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Randomized Controlled Trial
. 2024 Jul;30(7):2058-2066.
doi: 10.1038/s41591-024-03015-5. Epub 2024 May 25.

Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial

Helen M Colhoun  1 , Ildiko Lingvay  2 , Paul M Brown  3 , John Deanfield  4 , Kirstine Brown-Frandsen  3 , Steven E Kahn  5 , Jorge Plutzky  6 , Koichi Node  7 , Alexander Parkhomenko  8 , Lars Rydén  9 , John P H Wilding  10 , Johannes F E Mann  11 , Katherine R Tuttle  12 , Thomas Idorn  3 , Naveen Rathor  3 , A Michael Lincoff  13
Affiliations
Randomized Controlled Trial

Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial

Helen M Colhoun et al. Nat Med. 2024 Jul.

Abstract

The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide (n = 8,803) versus placebo (n = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min-1 1.73 m-2, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min-1 1.73 m-2 (95% CI 0.43, 1.06; P < 0.001) overall and 2.19 ml min-1 1.73 m-2 (95% CI 1.00, 3.38; P < 0.001) in patients with baseline eGFR <60 ml min-1 1.73 m-2. These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes.ClinicalTrials.gov identifier: NCT03574597 .

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Conflict of interest statement

P.M.B. declares being an employee of and stakeholder in Novo Nordisk. H.M.C. declares serving on advisory panels for Novo Nordisk and Bayer; receiving research funding from Sanofi, Roche and IQVIA; receiving grants from the Chief Scientist Office, Diabetes UK, the European Commission, the Juvenile Diabetes Research Foundation and the Medical Research Council (MRC); serving on a speaker’s bureau for Novo Nordisk; and holding stock in Roche and Bayer. J.D. declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk and Bayer and research grants from the British Heart Foundation, the MRC, the National Institute for Health and Care Research, Public Health England, Merck Sharp & Dohme (MSD), Pfizer, Aegerion, Colgate and Roche. K.B.-F. declares being an employee of and stockholder in Novo Nordisk. S.E.K., for the period over which SELECT was conducted, declares receiving advisory board/consulting fees from AltPep, Bayer, Boehringer Ingelheim, Casma Therapeutics, Eli Lilly, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer and Third Rock Ventures. T.I. declares being an employee of and stockholder in Novo Nordisk. I.L. declares having received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals, Novo Nordisk, Pfizer and Sanofi US Services; service as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals, Biomea Fusion, Boehringer Ingelheim, Carmot, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, MannKind Corporation, Merck, Novo Nordisk, Pfizer, Sanofi US Services, Shionogi, Structure Therapeutics, Target Pharma, Valeritas and Zealand Pharma A/S; and having received travel expenses from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson Medical Devices & Diagnostics Group– Latin America, Novo Nordisk, Sanofi US Services and Zealand Pharma A/S. A.M.L. declares having received honoraria from Akebia, Alnylam, Ardelyx, Becton Dickinson, Brainstorm Cell, Eli Lilly, Endologix, FibroGen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Novo Nordisk, Provention Bio and ReCor and consulting activities and research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion and Novartis. J.F.E.M. reports personal fees from AstraZeneca, Amgen, Braun, ACI and Fresenius; grants and personal fees from Celgene; personal fees from Gambro; grants from the European Union and McMaster University (Canada); grants and personal fees from AbbVie; personal fees from Medice; grants and personal fees from Novo Nordisk, Roche and Sandoz; and personal fees from Lanthio, Sanifit, Relypsa and ZS Pharma, all outside the submitted work. K.N. declares having received honoraria from AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Daiichi Sankyo, Eli Lilly Japan, Kowa, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Otsuka and Tsumura; research grants from Astellas, Bayer Yakuhin, Boehringer Ingelheim Japan, Fuji Yakuhin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical and Novartis Pharma; and scholarships from Abbott, Boehringer Ingelheim Japan, Daiichi Sankyo, Mitsubishi Tanabe Pharma and Teijin Pharma. A.P. declares having received research grants and personal fees during the study from Novo Nordisk. J.P. declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis and Novo Nordisk and having received a grant, paid to his institution, from Boehringer Ingelheim. J.P. also holds the position of Director, Preventive Cardiology, at Brigham and Women’s Hospital. L.R. declares research grants from Amgen, Bristol Myers Squibb, the Erling Persson Foundation, Novo Nordisk and the Swedish Heart Lung Foundation and lecture/consultant honoraria from Bayer, Eli Lilly and Novo Nordisk. N.R. declares being an employee of and stockholder in Novo Nordisk. K.R.T. declares receiving research grants from the National Institutes of Health and Travere Therapeutics and consultancy and/or speaker fees from Bayer, Boehringer Ingelheim, Eli Lilly and Novo Nordisk. J.P.H.W. is contracted via the University of Liverpool (no personal payment) to undertake consultancy for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Eli Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern, Shionogi and Ysopia and declares personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Menarini, Napp, Novo Nordisk and Rhythm.

