had access to the full data another 4 weeks, followed by a maintenance
set, made the decision to submit the manuscript dose of 1.0 mg per week throughout the remain-
for publication, and vouch for the accuracy and der of the treatment period. If unacceptable ad-
completeness of the data and for the fidelity of verse effects occurred, dose-escalation intervals
the trial to the protocol (available at NEJM.org). could be extended, treatment could be paused,

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 Effects of Semaglutide on Chronic Kidney Disease

or lower maintenance doses could be used. Labo- proportional-hazards model with randomization
ratory-based inclusion criteria were based on local assignment (semaglutide or placebo) as a fixed
laboratory values recorded within 90 days before factor and stratified according to SGLT2 inhibi-
the screening visit or central laboratory values tor use at baseline. P values were obtained from
recorded at screening or at optional prescreen- a score test. For the primary outcome, the hazard
ing visits. ratio, 95% confidence interval, and P value were
adjusted for the group sequential design with
Trial Outcomes the use of likelihood-ratio ordering. The eGFR
The primary outcome was major kidney disease slope was analyzed with a linear mixed-effects
events, a composite of onset of kidney failure (ini- model with randomization assignment, SGLT2
tiation of long-term dialysis, kidney transplanta- inhibitor use at baseline, time, and the interac-
tion, or a reduction in the eGFR to <15 ml per tion between randomization assignment and time
minute per 1.73 m2 sustained for ≥28 days), a as fixed effects, participant as a random intercept,
sustained (for ≥28 days) 50% or greater reduc- and time as a random slope. Missing data were not
tion in eGFR from baseline, or death from kid- imputed.
ney-related or cardiovascular causes. Three key If superiority was confirmed for the primary
confirmatory secondary outcomes were defined outcome, testing of the confirmatory secondary
and assessed with the use of a formal hierarchi- outcomes was performed in a prespecified hier-
cal testing strategy: total eGFR slope (i.e., the archical order to ensure type I error control. To
annual rate of change in eGFR from randomiza- account for the prespecified interim analysis, the
tion to the end of the trial); major cardiovascular nominal significance level for the primary and
events (a composite of nonfatal myocardial in- confirmatory secondary outcomes was calculated
farction, nonfatal stroke, or death from cardio- with the Lan–DeMets alpha-spending function
vascular causes), assessed in a time-to-first-event and the actual observed number of primary-out-
analysis; and death from any cause. A range of come events available for the primary analysis. On
additional supportive secondary, exploratory, and the basis of the available number of events, the
other outcomes were also prespecified and are one-sided nominal significance level for the pri-
listed in the Supplementary Appendix. mary and confirmatory secondary outcomes was
Safety was assessed by collecting data on all updated to 0.0161 (equivalent to a two-sided level
serious adverse events, adverse events leading to of 0.0322, which is used in this report). Details
discontinuation of semaglutide or placebo, and are provided in the Supplementary Appendix.
adverse events of special interest. Primary and sec- Continuous supportive secondary outcomes
ondary outcomes other than eGFR assessments were assessed by analysis of covariance with the
derived from the central laboratory were adjudi- use of multiple imputation for missing values
cated in a blinded fashion by an event adjudication under a missing-at-random assumption. Analyses
committee (see the Supplementary Appendix). of supportive and exploratory outcomes were not
adjusted for multiplicity, and confidence intervals
Statistical Analysis for these outcomes should not be used in place
This trial was event driven. We calculated that a of hypothesis testing. All statistical analyses were
minimum of 854 primary-outcome events would performed with SAS software, version 9.4 TS1M5
provide 90% power to detect a 20% lower relative (SAS Institute).
risk in the semaglutide group than in the placebo
group at an overall one-sided significance level of R e sult s
2.5%. An interim analysis of efficacy was planned
for after two thirds of the total planned number Trial Participants
of primary-outcome events had occurred. The trial was conducted at 387 sites in 28 coun-
Efficacy analyses were based on the intention- tries (see the Supplementary Appendix), with re-
to-treat principle and included all unique partici- cruitment occurring from June 2019 through May
pants who underwent randomization, irrespective 2021. Among the 5581 screened candidates (Fig. S1
of adherence to semaglutide or placebo or chang- in the Supplementary Appendix), 3533 met the
es to background medications. Time-to-first-event entry criteria and were randomly assigned to the
outcomes were analyzed with a stratified Cox semaglutide group (1767 participants) or the pla-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Characteristics of the Participants at Baseline.*

Semaglutide Placebo Total

Characteristic (N = 1767) (N = 1766) (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±20.5
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 m ¶ 2
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 m 2
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)

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 Effects of Semaglutide on Chronic Kidney Disease

Table 1. (Continued.)

