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Jump to Key Points The investigational once-weekly combination of semaglutide and basal insulin icodec (IcoSema, Novo Nordisk) produced greater A1c reductions and weight loss with less hypoglycemia than once-daily insulin glargine U100 in people with type 2 diabetes (T2D) taking oral glucose-lowering medications, new data showed.
The findings come from COMBINE 4, a 40-week, multinational, randomized, open-label, treat-to-target phase 3b trial in adults with T2D who were naive to insulin and GLP-1 receptor agonists. Reductions in A1c and body weight were superior with IcoSema than with glargine U100, and clinically significant or severe hypoglycemia occurred less frequently.
Taken together, the findings suggested that IcoSema “might be a feasible treatment option” for insulin-naive individuals with T2D and provided “reassurance regarding concerns around hypoglycaemia and weight gain that may accompany insulin intensification after oral glucose-lowering medications while reducing the injection burden associated with once-daily therapies,” wrote Linong Ji, MD, professor of medicine at Peking University and director of the Peking University Diabetes Center at Peking University People’s Hospital, Beijing, China, and colleagues.
The findings were published in The Lancet Diabetes & Endocrinology.
- IcoSema ↓ A1c more than glargine U100: 9.57%→6.22% vs 9.50%→7.10%.
- Weight loss with IcoSema; glargine U100 caused +3.81 kg gain.
- Clinically significant hypoglycemia lower with IcoSema: 9% vs 22%.
- Severe hypoglycemia also fewer with IcoSema: 3 vs 6 episodes.
- GI AEs more common with IcoSema; discontinuation 4 vs 0.
Improved A1c, Weight, and Hypoglycemia
A total of 243 participants were randomly assigned to IcoSema and 242 to glargine U100. More than 90% of participants in both groups completed the 40-week treatment period. At baseline, 87% were taking metformin and about a third were taking SGLT2 inhibitors, with smaller proportions taking other oral glucose-lowering drugs.
From baseline to week 40, mean A1c decreased from 9.57% to 6.22% with IcoSema vs from 9.50% to 7.10% with glargine U100, with a significant between-group difference of 0.88 percentage points confirming superiority (P < .001). Mean fasting plasma glucose showed similar decreases in both groups.
At 40 weeks, body weight decreased by an average of 0.79 kg (1.7 lbs) with IcoSema compared with an increase of 3.81 kg (8.4 lbs) with glargine U100, also confirming the superiority of IcoSema (P < .001).
At least one episode of clinically significant hypoglycemia occurred in 9% of participants receiving IcoSema compared with 22% of those receiving glargine U100. Three severe hypoglycemic episodes occurred in two participants receiving IcoSema compared with six episodes in five participants receiving glargine U100. From baseline to week 45, the overall rates of combined clinically significant and severe hypoglycemia per person-year of exposure were 0.29 with IcoSema and 0.59 with glargine U100 (P = .04).
Gastrointestinal adverse events were more common with IcoSema than with glargine U100 (56% vs 21%) and led to treatment discontinuation in four vs zero, respectively.
Earlier phase 3a COMBINE 1-3 trials showed the efficacy and safety of IcoSema compared with insulin icodec alone, semaglutide alone, and once-daily basal insulin glargine plus premeal insulin aspart in people who had not achieved glycemic targets with basal insulin alone.
Not Yet Filed for US Approval
IcoSema is approved under the brand name Kyinsu in the EU, China, Japan, South Korea, and other countries.
In the US, insulin icodec was approved by the FDA in March 2026 under the brand name Awiqli for adults with T2D. The approval for T2D followed an initial “complete response letter” when approval had been sought for both type 1 diabetes and T2D, in part due to concerns over increased hypoglycemia.
Novo Nordisk has not filed a Biologics License Application for IcoSema in the US.
“We continue to assess the situation and determine whether and when a future filing may be appropriate,” a Novo Nordisk spokesperson told Medscape Medical News.
The study was funded by Novo Nordisk. Ji reported receiving research support and consultant fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Gan & Lee, Haisco Pharmaceutical, Innovent Biologics, Merck, MSD, Novo Nordisk, Sanofi-Aventis, Sibionics, and Sinocare; serving on advisory panels for Haisco Pharmaceutical; and receiving honoraria from Eli Lilly, Innovent Biologics, Novo Nordisk, and Sanofi-Aventis.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.
