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Cited by 98Chronic Kidney Disease and DiabetesDiabetes Treatment and ManagementPharmacology and Obesity Treatment

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

Open access
Heerspink, Hiddo J.L., Apperloo, Ellen, Davies, Melanie, Dicker, Dror, Kandler, Kristian, Rosenstock, Julio, Sørrig, Rasmus, Lawson, Jack +2 more·2023·Diabetes Care
DOI 10.2337/dc22-1889PMC PMC10090901
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Abstract

OBJECTIVE: These post hoc analyses of the Semaglutide Treatment Effect in People with obesity (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 −14.8% and −20.6% with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (between-group differences [95% CI] vs. placebo: −28.0% [−37.3, −17.3], P < 0.0001 for semaglutide 1.0 mg; −32.9% [−41.6, −23.0], P = 0.003 for semaglutide 2.4 mg). UACR status improved in greater proportions of patients with semaglutide 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 diabetes. In participants with normal kidney function, semaglutide did not have an effect on eGFR decline.

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  • Findingown data

    UACR reduction was numerically higher with semaglutide 2.4 mg than with 1.0 mg.

    “Numerically, a higher UACR reduction was observed with semaglutide 2.4 mg compared with the 1.0 mg dose, which seems to confirm the albuminuria-lowering effect of semaglutide.”
    Quote in the paperNot a substantial claim
  • Findingown data

    After adjustment for week 68 changes in HbA1c, body weight, and systolic blood pressure, the placebo-corrected effect of semaglutide 2.4 mg on UACR was 58.6% (95% CI 26.5 to 97.8).

    “The effect of semaglutide 2.4 mg compared with placebo after adjustment for HbA1c, body weight, and systolic 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).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The mediation analysis assumes no other variables confound the effect of semaglutide on albuminuria, HbA1c, or body weight, or the associations among these.
  • Findingown data

    In STEP 3, there were no events of acute renal failure reported.

    “In STEP 3, there were no events of acute renal failure reported (Table 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    By week 68, normoalbuminuria was more common with semaglutide 2.4 mg and 1.0 mg than with placebo (87.1% vs 84.9% vs 72.8%).

    “A higher proportion of patients on semaglutide 2.4 mg and semaglutide 1.0 mg had normoalbuminuria by week 68 compared with those receiving placebo (87.1% vs. 84.9% vs. 72.8%, respectively) (Fig. 1B).”
    Quote in the paperSubstantial claim
  • Findingown data

    The albuminuria-lowering effects of semaglutide were consistent in patients using or not using SGLT2 inhibitors.

    “These analyses also report for the first time that the albuminuria-lowering effects of semaglutide were consistent in patients using or not using SGLT2 inhibitors.”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 24
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The week-68 mean UACR difference versus placebo was −28.0% (95% CI −37.3, −17.3; P < 0.0001) for semaglutide 1.0 mg and −32.9% (95% CI −41.6, −23.0; P = 0.003) for semaglutide 2.4 mg.

    “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 semaglutide 1.0 mg and 2.4 mg groups, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Improvement from macroalbuminuria or microalbuminuria to a lower category occurred in 57.9% with semaglutide 1.0 mg (P = 0.0004) and 56.1% with semaglutide 2.4 mg (P = 0.0014), versus 29.2% with placebo.

    “The corresponding proportions of patients who improved from macroalbuminuria or microalbuminuria categories to a lower category (microalbuminuria or normoalbuminuria) were 57.9% for semaglutide 1.0 mg (P = 0.0004) and 56.1% for semaglutide 2.4 mg (P = 0.0014) versus 29.2% for placebo (Fig. 1C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the pooled STEP 1-3 population, baseline mean eGFR was 99.3 ± 17.0 mL/min/1.73 m2.

