Effects of Semaglutide on Albuminuria and Kidney Function in
`People With Overweight or Obesity With or Without Type 2
`Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials
`
`Hiddo J.L. Heerspink, Ellen Apperloo, Melanie Davies, Dror Dicker, Kristian Kandler, Julio Rosenstock,
`Rasmus Sørrig, Jack Lawson, Niels Zeuthen, and David Cherney
`
`Diabetes Care 2023;46(4):801–810 | https://doi.org/10.2337/dc22-1889
`
`Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or
`Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials
`Hiddo J.L. Heerspink, Ellen Apperloo, Melanie Davies, Dror Dicker, Kristian Kandler, Julio Rosenstock, Rasmus Sørrig, Jack Lawson, Niels Zeuthen, and David Cherney
`Semaglutide improves albuminuria in people with overweight or obesity and type 2 diabetes
`Context and Objective(s)
`Design and Methods
`Results
`Participants:
`UACR changes at week 68:
`24
`STEP 1 and 3: adults with
`12
`overweight or obesity
`0
`STEP 2: adults with overweight
`-12
`or obesity and type 2 diabetes
`-24
`
`18.3
`
`1.0 mg semagluƟde
`2.4 mg semagluƟde
`placebo
`
`–14.8
`
`–20.6
`
`––
`
`UACR(%)
`
`STEP 1–3 post hoc analyses
`explored the effects of
`semaglutide 1.0 mg and 2.4 mg
`versus placebo on kidney function
`
`Treatment arms:
`1.0 mg semaglutide (STEP 2)
`2.4 mg semaglutide
`Placebo
`End points assessed:
`Changes in urine albumin-to-
`creatinine ratio (UACR) and
`UACR status (STEP 2)
`Changes in estimated
`glomerular filtration rate
`(eGFR) (STEP 1–3 pooled)
`
`58.6% of the UACR- lowering effect was
`58 6% of the UACR lowering effect was
`statistically independent of changes in
`glycated hemoglobin (HbA1c) or body weight
`The effect of semaglutide versus placebo was
`consistent across subgroups by baseline
`BMI, HbA1c, eGFR, or use of
`renin–angiotensin system or sodium–glucose
`cotransporter-2 inhibitors
`eGFR changes at week 68:
`No difference between semaglutide 1.0 mg
`and 2.4 mg semaglutide and placebo
`
`The STEP 1–3 trials (NCT03548935, NCT03552757, and NCT03611582) were funded by Novo Nordisk
`A/S. The authors thank the trial participants, the investigators, and trial site staff who conducted the trial.
`
`| 1
`
`ARTICLE HIGHLIGHTS
`
`(cid:129) The objective of the study was to explore the effects of semaglutide on kidney parameters in people with over-
`weight or obesity.
`(cid:129) The study sought to answer the question of whether semaglutide effectively reduces albuminuria and improves
`estimated glomerular filtration rate.
`(cid:129) In people living with overweight/obesity and type 2 diabetes, semaglutide reduced albuminuria by 30% and
`improved urine albumin-to-creatinine ratio status but did not affect estimated glomerular filtration rate in people
`with overweight/obesity with or without type 2 diabetes.
`(cid:129) The reduction in albuminuria and improvement in urine albumin-to-creatinine ratio status support ongoing trials
`assessing the effects of semaglutide on long-term clinical kidney outcomes.
`
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`

`Diabetes Care Volume 46, April 2023
`
`801
`
`ORIGINAL ARTICLE
`
`Hiddo J.L. Heerspink,1 Ellen Apperloo,1
`Melanie Davies,2,3,4 Dror Dicker,5,6
`Kristian Kandler,7 Julio Rosenstock,8
`Rasmus Sørrig,9 Jack Lawson,9
`Niels Zeuthen,10 and David Cherney 11
`
`Effects of Semaglutide on
`Albuminuria and Kidney
`Function in People With
`Overweight or Obesity With or
`Without Type 2 Diabetes:
`Exploratory Analysis From the
`STEP 1, 2, and 3 Trials
`
`Diabetes Care 2023;46:801–810 | https://doi.org/10.2337/dc22-1889
`
`OBJECTIVE
`These post hoc analyses of the Semaglutide Treatment Effect in People with obe-
`sity (STEP) 1–3 trials (NCT03548935, NCT03552757, and NCT03611582) explored
`the effects of semaglutide (up to 2.4 mg) on kidney function.
`
`RESEARCH DESIGN AND METHODS
`STEP 1–3 included adults with overweight/obesity; STEP 2 patients also had type 2
`diabetes. Participants received once-weekly subcutaneous semaglutide 1.0 mg (STEP
`2 only), 2.4 mg, or placebo for 68 weeks, plus lifestyle intervention (STEP 1 and 2) or
`intensive behavioral therapy (STEP 3). Changes in urine albumin-to-creatinine ratio
`(UACR) and UACR status from baseline to week 68 were assessed for STEP 2.
