Insulin Icodec: Physiology and What Research Reports

Insulin icodec is a long-acting basal insulin analogue designed so that a single subcutaneous administration can cover approximately one week of basal insulin requirement. It appears in endocrinology literature, in the phase 3a ONWARDS trial programme, and in regulatory summaries, which is why readers of peptide and protein-therapeutic literature encounter the term. This page is for educational purposes only and is not medical advice; consult a licensed physician for any question about diabetes, insulin or other prescription therapy.

What Insulin Icodec Is

Insulin is a 51-amino-acid peptide hormone produced by the beta cells of the pancreatic islets of Langerhans. It is secreted in response to rising glucose and amino acid concentrations, and it signals through the insulin receptor to promote glucose uptake in muscle and adipose tissue, suppress hepatic glucose output, and inhibit lipolysis. Endogenous insulin circulates with a half-life measured in minutes, which is why exogenous analogues have historically required daily or more frequent administration.

Icodec is a synthetic analogue of that hormone rather than a naturally produced peptide. The molecular and pharmacological characterisation paper described three amino acid substitutions and a C20 fatty diacid side chain attached via a linker, a design intended to give strong but reversible albumin binding, reduced insulin receptor affinity and reduced receptor-mediated clearance, together supporting a half-life compatible with once-weekly dosing (PMID 34413118).

The albumin-depot concept

Because the fatty diacid moiety binds circulating albumin, most of the administered molecule is held in an inactive, bound reservoir. Only the small unbound fraction is free to engage insulin receptors, and as that fraction is consumed more is released from the albumin pool. The endocrine review of weekly insulin therapy framed this slow-release, low-clearance strategy as the shared basis for weekly insulins including icodec and insulin efsitora alfa (PMID 38224978).

How It Is Studied and Measured

Preclinical work on icodec used receptor-binding assays, cell-based signalling readouts and animal pharmacokinetic models to characterise affinity, potency and clearance before human trials (PMID 34413118). In clinical research, the standard endpoints were:

• Glycated haemoglobin (HbA1c) — the primary efficacy endpoint across the ONWARDS trials, usually change from baseline to a fixed week.
• Continuous glucose monitoring (CGM) — used to derive time in the target glucose range, reported as a secondary endpoint in several ONWARDS trials (PMID 37354562).
• Hypoglycaemic episode rates — counted by severity level and reported as safety outcomes.
• Treat-to-target design — trials such as ONWARDS 2 and ONWARDS 4 titrated both arms toward a common glucose target so that comparisons reflected the insulin rather than differing targets (PMID 37148899, PMID 37156252).

What the Clinical Literature Reported

The ONWARDS programme spanned insulin-naive type 2 diabetes, basal-treated type 2 diabetes, basal-bolus regimens, and type 1 diabetes. The table below summarises the comparator and population of the trials cited on this page.

Type 2 diabetes

In insulin-naive type 2 diabetes, researchers reported in ONWARDS 3 that once-weekly icodec was non-inferior to once-daily degludec for HbA1c reduction over the trial period (PMID 37354562). The ONWARDS 1 trial compared weekly icodec with daily glargine U100 in the same broad population and reported HbA1c outcomes favouring icodec at the primary endpoint (PMID 37356066). ONWARDS 5, conducted with a dosing guide app in a design intended to resemble routine care, also reported HbA1c results with once-weekly icodec compared with once-daily basal analogues (PMID 37748181).

In people already using basal insulin, the study reported that switching to once-weekly icodec was non-inferior to continuing once-daily degludec for HbA1c change in ONWARDS 2 (PMID 37148899). ONWARDS 4 applied the same switch question within a basal-bolus regimen and reported non-inferiority versus once-daily glargine U100 (PMID 37156252).

Type 1 diabetes

ONWARDS 6 examined icodec as the basal component of a basal-bolus regimen in type 1 diabetes and reported HbA1c non-inferiority against once-daily degludec, alongside hypoglycaemia rates that distinguished the two arms (PMID 37863084).

Combination research

A related line of work combined icodec with semaglutide in a single weekly injection. The COMBINE 3 trial compared once-weekly IcoSema with multiple daily insulin injections in type 2 diabetes in an open-label, treat-to-target, non-inferiority design (PMID 40482670).

Hypoglycaemia and Tolerability: What Studies Report

Hypoglycaemia was the safety signal researchers watched most closely, because a weekly depot cannot be withdrawn once administered. In type 1 diabetes, the ONWARDS 6 investigators reported higher rates of clinically significant or severe hypoglycaemia with icodec than with degludec (PMID 37863084). In insulin-naive type 2 diabetes, ONWARDS 3 reported low overall hypoglycaemia rates in both arms (PMID 37354562), and ONWARDS 2 reported hypoglycaemia outcomes in participants switching from daily basal insulin (PMID 37148899). A 2025 practical-guidance review synthesised these trial data into considerations for titration intervals, switching and situations such as illness or reduced intake (PMID 40802020).

Why the Term Matters

Icodec is a worked example of peptide engineering: a native hormone modified with a lipid side chain to exploit albumin binding and extend duration from minutes to roughly a week. The same albumin-binding strategy underpins several other long-acting peptide therapeutics, which is why the molecular characterisation paper is frequently referenced outside diabetes research (PMID 34413118).

A second reason the term appears in the literature is behavioural. A 2024 review of barriers to initiating insulin in type 2 diabetes described injection burden, fear of hypoglycaemia and regimen complexity among the obstacles clinicians encounter (PMID 38559691), and the weekly-insulin review positioned reduced injection frequency as one rationale for developing these molecules (PMID 38224978).

Regulatory Status

Insulin icodec is a prescription pharmaceutical, not a research chemical. A 2024 regulatory summary documented its first approval as a once-weekly basal insulin for the treatment of diabetes mellitus (PMID 39031321). Approval status differs between jurisdictions and changes over time. Nothing here describes how any person should use insulin; dosing and titration of insulin are clinical decisions made by prescribers.

References

• Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing (BMJ Open Diabetes Research & Care, 2021)
• Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2) (The Lancet Diabetes & Endocrinology, 2023)
• Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4) (The Lancet, 2023)
• Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial (JAMA, 2023)
• Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin (New England Journal of Medicine, 2023)
• Once-Weekly Insulin Icodec With Dosing Guide App Versus Once-Daily Basal Insulin Analogues in Insulin-Naive Type 2 Diabetes (ONWARDS 5) (Annals of Internal Medicine, 2023)
• Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6) (The Lancet, 2023)
• The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa (Endocrine Reviews, 2024)
• Current barriers to initiating insulin therapy in individuals with type 2 diabetes (Frontiers in Endocrinology, 2024)
• Insulin Icodec: First Approval (BioDrugs, 2024)
• Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3) (The Lancet Diabetes & Endocrinology, 2025)
• Clinical Use of Once-Weekly Insulin Icodec: Translating Clinical Trial Data into Practical Guidance for Diabetes Management (Drugs, 2025)