    “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%) participants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In STEP 2, baseline eGFR averaged 95.4 ± 18.1 mL/min/1.73 m2 for semaglutide 1.0 mg, 96.3 ± 18.5 for semaglutide 2.4 mg, and 94.6 ± 19.3 for placebo.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Progression from normoalbuminuria or microalbuminuria to a higher category occurred in 4.3% with semaglutide 1.0 mg and 3.9% with semaglutide 2.4 mg (P < 0.0001 for both vs placebo), versus 13.7% with placebo.

    “The proportions of patients who showed progression from normoalbuminuria or microalbuminuria 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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Urinary albumin concentration changed from baseline to week 68 by −8.6% with semaglutide 1.0 mg (estimated treatment difference −22.6 [95% CI −34.1, −9.1]) and −12.6% with semaglutide 2.4 mg (estimated treatment difference −26.0 [95% CI −37.0, −13.1]), versus +18.1% with placebo.

    “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 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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide was well tolerated with no increase in adverse events leading to study drug discontinuation.

    “Overall, semaglutide was well tolerated with no increase in adverse events leading to study drug discontinuation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    By week 68, UACR rose 18.3% with placebo and fell 14.8% with semaglutide 1.0 mg and 20.6% with semaglutide 2.4 mg.

    “In the placebo group, UACR increased by 18.3%. In the semaglutide 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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In STEP 2, baseline UACR geometric means were 13.7 mg/g for semaglutide 1.0 mg, 12.5 mg/g for semaglutide 2.4 mg, and 13.2 mg/g for placebo.

    “The geometric 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, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Frequency of adverse events potentially related to kidney function were similar across STEP 1 and 2 and relatively low.

    “Frequency of adverse events potentially related to kidney function (i.e., renal and urinary disorders, acute kidney injury, and renal impairment) were similar across the STEP 1 and 2 trials and were relatively low.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Baseline eGFR in STEP 1 was 97.9 ± 16.9 mL/min/1.73 m2 for semaglutide 2.4 mg and 97.4 ± 16.7 for placebo; in STEP 3, it was 98.6 ± 19.3 for semaglutide 2.4 mg and 98.5 ± 19.3 for placebo.

    “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 placebo. 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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A >30% UACR reduction at week 68 occurred in 37.4% with semaglutide 1.0 mg (P = 0.0014 vs placebo) and 38.0% with semaglutide 2.4 mg (P = 0.0008 vs placebo), versus 25.9% with placebo.

    “The proportion of patients with a >30% reduction in UACR at week 68 in the semaglutide 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, compared with 25.9% in the placebo group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In post hoc exploratory analyses from STEP, semaglutide significantly reduced albuminuria and increased the likelihood of improvement from a high to lower albuminuria category in people with type 2 diabetes.

    “In these post hoc exploratory analyses from the STEP program, semaglutide significantly reduced albuminuria and increased the likelihood of improvement from a high to lower albuminuria category in the population with type 2 diabetes (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Davies M, Færch L, Jeppesen OK,.; STEP 2 Study Group. 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 33667417 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    With the treatment policy estimand, the week-68 mean UACR difference versus placebo was −27.2% (95% CI −37.6, −15.0; P < 0.0001) for semaglutide 1.0 mg and −30.5% (95% CI −40.3, −19.1; P < 0.0001) for semaglutide 2.4 mg.

    “Mean percentage UACR difference compared 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.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    For semaglutide 1.0 mg, the adjusted effect on UACR was similar to that for 2.4 mg.

    “Repeating the analysis for semaglutide 1.0 mg revealed similar results (Supplementary Fig. 4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    At baseline, 248 participants had UACR of 30 mg/g or higher.

    “A total of 248 participants had UACR of ≥30 mg/g at baseline.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both doses of semaglutide increased the probability of regression in albuminuria categories and reduced the likelihood of progression to worsening albuminuria categories.

    “Moreover, both doses of semaglutide increased the probability of regression in albuminuria categories and reduced the likelihood of progression to worsening albuminuria categories.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Semaglutide 2.4 mg once weekly has been approved for treating overweight and obesity.

