Highlights

Since its first therapeutic use in 1922 to save the diabetic patient, insulin has been a great example of scientific innovation. Despite the many advances that have provided improvements in insulin therapy, pharmacological advances to further improve insulin have never definitively solved the problem of optimizing treatment.

Over the past 100 years we have learned that insulin is a complex pharmacological agent with a narrow therapeutic window. Each decade has had its pioneering milestones, indicative of efforts and advances in various scientific disciplines, basic and applied. A host of insulin dosing issues had to be addressed to accurately match the ever-changing need for insulin throughout the day, with rapid bolus insulin action required during meals and slow and steady basal insulin action required between meals and at night. For a century, science has been working to create and develop molecular analogues of insulin and its pharmaceutical formulation, chemical engineering production, and delivery biotechnology to mimic as closely as possible the natural patterns of insulin release from pancreatic beta cells and reduce the time spent in a state of hyper- or hypoglycemia.

The latest achievement in insulin therapy is the emergence of long-acting insulin analogues, which have taken patients’ lives to a whole new level. The once-daily basal insulins Lantus (insulin glargine) and Levemir (insulin detemir), first offered by Sanofi and Novo Nordisk in April 2000 and June 2004, followed by Tresiba (insulin degludec) and Toujeo (insulin glargine), prepared by the Danish and French pharmaceutical companies in January 2013 and February 2015, made it possible both to reduce the burden of insulin injections and to achieve more or less acceptable glycemic control.

Still, the overall level of stable glycemic control in type 1 and type 2 diabetes remains far from normalization.

In the near future, Novo Nordisk will release insulin icodec, a basal insulin that is injected subcutaneously once a week.

The emergence of weekly basal insulin is expected to increase patient adherence to insulin therapy, which in turn will be reflected in improved glycemic control of diabetes. From a practical standpoint, everything is transparent: 52 injections per year instead of 365 injections.

The supposed trademark for insulin icodec is Awiqli, Aweeqli, Simwekli, or Wunzeek. Other possible brands include Bemrelfy, Iwelby, and Onwelby.

 

Why Is Ultra-Long Acting Insulin Needed?

Despite a growing armamentarium of highly effective blood glucose-lowering medications, many patients with type 2 diabetes eventually require insulin therapy. [1]

Modern basal insulins are highly effective and have a reduced risk of hypoglycemia compared to previous generations. However, insulin therapy is often delayed even when indicated. This happens because of clinical inertia and fears of patients and medical professionals. [2] [3] Among the reasons: fear of hypoglycemia, weight gain, injections, expectation of problems with treatment adherence and reduced quality of life. [4] [5] [6] [7] [8] [9] [10] [11]

Even if insulin therapy is eventually initiated, poor adherence to daily insulin administration is common and is associated with inadequate glycemic control and high costs to the health care system. [12] [13] In some cases, basal insulin therapy is administered suboptimally (e.g., ineffective dose selection methods are used), which leads to poor clinical outcomes and treatment adherence. [14] Insufficient duration of insulin treatment is another obstacle to achieving glycemic control, [15] and the need for frequent insulin injections is one of the most important factors. [16] [17] [18] [19]

If basal insulin could be administered just once a week, this would result in less clinical inertia, increased compliance, and improved quality of life for patients, assuming the risk of hypoglycemia remains low. Such optimistic speculation is extrapolated from outcomes comparing weekly and daily administration of glucagon-like peptide-1 receptor (GLP1R) agonists. [20] [21] [22] [23]

 

Design Features of Insulin Icodec

Long-acting insulin analogs achieve pharmacokinetic profiles suitable for once-daily subcutaneous injections in various ways. [1] [2]

Thus, insulin glargine was developed with an elevated isoelectric point (pH shift from 5.4 to 6.7), which leads to the formation of slowly absorbing precipitates of insulin hexamers at physiological pH in vivo, thereby providing a subcutaneous insulin depot. Subsequently, an improved version of insulin glargine was designed in which it is delivered in a smaller volume of fluid, resulting in an even longer and more even effect due to the reduced surface area of the more compact injectable depot. [3] [4] [5]

Insulin detemir is acylated with 14-carbon fatty acid, which helps to slow down absorption due to dimerization of insulin hexamers and reversible binding to albumin both in the subcutaneous depot and in the circulatory system. [6] [7]

Insulin degludec is acylated with a 16-carbon fatty acid. Insulin degludec dihexamers assemble into multihexamers in the subcutaneous depot, with the fatty acid side chains binding the hexamers like “pearls on a string,” thereby prolonging the time they remain in the injectable depot. The fatty acid also promotes the reversible binding of insulin degludec monomers to albumin, which helps to increase its half-life. [8]

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It should be understood that the development of weekly basal insulin is not solely about extending its half-life. In order to reduce the risk of hypoglycemia, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles should be more predictable than those of existing daily insulins, along with less inter- and intrapatient variation.