Semaglutide Placebo Total

Characteristic (N = 1767) (N = 1766) (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.

cebo group (1766 participants) and included in and consistent with those in previous trials,4,5,8
the analyses. Four participants underwent ran- as described in Table S2.
domization more than once, and only the first A prespecified single interim analysis was
randomization was included in analyses; one par- triggered in October 2023 after approximately
ticipant was excluded from the analysis because of 570 primary-outcome events had accrued. An in-
a lack of adherence to Good Clinical Practice dependent data and safety monitoring committee
guidelines at the relevant site. reviewed the data and recommended early com-
The baseline characteristics of the participants pletion of the trial for efficacy. This recommen-
were well balanced between the groups (Table 1 dation was accepted, participants were recalled
and Table S1). The mean age was 66.6 years, and for final visits, and the trial was completed with
1069 participants (30.3%) were women. The mean the final participant visit occurring on January 9,
eGFR was 47.0 ml per minute per 1.73 m2, and 2024. At the time of completion of the trial, the
the median urinary albumin-to-creatinine ratio median participant follow-up was 3.4 years
(with albumin measured in milligrams and cre- (range, 0 to 4.5). The trial was closed early at
atinine measured in grams) was 567.6. According two sites in Russia that had been sanctioned by
to the Kidney Disease: Improving Global Out- the sponsor, and 14 participants at the affected
comes risk calculators,14 68% of the participants sites ended participation early. In total, 34 par-
were at very high risk for kidney disease pro- ticipants withdrew consent, and vital status was
gression, kidney failure, cardiovascular events, able to be confirmed at the end of trial for 3482
or death. The participants in the trial were participants (98.6%). Semaglutide or placebo was
broadly representative of the relevant population permanently discontinued by 26% of participants

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A First Major Kidney Disease Event B First Kidney-Specific Component Event

100 35 100 25
Hazard ratio, 0.76 (95% CI, 0.66–0.88) Hazard ratio, 0.79 (95% CI, 0.66–0.94)
90 30 P=0.0003 90 20
25
Percentage of Participants

Percentage of Participants
80 Placebo 80 15
20
70 15 70 10 Placebo
10 Semaglutide Semaglutide
60 60
5 5
50 50
0 0
40 0 6 12 18 24 30 36 42 48 40 0 6 12 18 24 30 36 42 48
30 30
20 20
10 10
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Placebo 1766 1736 1682 1605 1516 1408 1048 660 354 Placebo 1766 1736 1682 1605 1516 1408 1048 660 354
Semaglutide 1767 1738 1693 1640 1572 1489 1131 742 392 Semaglutide 1767 1738 1693 1640 1572 1489 1131 742 392

C Death from Cardiovascular Causes D Total eGFR Slope

100 15 48
Hazard ratio, 0.71 (95% CI, 0.56–0.89)
90
46
Percentage of Participants

80 10
Placebo eGFR (ml/min/1.7 3m2)
70 44 Semaglutide
5
60 Semaglutide
42
50
0
40 0 6 12 18 24 30 36 42 48 40
30 Placebo
38
20 Difference in annual slope, 1.16 ml/min/1.73 m2/yr
(95% CI, 0.86–1.47)
10 36
P<0.001
0 0
0 6 12 18 24 30 36 42 48 0 12 52 104 156 208
Months since Randomization Weeks since Randomization
No. at Risk No. at Risk
Placebo 1766 1737 1697 1641 1601 1544 1185 772 437 Placebo 1766 1663 1573 1609 1490 1441 1284 876 609 199
Semaglutide 1767 1739 1703 1665 1627 1583 1234 838 460 Semaglutide 1766 1665 1590 1606 1521 1468 1345 952 651 218

E First Major Cardiovascular Event F Death from Any Cause

100 20 100 25
Hazard ratio, 0.82 (95% CI, 0.68–0.98) Hazard ratio, 0.80 (95% CI, 0.67–0.95)
90 P=0.029 90 20 P=0.01
15
Percentage of Participants

