Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo

Glucagon-like peptide-1 receptor agonists reduce albuminuria and may stabilize the estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D). In this post hoc analysis of the SUSTAIN 6/PIONEER 6 trials encompassing 6480 participants at high cardiovascular risk (semaglutide, 3239 participants; placebo, 3241 participants), we investigated the effects of semaglutide versus placebo on eGFR decline. Pooled data by treatment were evaluated for annual eGFR change (total annual eGFR slope in ml/min per 1.73 m2) from baseline to end of treatment and time to persistent eGFR reductions of 30%, 40%, 50% and 57% or more, including subgroup analyses by baseline eGFR (30 to under 60 or 60 and over ml/min per 1.73 m2). In the overall population, the estimated treatment difference (ETD; semaglutide versus placebo) in annual eGFR slope was significant at 0.59 ml/min per 1.73 m2 (95% confidence interval 0.29; 0.89). The ETD was numerically largest in the 30 to under 60 ml/min per 1.73 m2 eGFR subgroup, 1.06 ml/min per 1.73 m2 (0.45; 1.67), but no significant interaction was observed for treatment effect by subgroup. Hazard ratios (semaglutide versus placebo) for time to persistent eGFR decline were under 1.0 for all eGFR thresholds in the overall population; and were numerically lower in the baseline eGFR 30 to under 60 ml/min per 1.73 m2 subgroup versus the overall population, although no significant interaction was observed for treatment effect by subgroup. Thus, pooled analyses of clinical trial data in patients with T2D suggest that semaglutide may reduce the rate of eGFR decline. Glucagon-like peptide-1 receptor agonists reduce albuminuria and may stabilize the estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D). In this post hoc analysis of the SUSTAIN 6/PIONEER 6 trials encompassing 6480 participants at high cardiovascular risk (semaglutide, 3239 participants; placebo, 3241 participants), we investigated the effects of semaglutide versus placebo on eGFR decline. Pooled data by treatment were evaluated for annual eGFR change (total annual eGFR slope in ml/min per 1.73 m2) from baseline to end of treatment and time to persistent eGFR reductions of 30%, 40%, 50% and 57% or more, including subgroup analyses by baseline eGFR (30 to under 60 or 60 and over ml/min per 1.73 m2). In the overall population, the estimated treatment difference (ETD; semaglutide versus placebo) in annual eGFR slope was significant at 0.59 ml/min per 1.73 m2 (95% confidence interval 0.29; 0.89). The ETD was numerically largest in the 30 to under 60 ml/min per 1.73 m2 eGFR subgroup, 1.06 ml/min per 1.73 m2 (0.45; 1.67), but no significant interaction was observed for treatment effect by subgroup. Hazard ratios (semaglutide versus placebo) for time to persistent eGFR decline were under 1.0 for all eGFR thresholds in the overall population; and were numerically lower in the baseline eGFR 30 to under 60 ml/min per 1.73 m2 subgroup versus the overall population, although no significant interaction was observed for treatment effect by subgroup. Thus, pooled analyses of clinical trial data in patients with T2D suggest that semaglutide may reduce the rate of eGFR decline. Lay SummaryPatients with type 2 diabetes (T2D) often develop chronic kidney disease. Semaglutide is a medicine used to treat T2D; previous studies have shown these medicines may also reduce the decline of kidney function. However, more studies are needed to confirm the kidney benefits with semaglutide. In 2 clinical trials, 6480 patients with T2D and at high risk of a cardiovascular event were treated with semaglutide or placebo. We used the results of kidney function tests from these studies to assess how fast kidney function declined in those treated with semaglutide or placebo. Our analysis showed that semaglutide significantly slowed the rate of kidney function decline and non-significantly extended the time taken to reach specified estimated glomerular filtration rate thresholds. We also saw that kidney function at the start of the trial did not impact these findings. Patients with type 2 diabetes (T2D) often develop chronic kidney disease. Semaglutide is a medicine used to treat T2D; previous studies have shown these medicines may also reduce the decline of kidney function. However, more studies