Pharmacy powerpoint

September 26, 2025 Claire B 0 Comments

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 109

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.

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 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*

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

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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

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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-

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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±20.5

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 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)

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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.)

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6 12 18 24 42 48

Months since Randomization

A First Major Kidney Disease Event

Hazard ratio, 0.76 (95% CI, 0.66–0.88) P=0.0003

Placebo Semaglutide

1766 1767

1736 1738

1682 1693

1605 1640

1516 1572

1408 1489

30 25

5 10 15

0 0 6 12 18 24 42 4830 36

1048 1131

660 742

354 392

Pe rc

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f P ar

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an ts

100

0 0

Pe rc

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100

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Pe rc

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an ts

100

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No. at Risk

Pe rc

en ta

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f P ar

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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<0.001

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

1544 1583

0 0 6 12 18 24 42 4830 36

1185 1234

772 838

437 460

e G

FR (m

l/ m

in /1

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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

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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.

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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

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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

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Male

Age

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≥65 to <75 yr

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Body-mass index

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>30

Duration of diabetes

<15 yr

≥15 yr

Glycated hemoglobin

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Geographic region

North America

Europe

Asia

Other

Race or ethnic group

Asian

Black

White

Other

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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.

References 1. GBD Chronic Kidney Disease Collab- oration. Global, regional, and national burden of chronic kidney disease, 1990- 2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020; 395: 709-33. 2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and car- diovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-9. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angio- tensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-60. 4. Perkovic V, Jardine MJ, Neal B, et al. Canaglif lozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295-306. 5. Heerspink HJL, Stefánsson BV, Correa- Rotter R, et al. Dapaglif lozin in patients with chronic kidney disease. N Engl J Med 2020; 383: 1436-46. 6. The EMPA-KIDNEY Collaborative Group. Empaglif lozin in patients with chronic kidney disease. N Engl J Med 2023; 388: 117-27. 7. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219-29. 8. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252-63. 9. de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kid- ney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Out-

comes (KDIGO). Diabetes Care 2022; 45: 3075-90. 10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2024; 105: Suppl 4: S117-S314. 11. Mann JFE, Buse JB, Idorn T, et al. Po- tential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab 2021; 23: 2058-66. 12. 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. Nephrol Dial Transplant 2023; 38: 2041-51. 13. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-12. 14. Levey AS, Eckardt KU, Dorman NM, et al. Nomenclature for kidney function and disease-executive summary and glos- sary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus con- ference. Eur Heart J 2020; 41: 4592-8. 15. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021; 9: 653-62. 16. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney

disease (AWARD-7): a multicentre, open- label, randomised trial. Lancet Diabetes Endocrinol 2018; 6: 605-17. 17. Naaman SC, Bakris GL. Diabetic ne- phropathy: update on pillars of therapy slowing progression. Diabetes Care 2023; 46: 1574-86. 18. Tuttle KR, Lakshmanan MC, Rayner B, Zimmermann AG, Woodward B, Botros FT. Body weight and eGFR during dula- glutide treatment in type 2 diabetes and moderate-to-severe chronic kidney dis- ease (AWARD-7). Diabetes Obes Metab 2019; 21: 1493-7. 19. Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on cystatin C-based kidney func- tion: a SURPASS-4 post hoc analysis. Dia- betes Care 2023; 46: 1501-6. 20. Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clini- cal evidence. Nat Rev Nephrol 2021; 17: 227-44. 21. Tuttle KR, Wilson JM, Lin Y, et al. In- dicators of kidney fibrosis in patients with type 2 diabetes and chronic kidney disease treated with dulaglutide. Am J Nephrol 2023; 54: 74-82. 22. Dalbøge LS, Christensen M, Madsen MR, et al. Nephroprotective effects of semaglutide as mono- and combination treatment with lisinopril in a mouse model of hypertension-accelerated diabetic kid- ney disease. Biomedicines 2022; 10: 1661. 23. Alicic RZ, Neumiller JJ, Tuttle KR. Mechanisms and clinical applications of incretin therapies for diabetes and chron- ic kidney disease. Curr Opin Nephrol Hy- pertens 2023; 32: 377-85. Copyright © 2024 Massachusetts Medical Society.

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

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

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

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

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

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

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.

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