Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial.

Autor: Mathieu C; Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Leuven, Belgium. Electronic address: chantal.mathieu@uzleuven.be., Ásbjörnsdóttir B; Novo Nordisk A/S, Søborg, Denmark., Bajaj HS; LMC Diabetes and Endocrinology, Brampton, ON, Canada., Lane W; Mountain Diabetes and Endocrine Center, Asheville, NC, USA., Matos ALSA; Novo Nordisk A/S, Søborg, Denmark., Murthy S; Lifecare Hospital and Research Centre, Bangalore, India., Stachlewska K; Novo Nordisk A/S, Søborg, Denmark., Rosenstock J; Velocity Clinical Research at Medical City, Dallas, TX, USA.
Jazyk: angličtina
Zdroj: Lancet (London, England) [Lancet] 2023 Jun 10; Vol. 401 (10392), pp. 1929-1940. Date of Electronic Publication: 2023 May 05.
DOI: 10.1016/S0140-6736(23)00520-2
Abstrakt: Background: Insulin icodec (icodec) is a basal insulin analogue suitable for once-weekly dosing. ONWARDS 4 aimed to assess the efficacy and safety of once-weekly icodec compared with once-daily insulin glargine U100 (glargine U100) in individuals with long-standing type 2 diabetes on a basal-bolus regimen.
Methods: In this 26-week, phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial, adults from 80 sites (outpatient clinics and hospital departments) across nine countries (Belgium, India, Italy, Japan, Mexico, the Netherlands, Romania, Russia, and the USA) with type 2 diabetes (glycated haemoglobin [HbA 1c ] 7·0-10·0%) were randomly assigned (1:1) to receive once-weekly icodec or once-daily glargine U100 combined with 2-4 daily bolus insulin aspart injections. The primary outcome was change in HbA 1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points). The primary outcome was evaluated in the full analysis set (ie, all randomly assigned participants). Safety outcomes were evaluated in the safety analysis set (ie, all participants randomly assigned who received at least one dose of trial product). This trial is registered with ClinicalTrials.gov, NCT04880850.
Findings: Between May 14 and Oct 29, 2021, 746 participants were screened for eligibility, of whom 582 (78%) were randomly assigned (291 [50%] to icodec treatment and 291 [50%] to glargine U100 treatment). Participants had a mean duration of type 2 diabetes of 17·1 years (SD 8·4). At week 26, estimated mean change in HbA 1c was -1·16 percentage points in the icodec group (baseline 8·29%) and -1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points [95% CI -0·11 to 0·15], p<0·0001). Overall, 171 (59%) of 291 participants in the icodec group and 167 (57%) of 291 participants in the glargine U100 group had an adverse event. 35 serious adverse events were reported in 22 (8%) of 291 participants in the icodec group and 33 serious adverse events were reported in 25 (9%) of 291 participants receiving glargine U100. Overall, combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec.
Interpretation: In people with long-standing type 2 diabetes on a basal-bolus regimen, once-weekly icodec showed similar improvements in glycaemic control, with fewer basal insulin injections, lower bolus insulin dose, and with no increase in hypoglycaemic rates compared with once-daily glargine U100. Key strengths of this trial include the use of masked continous glucose monitoring; the high trial completion rate; and the inclusion of a large, diverse, and multinational population. Limitations include the relatively short trial duration and the open-label design.
Funding: Novo Nordisk.
Competing Interests: Declaration of interests CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp & Dohme, Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, MannKind, Sandoz, and Vertex. Financial compensation for these activities has been received by Katholieke Universiteit Leuven (Leuven, Belgium); Katholieke Universiteit Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi, and ActoBio Therapeutics; CM serves or has served on the speakers' bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, and Novartis. Financial compensation for these activities has been received by KU Leuven. BÁ, ALSAM, and KS are employees of Novo Nordisk and might hold stock in Novo Nordisk. HSB reports trial fees paid to his institution by Novo Nordisk during ONWARDS 3 and 5; and trial fees paid to his institution by Amgen, AstraZeneca, Boehringer Ingelheim, Ceapro, Eli Lilly and Company, Gilead, Janssen, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sanofi, and Tricida, outside the submitted work. WL has served on the speakers' bureau for Dexcom and Novo Nordisk and has served on advisory boards for Arecor and Novo Nordisk. SM has served on advisory councils for Novo Nordisk, Sanofi India, Sun Pharmaceutical Industries, Torrent Pharmaceuticals, and USV, and has been part of clinical trials for Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk, and Sanofi India. JR has served on advisory panels for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Novo Nordisk, Oramed, Hanmi, Sanofi, and Zealand, and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, and Sanofi.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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