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.
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.