are needed to confirm the kidney benefits with semaglutide. In 2 clinical trials, 6480 patients with T2D and at high risk of a cardiovascular event were treated with semaglutide or placebo. We used the results of kidney function tests from these studies to assess how fast kidney function declined in those treated with semaglutide or placebo. Our analysis showed that semaglutide significantly slowed the rate of kidney function decline and non-significantly extended the time taken to reach specified estimated glomerular filtration rate thresholds. We also saw that kidney function at the start of the trial did not impact these findings. Type 2 diabetes (T2D) markedly increases the risk of both cardiovascular (CV) disease and chronic kidney disease (CKD).1Thomas M.C. Cooper M.E. Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease.Nat Rev Nephrol. 2016; 12: 73-81Crossref PubMed Scopus (371) Google Scholar,2Sarwar N. Gao P. Seshasai S.R. et al.Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.Lancet. 2010; 375: 2215-2222Abstract Full Text Full Text PDF PubMed Scopus (3347) Google Scholar Approximately 40% of patients with T2D will develop CKD, and T2D is now the most common cause of progression to kidney failure worldwide.3Drüeke T.B. Floege J. Cardiovascular complications of chronic kidney disease: pioneering studies.Kidney Int. 2020; 98: 522-526Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,4Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (1284) Google Scholar Moreover, most of the diabetes-associated excess CV disease risk in individuals with T2D, compared with the general population, occurs in those with T2D who also have CKD.5Pálsson R. Patel U.D. Cardiovascular complications of diabetic kidney disease.Adv Chronic Kidney Dis. 2014; 21: 273-280Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar,6Afkarian M. Sachs M.C. Kestenbaum B. et al.Kidney disease and increased mortality risk in type 2 diabetes.J Am Soc Nephrol. 2013; 24: 302-308Crossref PubMed Scopus (761) Google Scholar Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an effective treatment for people with T2D and have been shown to have a beneficial effect on glycemic control and weight loss.7Chun J.H. Butts A. Long-acting GLP-1RAs: an overview of efficacy, safety, and their role in type 2 diabetes management.JAAPA. 2020; 33: 3-18Crossref Scopus (11) Google Scholar Furthermore, findings from CV outcomes trials with GLP-1RAs have demonstrated the CV safety of these medications, with some agents within the class demonstrating CV benefits in individuals with T2D.8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar, 9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar, 10Buse J.B. Bain S.C. Mann J.F.E. et al.Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial.Diabetes Care. 2020; 43: 1546-1552Crossref PubMed Scopus (71) Google Scholar, 11Gerstein H.C. Colhoun H.M. Dagenais G.R. et al.Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.Lancet. 2019; 394: 121-130Abstract Full Text Full Text PDF PubMed Scopus (1431) Google Scholar As a result, clinical guidelines recommend that in individuals with T2D at high risk of, or with established, atherosclerotic CV disease or CKD, GLP-1RAs or sodium–glucose cotransporter-2 inhibitors with proven CV benefit should be prescribed,12Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work GroupKDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease.Kidney Int. 2022; 102: S1-S127PubMed Scopus (128) Google Scholar the latter only if estimated glomerular filtration rate (eGFR) is ≥20 ml/min per 1.73 m2.13de Boer I.H. 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: 3075-3090Crossref PubMed Scopus (69) Google Scholar Many of the CV outcomes trials of GLP-1RAs included kidney disease outcomes as secondary endpoints, and the accumulating evidence suggests that GLP-1RAs have beneficial effects on such outcomes.14Alicic R.Z. Cox E.J. Neumiller J.J. et al.Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence.Nat Rev Nephrol. 2021; 17: 227-244Crossref PubMed Scopus (70) Google Scholar,15Yin W.L. Bain S.C. Min T. The effect of glucagon-like peptide-1 receptor agonists on renal outcomes in type 2 diabetes.Diabetes Ther. 2020; 11: 835-844Crossref PubMed Scopus (27) Google Scholar In particular, a reduction in the onset and progression of macroalbuminuria and slowing in the rate of decline in eGFR has been reported.14Alicic R.Z. Cox E.J. Neumiller J.J. et al.Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence.Nat Rev Nephrol. 2021; 17: 227-244Crossref PubMed Scopus (70) Google Scholar,15Yin W.L. Bain S.C. Min T. The effect of glucagon-like peptide-1 receptor agonists on renal outcomes in type 2 diabetes.Diabetes Ther. 2020; 11: 835-844Crossref PubMed Scopus (27) Google Scholar However, more information is needed to confirm these effects. Semaglutide is a GLP-1RA that reduces the risk of adverse atherosclerotic CV events and development of macroalbuminuria in patients with T2D at high CV risk.8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar Semaglutide is available as either a once-weekly subcutaneous (s.c.) formulation or a once-daily oral formulation. The half-life (∼7 days), pharmacokinetics, and clinical effects of semaglutide have been shown to be similar, irrespective of mode of administration.16Granhall C. Donsmark M. Blicher T.M. et al.Safety and pharmacokinetics of single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 diabetes.Clin Pharmacokinet. 2019; 58: 781-791Crossref PubMed Scopus (89) Google Scholar, 17Davies M. Pieber T.R. Hartoft-Nielsen M.L. et al.Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial.JAMA. 2017; 318: 1460-1470Crossref PubMed Scopus (262) Google Scholar, 18Overgaard R.V. Navarria A. Ingwersen S.H. et al.Clinical pharmacokinetics of oral semaglutide: analyses of data from clinical pharmacology trials.Clin Pharmacokinet. 2021; 60: 1335-1348Crossref PubMed Scopus (27) Google Scholar The 2 formulations were studied in separate CV outcomes trials: the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN 6; s.c. once-weekly semaglutide) and the Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6; once-daily oral semaglutide). The trials had similar designs, trial populations, and prespecified outcomes, but different lengths of follow-up.8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar A pooled analysis of SUSTAIN 6 and PIONEER 6 showed beneficial effects on major adverse cardiovascular events,19Husain M. Bain S.C. Jeppesen O.K. et al.Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.Diabetes Obes Metab. 2020; 22: 442-451Crossref PubMed Scopus (80) Google Scholar and these CV outcomes trials also showed reductions in glycated hemoglobin (HbA1c)8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar; a mediation analysis of SUSTAIN 6 and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) data showed that reductions in HbA1c might only partially mediate the kidney effects of semaglutide and liraglutide.20Mann J.F.E. Buse J.B. Idorn T. et al.Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis.Diabetes Obes Metab. 2021; 23: 2058-2066Crossref PubMed Scopus (22) Google Scholar The aim of this post hoc pooled analysis of SUSTAIN 6 and PIONEER 6 data was to investigate the effects of semaglutide versus placebo on eGFR over time by a more robust and novel assessment of the potential kidney benefits of semaglutide, using eGFR slope as a measure of kidney-disease progression.21Inker L.A. Heerspink H.J.L. Tighiouart H. et al.GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.J Am Soc Nephrol. 2019; 30: 1735-1745Crossref PubMed Scopus (123) Google Scholar The trial designs for SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) have been reported previously.8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar In brief, adults with T2D at high risk of a CV event were randomized to semaglutide or placebo in addition to standard-of-care treatment. Having a high CV risk was defined as being aged ≥50 years and having established CV disease or CKD, or being aged ≥60 years with CV risk factors. Exclusion criteria for both trials included kidney failure treated by chronic hemodialysis or peritoneal dialysis; PIONEER 6 additionally excluded those with an eGFR <30 ml/min per 1.73 m2.8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar In SUSTAIN 6, participants received s.c. once-weekly semaglutide 0.5 or 1.0 mg (median follow-up of 104 weeks), whereas participants in PIONEER 6 received once-daily oral semaglutide 14 mg (median observation period of 15.9 months).8Marso S.P. Bain S.C. Consoli A. et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844Crossref