`Changes in estimated glomerular filtration rate (eGFR) were assessed from pooled
`STEP 1–3 data.
`
`RESULTS
`In STEP 2, 1,205 (99.6% total cohort) patients had UACR data; geometric mean
`baseline UACR was 13.7, 12.5, and 13.2 mg/g with semaglutide 1.0 mg, 2.4 mg,
`and placebo, respectively. At week 68, UACR changes were 214.8% and 220.6%
`with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (be-
`tween-group differences [95% CI] vs. placebo: 228.0% [237.3, 217.3], P <
`0.0001 for semaglutide 1.0 mg; 232.9% [241.6, 223.0], P = 0.003 for semaglu-
`tide 2.4 mg). UACR status improved in greater proportions of patients with sema-
`glutide 1.0 mg and 2.4 mg versus placebo (P = 0.0004 and P = 0.0014, respectively).
`In the pooled STEP 1–3 analyses, 3,379 participants had eGFR data; there was
`no difference between semaglutide 2.4 mg and placebo in eGFR trajectories at
`week 68.
`
`CONCLUSIONS
`Semaglutide improved UACR in adults with overweight/obesity and type 2 diabe-
`tes. In participants with normal kidney function, semaglutide did not have an ef-
`fect on eGFR decline.
`
`1Department of Clinical Pharmacy and Pharma-
`cology, University of Groningen, Groningen, the
`Netherlands
`2Diabetes Research Centre, University of Leicester,
`Leicester, U.K.
`3Leicester Diabetes Centre, University Hospitals
`of Leicester NHS Trust, Leicester, U.K.
`4NIHR Leicester Biomedical Research Centre,
`Leicester, U.K.
`5Internal Medicine D, Hasharon Hospital-Rabin
`Medical Center, Petach-Tikva, Israel
`6Sackler School of Medicine, Tel Aviv University,
`Tel-Aviv, Israel
`7Medical & Science, Novo Nordisk A/S, Søborg,
`Denmark
`8Velocity Clinical Research at Medical City, Dallas,
`TX
`9Global Medical Affairs, Novo Nordisk A/S,
`Søborg, Denmark
`10Biostatistics Obesity & Metabolism, Novo Nordisk
`A/S, Søborg, Denmark
`11Division of Nephrology, Department of Medicine,
`University Health Network and University of
`Toronto, Toronto, Ontario, Canada
`
`Corresponding author: Hiddo J.L. Heerspink,
`h.j.lambers.heerspink@umcg.nl
`
`Received 28 September 2022 and accepted 11
`January 2023
`
`Clinical trial reg. nos. NCT03548935, NCT03552757,
`and NCT03611582, clinicaltrials.gov
`
`This article contains supplementary material online
`at https://doi.org/10.2337/figshare.21893931.
`
`© 2023 by the American Diabetes Association.
`Readers may use this article as long as the
`work is properly cited, the use is educational
`and not for profit, and the work is not altered.
`More information is available at https://www
`.diabetesjournals.org/journals/pages/license.
`
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`802
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`Semaglutide Improves Albuminuria in Obesity
`
`Diabetes Care Volume 46, April 2023
`
`Clinical practice guidelines for patients
`with type 2 diabetes recommend lifestyle
`interventions, including increased physical
`activity and weight loss, glucose-lowering
`agents to optimize glycemic control, and
`pharmacological treatment with renin–
`angiotensin system (RAS) inhibitors and
`sodium–glucose cotransporter 2 (SGLT2)
`inhibitors to slow progression of kidney
`function loss and reduce the incidence
`of cardiovascular disease (CVD) events
`(1,2). Despite the fact that clinical trials
`have demonstrated the efficacy of these
`lifestyle and pharmacological
`interven-
`tions (3–10), residual cardiovascular (CV)
`and kidney risk remains present even
`with guideline-recommended treatment
`(8,10). Part of this high residual risk of
`kidney function decline is associated with
`the biomarker of persistently elevated
`levels of albuminuria (11). New treat-
`ment strategies that further reduce body
`weight, improve glycemic control, and di-
`rectly or indirectly reduce albuminuria
`are therefore needed.
`Glucagon-like peptide 1 receptor ago-
`nists (GLP-1RAs) are recommended by
`clinical practice guidelines for the treat-
`ment of type 2 diabetes and obesity to
`reduce CV risk (1,12). CV outcomes trials
`with GLP-1RAs, including semaglutide,
`have demonstrated that these agents
`reduce CV risk and slow kidney function
`decline. These benefits may be partially
`due to improvements in glycemic control
`but are likely also mediated by other ef-
`fects, such as reductions in blood pressure,
`body weight, and albuminuria, beneficial
`effects on endothelial function, and inhibi-
`tion of proinflammatory mediators (13).