    “A higher dose (2.4 mg once weekly) has been approved for the treatment of overweight and obesity (15,16).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Wegovy: highlights of prescribing information, 2021. Accessed 7 September 2022. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf

      Not checked in the free run.

    • cites [16] Wegovy: product information, 2022. Accessed 7 September 2022. Available from https://www.ema.europa.eu/en/documents/product-information/wegovy-epar-product-information_en.pdf

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    STEP 1-3 were phase 3a, double-blind, placebo-controlled, multicenter trials.

    “In brief, STEP 1–3 (NCT03548935, NCT03552757, and NCT03611582) were all phase 3a, double-blind, placebo-controlled, multicenter trials.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    STEP 1 and 3 randomly assigned participants 2:1 to semaglutide (up to 2.4 mg weekly) or placebo for 68 weeks, alongside lifestyle intervention or intensive behavioral therapy.

    “In STEP 1 and 3, participants were randomized 2:1 to escalating doses of semaglutide up to 2.4 mg/week or placebo for 68 weeks as an adjunct to either lifestyle intervention”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Wilding JPH, Batterham RL, Calanna S,.; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989– 1002 33567185 source

      Not checked in the free run.

    • cites [19] Wadden TA, Bailey TS, Billings LK,.; STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021; 325: 1403– 1413 33625476 PMC7905697 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    STEP 2 randomly assigned participants 1:1:1 to semaglutide 2.4 mg, 1.0 mg, or placebo for 68 weeks, all with lifestyle intervention.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Davies M, Færch L, Jeppesen OK,.; STEP 2 Study Group. 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 33667417 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trials of cardiovascular outcomes for GLP-1 receptor agonists, semaglutide included, indicate lower cardiovascular risk and slower kidney function decline.

    “CV outcomes trials with GLP-1RAs, including semaglutide, have demonstrated that these agents reduce CV risk and slow kidney function decline.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Muskiet MHA, Tonneijck L, Smits MM,. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017; 13: 605– 628 28869249 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Guidelines recommend lifestyle interventions, glucose-lowering agents, and RAS/SGLT2 inhibitors for type 2 diabetes patients to slow kidney function loss and reduce CVD events.

    “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 inc”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] de Boer IH, Caramori ML, Chan JCN,. Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment. Kidney Int 2020; 98: 839– 848 32653403 source

      Not checked in the free run.

    • cites [2] American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022; 45(Suppl. 1): S113– S124 34964843 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The STEP program tested whether semaglutide 2.4 mg changes body weight relative to placebo in overweight or obesity.

    “The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial program examined the effect of semaglutide 2.4 mg (administered subcutaneously once weekly) on body weight compared with placebo in people with overweight or obesity (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kushner RF, Calanna S, Davies M,. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring) 2020; 28: 1050– 1061 32441473 PMC7318657 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Data from randomized participants were included only up to first treatment discontinuation or rescue intervention.

    “The analyses only included data from all randomized assigned participants until first treatment discontinuation or use of a rescue intervention (initiation of other antiobesity medications or bariatric surgery).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In STEP 1-4, semaglutide 2.4 mg versus placebo, added to lifestyle management or intensive behavioral therapy, produced mean weight reductions of 6-15% in people with and without type 2 diabetes.

    “The STEP 1, 2, 3, and 4 trials demonstrated that semaglutide 2.4 mg compared 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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [14] Davies M, Færch L, Jeppesen OK,.; STEP 2 Study Group. 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 33667417 source

      Not checked in the free run.

    • cites [18] Wilding JPH, Batterham RL, Calanna S,.; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989– 1002 33567185 source

      Not checked in the free run.

    • cites [19] Wadden TA, Bailey TS, Billings LK,.; STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021; 325: 1403– 1413 33625476 PMC7905697 source

      Not checked in the free run.

