Efficacy and Safety of Intensifying Once-Weekly Insulin Icodec Treatment With Once-Weekly Semaglutide in Adults With Type 2 Diabetes: A Single-Arm, Open-Label, Treat-to-Target, Phase 3b Trial (ONWARDS 8)

Adding once-weekly semaglutide to once-weekly insulin icodec in adults with type 2 diabetes whose HbA1c remained above 7.0% after an icodec run-in led to a clinically meaningful reduction in HbA1c and body weight, with a low rate of clinically significant or severe hypoglycaemia. The single-arm trial enrolled 148 adults, and 94 went on to intensify treatment with semaglutide.

Late-phase clinical trial — Single-arm, open-label, treat-to-target, Phase 3b trial. Population: Adults with type 2 diabetes, HbA1c 7.5%-10.5%, receiving daily basal insulin and not receiving a GLP-1 receptor agonist. Sample size: 148 participants enrolled; 94 initiated semaglutide. Follow-up: 26-week icodec run-in plus 26-week semaglutide intensification, with follow-up to Week 57. Interventions: once-weekly insulin icodec; once-weekly semaglutide up to 1.0 mg.

Mean HbA1c decreased from 7.88% (observed) to 6.66% (estimated), an estimated mean change of -1.23 percentage points (95% CI -1.39 to -1.07; p < 0.0001). Significant changes from baseline to Week 52 were seen in the 7-point self-measured blood glucose profile (-1.72 mmol/L), postprandial glucose increment (-1.31 mmol/L) and body weight (-3.85 kg). Mean weekly insulin icodec dose decreased by 24% from Week 25 to Week 52, and 69.1% of participants had their icodec dose reduced by 20% at Week 26 per protocol. From baseline to Week 57, the rate of combined clinically significant or severe hypoglycaemia was 0.24 episodes per person-year of exposure.

This paper is filed under Semaglutide on PeptideAtlas, and researchers studying semaglutide will want it because it provides Phase 3b evidence on adding once-weekly semaglutide to once-weekly insulin icodec in type 2 diabetes, showing improved glycaemic control, weight loss and insulin dose reduction with low hypoglycaemia rates. It does not establish semaglutide's comparative effectiveness against other add-on therapies, nor does it provide dosing recommendations or mechanism-level peptide evidence.

Key findings

Mean HbA1c fell from 7.88% to 6.66%, with an estimated mean change of -1.23 percentage points (95% CI -1.39 to -1.07; p < 0.0001).
The 7-point self-measured blood glucose profile changed by -1.72 mmol/L and postprandial glucose increment by -1.31 mmol/L (both p < 0.0001).
Body weight decreased by -3.85 kg from baseline to Week 52 (p < 0.0001).
Mean weekly insulin icodec dose decreased by 24% from Week 25 to Week 52, with 69.1% of participants having their dose reduced by 20% at Week 26 per protocol.
The rate of combined clinically significant or severe hypoglycaemia from baseline to Week 57 was 0.24 episodes per person-year of exposure.

Limitations

Single-arm design with no control group, so the observed effects cannot be attributed specifically to semaglutide intensification compared with other strategies
Open-label design may introduce bias in outcome assessment or expectations
Only participants who completed the icodec run-in and still met HbA1c criteria were eligible for intensification, which may limit generalisability
Follow-up is limited to 57 weeks, so longer-term safety and durability are not established

The record

Journal: Diabetes, obesity & metabolism 28(9): 8515-8522
Published: 2026-07-01
PMID: 42387310 — DOI: 10.1111/dom.71049
MeSH terms: Humans, Diabetes Mellitus, Type 2, Hypoglycemia, Insulin, Blood Glucose, Hypoglycemic Agents, Treatment Outcome, Drug Therapy, Combination, Drug Administration Schedule, Adult, Aged, Middle Aged, Female, Male, Glucagon-Like Peptides, Glycated Hemoglobin, Semaglutide
Funding: Novo Nordisk A/S
Author countries: Denmark, Germany, India, Poland, USA

Peptide profiles: Semaglutide.

All indexed evidence: Semaglutide trials & papers.