`The body weight–lowering effects of
`GLP-1RAs are clinically important as the
`prevalence of obesity continues to rise.
`In people with type 2 diabetes, once-
`weekly subcutaneous semaglutide doses
`of 1.0 and 2.0 mg reduce body weight
`(14). A higher dose (2.4 mg once weekly)
`has been approved for the treatment of
`overweight and obesity (15,16). The Sem-
`aglutide Treatment Effect in People with
`obesity (STEP) clinical trial program exam-
`ined the effect of semaglutide 2.4 mg (ad-
`ministered subcutaneously once weekly)
`on body weight compared with placebo
`in people with overweight or obesity
`(17). The STEP 1, 2, 3, and 4 trials demon-
`strated that semaglutide 2.4 mg com-
`pared with placebo, as adjunct to lifestyle
`management or intensive behavioral
`
`therapy, led to mean weight losses of
`6–15% in participants with and without
`type 2 diabetes (14,18–20). The effects
`of semaglutide 2.4 mg on albuminuria
`and estimated glomerular filtration rate
`(eGFR) are unknown, as are the potential
`benefits of semaglutide in patients using
`and not using SGLT2 inhibitors. It is also
`unknown whether the effects on albu-
`minuria can be explained by concomitant
`changes in glycated hemoglobin (HbA1c),
`body weight, and blood pressure.
`The aims of these post hoc analyses
`were to first explore the effect of sema-
`glutide compared with placebo on albu-
`minuria in patients with type 2 diabetes,
`as albuminuria was only measured in the
`STEP 2 trial, and second, to assess the ef-
`fects of semaglutide on eGFR in a pooled
`analysis of the STEP 1–3 trials.
`
`RESEARCH DESIGN AND METHODS
`Trial Designs
`The current study is a post hoc analysis
`of the STEP 1–3 trials. The full methods,
`trial profile and patient flow, and primary
`results for the STEP 1–3 trials have previ-
`ously been described (14,18,19). In brief,
`STEP 1–3 (NCT03548935, NCT03552757,
`and NCT03611582) were all phase 3a, dou-
`ble-blind, placebo-controlled, multicenter
`trials. In STEP 1 and 3, participants were
`randomized 2:1 to escalating doses of sem-
`aglutide up to 2.4 mg/week or placebo for
`68 weeks as an adjunct to either lifestyle
`intervention (counseling on diet and physi-
`cal activity; STEP 1) or an initial meal-
`replacement diet plus intensive behavioral
`therapy (low-calorie diet and intensive
`counseling on diet and physical activity fol-
`lowed by randomization to semaglutide or
`placebo to assess maintenance and/or fur-
`ther weight loss; STEP 3) (18,19). In STEP 2,
`participants were randomized 1:1:1 to
`68 weeks of semaglutide 2.4 mg, 1.0 mg,
`or placebo, all plus lifestyle intervention
`(similar to that in STEP 1) (14). In all trials,
`semaglutide was initiated at 0.25 mg once
`weekly and escalated every 4 weeks until
`the target dose was achieved (2.4 mg over
`16 weeks, or 1.0 mg over 8 weeks for par-
`ticipants assigned that dose in STEP 2). At
`the end of the 68-week double-blind treat-
`ment period, participants proceeded to a
`7-week off-drug follow-up period in each
`trial. All three trials were conducted ac-
`cording to the International Conference
`on Harmonisation Good Clinical Practice
`
`Guideline and the Declaration of Helsinki;
`all participants provided written informed
`consent (14,18,19). STEP 4 was not in-
`cluded in this analysis because key differ-
`ences in trial design, including its 20-week
`run-in period in which all participants re-
`ceived semaglutide, made it unsuitable to
`pool the results with the STEP 1–3 trials.
`
`Participants
`Male or female adults ($18 years of age)
`with a stable body weight (#5 kg weight
`change within 90 days before screening)
`and a history of at least one self-reported
`unsuccessful dietary effort to lose body
`weight were eligible for the STEP 1–3 tri-
`als (14,18,19). In addition, participants in
`STEP 1 and 3 were required to have ei-
`ther a BMI of $30 kg/m2 or $27 kg/m2
`plus at least one weight-related comor-
`bidity (excluding type 2 diabetes) (18,19).
`In STEP 2, participants were required to
`have a BMI of $27 kg/m2, a diagnosis of
`type 2 diabetes that was managed by
`diet and physical activity or #3 oral
`glucose-lowering therapies, and an HbA1c
`of 7–10% (53–86 mmol/mol) (14). Partici-
`pants were excluded from the trials if they
`had an eGFR of <15 mL/min/1.73 m2 in
`STEP 1 and 3 (18,19) and of <30 mL/min/
`1.73 m2 (<60 mL/min/1.73 m2 in those re-
`ceiving SGLT2 inhibitors) in STEP 2 (14).