Insulin icodec, as an acylated insulin analog, is based on a re-engineered version of the experimental oral basal insulin OI338. The addition of a 20-carbon fatty diacid (icosanedioic acid) to the B-chain of the insulin molecule provided strong reversible binding to albumin. Three amino acid substitutions (at positions A14, B16, and B25) increased stability and minimized enzymatic degradation. The above modifications also reduced affinity for insulin receptor and subsequent clearance, which was reflected by a longer half-life. [9] [10] [11]

Insulin icodec is designed to have a prolonged PK profile with a slow and sustained glucose-lowering effect mainly due to reduced binding to insulin receptors and reduced clearance rate rather than prolonged release from the injection site. [12] For example, the affinity of insulin icodec for insulin receptors is only 0.03% of that of native insulin, but the weekly dose of insulin icodec is reduced by one-quarter that of daily insulin glargine. [13] Therefore, the PD profile of insulin icodec is more clinically relevant than its PK profile. Stable state PD simulations have shown that the glucose-lowering effects mediated by insulin icodec are evenly distributed over a one-week dosing period. [14]

 

Clinical Efficacy and Safety of Insulin Icodec

Novo Nordisk is verifying the efficacy and safety of insulin icodec in a large-scale ONWARDS phase 3 clinical program enrolling adult patients (n=3765) with type 2 diabetes mellitus:

  • ONWARDS 1 (NCT04460885), 78 weeks, 984 patients. Weekly insulin icodec — versus daily insulin glargine. Both insulins are on any non-insulin antidiabetic drugs. In insulin-naïve patients.
  • ONWARDS 2 (NCT04770532), 26 weeks, 526 patients. Weekly insulin icodec — vs. daily insulin degludec. In patients had previously received basal insulin (neutral protamine Hagedorn insulin [isophane insulin], insulin degludec, insulin detemir, insulin glargine).
  • ONWARDS 3 (NCT04795531), 26 weeks, 588 patients. Weekly insulin icodec — vs. daily insulin degludec. In insulin-naïve patients.
  • ONWARDS 4 (NCT04880850), 26 weeks, 582 patients. Weekly insulin icodec — vs. daily insulin degludec. Both insulins are on bolus insulin aspart 2–4 times a day. In patients had previously received basal insulin (neutral protamine Hagedorn insulin [isophane insulin], insulin degludec, insulin detemir, insulin glargine) and bolus insulin (insulin aspart, insulin lispro, insulin glulisine).
  • ONWARDS 5 (NCT04760626), 52 weeks, 1085 patients. Weekly insulin icodec — vs. daily insulin glargine or insulin degludec. In insulin-naïve patients.

The 52-week ONWARDS 6 (NCT04848480) clinical trial invited adult patients (n=582) with type 1 diabetes who had previously received basal and bolus insulin. Participants were given weekly insulin icodec or daily insulin degludec. Both insulins are on bolus insulin aspart 2–4 times a day.

Insulin Icodec: ONWARDS Phase 3 Clinical Program

StudyPatientsControlHbA1c reduction, %Hypoglycemia rate, events per patient-year
Weekly insulinDaily insulinWeekly insulinDaily insulin
ONWARDS 1 (NCT04460885)Insulin-naïve, n=984Insulin glargine, both groups are on any non-insulin antidiabetics1.55*1.350.300.16
ONWARDS 2 (NCT04770532)Previously received basal insulin, n=526Insulin degludec0.93*0.710.730.27
ONWARDS 3 (NCT04795531)Insulin-naïve, n=588Insulin degludec1.57*1.360.310.15
ONWARDS 4 (NCT04880850)Previously received basal and bolus insulin, n=582Insulin degludec, both groups are on bolus insulin aspart1.16**1.185.645.62
ONWARDS 5 (NCT04760626)Insulin-naïve patients, n=1085Insulin glargine or insulin degludec
ONWARDS 6 (NCT04848480)Previously received basal and bolus insulin, n=582Insulin degludec, both groups are on bolus insulin aspart0.47**0.5119.9310.37
Hypoglycemia refers to severe or clinically significant hypoglycemia (blood glucose levels below 54 mg/dL [3 mmol/L]).
* — Weekly insulin icodec was statistically significantly better than daily comparison insulin.
** — Weekly insulin icodec is no worse than daily comparison insulin.

