Insulin icodec
icodec, NN1436, once-weekly basal insulin analogue, insulin icodec-abae
Insulin icodec is the first basal insulin designed for once-weekly injection, with a half-life of about 196 hours, roughly eight days. It achieves this through three amino acid substitutions that slow its own receptor-mediated clearance, combined with a twenty-carbon fatty diacid side chain that binds albumin very tightly. It was approved in the European Union and several other jurisdictions in 2024 and by the FDA in 2026, but the US licence covers type 2 diabetes only; the type 1 diabetes indication was refused there because of a roughly doubled rate of significant hypoglycaemia in that population.
Mechanism
Insulin icodec carries four changes to the peptide plus one acylation. Three amino acid substitutions (tyrosine A14 to glutamate, tyrosine B16 to histidine and phenylalanine B25 to histidine) deliberately reduce affinity for the insulin receptor and increase chemical and enzymatic stability. That deliberate weakening is the conceptual core of the design. Insulin is normally cleared largely by receptor-mediated endocytosis and degradation: the receptor is a sink as well as a signal. Reducing receptor affinity therefore slows clearance disproportionately, which is exactly what a once-weekly molecule requires. The B30 threonine is deleted, and the epsilon-amino group of lysine B29 is acylated with 1,20-icosanedioic acid, a twenty-carbon fatty diacid, connected through a gamma-glutamyl spacer and two short polyethylene glycol-like linkers (2-[2-(2-aminoethoxy)ethoxy]acetyl units).
The C20 diacid is a step up from the C16 diacid used in insulin degludec and confers markedly stronger, still reversible, albumin binding. Around 99% of circulating icodec is albumin-bound. The bound fraction is pharmacologically inactive but constitutes a large circulating depot in equilibrium with a small free fraction, so plasma free insulin concentrations remain low and remarkably steady across seven days. The two mechanisms compound: albumin binding limits how much drug is available at any moment, while reduced receptor affinity limits how fast the available drug is destroyed. The measured half-life in humans is approximately 196 hours, with glucose-lowering activity distributed evenly across the weekly interval and steady state reached after three to four weekly doses. Affinity for the IGF-1 receptor is reduced proportionately more than insulin receptor affinity, preserving a favourable metabolic-to-mitogenic ratio. Signalling once the receptor is engaged is entirely conventional: autophosphorylation, IRS/PI3K/AKT, GLUT4 translocation, and suppression of hepatic gluconeogenesis and glycogenolysis.
What the research shows
The ONWARDS programme is unusually complete for a new insulin: six phase 3a trials covering insulin-naive type 2 diabetes against both glargine and degludec, switching from daily basal, switching from basal-bolus, a pragmatic real-world-like trial, and type 1 diabetes. In type 2 diabetes the results are consistently favourable. HbA1c reductions were non-inferior in every trial and statistically superior in several, with differences of roughly 0.2 to 0.4 percentage points, and time in range was generally higher. Rates of clinically significant and severe hypoglycaemia were low across the type 2 trials and broadly comparable to daily basal insulin, though usually numerically a little higher with icodec. ONWARDS 3 deserves particular weight because it was double-blind and double-dummy, which is rare in insulin trials and removes the reporting bias that inflates open-label hypoglycaemia comparisons.
The type 1 diabetes result is the one that matters most for an honest assessment. In ONWARDS 6, icodec matched degludec on HbA1c but produced 19.9 against 10.4 combined level 2 and level 3 hypoglycaemia events per patient-year, a rate ratio of 1.9. That is precisely the failure mode a very long half-life predicts: in type 1 diabetes, where there is no endogenous insulin reserve and requirements swing with illness, exercise and menstrual cycle, a basal insulin that cannot be reduced for a week is a liability. An FDA advisory committee found the benefit-risk profile unfavourable and the agency declined the type 1 indication, while EU regulators licensed the drug for both types, a genuine and instructive regulatory divergence over the same dataset. ONWARDS 5 is worth reading sceptically for a different reason: the superiority result was obtained with a dosing-guide app in the icodec arm and usual care in the comparator arm, so part of the benefit is plausibly attributable to titration support rather than to the molecule. What remains untested is long-term outcome: there is no cardiovascular outcome trial for icodec, no complication data, and no randomised experience beyond about 18 months.