PubMed Scopus (3395) Google Scholar,9Husain M. Birkenfeld A.L. Donsmark M. et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2019; 381: 841-851Crossref PubMed Scopus (851) Google Scholar Participants were instructed to take oral semaglutide with up to 120 ml of water, in a fasting state in the morning, and to fast (no eating, drinking, or taking any other oral medication) for at least 30 minutes post-dose. In both trials, a dose-escalation schedule was used for semaglutide, and the comparator was placebo. Both trials were approved by independent ethics committees and institutional review boards at each participating center and were conducted in compliance with the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. All participants provided written informed consent before any trial-related activities. In this post hoc analysis, data from the SUSTAIN 6 and PIONEER 6 trials were pooled by treatment (semaglutide [once-weekly 0.5 and 1.0 mg s.c., once-daily 14 mg oral] or placebo) and analyzed overall or in subgroups based on eGFR at baseline (30–<60 ml/min per 1.73 m2 or ≥60 ml/min per 1.73 m2 for efficacy, and <60 ml/min per 1.73 m2 or ≥60 ml/min per 1.73 m2 for safety). Data were also stratified by renin–angiotensin system (RAS) inhibitor use (an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker [yes/no]) at baseline. Data from participants with a baseline eGFR <30 ml/min per 1.73 m2 were included in the analyses. However, as baseline eGFR <30 ml/min per 1.73 m2 was an exclusion criterion in PIONEER 6, only estimates (including results from interaction analyses) pertaining to eGFR ≥30 ml/min per 1.73 m2 are presented. Change in eGFR was evaluated over time, in the overall population and in the 2 eGFR subgroups, both in a pooled analysis and in separate SUSTAIN 6 and PIONEER 6 analyses. All available data points from the 2 trials were used until week 104 for SUSTAIN 6 and week 83 for PIONEER 6. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation. eGFR, evaluated as a treatment effect on annual eGFR slope, has been shown to be predictive of kidney failure endpoints, based on a meta-analysis of 47 clinical trials evaluating CKD treatments in 60,620 participants.21Inker L.A. Heerspink H.J.L. Tighiouart H. et al.GFR slope as a surrogate end point for kidney disease progression in clinical trials: a meta-analysis of treatment effects of randomized controlled trials.J Am Soc Nephrol. 2019; 30: 1735-1745Crossref PubMed Scopus (123) Google Scholar In SUSTAIN 6, visits occurred at weeks 0, 2, 4, 8, 16, 30, 44, 56, 68, 80, 92, and 104. In PIONEER 6, visits occurred at weeks 0, 4, 8, 14, 26, 38, 50, 62, 76, and 83. Annual eGFR slope was assessed post hoc in the overall population and in the 2 eGFR subgroups, both in a pooled analysis and in separate SUSTAIN 6 and PIONEER 6 analyses. As differences in the treatment effect of other glucose-lowering medication classes (e.g., sodium–glucose cotransporter-2 inhibitors) have been observed according to whether patients were also receiving RAS inhibitors,22Kitamura K. Hayashi K. Ito S. et al.Effects of SGLT2 inhibitors on eGFR in type 2 diabetic patients—the role of antidiabetic and antihypertensive medications.Hypertens Res. 2021; 44: 508-517Crossref PubMed Scopus (12) Google Scholar the mean annual eGFR slope analyses (overall population and eGFR subgroups) were also evaluated in 2 subgroups according to use (yes/no) of RAS blockade at baseline. The change over time in estimated urinary albumin-to-creatinine ratio (UACR) was also assessed post hoc in the overall population of the SUSTAIN 6 trial, and in the 2 eGFR subgroups. These data were not collected in the PIONEER 6 trial. Safety was assessed by incidence of adverse events (AEs), serious AEs, severe AEs, gastrointestinal (GI) AEs, severe hypoglycemic AEs, AEs leading to premature treatment discontinuation, and acute renal failure (acute kidney injury). Descriptive baseline characteristics were based on the full analysis set (all randomized participants). All available eGFR measurements from the full analysis set were included (in-trial data), regardless of whether participants discontinued treatment, developed kidney failure, or experienced a fatal event. All safety analyses were performed using in-trial data from the full analysis set and summarized overall and per subgroup. eGFR