    • cites [20] Rubino D, Abrahamsson N, Davies M,.; STEP 4 Investigators. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021; 325: 1414– 1425 33755728 PMC7988425 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    A sensitivity analysis used the treatment policy estimand, which assesses effects in all randomized participants regardless of treatment discontinuation or rescue medication.

    “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 discontinuation of randomized treatment or use of rescue medication.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For type 2 diabetes patients, subcutaneous semaglutide given once weekly at 1.0 or 2.0 mg lowers body weight.

    “In people with type 2 diabetes, once-weekly subcutaneous semaglutide doses of 1.0 and 2.0 mg reduce body weight (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Davies M, Færch L, Jeppesen OK,.; STEP 2 Study Group. 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 33667417 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The cardiovascular and kidney benefits of GLP-1 receptor agonists may be partly due to improved glycemic control but are likely also mediated by other effects, including reductions in blood pressure, body weight, and albuminuria, improved endothelial function, and inhibition of proinflammatory mediators.

    “These benefits may be partially due to improvements in glycemic control but are likely also mediated by other effects, such as reductions in blood pressure, body weight, and albuminuria, beneficial effects on endothelial function, and inhibition of proinflammatory mediators (13).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Muskiet MHA, Tonneijck L, Smits MM,. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017; 13: 605– 628 28869249 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even with guideline-recommended treatment, residual cardiovascular and kidney risk remains despite trials showing efficacy of lifestyle and pharmacological interventions.

    “Despite the fact that clinical trials have demonstrated the efficacy of these lifestyle and pharmacological interventions (3–10), residual cardiovascular (CV) and kidney risk remains present even with guideline-recommended treatment (8,10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Bakris GL, Agarwal R, Anker SD,.; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219– 2229 33264825 source

      Not checked in the free run.

    • cites [10] Perkovic V, Jardine MJ, Neal B,.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295– 2306 30990260 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    All three trials followed Good Clinical Practice and the Declaration of Helsinki, and every participant gave written informed consent.

    “All three trials were conducted according to the International Conference on Harmonisation Good Clinical Practice Guideline and the Declaration of Helsinki; all participants provided written informed consent (14,18,19).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Davies M, Færch L, Jeppesen OK,.; STEP 2 Study Group. 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 33667417 source

      Not checked in the free run.

    • cites [18] Wilding JPH, Batterham RL, Calanna S,.; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989– 1002 33567185 source

      Not checked in the free run.

    • cites [19] Wadden TA, Bailey TS, Billings LK,.; STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021; 325: 1403– 1413 33625476 PMC7905697 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The analyses used the trial product estimand, which estimates treatment effect in all randomized participants if each drug was taken as intended.

    “Statistical analyses were based on the trial product estimand (the secondary estimand in the STEP trials), which assessed the treatment effect in all randomized participants when each drug was taken as intended.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GLP-1 receptor agonists are recommended by guidelines for treating type 2 diabetes and obesity to reduce cardiovascular risk.

    “Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are recommended by clinical practice guidelines for the treatment of type 2 diabetes and obesity to reduce CV risk (1,12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] de Boer IH, Caramori ML, Chan JCN,. Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment. Kidney Int 2020; 98: 839– 848 32653403 source

      Not checked in the free run.

    • cites [12] Garvey WT, Mechanick JI, Brett EM,.; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016; 22(Suppl. 3): 1– 203 27219496 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a post hoc analysis of SUSTAIN-6 and LEADER, semaglutide or liraglutide slowed eGFR decline and reduced the risk of substantial loss of kidney function in patients with type 2 diabetes, with greater effects among those with preexisting CKD.