`
`Outcomes
`The coprimary outcome in STEP 1–3
`was the percent change from baseline
`in body weight (alongside the achieve-
`ment of $5% weight loss) as reported
`previously (14,18,19). Changes in albu-
`minuria and eGFR were assessed as ex-
`ploratory post hoc outcomes (14,18,19).
`Albuminuria was expressed as urine albu-
`min-to-creatinine ratio (UACR). Urinary al-
`bumin and creatinine were measured in a
`central
`laboratory at weeks 0, 20, and
`68 in STEP 2 only; UACR was not measured
`in STEP 1 or 3. The albuminuria-related
`outcomes assessed from baseline to
`week 68 were: mean percent change in
`urinary albumin concentration, mean per-
`cent change in UACR in the overall popula-
`tion and in patient subgroups; proportions
`of patients with normoalbuminuria (UACR
`<30 mg/g), microalbuminuria (UACR $30
`to #300 mg/g), and macroalbuminuria
`(UACR >300 mg/g); and proportions of
`patients whose UACR status improved
`or worsened. For the subgroup analyses
`of the change in UACR, patients were
`
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`diabetesjournals.org/care
`
`Heerspink and Associates
`
`803
`
`grouped according to the following varia-
`bles: baseline UACR (<30 or $30 mg/g),
`baseline systolic blood pressure (<130 or
`$130 mmHg), baseline eGFR (<90 or
`$90 mL/min/1.73 m2), baseline HbA1c
`(<8.0 or $8.0%), baseline BMI (<35 or
`$35 kg/m2), SGLT2 inhibitor use (yes/no),
`and RAS inhibitor use (yes/no). For the
`analysis of change in UACR status, an im-
`provement was defined as regression from
`microalbuminuria at baseline to normoal-
`buminuria, or macroalbuminuria at base-
`line to micro-/normoalbuminuria by week
`68, while a worsening was defined as ei-
`ther progression from normoalbuminuria
`at baseline to micro-/macroalbuminuria,
`or microalbuminuria at baseline to macro-
`albuminuria by week 68. A mediation anal-
`ysis was performed to investigate whether
`the effect of semaglutide in reducing UACR
`was mediated by concomitant changes in
`HbA1c, body weight, and blood pressure
`from baseline to week 68.
`Serum creatinine was measured at
`screening and at weeks 20, 52, and 68
`in STEP 1–3. eGFR was calculated using
`the Chronic Kidney Disease Epidemiology
`Collaboration 2009 creatinine equation (21).
`A sensitivity analysis was performed using
`the race-free Chronic Kidney Disease Epide-
`miology Collaboration 2021 creatinine equa-
`tion (22). The change from baseline to week
`68 in eGFR was assessed in STEP 1–3.
`
`Statistical Analysis
`Statistical analyses were based on the
`trial product estimand (the secondary
`estimand in the STEP trials), which as-
`sessed the treatment effect in all ran-
`domized participants when each drug
`was taken as intended. The analyses
`only included data from all randomized
`assigned participants until first treat-
`ment discontinuation or use of a rescue in-
`tervention (initiation of other antiobesity
`medications or bariatric surgery). Observed
`data from the on-treatment observation
`period (during treatment with trial product;
`any dose of trial medication administered
`within the previous 2 weeks [i.e., any pe-
`riod of temporary treatment interruption
`with trial product was excluded]) are re-
`ported for the following outcomes (STEP 2
`only unless otherwise stated): urinary albu-
`min by week, UACR by week, proportions
`of patients by UACR status, proportions of
`patients with an improvement or worsen-
`ing in UACR status, and eGFR by week
`(STEP 1–3). In a sensitivity analysis, the
`
`effects of semaglutide versus placebo were
`analyzed according to the treatment policy
`estimand, which assessed the effect in all
`randomized participants irrespective of dis-
`continuation of randomized treatment or
`use of rescue medication. The proportions
`of patients whose UACR status improved
`were compared by treatment using a
`Chi-square test.
`The changes from baseline to week 68
`in urinary albumin concentration (STEP 2),
`UACR (STEP 2), and eGFR (STEP 1–3) were
`assessed using a mixed model for re-
`peated measurements with randomized
`treatment, randomization stratification
`groups (background type 2 diabetes
`medication and HbA1c; STEP 2 only),
`and the interaction between stratifica-
`tion groups (STEP 2 only) as factors and
`baseline value of the outcome measure
`of interest as a covariate, all nested
`within visit. For the subgroup analysis
`of the change in UACR, subgroup and
`the interaction between treatment and
`subgroup were also included in the
`model as factors. None of the analyses
`were adjusted for multiplicity.
`The mediation analysis was performed
`using the medflex package in R (23). A
`natural effects model was fitted using an
`imputation-based procedure (24), allow-
`ing for decomposition of the treatment
`effect estimates into natural direct and
`indirect effect estimates. The percent me-
`diated was then calculated as the natural
`indirect effect divided by the total treat-
`ment effect and the CI obtained using
`Fieller’s method (25).