Figures

Fig. 1
Fig. 1. Time to first occurrence of the main 5-component kidney composite endpointa.
Data are the observed (that is, as measured) probability of patients experiencing their first occurrence of the main 5-component kidney composite endpoint during the in-trial period, analyzed using the Kaplan–Meier method, and the estimated HR, analyzed using a Cox regression model. Tied events were handled using the Exact method, if possible, or Efron’s method, if not. Numbers below the graph are the number of patients at risk. P values are two-sided and were not adjusted for multiplicity. a The main 5-component kidney composite endpoint included death from kidney causes, initiation of chronic kidney replacement therapy (dialysis or transplantation), onset of persistent eGFR <15 ml min−1 1.73 m−2, persistent ≥50% reduction in eGFR compared to baseline or onset of persistent macroalbuminuria.
Fig. 2
Fig. 2. Effect of semaglutide 2.4 mg on the main 5-component kidney composite endpoint.
Data are the observed (that is, as measured) n (%) of patients experiencing the first event that contributed to the main 5-component kidney composite endpoint from the in-trial observation period and the HR, and 95% CI was estimated using a Cox regression model. The symbols are the HRs, and the error bars are the 95% CIs. P values are two-sided and were not adjusted for multiplicity. a Dialysis or kidney transplantation. b Percent reduction is defined from baseline; the denominator is, therefore, reduced because of patients missing a baseline score. N/A, not applicable.
Fig. 3
Fig. 3. Effect of semaglutide 2.4 mg on the main 5-component kidney composite endpointa by subgroup.
Data are the observed (that is, as measured) n (%) of patients experiencing their first occurrence of the main 5-component kidney composite endpoint from the in-trial observation period and the HR, and 95% CI was estimated using a Cox regression model, assessed according to patient baseline characteristics. The symbols are the HRs, and the error bars are the 95% CIs. a The main 5-component kidney composite endpoint included death from kidney causes, initiation of chronic kidney replacement therapy (dialysis or transplantation), onset of persistent eGFR <15 ml min−1 1.73 m−2, persistent ≥50% reduction in eGFR compared to baseline or onset of persistent macroalbuminuria. b P value for the treatment difference by subgroup. Interaction P values were calculated using the score test. P values are two-sided and were not adjusted for multiplicity. c Ischemic or hemorrhagic stroke. d A combination of two or more events. CVA, cardiovascular accident; PAD, peripheral artery disease.
Fig. 4
Fig. 4. Effect of semaglutide 2.4 mg on changes in eGFR and UACR over time in the overall population.
Data are estimated mean (CI) changes from the estimated baseline value in eGFR (a) and UACR (b), analyzed using an MMRM. The change in UACR was analyzed as the estimated mean ratio to baseline; for ease of interpretation; these ratios were converted to relative percentage changes from baseline using the formula (estimated ratio − 1) × 100. Numbers below the graphs are the number of patients contributing to the analysis. a Given gradual entry to the trial across the enrolment period and variable follow-up duration, data at 156 weeks and 208 weeks are sparser compared to previous timepoints.
Fig. 5
Fig. 5. Effect of semaglutide 2.4 mg on changes in eGFR and UACR over time by subgroup.
Data are estimated mean (CI) changes from the estimated baseline value in eGFR (a) and UACR (b), analyzed using an MMRM. The change in UACR was analyzed as the estimated mean ratio to baseline; for ease of interpretation, these ratios were converted to relative percentage changes from baseline using the formula (estimated ratio − 1) × 100. Darker lines are used for the larger subgroups. Numbers below the graphs are the number of patients contributing to the analysis. Changes in UACR by baseline UACR subgroup at 208 weeks are not presented because of small patient numbers. a Given gradual entry to the trial across the enrollment period and variable follow-up duration, data at 156 weeks and 208 weeks are sparser compared to previous timepoints.
Extended Data Fig. 1
Extended Data Fig. 1. Effect of semaglutide 2.4 mg on changes in eGFR over time by baseline UACR.
Data are estimated mean (CI) changes from the estimated baseline value in eGFR, analysed using a mixed model for repeated measurements. Darker lines are used for the larger subgroups. CI, confidence interval; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio.
Extended Data Fig. 2
Extended Data Fig. 2. Effect of semaglutide 2.4 mg on changes in UACR over time by baseline eGFR.
Data are estimated mean (CI) changes from the estimated baseline value in UACR, analysed using a mixed model for repeated measurements. The change in UACR was analysed as the estimated mean ratio to baseline; for ease of interpretation, these ratios have been converted to relative percentage changes from baseline using the formula (estimated ratio − 1) × 100. Darker lines are used for the larger subgroups. Numbers below the graphs are the number of patients contributing to the analysis. CI, confidence interval; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio.
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