    “Similarly, in a post hoc analysis of the SUSTAIN-6 and LEADER trials, treatment with semaglutide or liraglutide slowed eGFR decline and reduced the risk of substantial loss of kidney function in patients with type 2 diabetes, with greater effects among those with preexisting CKD (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Shaman AM, Bain SC, Bakris GL,. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation 2022; 145: 575– 585 34903039 PMC8860212 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SUSTAIN 6, semaglutide 1.0 mg reduced albuminuria and the risk of new-onset macroalbuminuria in patients with type 2 diabetes.

    “In patients with type 2 diabetes who participated in the SUSTAIN 6 trial, semaglutide 1.0 mg reduced albuminuria and the risk of new-onset macroalbuminuria (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Mann JFE, Hansen T, Idorn T,. Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1-7 randomised controlled trials. Lancet Diabetes Endocrinol 2020; 8: 880– 893 32971040 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An acute reduction in eGFR occurs with other kidney-protective therapies such as RAS inhibitors and SGLT2 inhibitors and has been associated with long-term kidney protection.

    “An acute reduction in eGFR occurs with other classes of kidney-protective therapies, such as RAS inhibitors and SGLT2 inhibitors, and has been associated with long-term kidney protection (6,11,31,32).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Jardine MJ, Mahaffey KW, Neal B,.; CREDENCE study investigators. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol 2017; 46: 462– 472 29253846 PMC5804835 source

      Not checked in the free run.

    • cites [11] Oshima M, Neuen BL, Li J,. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a post hoc analysis from the CREDENCE Trial. J Am Soc Nephrol 2020; 31: 2925– 2936 32998938 PMC7790219 source

      Not checked in the free run.

    • cites [31] Holtkamp FA, de Zeeuw D, Thomas MC,. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011; 80: 282– 287 21451458 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    SGLT2 inhibitors are guideline-recommended therapies for kidney protection in people with type 2 diabetes, and guidelines suggest semaglutide can be prescribed as an adjunct to RAS inhibitors and SGLT2 inhibitors to further reduce albuminuria.

    “This is clinically relevant since SGLT2 inhibitors are now guideline-recommended therapies for kidney protection in people with type 2 diabetes, and guidelines suggest that semaglutide can be prescribed as an adjunct to RAS inhibitors and SGLT2 inhibitors to further reduce albuminuria (1,2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] de Boer IH, Caramori ML, Chan JCN,. Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment. Kidney Int 2020; 98: 839– 848 32653403 source

      Not checked in the free run.

    • cites [2] American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022; 45(Suppl. 1): S113– S124 34964843 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No multiplicity adjustment was applied to any analysis.

    “None of the analyses were adjusted for multiplicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dulaglutide, compared with insulin glargine, reduced albuminuria and slowed the decline in kidney function in patients with type 2 diabetes and CKD.

    “Dulaglutide, compared with insulin glargine, also reduced albuminuria and slowed the decline in kidney function in patients with type 2 diabetes and CKD (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tuttle KR, Lakshmanan MC, Rayner B,. 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– 617 29910024 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dulaglutide and efpeglenatide reduced albuminuria and the risk of a composite kidney endpoint in two cardiovascular outcomes trials in patients with type 2 diabetes at early stages of CKD.

    “Dulaglutide and efpeglenatide reduced albuminuria and the risk of a composite kidney end point in two CV outcomes trials involving patients with type 2 diabetes at early stages of CKD (33,34).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Gerstein HC, Colhoun HM, Dagenais GR,.; REWIND Investigators. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019; 394: 131– 138 31189509 source

      Not checked in the free run.

    • cites [34] Gerstein HC, Sattar N, Rosenstock J,.; AMPLITUDE-O Trial Investigators. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021; 385: 896– 907 34215025 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    STEP 2 baseline characteristics were well balanced across the three treatment arms.

    “In STEP 2, the baseline characteristics were well balanced among the three treatment groups (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    UACR data were available for 1,205 patients in STEP 2, 99.6% of the total cohort.

    “In STEP 2, 1,205 (99.6% total cohort) patients had UACR data”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Multiple comparisons were not adjusted for, so all findings are exploratory.