Evidence assessment
High-quality evidence
Six adequately powered phase 3a randomised treat-to-target trials (ONWARDS 1 to 6) enrolling several thousand participants across insulin-naive type 2 diabetes, basal-treated type 2 diabetes, basal-bolus type 2 diabetes and type 1 diabetes, published in the New England Journal of Medicine, the Lancet, JAMA and Annals of Internal Medicine, with regulatory approval in the European Union, Japan, Canada, Australia and the United States. The evidence is strong for type 2 diabetes and strong in the opposite direction for type 1 diabetes, where the trial data led the FDA to conclude the benefit-risk balance was unfavourable.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin Preclinical only
HbA1c fell by approximately 1.55 percentage points with icodec versus 1.35 with glargine U100 at week 52, establishing both non-inferiority and superiority (estimated difference around −0.19 points). Time in range was higher with icodec. Rates of clinically significant or severe hypoglycaemia were low in both arms and numerically slightly higher with icodec, without reaching significance.
Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial Preclinical only
Icodec was superior to degludec for HbA1c reduction at 26 weeks (approximately −1.57 versus −1.36 percentage points). This was the only double-blind trial in the programme, which strengthens its hypoglycaemia comparison; rates of clinically significant or severe hypoglycaemia were low and numerically slightly higher with icodec.
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 Preclinical only
Icodec was non-inferior to glargine U100 for HbA1c (reductions of approximately 1.16 versus 1.18 percentage points) with comparable rates of clinically significant or severe hypoglycaemia. This trial tested the harder scenario (switching people already on multiple daily injections) and found no efficacy penalty.
Once-Weekly Insulin Icodec With Dosing Guide App Versus Once-Daily Basal Insulin Analogues in Insulin-Naive Type 2 Diabetes (ONWARDS 5): A Randomized Trial Preclinical only
Icodec with a dosing-guide app gave a greater HbA1c reduction than usual-care daily basal analogues (approximately −1.68 versus −1.31 percentage points), with superiority confirmed in prespecified testing and low, similar rates of clinically significant or severe hypoglycaemia. The pragmatic design makes this the most externally valid trial in the programme, though the app confounds the insulin's own contribution.
Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial Preclinical only
Icodec was non-inferior to degludec for HbA1c (reductions of 0.47 versus 0.51 percentage points at week 26; estimated difference 0.05 points). Combined clinically significant (level 2) and severe (level 3) hypoglycaemia occurred at 19.9 versus 10.4 events per patient-year of exposure, an estimated rate ratio of 1.9 (95% CI 1.5 to 2.3, p<0.0001). This is the trial that led the FDA advisory committee and subsequently the FDA to conclude that the benefit-risk balance in type 1 diabetes was unfavourable, and it is the most important negative result in the programme.
Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans Preclinical only
Documents the design logic: lengthening the fatty diacid to strengthen albumin binding, and introducing substitutions that reduce insulin receptor affinity and therefore receptor-mediated clearance. Reports the resulting human plasma half-life of about 196 hours. Essential reading for understanding why deliberately weakening a drug at its own receptor can extend its duration.