Percentage of Participants

80 Placebo 80 15
10 Placebo
70 Semaglutide 70 10
Semaglutide
60 5 60
5
50 50
0 0
40 0 6 12 18 24 30 36 42 48 40 0 6 12 18 24 30 36 42 48
30 30
20 20
10 10
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Placebo 1766 1721 1663 1583 1535 1478 1133 731 418 Placebo 1766 1737 1697 1641 1601 1544 1185 772 437
Semaglutide 1767 1725 1672 1622 1575 1515 1176 793 430 Semaglutide 1767 1739 1703 1665 1627 1583 1234 838 460

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 Effects of Semaglutide on Chronic Kidney Disease

Figure 1 (facing page). Primary and Confirmatory

group (331 first events [5.8 per 100 patient-years
Secondary Outcomes. of follow-up] vs. 410 first events [7.5 per 100 pa-
Shown are cumulative incidence plots of the primary tient-years]), which resulted in a 24% lower rela-
outcome, major kidney disease events (a composite of tive risk of the primary outcome in the semaglu-
the onset of kidney failure [dialysis, transplantation, or tide group (hazard ratio, 0.76; 95% confidence
an estimated glomerular filtration rate {eGFR} of interval [CI], 0.66 to 0.88; P = 0.0003) (Fig. 1 and
<15 ml per minute per 1.73 m2 of body-surface area],
≥50% reduction in eGFR from baseline, or death from
Table 2). The number of persons who would
kidney-related or cardiovascular causes) and several need to be treated over 3 years to prevent one
confirmatory secondary outcomes: kidney-specific primary-outcome event was 20 (95% CI, 14 to 40).
components of the primary outcome (persistent Lower risk with semaglutide was also observed
≥50% reduction in eGFR, persistent eGFR of <15 ml for a composite of the kidney-specific compo-
per minute per 1.73 m2, initiation of long-term renal-
replacement therapy, or death from kidney-related
nents of the primary outcome (hazard ratio, 0.79;
causes), death from cardiovascular causes, total eGFR 95% CI, 0.66 to 0.94), as well as for death from
slope, major cardiovascular events (a composite of cardiovascular causes (hazard ratio, 0.71; 95% CI,
nonfatal myocardial infarction, nonfatal stroke, or 0.56 to 0.89) (Table 2). Results were consistent
death from cardiovascular causes), and death from across the range of prespecified sensitivity analy-
any cause. Cumulative incidence estimates are based
on the time from randomization to the first event,
ses (Table S3) and were broadly consistent across
with death not included in the outcome modeled as a prespecified participant subgroups (Fig. 2).
competing risk with the use of the Aalen–Johansen es-
timator. Data from participants without events of in- Confirmatory Secondary Outcomes
terest were censored at the end of each participant’s Benefits were observed for the three confirma-
in-trial observation period. Estimates are based on a
Cox proportional-hazards model with treatment as a
tory secondary outcomes tested in a hierarchical
categorical fixed factor and stratified according to so- fashion, all of which had two-sided P values be-
dium–glucose cotransporter 2 (SGLT2) inhibitor use low the prespecified interim analysis threshold of
at baseline. The eGFR data are least-squares means 0.0322 (Table 2). The mean annual slope of the
from a mixed model for repeated measures with treat- eGFR was significantly less steep (indicating a
ment as a fixed factor; I bars indicate the standard er-
ror. The annual rate of change in eGFR was analyzed
slower decrease) in the semaglutide group than
with a linear random-effects model with randomiza- in the placebo group (−2.19 vs. −3.36 ml per
tion assignment, SGLT2 inhibitor use at baseline, time minute per 1.73 m2 per year; between-group dif-
(as a continuous variable), and the interaction of ran- ference, 1.16; 95% CI, 0.86 to 1.47; P<0.001)
domization with time as fixed effects and including (Fig. 1D).
the participant effect as a random intercept and time
as a random slope. On the basis of the available num-
The risk of major cardiovascular events was
ber of primary-outcome events, the nominal signifi- 18% lower in the semaglutide group than in the
cance level was updated to 0.0322 with the use of the placebo group (212 vs. 254 events; hazard ratio,
Lan–DeMets alpha-spending function. Events that are 0.82; 95% CI, 0.68 to 0.98; P = 0.029) (Fig. 1E).
not related to eGFR were confirmed by the event adju- Effects on the individual components of this com-
dication committee. The eGFR was calculated with the
serum creatinine level and the Chronic Kidney Disease
posite outcome are shown in Table 2; findings for
Epidemiology Collaboration (CKD-EPI) 2009 formu- myocardial infarction and death from cardiovascu-
la.13 The P value cutoff for significance was 0.032 in lar causes were consistent with those in the pri-
Panels A, D, E, and F. Insets show the same data on mary analysis, but the findings for stroke showed
an expanded y axis. 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-
during the trial, with adherence to the trial regi- cebo group (227 vs. 279 events; hazard ratio,
men averaging 89% of the planned time during 0.80; 95% CI, 0.67 to 0.95, P = 0.01) (Fig. 1F).
the trial period. Over 3 years, 45 persons (95% CI, 23 to 623)
would need to be treated to prevent one major
Primary Outcome cardiovascular event, and 39 (95% CI, 21 to 238)
Primary-outcome events occurred less frequently would need to be treated to prevent one death
in the semaglutide group than in the placebo from any cause.