    “No adjustment for multiple comparisons was made, and as such, all results should be considered exploratory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The initial reduction in eGFR with semaglutide may suggest a favorable hemodynamic effect on kidney function since eGFR did not further decline during the subsequent 48 weeks.

    “This initial reduction in eGFR may suggest a favorable hemodynamic effect on kidney function since eGFR did not further decline during the subsequent 48 weeks.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The pooled STEP 1-3 analysis included 3,379 participants with eGFR data.

    “In the pooled STEP 1–3 analyses, 3,379 participants had eGFR data”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The lack of effect of semaglutide on slowing progressive kidney function loss was not unexpected because baseline kidney function was mostly normal, placebo eGFR decline was modest, and trial duration was relatively short.

    “Since kidney function was in the normal range in the vast majority of participants at baseline, eGFR was only modestly decreased in the placebo group, and thus, it was not unexpected that there was no effect with semaglutide in slowing progressive kidney function loss, given the relatively short trial duration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    These results support ongoing trials examining the impact of semaglutide on kidney protection in individuals at high risk of kidney disease progression.

    “These results support ongoing trials examining the impact of semaglutide on kidney protection in individuals at high risk of kidney disease progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study was a post hoc analysis of randomized controlled trials, so the results are hypothesis generating.

    “First, the study was a post hoc analysis of randomized controlled trials. Our results are therefore hypothesis generating.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because STEP 2 was not a dedicated kidney outcome trial and few participants had established CKD, effects on albuminuria cannot be directly generalized to people with more advanced stages of CKD.

    “Second, we recognize that by design, the STEP 2 trial was not a dedicated kidney outcome trial, and relatively few participants had established CKD. Accordingly, since many participants had baseline clinical kidney parameters in the normal range, effects on albuminuria cannot be directly generalized to people with more advanced stages of CKD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Albuminuria was not measured in STEP 1 or STEP 3, so the albuminuria-lowering effects of semaglutide cannot be generalized to people with overweight or obesity but without diabetes.

    “Fourth, albuminuria was not measured in the STEP 1 or STEP 3 trials, and we are therefore unable to generalize the albuminuria-lowering effects of semaglutide to people with overweight or obesity but without diabetes.”
    Quote in the paperSubstantial claim
50 of 50

  • The paper relies on this without support.

    It is unknown what semaglutide 2.4 mg does to albuminuria and eGFR.

    “The effects of semaglutide 2.4 mg on albuminuria and estimated glomerular filtration rate (eGFR) are unknown”

  • The paper relies on this without support.

    Whether semaglutide benefits patients on or off SGLT2 inhibitors is unknown.

    “as are the potential benefits of semaglutide in patients using and not using SGLT2 inhibitors.”

  • The paper relies on this without support.

    It is unknown whether albuminuria effects are explained by simultaneous changes in HbA1c, body weight, and blood pressure.

    “It is also unknown whether the effects on albuminuria can be explained by concomitant changes in glycated hemoglobin (HbA1c), body weight, and blood pressure.”

  • The authors state this as an assumption.

    The mediation analysis assumes no other variables confound the effect of semaglutide on albuminuria, HbA1c, or body weight, or the associations among these.

    “the mediation analysis requires an assumption that no other variables confound either the effect of semaglutide on albuminuria, HbA1c, or body weight, or the associations among these.”

  • The paper relies on this without support.

    Semaglutide reduces body weight, which may affect serum creatinine and eGFR.

    “semaglutide reduces body weight, which may affect serum creatinine and eGFR.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In patients with CKD and T2D, sustained reductions in albuminuria have been observed with the GLP-1 receptor agonists, semaglutide and dulaglutide.