Safety
Hypoglycaemia is the dose-limiting adverse effect, and the once-weekly profile changes its character rather than its existence. Because the half-life is about eight days, a dose cannot be withdrawn once given: if hypoglycaemia occurs, or if circumstances change (illness, reduced food intake, unplanned exercise, a hospital admission, a period of fasting), the basal insulin effect will persist for days regardless. This is why the type 1 diabetes hypoglycaemia signal in ONWARDS 6 was roughly double that of daily degludec and why regulators reached different conclusions about acceptability. Steady state takes three to four weeks, so dose changes reveal their full effect slowly and titration must be patient; conversely, initiating or switching requires care with the loading approach specified in the product information. The formulation is highly concentrated at 700 units/mL, which is a novel concentration in the insulin market and a serious potential source of tenfold or greater dosing error. Device and concentration must be confirmed at every step. Weight gain, hypokalaemia, injection-site lipohypertrophy and local reactions occur as with all insulins. Uncommon effects include systemic insulin allergy, lipoatrophy, peripheral oedema, transient refractive change and anti-insulin antibodies. Renal or hepatic impairment reduces insulin clearance. Concurrent thiazolidinedione therapy increases fluid retention and heart-failure risk. There is no cardiovascular outcome trial and no long-term complication data. Non-medical use of any insulin by people without diabetes has caused deaths and permanent hypoglycaemic brain injury; with an eight-day half-life such an episode would be extraordinarily difficult to manage.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Not asserted. Icodec was authorised in the European Union in May 2024 for the treatment of diabetes mellitus in adults, a licence that, unlike the US one, covers type 1 as well as type 2 diabetes, a genuine divergence in how the same ONWARDS 6 hypoglycaemia data were weighed. The United Kingdom is no longer covered by EU authorisations and requires a separate MHRA authorisation; the draft's claim that UK licensing followed automatically from the European Commission decision was incorrect and has been removed. Current UK status should be checked against the MHRA products database. Approvals have also been granted in Canada and Australia (2024), Japan and Switzerland, and in China for type 2 diabetes only. |
| United States | FDA-approved in 2026 as insulin icodec-abae, a 700 units/mL once-weekly basal insulin, as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes. It is not approved for type 1 diabetes or for children and adolescents. A Complete Response Letter issued in 2024 had raised manufacturing questions and rejected the type 1 diabetes indication, following an advisory committee that judged the benefit-risk profile in type 1 diabetes unfavourable; the application was subsequently resubmitted for type 2 diabetes only. Prescription-only. (The precise approval date within 2026 could not be independently confirmed and is deliberately not stated.) |
| WADA (sport) | Prohibited at all times, in and out of competition, under section S4 of the WADA Prohibited List covering insulins and insulin-mimetics. Athletes with diabetes require a Therapeutic Use Exemption. |
Questions
Two mechanisms compound. A twenty-carbon fatty diacid side chain binds albumin very tightly but reversibly, so around 99% of the drug circulates inactive in a large depot in equilibrium with a small active free fraction. Separately, three amino acid substitutions deliberately weaken binding to the insulin receptor, and since receptor-mediated uptake is the main route by which insulin is destroyed, weakening that binding slows clearance. The result is a 196-hour half-life.
Because of the ONWARDS 6 trial. In type 1 diabetes, icodec matched degludec on HbA1c but produced 19.9 versus 10.4 clinically significant or severe hypoglycaemia events per patient-year, a rate ratio of 1.9. In type 1 diabetes there is no endogenous insulin reserve and requirements fluctuate sharply, so an insulin that cannot be dialled back for a week is hazardous. An FDA advisory committee judged the benefit-risk balance unfavourable and the FDA declined that indication. EU regulators weighed the same data differently and licensed it for both types.
The dose cannot be taken back. Unlike a daily basal insulin, where skipping or reducing the next dose changes matters within a day, icodec's effect continues for days. That is the central practical consideration for anyone using it, and it is why illness, planned surgery, fasting, significant weight loss or a change in activity all require anticipatory planning with the diabetes team rather than reactive adjustment.
In type 2 diabetes the ONWARDS trials showed non-inferior and in several cases modestly superior HbA1c (differences of about 0.2 to 0.4 percentage points) with comparable low rates of severe hypoglycaemia, alongside a reduction from 365 to 52 injections a year. In type 1 diabetes it was clearly worse on hypoglycaemia. There is no cardiovascular outcome trial and no long-term complication data for icodec in either population.
Both are acylated at lysine B29 with B30 removed, but icodec uses a longer twenty-carbon diacid with an extended linker, giving much stronger albumin binding, and additionally carries three amino acid substitutions that deliberately reduce insulin receptor affinity to slow clearance. Degludec, by contrast, relies on forming soluble multihexamer chains in the subcutaneous depot and retains near-normal receptor affinity. The half-lives are about 196 hours and 25 hours respectively.