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 116
Table 2. Efficacy and Safety Outcomes.*

Semaglutide Placebo Hazard Ratio Estimated Difference

Outcome (N = 1767) (N = 1766) (95% CI) (95% CI) P Value
Primary outcome: major kidney disease events — no. (%)† 331 (18.7) 410 (23.2) 0.76 (0.66 to 0.88) — 0.0003
Components of primary outcome — no. (%)
Persistent ≥50% reduction from baseline in eGFR 165 (9.3) 213 (12.1) 0.73 (0.59 to 0.89) — —
Persistent eGFR <15 ml/min/1.73 m2 92 (5.2) 110 (6.2) 0.80 (0.61 to 1.06) — —
Initiation of kidney-replacement therapy 87 (4.9) 100 (5.7) 0.84 (0.63 to 1.12) — —
Death from kidney-related causes 5 (0.3) 5 (0.3) 0.97 (0.27 to 3.49) — —
Death from cardiovascular causes 123 (7.0) 169 (9.6) 0.71 (0.56 to 0.89) — —
The

Composite of kidney-specific components of the primary outcome 218 (12.3) 260 (14.7) 0.79 (0.66 to 0.94) — —
Confirmatory secondary outcomes
Mean annual rate of change in eGFR — ml/min/1.73 m2 –2.19 –3.36 — 1.16 (0.86 to 1.47) <0.001
Major cardiovascular events — no. (%) 212 (12.0) 254 (14.4) 0.82 (0.68 to 0.98) — 0.029
Death from cardiovascular causes 123 (7.0) 169 (9.6) 0.71 (0.56 to 0.89) — —
Nonfatal myocardial infarction 52 (2.9) 64 (3.6) 0.80 (0.55 to 1.15) — —

n engl j med 391;2

Nonfatal stroke 63 (3.6) 51 (2.9) 1.22 (0.84 to 1.77) — —
Death from any cause — no. (%) 227 (12.8) 279 (15.8) 0.80 (0.67 to 0.95) — 0.01
Supportive secondary outcomes

nejm.org
n e w e ng l a n d j o u r na l

Ratio of urinary albumin-to-creatinine ratio at week 104 to urinary 0.60 0.88 0.68 (0.62 to 0.75)‡ — —
of

albumin-to-creatinine ratio at baseline

Mean change in body weight from baseline to week 104 — kg –5.55 –1.45 — –4.10 (–4.56 to –3.65) —

July 11, 2024

Mean change in glycated hemoglobin level from baseline to week –0.87 –0.06 — –0.81 (–0.90 to –0.72) —
104 — percentage points
m e dic i n e

Mean change in systolic blood pressure from baseline to week –3.79 –1.55 — –2.23 (–3.33 to –1.13) —
104 — mm Hg
Mean change in diastolic blood pressure from baseline to week –0.23 –1.01 — 0.78 (0.16 to 1.41) —
104 — mm Hg

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Mean change in eGFR from baseline to week 12 — ml/min/1.73 –1.07 –1.05 — –0.03 (–0.56 to 0.51) —

No other uses without permission. Copyright © 2024 Massachusetts Medical Society. All rights reserved.
m2
Mean annual rate of change in eGFR from week 12 to end of trial –2.36 –3.30 — 0.94 (0.62 to 1.26) —