`Urinary albumin and UACR were ana-
`lyzed on a log scale as estimated ratios to
`baseline (within treatment groups) and esti-
`mated treatment ratios (between treat-
`ment groups). For interpretation, data are
`expressed as relative percent changes and
`estimated relative percent differences be-
`tween groups, respectively, calculated using
`the formula (estimated ratio 1) × 100.
`P values <0.05 were considered to indicate
`statistical significance. Analyses were per-
`formed with R version 4.20/SAS version 9.4.
`No adjustment for multiple comparisons
`was made, and as such, all results should be
`considered exploratory.
`
`Data and Resource Availability
`Data will be shared with bona fide research-
`ers who submit a research proposal ap-
`proved by the independent review board.
`Individual patient data will be shared in
`
`data sets in a de-identified and anonymized
`format. Data will be made available after
`research completion and approval of the
`product and product use in the European
`Union and U.S. Information about data
`access request proposals can be found at
`https://www.novonordisk-trials.com.
`
`RESULTS
`Participants
`In STEP 2, the baseline characteristics
`were well balanced among the three
`treatment groups (Table 1). The geomet-
`ric mean (coefficient of variation)
`for
`UACR at baseline was 13.2 (199.8) mg/g
`in the placebo group and 13.7 (249.6) mg/g
`and 12.5 (225.1) mg/g in the semaglutide
`1.0 mg and 2.4 mg treatment groups, re-
`spectively. A total of 248 participants had
`UACR of $30 mg/g at baseline. In STEP 2,
`the mean ± SD for eGFR at baseline was
`95.4 ± 18.1 and 96.3 ± 18.5 mL/min/
`1.73 m2 in the semaglutide 1.0 mg and
`2.4 mg groups and 94.6 ± 19.3 mL/min/
`1.73 m2 in the placebo group.
`Baseline characteristics for STEP 1 and
`STEP 3 are presented in Supplementary
`Tables 1 and 2. The mean ± SD for eGFR
`at baseline in STEP 1 was 97.9 ± 16.9
`mL/min/1.73 m2 for semaglutide 2.4 mg
`and 97.4 ± 16.7 mL/min/1.73 m2 for pla-
`cebo. In STEP 3, the mean ± SD for eGFR at
`baseline was 98.6 ± 19.3 mL/min/1.73 m2
`for semaglutide 2.4 mg and 98.5 ± 19.3 mL/
`min/1.73 m2 for placebo.
`
`Effect of Semaglutide Versus Placebo
`on UACR (STEP 2)
`Figure 1A shows the albuminuria change
`from baseline to week 68, and Supple-
`mentary Fig. 1 shows the change over time
`in UACR by week. In the placebo group,
`UACR increased by 18.3%. In the semaglu-
`tide 1.0 mg and 2.4 mg dose groups dose
`groups, UACR changed from baseline by
`14.8% and 20.6%, respectively, at
`week 68. Accordingly, mean percentage
`UACR difference compared with placebo
`at week 68 was 28.0% (95% CI 37.3,
`17.3) (P < 0.0001) and 32.9% (95% CI
`41.6, 23.0) (P = 0.003) in the semaglu-
`tide 1.0 mg and 2.4 mg groups, respectively.
`Changes in urinary albumin concentration
`from baseline to week 68 were 8.6% in
`the semaglutide 1.0 mg treatment group
`(estimated treatment difference, 22.6
`[95% CI 34.1, 9.1]) and 12.6% in
`
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`804
`
`Semaglutide Improves Albuminuria in Obesity
`
`Diabetes Care Volume 46, April 2023
`
`Table 1—Baseline demographics and clinical characteristics (STEP 2)
`
`Semaglutide 1.0 mg (n = 403)
`
`Semaglutide 2.4 mg (n = 404)
`
`Placebo (n = 403)
`
`Age, years, mean (SD)
`
`Sex
`Male
`Female
`
`Race
`American Indian or Alaska Native
`Asian
`Black or African American
`White
`Other
`Native Hawaiian or Other Pacific Islander
`
`Duration of diabetes, years [no.*], mean (SD)
`
`HbA1c, mmol/mol, mean (SD)
`
`HbA1c, %
`
`Body weight, kg, mean (SD)
`
