Summary: In a small phase 1 crossover study of 31 adults with type 2 diabetes, the once-weekly fixed-ratio combination IcoSema (175 U insulin icodec plus 0.5 mg semaglutide) left icodec exposure unchanged versus separate injection, but raised the semaglutide peak concentration roughly two-fold (Cmax ratio 1.99, 90% CI 1.84 to 2.15) and brought it forward (tmax 12 versus 84 hours), while total semaglutide exposure was preserved. These are pharmacokinetic findings only, not glycaemic outcomes.
PICO Summary
| Element | Detail |
|---|---|
| Population | 31 adults with type 2 diabetes (18 to 64 years, body weight 80 to 120 kg, HbA1c 6.0 to 8.5%); randomised, double-blind, three-period crossover phase 1 study (Germany; ClinicalTrials.gov NCT03789578). |
| Intervention | Single subcutaneous injection of IcoSema, a fixed-ratio combination of 175 U insulin icodec plus 0.5 mg semaglutide; all 31 participants received this period in crossover. |
| Comparison | Separate single subcutaneous injections of insulin icodec 175 U alone and semaglutide 0.5 mg alone, with 6 to 9 weeks washout between periods; all 31 participants received each comparator. |
| Outcome | Icodec PK unaffected: AUC ratio (IcoSema/icodec) 1.06 (90% CI 1.01 to 1.12) and Cmax ratio 1.12 (1.06 to 1.18), both within the 0.80 to 1.25 bioequivalence range. Semaglutide total exposure preserved: AUC ratio 1.11 (1.05 to 1.17). Semaglutide peak raised and earlier: Cmax ratio 1.99 (1.84 to 2.15), tmax 12 versus 84 hours. No formal p-values, ARR or NNT reported (exposure-ratio design). More gastrointestinal adverse events with IcoSema than with either component alone. |
Expert Commentary
This is a clean phase 1 pharmacokinetic study, and its verdict should be read as mechanistic rather than clinical. The crossover design was well controlled, with each participant serving as their own control across three periods and an adequate washout, and the headline signal is credible: icodec exposure was unchanged by co-formulation, whereas semaglutide reached a higher and markedly earlier peak when delivered with icodec, attributed by the authors to local competition for albumin binding at the injection site. Total semaglutide exposure was preserved, so the change is one of shape rather than overall amount. The principal limitation is that this is a single-dose study in only 31 carefully selected participants, so it speaks to exposure, not to glycaemic control, weight, hypoglycaemia or cardiovascular outcomes; the more frequent gastrointestinal events with the combination are consistent with the faster semaglutide rise but are not powered safety findings. Can I use this with my patients? Not yet, because IcoSema is an investigational fixed-ratio product and these data only inform dose selection for later trials, not bedside prescribing. Readers should also note that the study was sponsored and conducted by the manufacturer, with most authors employed by the company, so independent confirmation in the phase 3 programme is needed before the convenience of a single weekly injection can be weighed against the altered semaglutide profile.
References
Westergaard L, Alifrangis L, Buckley ST, Coester HV, Klitgaard T, Kristensen NR, et al. 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. Clin Drug Investig. 2024;44(11):849-861. doi:10.1007/s40261-024-01405-8
