Once-Weekly Insulin-Plus-Semaglutide Combo Pen Changes How Semaglutide Is Absorbed — Higher, Faster Peak Levels | Research

The takeaway

When insulin icodec and semaglutide are combined in IcoSema, icodec pharmacokinetics are unaffected but semaglutide reaches a nearly 2-fold higher peak concentration 72 hours earlier due to competition for albumin binding at the injection site.

1.99× higher semaglutide peak
When combined with insulin icodec in IcoSema, semaglutide reached nearly double the peak concentration at 12 hours instead of 84 hours, due to albumin binding competition at the injection site

What the researchers found

IcoSema preserves icodec PK (AUC ratio 1.06, Cmax ratio 1.12, within bioequivalence bounds) but produces a 99% higher semaglutide Cmax (ratio 1.99) occurring 72 hours earlier (12 vs 84 h), attributed to albumin binding competition at the injection site.

Why it matters

IcoSema could become the first once-weekly insulin-plus-GLP-1 combination — simplifying diabetes management to a single weekly injection. Understanding how the two drugs interact pharmacokinetically is essential for safe, effective dosing of the combination product.

The numbers in context

31 participants with T2DM, ages 18-64, body weight 80-120 kg. Three-period crossover design comparing combined versus separate administration.

How the study worked

Randomized, double-blind, three-period crossover study (NCT03789578) in 31 adults with T2DM (age 18-64, BMI-matched 80-120 kg, HbA1c 6.0-8.5%). Single SC injections of IcoSema (175 U icodec + 0.5 mg semaglutide), icodec alone, or semaglutide alone with 6-9 week washout. PK blood sampling to 840 hours post-dose. Supported by in vitro albumin binding and animal PK studies.

Who was studied

Adults with type 2 diabetes, ages 18-64, BMI 80-120 kg

What this study cannot tell us

Single-dose PK study — steady-state behavior may differ. The doubled semaglutide Cmax could theoretically increase gastrointestinal side effects, which was supported by more GI adverse events with IcoSema in this study. Only one dose level tested (175 U/0.5 mg). Small sample size (n=31) though adequate for PK crossover design.

How to read the evidence

Moderate evidence from a well-designed randomized crossover PK trial with mechanistic confirmation through in vitro and animal studies. Single-dose design limits steady-state conclusions.

When this study was published

Published in 2024, part of the ongoing clinical development program for IcoSema, which is expected to be one of the first once-weekly insulin+GLP-1 combination products.

The bigger picture

The trend in diabetes treatment is toward simplification — fewer injections, more convenience. IcoSema represents the cutting edge: once-weekly insulin and GLP-1 agonist in one pen. This PK study shows the combination is feasible but requires careful dose selection because semaglutide absorption is altered. If approved, IcoSema could dramatically simplify treatment for the many T2DM patients who need both drug classes.

Questions still open

Does the higher semaglutide Cmax with IcoSema translate to more gastrointestinal side effects at steady state?
Will the altered semaglutide absorption profile affect efficacy or safety in long-term use?
What dose combinations will be chosen for the commercial IcoSema product based on these PK findings?

Common questions

What is IcoSema and when will it be available?

IcoSema is a once-weekly combination injection being developed by Novo Nordisk that contains both insulin icodec (a long-acting weekly insulin) and semaglutide (the GLP-1 agonist in Ozempic/Wegovy) in a single pen. It's still in clinical development and hasn't been approved yet. If successful, it would allow people with T2DM who need both insulin and a GLP-1 drug to take just one weekly injection instead of two.

Why does semaglutide reach a higher peak when combined with insulin icodec?

Both drugs normally bind to albumin (a blood protein) at the injection site, which slows their absorption into the bloodstream. When given together, insulin icodec is better at grabbing albumin, leaving semaglutide with less albumin to bind. Without albumin anchoring it at the injection site, semaglutide enters the bloodstream faster, causing a higher and earlier peak. Total exposure is similar — it's the timing that changes, not the total amount absorbed.

Read the original research

Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.

Clinical drug investigation, 44(11), 849-861

View on PubMed ↗Publisher’s paper ↗

Citation

Westergaard, Lisbet; Alifrangis, Lene; Buckley, Stephen T; Coester, Hans Veit; Klitgaard, Thomas; Kristensen, Niels R; Nishimura, Erica; Nørgreen, Lea; Rocha, Thaís M P; Steensgaard, Dorte B; Vegge, Andreas; Plum-Mörschel, Leona. (2024). Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.. Clinical drug investigation, 44(11), 849-861. https://doi.org/10.1007/s40261-024-01405-8