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Not Approved (US) Metabolic & Weight Loss

Insulin icodec

also known as: Awiqli, NN1436

Novo Nordisk's once-weekly basal insulin (Awiqli, EMA 2024) — the first weekly insulin to reach market; FDA refused to approve in July 2024 (CRL citing type 1 diabetes hypoglycemia data), leaving it approved in the EU, UK, Canada, Switzerland, and Japan while pending US resubmission.

The first once-weekly basal insulin analog — three amino-acid substitutions reduce insulin receptor affinity (and therefore clearance), while a C20 fatty diacid side chain at B29 enables ultra-high reversible albumin binding, producing a plasma half-life of approximately 196 hours. EMA-approved as Awiqli in 2024 for both T1DM and T2DM; the FDA issued a Complete Response Letter in July 2024 citing hypoglycemia concerns in type 1 diabetes, leaving Awiqli approved in the EU, UK, Switzerland, Canada, and Japan but not the US as of this writing.

Mechanism of action

Once-weekly insulin receptor agonism via three mechanisms: (1) the A14, B16, B25 substitutions reduce insulin receptor binding affinity, which paradoxically extends half-life by slowing receptor-mediated clearance; (2) the C20 fatty diacid side chain produces extremely high reversible albumin binding (>99%), creating a large circulating reservoir; (3) the dose is administered as a pre-amplified weekly equivalent (~7× daily glargine), which steady-state-titrates to a stable weekly area-under-curve equivalent to daily dosing.

Primary uses

  • Type 2 diabetes mellitus (basal, EU-approved)
  • Type 1 diabetes mellitus (basal, EU-approved)

Typical dosing

once weekly (subcutaneous)

T2DM starting dose typically 70 units weekly; titrated weekly to fasting glucose target. T1DM initiation requires careful protocol given hypoglycemia risk.

Regulatory status

EMA-approved March 2024 as Awiqli (Novo Nordisk) for T1DM and T2DM. Approved in the UK, Canada, Switzerland, and Japan. FDA Complete Response Letter issued July 2024 — the agency declined to approve based on hypoglycemia data in the ONWARDS 6 type 1 diabetes trial, requesting additional information before resubmission.

References

  1. [pubmed] Rosenstock J, et al. "Once-weekly insulin icodec versus once-daily insulin degludec in adults with type 2 diabetes (ONWARDS 2)." Lancet, 2023;402:713-724.
  2. [pubmed] Russell-Jones D, et al. "Once-weekly insulin icodec versus once-daily insulin glargine in adults with type 1 diabetes (ONWARDS 6)." Lancet, 2023;402:1636-1647.
  3. [manufacturer] Novo Nordisk. Press release: FDA Complete Response Letter for insulin icodec, July 2024.

Related peptides

Insulin glargine

The dominant once-daily basal insulin for two decades (Lantus, Sanofi, 2000) — the pI-shift design causes microprecipitation in subcutaneous tissue for a nearly peakless 24-hour absorption profile; Toujeo (U-300) is the same molecule at 3× concentration.

Insulin degludec

Novo Nordisk's ultra-long-acting insulin (Tresiba, 2015) — forms soluble multi-hexamers in SC tissue that slowly dissociate for a >42-hour half-life and a flat, forgiving dosing window; the basal insulin with the lowest hypoglycemia risk profile.

Insulin efsitora alfa

Lilly's once-weekly basal insulin candidate — Phase 3 QWINT program completed 2024 in T1DM and T2DM; NDA submission 2025. Competes head-to-head with Novo's insulin icodec, using Fc fusion rather than albumin binding to achieve the weekly profile.

Guides & tools

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.