`BMI, kg/m2, mean (SD)
`
`eGFR, CKD-EPI, mL/min/1.73 m2
`Mean (SD)
`Distribution† [no.*]
`$90
`<90
`
`UACR, mg/g† [no.*]
`Geometric mean (CV)
`Normal albuminuria (UACR <30)
`Microalbuminuria (UACR $30 to <300)
`Macroalbuminuria (UACR $300)
`
`Blood pressure, mmHg, mean (SD)
`Systolic blood pressure
`Diastolic blood pressure
`
`History of CV
`
`SGLT2 inhibitor use
`
`Agents acting on the RAS
`
`56 (10)
`
`200 (49.6)
`203 (50.4)
`
`0
`97 (24.1)
`28 (6.9)
`272 (67.5)
`6 (1.5)
`0
`
`7.7 (5.9)
`
`65.4 (8.5)
`
`8.1 (0.8)
`
`99.0 (21.1)
`
`35.3 (5.9)
`
`95.4 (18.1)
`[402]
`265 (65.9)
`137 (34.1)
`
`[402]
`13.7 (249.6)
`306 (77.5)
`72 (18.2)
`17 (4.3)
`
`130 (14)
`80 (9)
`
`90 (22.3)
`
`90 (22.3)
`
`244 (60.5)
`
`55 (11)
`
`55 (11)
`
`181 (44.8)
`223 (55.2)
`
`4 (1.0)
`112 (27.7)
`35 (8.7)
`237 (58.7)
`16 (4.0)
`0
`
`8.2 (6.2)
`
`65.3 (8.7)
`
`8.1 (0.8)
`
`99.9 (22.5)
`
`35.9 (6.4)
`
`96.3 (18.5)
`[403]
`270 (67.0)
`133 (33.0)
`
`[403]
`12.5 (225.1)
`318 (80.5)
`64 (16.2)
`13 (3.3)
`
`130 (13)
`80 (9)
`
`58 (14.4)
`
`95 (23.5)
`
`216 (53.5)
`
`213 (52.9)
`190 (47.1)
`
`2 (0.5)
`108 (26.8)
`37 (9.2)
`242 (60.0)
`13 (3.2)
`1 (0.2)
`
`8.2 (6.2) [402]
`
`65.3 (9.0)
`
`8.1 (0.8)
`
`100.5 (20.9)
`
`35.9 (6.5)
`
`94.6 (19.3)
`[402]
`259 (64.4)
`143 (35.6)
`
`[402]
`13.2 (199.8)
`317 (79.4)
`71 (17.8)
`11 (2.8)
`
`130 (13)
`80 (9)
`
`69 (17.1)
`
`99 (24.6)
`
`241 (59.8)
`
`Data are n (%) and are for the full analysis set unless otherwise indicated. n is number of patients. Novo Nordisk data published in Davies M,
`Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised,
`double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971–984. CKD-EPI, Chronic Kidney Disease Epidemiology Collabo-
`ration; CV, coefficient of variation. *[no.] is number of participants analyzed (where different from the number in the full analysis set). †Data
`are for the safety analysis set.
`
`the semaglutide 2.4 mg treatment group
`(estimated treatment difference, 26.0
`[95% CI 37.0, 13.1]) versus 18.1% in
`the placebo group. The change over time
`in urinary albumin by week is shown in
`Supplementary Fig. 2. Results were essen-
`tially similar when we repeated the analysis
`according to the treatment policy estimand.
`Mean percentage UACR difference com-
`pared with placebo at week 68 was
`27.2% (95% CI 37.6, 15.0) (P <
`0.0001) and 30.5% (95% CI 40.3,
`19.1) (P < 0.0001) in the semaglutide
`1.0 mg and 2.4 mg groups, respectively.
`Estimated changes in UACR by sub-
`groups of patients are shown in Fig. 2.
`
`The effect of semaglutide compared with
`placebo was consistent in subgroups by
`baseline BMI, HbA1c, eGFR, or use of RAS
`or SGLT2 inhibitors. The reduction in
`UACR with semaglutide 2.4 mg compared
`with placebo was more pronounced in
`patients with microalbuminuria or macro-
`albuminuria compared with patients with
`normoalbuminuria (P = 0.0009).
`A higher proportion of patients on sem-
`aglutide 2.4 mg and semaglutide 1.0 mg
`had normoalbuminuria by week 68 com-
`pared with those receiving placebo (87.1%
`vs. 84.9% vs. 72.8%, respectively) (Fig. 1B).
`The percentage of patients with microalbu-
`minuria and macroalbuminuria at week 68
`
`was lower in the semaglutide 2.4 mg and
`1.0 mg treatment groups compared with
`placebo (11.5% and 1.4% vs. 12.2%, and
`2.9% vs. 22.4% and 4.8%, respectively).
`The proportion of patients with a >30%
`reduction in UACR at week 68 in the sema-
`glutide 1.0 mg and 2.4 mg groups was
`37.4% (P = 0.0014 vs. placebo) and 38.0%
`(P = 0.0008 vs. placebo), respectively, com-
`pared with 25.9% in the placebo group.