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
— ml/min/1.73 m2
Mean change in eGFR by the cystatin C equation from baseline to –2.01 –5.41 — 3.39 (2.63 to 4.15) —
week 104 — ml/min/1.73 m2
 Effects of Semaglutide on Chronic Kidney Disease

Other Efficacy Outcomes

50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. Adjustment for the group sequential design was performed with the use of likelihood-ratio
SGLT2 inhibitor use at baseline. Data from participants without events of interest were censored at the end of their in-trial period. The nominal significance level was updated to 0.0322
The results for additional efficacy outcomes are

vascular events were analyzed in a time-to-first-event analysis with the use of a Cox proportional-hazards model with treatment as a categorical fixed factor and stratified according to

criteria. Death from cardiovascular causes, as confirmed by the event adjudication committee, includes both death from cardiovascular causes and death from undetermined causes
* Data are for the full analysis population from the in-trial period (from randomization to the end of trial participation). Composite kidney disease events and composite major cardio-

† 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
with the use of the Lan–DeMets alpha-spending function. The eGFR was calculated with serum creatinine level and the Chronic Kidney Disease Epidemiology Collaboration formula.
P Value

Events not related to the eGFR were confirmed by the event adjudication committee. “Persistent” was defined as two consecutive measurements at least 4 weeks apart fulfilling the
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
Estimated Difference

(95% CI, 25 to 38) in the semaglutide group

(95% CI)

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
1.02 (0.62 to 1.67)‡
0.56 (0.30 to 1.02)

0.93 (0.70 to 1.22)

Hazard Ratio

per 1.73 m2 (95% CI, 2.43 to 4.17).

(95% CI)

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
(N = 1766)
Placebo

(95% CI, 1.13 to 3.33). However, the mean reduc-

28

46
105

tion in diastolic blood pressure was 0.78 mm Hg

greater (95% CI, 0.16 to 1.41) with placebo than
‡ Value is the ratio of the value in the semaglutide group to the value in the placebo group.

with semaglutide.
Semaglutide
(N = 1767)

Safety Outcomes
16

47
99

Serious adverse events (Table 3 and Tables S4

and S5) were reported in fewer participants in
the semaglutide group than in the placebo group
Supplementary analysis: death from noncardiovascular and non–kid-
ney-related causes in a time-to-first-event analysis — no.
Major adverse limb event in a time-to-first-event analysis — no.

(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-
No. of severe hypoglycemic episodes

ceived placebo (53 [3.0%] vs. 30 [1.7%]), whereas

the numbers of systematically recorded diabetic
adjudicated by that committee.

retinopathy events were similar in the two groups

(504 events among 402 participants [22.8%] in
the semaglutide group and 483 events among
of events

of events

398 participants [22.5%] in the placebo group).

Adverse events leading to permanent discon-
tinuation of semaglutide or placebo were more
Outcome

ordering.

common in the semaglutide group than in the

placebo group (233 [13.2%] vs. 211 [11.9%]); this
finding was driven mainly by discontinuation

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Subgroup Semaglutide Placebo Hazard Ratio (95% CI)

