Weekly insulin is coming. Is it any good?

13th December 2020, Dr Chee Khoo


First, we have twice daily then once daily GLP1 injections. This was followed by weekly GLP1 injectables. The same is occurring with the insulins. Once daily insulins have been around for a few years and is well established as basal insulins in patients with type 1 and type 2 diabetes. We now have a weekly insulin coming onto the market. Wow, you would say but how does that compare with current insulins? Insulin icodec has just completed a 26-week randomised, double blind, double dummy phase 2 trial in patients new to insulin therapy. Naturally, it will be some years before it gets here but isn’t it exciting? Let’s have a look at the new technology.

Human insulin is composed of 51 amino acids. It is a combination of two peptide chains (dimer) named an A-chain and a B-chain, which are linked together by two disulfide bonds. The A-chain is composed of 21 amino acids, while the B-chain consists of 30 residues. The amino acid sequence of insulin is strongly conserved and varies only slightly between species.  Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one.

Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is an inactive form with long-term stability, which serves as a way to keep the highly reactive insulin protected, yet readily available. The hexamer-monomer conversion is one of the central aspects of insulin formulations for injection.

Substitution of amino acid in the insulin molecule reduces the formation of dimers and hexamers and allows for faster action of injectable insulins. This is the basis of the fast acting and rapid acting insulins. Insulin determir has a longer duration of action by binding to albumin. Insulin glargine forms microprecipitates when injected subcutaneously and small amounts of insulin is released. The newer insulin degludec forms multi-hexamers when injected subcutaneously resulting in the formation of a subcutaneous insulin depot.

Insulin icodec is a novel insulin analog with a half-life of ∼196 hours (i.e. ~8 days). Addition of a C20 fatty diacid containing side chain at B29K via a hydrophilic linker allows it to bind reversibly to albumin (10x stronger than that of insulin detemir). In addition, three amino acid substitutions (A14E, B16H and B25H) ensure reduced enzymatic degradation of icodec and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. The in vitro mitogenic effect of icodec in primary human mammary cells as well as in mammary and colon carcinoma cells (MCF-7 and COLO 205) was found to be low relative to that of human insulin.

How does icodec compare with current basal insulins?

A 26-week, randomized, double-blind, double-dummy, phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose T2D was inadequately controlled (HbA1c 7.0 to 9.5%) while taking metformin with or without a DPP4 inhibitor was conducted. The results was published in the NEJM last month.

As it was a phase 2 trial, it was only a small trial. A total of 247 participants were randomly assigned (1:1) to receive icodec or glargine. Baseline characteristics were similar in the two groups; the mean baseline HbA1c was 8.09% in the icodec group and 7.96% in the glargine group. The estimated mean change from baseline HbA1c was −1.33% in the icodec group and −1.15% in the glargine group at 26 weeks. There were no between group difference in the change from baseline HbA1c.  

The observed rates of moderate to severe hypoglycemia were low (icodec group, 0.53 events per patient-year; glargine group, 0.46 events per patient-year). There was no between-group difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low.

In other words, weekly icodec insulin appears to be as efficacious and as good as daily insulin glargine. Naturally, weekly insulin will be suitable for patients with T2D who currently require daily injections of a basal insulin. Patients who need prandial insulins (rapid acting insulin) will continue to need their prandial insulins. The availability of a weekly insulin will significantly reduce the number of injections and improve compliance. It could be suitable for patients with mild dementia who is visited by carers only a couple of times a week.


Rosenstock J, Bajaj HS, Janež A, Silver R, Begtrup K, Hansen MV, Jia T, Goldenberg R; NN1436-4383 Investigators. Once-Weekly Insulin for Type 2 Diabetes without Previous Insulin Treatment. N Engl J Med. 2020 Nov 26;383(22):2107-2116. doi: 10.1056/NEJMoa2022474. Epub 2020 Sep 22. PMID: 32960514.