`The corresponding proportions of patients
`who improved from macroalbuminuria or
`microalbuminuria categories to a lower
`category (microalbuminuria or normo-
`albuminuria) were 57.9% for semaglu-
`tide 1.0 mg (P = 0.0004) and 56.1% for
`
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`
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`

`diabetesjournals.org/care
`
`Heerspink and Associates
`
`805
`
`ETD [95% CI]: −28.0% [−37.3, −17.3]; P < 0.0001
`
`18.3
`
`−14.8
`
`−20.6
`
`ETD [95% CI]: −32.9% [−41.6, −23.0]; P = 0.003
`
`Semaglutide 1.0 mg
`
`Semaglutide 2.4 mg
`
`Placebo
`
`84.9
`77.5
`
`87.1
`80.5
`
`79.4
`72.8
`
`18.2
`12.2
`
`4.3
`
`2.9
`
`16.2
`11.5
`
`3.3
`
`1.4
`
`22.4
`17.8
`
`2.8
`
`4.8
`
`0
`68
`Normal
`albuminuria
`
`0
`68
`Micro-
`albuminuria
`
`0
`68
`Macro-
`albuminuria
`
`0
`68
`Normal
`albuminuria
`
`0
`68
`Micro-
`albuminuria
`
`0
`68
`Macro-
`albuminuria
`
`0
`68
`Normal
`albuminuria
`
`0
`68
`Micro-
`albuminuria
`
`0
`68
`Macro-
`albuminuria
`
`Semaglutide 1.0 mg
`
`Semaglutide 2.4 mg
`
`Placebo
`
`57.9
`
`56.1
`
`29.2
`
`13.7
`
`4.3
`
`3.9
`
`Improvement Worsening
`
`Improvement Worsening
`
`Improvement Worsening
`
`Semaglutide 1.0 mg
`
`Semaglutide 2.4 mg
`
`Placebo
`
`Semaglutide
`1.0 mg
`
`Semaglutide
`2.4 mg
`
`Placebo
`
`At baseline
`At week 68
`
`25
`20
`15
`10
`
`05
`
`−5
`−10
`−15
`−20
`−25
`
`Change in UACR (%)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Proportion of patients (%)
`
`A
`
`B
`
`0
`
`Week:
`Patients with:
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Proportion of patients (%)
`
`C
`
`0
`Patients with:
`
`Figure 1—A: Percent change in UACR from baseline to week 68. B: Distribution of patients by UACR status at baseline and week 68. Proportions
`are based on the number of patients in each UACR status category at the visit over the total number of patients with a UACR observation at the
`visit. The left-hand bar in each pair refers to baseline and the right-hand bar to week 68. C: Patients with changes in UACR status from baseline to
`week 68. Proportions are based on the number of patients with an improvement in UACR status from baseline to week 68 over the total number
`of patients with a UACR observation at both time points; a large proportion of patients were not included in this analysis because of missing data
`at baseline (n = 7 for semaglutide 1.0 mg, n = 8 for semaglutide 2.4 mg, and n = 3 for placebo) or week 68 (n = 57 for semaglutide 1.0 mg, n = 55
`for semaglutide 2.4 mg, and n = 67 for placebo). Improvement is regression of baseline macroalbuminuria to microalbuminuria/normal or microal-
`buminuria to normal at week 68. Worsening is progression of baseline normal albuminuria to microalbuminuria/macroalbuminuria or microalbu-
`minuria to macroalbuminuria at week 68. ETD, estimated treatment difference.
`
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`

`806
`
`Semaglutide Improves Albuminuria in Obesity
`
`Diabetes Care Volume 46, April 2023
`
`Overall population
`
` BMI <30 kg/m2
`
`BMI 30 to <35 kg/m2
`
`BMI 35 to <40 kg/m2
`
`BMI ≥40 kg/m2
`
`eGFR normal (no RI)
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`eGFR mild/
`moderate/severe RI
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Baseline HbA1c (<8%)
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`N
`
`ETD % [95% CI]
`
`320
`
`–28.02 [–37.33, –17.34]
`
`317
`
`–32.94 [–41.63, –22.96]
`
`66
`
`68
`
`–25.47 [–46.82, 4.45]
`
`–29.08 [–48.91, –1.53]
`
`163
`
`–34.84 [–48.28, –17.92]
`
`140
`
`–40.62 [–53.30, –24.48]
`
`100
`
`103
`
`74
`
`93
`
`–10.39 [–32.13, 18.31]
`
`–24.53 [–42.61, –0.76]
`
`–36.17 [–52.65, –13.96]
`
`–32.64 [–49.67, –9.86]
`
`265
`
`–29.90 [–40.92, –16.83]
`
`271
`
`–31.76 [–42.35, –19.22]
`
`138
`
`–24.52 [–40.39, –4.42]
`
`133
`
`–36.70 [–50.50, –19.04]
`
`186
`
`–29.36 [–42.09, –13.84]
`
`200
`
`–34.06 [–45.98, –19.51]