no. of participants with event/no. of participants in analysis
Primary analysis, all patients 331/1767 410/1766 0.76 (0.66–0.88)
Sex
Female 88/519 127/550 0.70 (0.53–0.92)
Male 243/1248 283/1216 0.79 (0.66–0.94)
Age
<65 yr 131/633 175/652 0.71 (0.57–0.90)
≥65 to <75 yr 160/816 170/773 0.85 (0.69–1.06)
≥75 yr 40/318 65/341 0.63 (0.42–0.93)
Body-mass index
≤30 142/734 164/733 0.82 (0.65–1.03)
>30 189/1031 244/1029 0.73 (0.61–0.89)
Duration of diabetes
<15 yr 148/774 153/753 0.90 (0.72–1.13)
≥15 yr 183/992 257/1013 0.68 (0.56–0.82)
Glycated hemoglobin
≤8.0% 200/1106 251/1093 0.75 (0.62–0.90)
>8.0% 131/659 159/672 0.79 (0.63–1.00)
≤7.0% 104/536 147/571 0.69 (0.54–0.89)
>7.0% 227/1229 263/1194 0.80 (0.67–0.96)
Geographic region
North America 98/423 102/442 0.98 (0.74–1.30)
Europe 65/472 104/491 0.61 (0.45–0.83)
Asia 98/478 98/434 0.85 (0.65–1.13)
Other 70/394 106/399 0.62 (0.46–0.84)
Race or ethnic group
Asian 95/439 95/407 0.86 (0.64–1.14)
Black 20/78 24/82 0.81 (0.44–1.46)
White 197/1155 260/1168 0.73 (0.61–0.88)
Other 11/56 21/69 0.63 (0.29–1.28)
Hispanic or Latinx ethnic group
Yes 57/273 89/283 0.61 (0.43–0.85)
No 261/1421 298/1411 0.83 (0.70–0.98)
Estimated GFR
≥60 ml/min/1.73 m2 41/366 59/353 0.64 (0.43–0.96)
≥45 to <60 ml/min/1.73 m2 80/515 103/540 0.78 (0.58–1.04)
≥30 to <45 ml/min/1.73 m2 137/667 181/691 0.74 (0.59–0.92)
<30 ml/min/1.73 m2 73/218 67/182 0.81 (0.58–1.13)
Urinary albumin‐to‐creatinine ratio
<300 55/561 62/552 0.86 (0.60–1.23)
≥300 276/1205 348/1214 0.74 (0.63–0.87)
Cardiovascular disease
No previous myocardial infarction or stroke 240/1345 308/1343 0.73 (0.62–0.87)
Previous myocardial infarction of stroke 87/405 93/403 0.91 (0.68–1.22)
Chronic heart failure
No 264/1424 322/1430 0.79 (0.67–0.93)
Yes 67/342 88/336 0.67 (0.49–0.93)
Insulin use
No 114/684 129/681 0.85 (0.66–1.09)
Yes 217/1083 281/1085 0.72 (0.61–0.86)
Metformin use
No 193/859 219/842 0.80 (0.66–0.97)
Yes 138/908 191/924 0.71 (0.57–0.88)
SGLT2 inhibitor use
No 290/1490 372/1493 0.73 (0.63–0.85)
Yes 41/277 38/273 1.07 (0.69–1.67)
0.25 0.50 1.00 2.00

Semaglutide Better Placebo Better

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 Effects of Semaglutide on Chronic Kidney Disease

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

diabetes and chronic kidney disease will reduce
Outcome. the risk of kidney failure and slow the decline in
For the primary analysis, the hazard ratio and confi- the eGFR, as well as reduce the risk of cardio-
dence interval were adjusted for the group sequential vascular events and death.
design with the use of likelihood-ratio ordering. For Few previous trials of GLP-1 receptor agonists
the subgroup analyses, estimated hazard ratios and have recruited substantial numbers of partici-
corresponding confidence intervals were calculated in
a stratified Cox proportional-hazards model with the
pants with considerably reduced kidney func-
interaction between randomly assigned group and the tion. The cardiovascular and survival benefits of
relevant subgroup as a fixed factor. The model is semaglutide in such patients are particularly im-
stratified according to SGLT2 inhibitor use at baseline. portant, since they are among the populations at
Gray shading highlights the 95% confidence interval highest risk for cardiovascular disease and death.
for the result in the overall population. The body-mass
index is the weight in kilograms divided by the square
Because three other guideline-directed medi-
of the height in meters. Race and ethnic group were cal therapies have been shown to have benefits
reported by the participants; “other” includes Ameri- in patients with type 2 diabetes and chronic kid-
can Indian or Alaska Native, Native Hawaiian or other ney disease (RAS inhibition, SGLT2 inhibition,
Pacific Islander, and “not reported.” For the urinary and mineralocorticoid-receptor antagonism with
albumin-to-creatinine ratio, albumin was measured in
milligrams and creatinine in grams.
finerenone),17 clinicians and patients will need
to consider the order and priority of use for
semaglutide (and, once studied, other GLP-1 re-
because of gastrointestinal disorders (79 [4.5%] ceptor agonists). Although studies of SGLT2 in-
vs. 20 [1.1%]). hibitors in patients with chronic kidney disease
have clearly identified important benefits with
respect to kidney outcomes,4-6 the findings re-
Discussion
garding effects on major cardiovascular events
In our trial involving patients with type 2 diabe- and death from any cause in this population
tes and chronic kidney disease, semaglutide at a have been mixed. In the context of the favorable
dose of 1.0 mg once weekly significantly reduced safety profile, the benefits for these outcomes
the risk of major kidney disease events (the pri- shown in the present trial provide a rationale for
mary outcome), by 24%. Semaglutide also reduced consideration of the use of semaglutide along
the risk of major cardiovascular events and death with these other proven therapies as part of the
from any cause while slowing the annual loss of initial therapeutic options in this patient popula-
kidney function by a mean of 1.16 ml per minute tion. Combination therapy is likely to be impor-
per 1.73 m2. These benefits reflect important tant in the future, and we found no clear hetero-
clinical effects on kidney, cardiovascular, and sur- geneity of effect among patients receiving SGLT2
vival outcomes among high-risk patients, particu- inhibitors at baseline as compared with those
larly given the reassuring safety findings, and who were not, although the statistical power of
support a therapeutic role for semaglutide in this analysis was limited. Further analyses of these
this population. data are planned, and studies assessing approach-
The use of GLP-1 receptor agonists in broader es to combination therapy should be a priority.
populations with type 2 diabetes has previously The mechanisms of kidney protection with
been shown to improve glycemic control, de- semaglutide are likely to be multifactorial. Al-
crease body weight, and reduce cardiovascular though a reduction in kidney and cardiovascular
events.11,15,16 However, previous dedicated trials risk factors may contribute, a previous mediation
addressing clinically important kidney outcomes, analysis showed that these factors only modestly
such as kidney failure or a substantial decline in mediated effects on kidney outcomes.11 In addi-
the eGFR, have been lacking. The effects on sec- tion, the effect of semaglutide was unrelated to
ondary and post hoc kidney outcomes in clinical changes in body weight regardless of whether
trials of GLP-1 receptor agonists for cardiovas- the eGFR was computed with serum creatinine,
cular outcomes and glycemic control have sug- cystatin C, or both,18,19 and consistent effects on
gested benefits.15 The magnitude of the benefits creatinine-based and cystatin C–based eGFR were
observed in our trial provides confidence that identified in this trial. On the basis of experi-
the use of semaglutide in patients with type 2 mental models and biomarker data, the direct