and UACR changes over time (per visit) were assessed using mixed models for repeated measurements with treatment group, subgroup, trial, and the interaction between treatment group and subgroup as fixed factors, and baseline value as a covariate, all nested within visit. The change from baseline in eGFR and the change from baseline in log-transformed UACR were evaluated at week 80 and 83 in the semaglutide and placebo groups, respectively. Annual eGFR slope was assessed as a continuous time variable using a linear random slope regression model with an interaction between slope and treatment group and with individual intercepts and time slope adjusted for baseline eGFR and trial as a fixed effect. The individual intercepts and time slopes were assumed to follow a bivariate normal distribution. The subgroup analyses included an interaction term between slope and treatment by subgroup. The annual eGFR slope was expressed as estimated treatment difference (ETD) between slopes with 95% confidence intervals (CIs). The P value for interaction evaluated the potential treatment heterogeneity across the 2 presented eGFR subgroups (30–<60 ml/min per 1.72 m2 and ≥60 ml/min per 1.72 m2). Time to persistent reductions in eGFR was based on the Modification of Diet in Renal Disease equation (used for the inclusion criteria and the adjudicated eGFR reduction component in the nephropathy endpoint in SUSTAIN 6) corresponding to the eGFR decline thresholds ≥30%, ≥40%, ≥50%, and ≥57%, and it was assessed in the overall population and the 2 eGFR subgroups using both pooled data and data separated by trial (SUSTAIN 6 and PIONEER 6). A persistent eGFR decline was defined as the time from randomization to the first visit at which the eGFR change threshold was attained, with this value confirmed at the subsequent visit. If no subsequent visit occurred, confirmation of the eGFR value was not required. Hazard ratios (HRs; semaglutide:placebo) and 95% CIs for time to persistent reductions in eGFR were estimated using a Cox proportional hazards model, with treatment and eGFR subgroups and the interaction between treatment group and eGFR subgroups as fixed factors, stratified by trial. The P value for interaction evaluated potential treatment heterogeneity across the 2 presented eGFR subgroups (30–<60 ml/min per 1.72 m2 and ≥60 ml/min per 1.72 m2). To explore whether the treatment effect on eGFR may be explained by changes in other parameters, 2 supplementary analyses were conducted using the random slope model—one adjusted for change from baseline in HbA1c across trial visits, and one adjusted for changes from baseline in HbA1c, body weight (BW), and systolic blood pressure (SBP), and baseline diuretic use (yes/no) across trial visits. A supplementary analysis excluding eGFR data before week 14 (PIONEER 6) or week 16 (SUSTAIN 6) was also conducted to assess the chronic effect of semaglutide on annual eGFR slope, as an early decline in eGFR was observed with GLP-1RAs in participants with eGFR >60 ml/min per 1.73 m2 in prior reports.23Mann J.F.E. Hansen T. Idorn T. et al.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: 880-893Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Hence, in the chronic slope analyses, change from week 14 or 16, respectively, was evaluated, with eGFR at week 14 or 16 considered the baseline. Statistical significance was achieved with a P value < 0.05. No adjustment was made for multiplicity. SUSTAIN 6 and PIONEER 6 included 6480 participants, of whom 3239 received semaglutide and 3241 received placebo; baseline characteristics were similar in the 2 groups (Table 1). The numbers of participants (semaglutide/placebo) in the 30–<60 ml/min per 1.73 m2 and ≥60 ml/min per 1.73 m2 eGFR subgroups were, respectively, 779/781 and 2382/2380. Baseline characteristics for the eGFR subgroups are detailed in Table 1. In SUSTAIN 6 and PIONEER 6, a total of 2668 of 3297 (81%) and 2569 of 3183 (81%) participants, respectively, were on RAS blockade at baseline.Table 1Baseline characteristicsBaseline eGFR, ml/min per 1.73 m2CharacteristicOverall population30–<60≥60Semaglutide pooled (N = 3239)Placebo pooled (N = 3241)Semaglutide pooled (n = 779)Placebo pooled (n = 781)Semaglutide pooled (n = 2382)Placebo pooled (n = 2380)Age, yr65.3 (7.2)65.5 (7.4)68.3 (7.2)68.8 (7.3)64.2 (6.9)64.3 (7.0)Sex, male, n (%)2097 (65)2081 (64)472 (61)486 (62)1579 (66)1554 (65)Body weight, kg91.7 (21.1)91.3 (20.8)94.0 (22.6)93.0 (21.4)91.1 (20.6)91.0 (20.6)Diabetes duration, yr14.4 (8.4)14.3 (8.3)16.6 (8.7)16.4 (8.8)13.6 (8.1)13.5 (8.0)HbA1c, %8.4 (1.5)8.4 (1.6)8.3 (1.5)8.2 (1.5)8.5 (1.6)8.5 (1.6)Systolic blood pressure, mm Hg135.7 (17.5)135.5 (17.2)136.0 (18.3)135.4 (17.7)135.4 (17.1)135.3 (16.9)Diastolic blood pressure, mm Hg76.6 (10.1)76.5 (10.0)75.1 (10.4)75.4 (10.2)77.0 (9.8)77.0 (9.8)eGFR (CKD-EPI), ml/min per 1.73 m275.0 (21.8)75.1 (22.1)47.4 (8.0)46.9 (7.9)85.5 (13.7)85.9 (13.7)Kidney function, eGFR, ml/min per 1.73 m2, n (%)≥901032 (32)1021 (32)001032 (43)1021 (43)60–>901350 (42)1359 (42)001350 (57)1359 (57)30–<60779 (24)781 (24)779 (100)781 (100)00<30aData from participants with a baseline eGFR <30 ml/min per 1.73 m2 were included in the analyses, and they are presented for the overall analyses but not for the subgroup analyses.71 (2)68 (2)0000UACR, mg/g, geometric mean (%CV)bAlbuminuria percentage is calculated based on number of participants from SUSTAIN 6 with a UACR measurement at baseline (semaglutide, n = 1616; placebo, n = 1622), as these data were not collected in PIONEER 6.24.7 (710.2)23.7 (779.4)48.9 (869.3)48.0 (1186)17.8 (480.0)17.1 (496.4)Albuminuria status, UACR, mg/g, n (%)bAlbuminuria percentage is calculated based on number of participants from SUSTAIN 6 with a UACR measurement at baseline (semaglutide, n = 1616; placebo, n = 1622), as these data were not collected in PIONEER 6. Normoalbuminuria (<30)948 (59)986 (61)155 (44)161 (44)785 (65)811 (68) Microalbuminuria (30–≤300)472 (29)412 (25)133 (38)114 (31)327 (27)290 (24) Macroalbuminuria (>300)196 (12)224 (14)66 (19)91 (25)95 (8)100 (8)CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CV, coefficient of variation; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; N/n, number of participants; PIONEER 6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; SUSTAIN 6, a Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; UACR, urinary albumin-to-creatinine ratio.Data from the full analysis set are mean (SD), unless stated otherwise. Kidney function is based on eGFR ml/min per 1.73 m2 calculated using the CKD-EPI 2009 equation.a Data from participants with a baseline eGFR <30 ml/min per 1.73 m2 were included in the analyses, and they are presented for the overall analyses but not for the subgroup analyses.b Albuminuria percentage is calculated based on number of participants from SUSTAIN 6 with a UACR measurement at baseline (semaglutide, n = 1616; placebo, n = 1622), as these data were not collected in PIONEER 6. Open table in a new tab CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CV, coefficient of variation; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; N/n, number of participants; PIONEER 6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; SUSTAIN 6, a Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; UACR, urinary albumin-to-creatinine ratio. Data from the full analysis set are mean (SD), unless stated otherwise. Kidney function is based on eGFR ml/min per 1.73 m2 calculated using the CKD-EPI 2009 equation. Overall changes in eGFR and change in eGFR by subgroup, in the pooled population and by trial, are shown in Figure 1 and Supplementary Figures S1–S3. Overall, mean eGFR decreased from baseline to week 80/83 by 2.47 ml/min per 1.73 m2 (2.54%) with semaglutide, and by 2.27 ml/min per 1.73 m2 (2.66%) with placebo, respectively, in the pooled population from the SUSTAIN 6 and PIONEER 6 trials (ETD –0.20 [95% CI –0.72; 0.32]; Figure 1). By week 104, mean eGFR decreased from baseline by 3.77 ml/min per 1.73 m2 with semaglutide, and by 4.33 ml/min per 1.73 m2 with placebo (ETD 0.56 [95% CI –0.12; 1.24]; P = 0.1046). eGFR also generally decreased over time when each trial was analyzed separately, although the change was greater in SUSTAIN 6 than in PIONEER 6 (Supplementary Figures S2 and S3). To reflect that eGFR <30 ml/min per 1.73 m2 was an exclusion criterion in PIONEER 6, trial effect (SUSTAIN 6 – PIONEER 6) was estimated as –‍0.98 ([95% CI –1.31; –0.66], P < 0.0001), and this trial effect was used to adjust the annual eGFR slope analyses. In the overall population and in both eGFR subgroups, semaglutide was associated with a significantly reduced annual rate of eGFR decline, co