Forecasting Trial Milestones: A Predictive Analysis for Early Termination of the SOUL Study.
MACE
Meta-analysis
Predictive analysis
SOUL
Semaglutide
Journal
Diabetes therapy : research, treatment and education of diabetes and related disorders
ISSN: 1869-6953
Titre abrégé: Diabetes Ther
Pays: United States
ID NLM: 101539025
Informations de publication
Date de publication:
08 Aug 2024
08 Aug 2024
Historique:
received:
02
07
2024
accepted:
25
07
2024
medline:
8
8
2024
pubmed:
8
8
2024
entrez:
8
8
2024
Statut:
aheadofprint
Résumé
Semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1RA), is available in both parenteral and oral preparations. Studies of injectable preparations have convincingly demonstrated its beneficial effect on major adverse cardiac events (MACE). This predictive analysis was undertaken to forecast early termination of the SOUL trial (oral semaglutide) as well as the primary events. SOUL is a multicenter, double-blind, placebo-controlled randomized controlled trial (RCT) evaluating the reduction in MACE associated with oral semaglutide versus placebo in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. A sample of 9642 participants will be followed for 5 years and 5 months. A random-effects model meta-analysis, pooling hazard ratios from previous RCTs, was conducted using R software to inform the predictive model. The background CV event rates from the placebo arms of previous RCTs with semaglutide were matched with the pre-adjudicated assumptions of the SOUL trial to create the predictive model. The truncated trial duration, MACE, and its individual components in the intervention and placebo arms were estimated. The predicted difference between the two groups was estimated using the chi-squared test. A pooled analysis of 10,013 patients revealed a significant reduction in the number of MACEs associated with semaglutide (HR 0.79, 95% CI 0.69-0.91). Predictive analysis indicated that 1225 events would be achieved by 3.78 years, suggesting premature termination. The mathematical model based on the meta-analysis predicts that the SOUL study on oral semaglutide will be terminated early, with oral semaglutide showing benefits in terms of MACE compared to placebo. If the SOUL study corroborates the findings of this model, it may not only form the basis for the calculation of power but also define the duration of such studies, reducing costs and easing the process of designing cardiovascular outcome trials (CVOTs). INPLASY202460061.
Identifiants
pubmed: 39115619
doi: 10.1007/s13300-024-01635-1
pii: 10.1007/s13300-024-01635-1
doi:
Types de publication
Journal Article
Langues
eng
Informations de copyright
© 2024. The Author(s).
Références
Martín-Timón I, Sevillano-Collantes C, Segura-Galindo A, Del Cañizo-Gómez FJ. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J Diabetes. 2014;15;5(4):444–70. https://doi.org/10.4239/wjd.v5.i4.444 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127581/
Ghaderian SB, Hayati F, Shayanpour S, Beladi Mousavi SS. Diabetes and end-stage renal disease; a review article on new concepts. J Renal Inj Prev. 2015;4(2):28–33. https://doi.org/10.12861/jrip.2015.07 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459725/
American Diabetes Association Professional Practice Committee; 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2024. Diabetes Care 2024; 47 (Supplement_1): S158–78. https://doi.org/10.2337/dc24-S009
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et.al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827 . https://pubmed.ncbi.nlm.nih.gov/27295427/
Giugliano D, Scappaticcio L, Longo M, Caruso P, Maiorino MI, Bellastella G, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021;20:189. https://doi.org/10.1186/s12933-021-01366-8 .
doi: 10.1186/s12933-021-01366-8
pubmed: 34526024
pmcid: 8442438
Dhillon S. Semaglutide: first global approval. Drugs. 2018;78:275–84. https://doi.org/10.1007/s40265-018-0871-0 .
doi: 10.1007/s40265-018-0871-0
pubmed: 29363040
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. https://doi.org/10.1056/NEJMoa1607141 . https://pubmed.ncbi.nlm.nih.gov/27633186/
Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2403347 . (Accessed on: 6th June 2024).
doi: 10.1056/NEJMoa2403347
pubmed: 38785209
Rasmussen MF. The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes. Diabetol Int. 2020;11(2):76–86. https://doi.org/10.1007/s13340-019-00423-8 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082439/
Brunton SA, Mosenzon O, Wright EE Jr. Integrating oral semaglutide into clinical practice in primary care: for whom, when, and how? Postgrad Med. 2020;132(sup2):48–60. https://doi.org/10.1080/00325481.2020.1798162 .
doi: 10.1080/00325481.2020.1798162
pubmed: 32815453
Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR et al. PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–51. https://doi.org/10.1056/NEJMoa1901118 . https://pubmed.ncbi.nlm.nih.gov/31185157/
McGuire DK, Busui RP, Deanfield J, Inzucchi SE, Mann JFE, Marx N et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes Metab. 2023;25(7):1932–41. https://doi.org/10.1111/dom.15058 . https://pubmed.ncbi.nlm.nih.gov/36945734/
Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021, 29;372:n160. https://doi.org/10.1136/bmj.n160 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005925/
The protocol for this systematic review was registered on INPLASY (ID: INPLASY202460061) and is available in full on inplasy.com.
Husain M, Bain SC, Jeppesen OK, Lingvay I, Sørrig R, Treppendahl MB et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020;22(3):442–51. https://doi.org/10.1111/dom.13955 . https://pubmed.ncbi.nlm.nih.gov/31903692/
Tuttle KR, Bosch-Traberg H, Cherney DZI, Hadjadj S, Lawson J, Mosenzon O et al. 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. Kidney Int. 2023;103(4):772–81. https://doi.org/10.1016/j.kint.2022.12.028 . https://pubmed.ncbi.nlm.nih.gov/36738891/
Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N et al. Effect of Linagliptin vs Placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA Randomized Clinical Trial. JAMA. 2019;321(1):69–79. https://doi.org/10.1001/jama.2018.18269 . https://jamanetwork.com/journals/jama/fullarticle/2714646
Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ et al. Effect of Linagliptin vs Glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA Randomized Clinical Trial. JAMA. 2019;322(12):1155–66. https://doi.org/10.1001/jama.2019.13772 . https://jamanetwork.com/journals/jama/fullarticle/2751398
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306. https://doi.org/10.1056/NEJMoa1811744 . https://pubmed.ncbi.nlm.nih.gov/30990260/
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720 . https://pubmed.ncbi.nlm.nih.gov/26378978/
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389 . https://pubmed.ncbi.nlm.nih.gov/30415602/
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA et al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827 . https://pubmed.ncbi.nlm.nih.gov/27295427/
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P et al. REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30. https://doi.org/10.1016/S0140-6736(19)31149-3 . https://pubmed.ncbi.nlm.nih.gov/31189511/
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB et al. EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39. https://doi.org/10.1056/NEJMoa1612917 . https://pubmed.ncbi.nlm.nih.gov/28910237/
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV et al. ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. https://doi.org/10.1056/NEJMoa1509225 . https://pubmed.ncbi.nlm.nih.gov/26630143/
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE et al. DAPA-CKD trial committees and investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46. https://doi.org/10.1056/NEJMoa2024816 . https://pubmed.ncbi.nlm.nih.gov/32970396/
The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117–27. https://doi.org/10.1056/NEJMoa2204233 . https://pubmed.ncbi.nlm.nih.gov/36331190/