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Safety Outcomes.

Semaglutide Placebo
Adverse Event (N = 1767) (N = 1766)

no. of participants (%)

Serious adverse event 877 (49.6) 950 (53.8)
Adverse event leading to permanent discontinuation of semaglutide 233 (13.2) 211 (11.9)
or placebo
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 0 1 (0.1)
agent through semaglutide or placebo

* 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.

effects of GLP-1 receptor agonists on the kidney pants who were receiving these agents at base-
may include decreases in inflammation, oxidative line was modest, which limited our ability to
stress, and fibrosis. Intrinsic kidney and immune assess the effects of combination therapy. The
cells contain the GLP-1 receptor, and GLP-1 recep- trial was also not powered to detect differences
tor agonists reduce cellular expression of proin- within and between important subgroups, and
flammatory and profibrotic mediators.20-23 most participants identified their race as White,
Our trial has important strengths. This trial whereas kidney disease disproportionately affects
of a GLP-1 receptor agonist in a population of marginalized populations, especially Black and
patients with chronic kidney disease and type 2 Indigenous persons. The effects on kidney func-
diabetes assessed clinically important outcomes, tion may not be generalizable to other popula-
and significant benefits were shown for kidney tions, such as those at lower risk, and the trial
and cardiovascular outcomes and death from any was not powered to separately detect effects on
cause. The trial was large and rigorous and pro- kidney failure. Finally, it is possible that modest
vides clear conclusions about benefits and risks. weight loss could slightly lower serum creatinine
It also has some important limitations. Because levels, but the almost identical effects on the
SGLT2 inhibitors and nonsteroidal MRAs had cystatin C–based and creatinine-based eGFR in-
not been approved for kidney protection at the dicate that this is unlikely to meaningfully influ-
time the trial was initiated, the number of partici- ence the trial results.

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 Effects of Semaglutide on Chronic Kidney Disease

In this trial, semaglutide reduced the risk of Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
clinically important kidney outcomes, major car- A data sharing statement provided by the authors is available
diovascular events, and death from any cause in with the full text of this article at NEJM.org.
participants with type 2 diabetes and chronic kid- We thank all the patients who participated in this trial, as
well as the site investigators and staff; and Isabella Goldsbrough
ney disease. Alves, Ph.D., of Apollo, OPEN Health Communications, for edi-
Supported by Novo Nordisk. torial assistance with earlier versions of the figures.

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