`
`Baseline HbA1c (≥8%)
`
`Normal albuminuria
`
`Micro-/
`macroalbuminuria
`
` RAS inhibitor use
`
`SBP <130 mmHg
`
`SBP >130 mmHg
`
`SGLT2i use
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`Semaglutide 1.0 mg vs. placebo
`
`Semaglutide 2.4 mg vs. placebo
`
`217
`
`–27.11 [–39.93, –11.54]
`
`204
`
`–32.26 [–44.18, –17.78]
`
`306
`
`–24.65 [–35.59, –11.85]
`
`319
`
`–24.56 [–35.43, –11.85]
`
`97
`
`85
`
`–40.84 [–55.61, –21.15]
`
`–57.31 [–68.31, –42.50]
`
`244
`
`–27.71 [–39.38, –13.80]
`
`216
`
`–34.01 [–45.10, –20.68]
`
`197
`
`–29.92 [–42.84, –14.10]
`
`200
`
`–28.20 [–41.32, –12.03]
`
`206
`
`–26.33 [–39.10, –11.00]
`
`204
`
`–37.10 [–48.03, –23.80]
`
`95
`
`99
`
`–29.70 [–47.04, –6.69]
`
`–36.87 [–51.99, –16.99]
`
`–80
`
`–60
`
`–40
`
`–20
`
`0
`
`20
`
`40
`
`ETD % [95% CI]
`
`Figure 2—Change in UACR by subgroup analyses. Data are for the trial product estimand (assesses treatment effect if all patients adhered to treat-
`ment without rescue intervention) unless otherwise stated. RI, renal impairment; SBP, systolic blood pressure; SGLT2i, SGLT2 inhibitor.
`
`semaglutide 2.4 mg (P = 0.0014) versus
`29.2% for placebo (Fig. 1C).The proportions
`of patients who showed progression
`
`from normoalbuminuria or microalbumi-
`nuria to a higher category for semaglutide
`1.0 mg and 2.4 mg were 4.3% and 3.9%
`
`(P < 0.0001 for both doses vs. placebo),
`respectively, versus 13.7% with placebo
`(Fig. 1C).
`
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`

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`
`Heerspink and Associates
`
`807
`
`Effect of Semaglutide on UACR
`Explained by Changes in HbA1c, Body
`Weight, and Systolic Blood Pressure
`(STEP 2)
`At week 68, patients receiving semaglutide
`2.4 mg had placebo-corrected changes in
`HbA1c of 1.5% (95% CI 1.7, 1.4). The
`corresponding changes in body weight and
`systolic blood pressure were 7.6% (95% CI
`8.6,6.6) and 4.8 mmHg (95% CI6.7,
`2.9), respectively, for semaglutide 2.4 mg
`versus placebo (14). To assess the extent to
`which the effect of semaglutide on albumin-
`uria could be explained by concomitant
`changes in HbA1c, body weight, or systolic
`blood pressure, the main analysis of change
`in UACR was repeated with adjustments for
`week 68 changes in these parameters
`(Supplementary Fig. 3). The effect of sema-
`glutide 2.4 mg compared with placebo after
`adjustment for HbA1c, body weight, and sys-
`tolic blood pressure was 58.6% (95% CI
`26.5, 97.8), suggesting that more than half
`of the effect of semaglutide on UACR may
`be related to its HbA1c, body weight, and
`systolic blood pressure–lowering effects
`(Supplementary Fig. 3). Repeating the anal-
`ysis for semaglutide 1.0 mg revealed simi-
`lar results (Supplementary Fig. 4).
`
`Effects on Overall eGFR Change
`(STEP 1–3)
`To characterize the effect of semaglutide
`on kidney function, we pooled the data
`from the STEP 1–3 clinical trials, involving
`3,379 participants with overweight or
`obesity with or without type 2 diabetes
`(data for the semaglutide 1.0 mg treat-
`ment arm from STEP 2 were not included
`in this analysis, but are included for base-
`line data). Of these participants, 1,262
`were assigned to placebo and 2,117 to
`semaglutide 2.4 mg. Mean ± SD eGFR at
`baseline was 99.3 ± 17.0 mL/min/1.73 m2
`
`for the total population, and eGFR was
`<60 mL/min/1.73 m2 in 85 (2.5%) partic-
`ipants. At week 68, no between-group
`differences in eGFR were observed. Dur-
`ing the total 68 weeks of treatment, the
`rate of change in eGFR from baseline
`did not differ between the semaglutide
`(0.70% [95% CI 1.17, 0.22]) and pla-
`cebo group (0.21% [95% CI 0.85,
`0.42]; P = 0.2351) (Supplementary Fig. 5).
`Results were similar for semaglutide 1.0
`mg treatment versus placebo in the STEP 2
`trial (Supplementary Fig. 6). Results were
`also similar when the Chronic Kidney
`Dise