    “In patients with CKD and T2D, sustained reductions in albuminuria have been observed with the GLP-1 receptor agonists, semaglutide and dulaglutide.19,20”

    From The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity (2025) · cites this paper as [19]

    The Results (STEP 2; page not provided) report reduced albuminuria with semaglutide at week 68 in people with type 2 diabetes. The Conclusions (page not provided) report reduced albuminuria with dulaglutide in people with type 2 diabetes and CKD, but note that the vast majority of STEP participants did not have CKD or had only very early-stage CKD. The paper therefore does not establish sustained albuminuria reductions with both drugs specifically in patients with CKD and type 2 diabetes. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Many of the cardiovascular outcome trials and other recent trials with incretin-based peptides have monitored renal function and shown a reno-protective effect of these treatments associated mainly with a reduction in the onset and severity of albuminuria.

    “Many of the cardiovascular outcome trials and other recent trials with incretin-based peptides have monitored renal function and shown a reno-protective effect of these treatments associated mainly with a reduction in the onset and severity of albuminuria [77-80].”

    From Recent advances in peptide-based therapies for obesity and type 2 diabetes (2024) · cites this paper as [79]

  • Albuminuria and reduced kidney function have been addressed as partially responsible for the residual CV risk persisting despite correction of common CV risk factors.

    “albuminuria and reduced kidney function have been addressed as partially responsible for the residual CV risk persisting despite correction of common CV risk factors79”

    From Incretin-based therapies for the treatment of obesity-related diseases (2024) · cites this paper as [79]

  • No significant difference in eGFR was found in patients treated with liraglutide 3.0 mg and semaglutide 2.4 mg in post-hoc analyses of the SCALE Obesity and Prediabetes, SCALE Diabetes and STEP 1-3 trials.

    “no significant difference in eGFR was found in patients treated with liraglutide 3.0 mg and semaglutide 2.4 mg in post-hoc analyses of the SCALE Obesity and Prediabetes, SCALE Diabetes and STEP 1–3 trials79,81”

    From Incretin-based therapies for the treatment of obesity-related diseases (2024) · cites this paper as [79]

  • Most of the beneficial effect of semaglutide on UACR reduction was mediated by HbA1c, BW and BP reduction.

    “Most of the beneficial effect of semaglutide on UACR reduction was mediated by HbA1c, BW and BP reduction79”

    From Incretin-based therapies for the treatment of obesity-related diseases (2024) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Albuminuria categories assign a UACR of 300 mg/g differently

    Minor

    The methods place a UACR of exactly 300 mg/g in the microalbuminuria category, whereas Table 1 places it in the macroalbuminuria category.

1 of 1

Cites

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4 of the 43 references couldn’t be matched to a known paper.

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Related

Authors
Heerspink, H. J. L., Apperloo, E., Davies, M., Dicker, D., Kandler, K., Rosenstock, J., Sørrig, R., Lawson, J., Zeuthen, N., & Cherney, D.
Affiliations
  • University of Groningen (NL)
  • University of Leicester (GB)
  • Tel Aviv University (IL)
  • Novo Nordisk (Denmark) (DK)
  • Medical City Dallas Hospital (US)
  • University Health Network (CA)
Corresponding author
Heerspink, Hiddo J.L.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2023-02-17
Volume
46
Issue
4
Pages
801-810
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc22-1889
PMC
PMC10090901
OpenAlex
W4321182840
Semantic Scholar
da49968d9092e9a77558c09b6cb1dae3bf219b6d
Cited by
98
References
43
Citations by year
2026: 19 · 2025: 31 · 2024: 42 · 2023: 6
FWCI
19.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes Care (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
Funders
Novo Nordisk A/S
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
albuminuria, renal function, obesity, overweight, type 2 diabetes, GLP-1 receptor agonists, albumin-creatinine ratio, estimated glomerular filtration rate, renal safety, STEP trial, lifestyle intervention, dose-response relationship, weight loss, cardiovascular risk reduction, glycemic control
MeSH terms
Semaglutide, Adult, Albuminuria, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Humans, Kidney, Obesity, Treatment Outcome, Overweight

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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