In parallel, a COMBINE phase 3 clinical program is underway to test the treatment of type 2 diabetes mellitus with a fixed-dose combination of insulin icodec and semaglutide (IcoSema):

  • COMBINE 1 (NCT05352815). IcoSema — versus insulin icodec
  • COMBINE 2 (NCT05259033). IcoSema — vs. semaglutide
  • COMBINE 3 (NCT05013229). IcoSema — vs basal insulin glargine with bolus insulin aspart.

 

Expert Comments

Of the five completed ONWARDS phase 3 clinical trials, in three trials, insulin icodec was statistically significantly superior to the comparison group in reducing glycated hemoglobin, and was no worse in the remaining two.

There was some concern about hypoglycemia: Those receiving weekly insulin experienced it more often than those following daily insulin therapy, although in most cases the difference in the frequency of severe hypoglycemia (blood glucose levels below 54 mg/dL [3 mmol/L]) was not statistically significant. An exception was observed in ONWARDS 6 among patients with type 1 diabetes mellitus.

At this point, it remains unclear whether the combination of the small advantage in glucose control efficacy of insulin icodec with the more than obvious convenience of its use will outweigh the increased risks of hypoglycemia that it carries, while the incidence of such in real clinical practice is likely to grow.

In any case, the emergence of high-quality, once-weekly basal insulin is a significant step forward in easing the injection burden and smoothing out pharmacokinetic and pharmacodynamic fluctuations. However, entirely new practical strategies for its introduction into clinical practice need to be developed that differ from the current daily insulin treatment of diabetes. It should be understood that the use of weekly insulin will not immediately produce rapid reductions in glucose levels, since it will take approximately three to four weeks to achieve stable steady state insulin concentration. Frequent dose adjustments are not possible, and therefore loading doses may be required initially, even in insulin-independent patients in whom antidiabetic agents do not provide adequate glycemic control. Loading doses may also be helpful in patients transitioning from daily insulin. A temporary adaptation of bolus insulin doses will be needed in type 1 diabetes mellitus. [1]

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As for possible hypoglycemic episodes during the use of weekly insulin icodec, they do not seem to last longer than with daily insulin and can be managed with standard approaches. In other words, treatment with weekly insulin should not be accompanied by any concern about worsening the severity of potential hypoglycemia in terms of duration and resistance. [2] [3] [4] [5] [6] [7]

Eli Lilly, which directly competes with Novo Nordisk in the field of diabetes, is still lagging behind in creating weekly insulin. So, basal insulin efsitora alfa (LY3209590), also known as basal insulin Fc (BIF), designed differently than insulin icodec, just this year moved into the QWINT phase 3 clinical program, with trial results expected in fall 2023 to spring 2024.

Basal insulin efsitora alfa is implemented by binding a single-chain insulin analog (with a number of amino acid substitutions) to the fragment crystallizable (Fc) region of immunoglobulin G (IgG). [8] [9]

Theoretically, this should increase the half-life, since the fusion protein benefits from the same recycling pathway that provides a relatively long half-life for endogenous IgG. [10] [11] When IgG enters cells by micropinocytosis, the Fc region binds to the membrane-bound neonatal Fc receptor (FcRn) in acidified endocytic vesicles. Recirculating endosomes return FcRn–IgG complexes to the cell surface, and the physiological pH of the extracellular medium allows the release of IgG.

The binding affinity of LY3209590 to the insulin receptor is two orders of magnitude lower than that of the native hormone, but full agonism persists. LY3209590 is characterized by low variability and a nearly peakless pharmacokinetic profile at one-week dosing. [12] [13] [14] [15]

In the NCT03736785 phase 2 clinical trial, weekly insulin efsitora alfa was found to be as good as daily insulin degludec in the task of reducing glycated hemoglobin levels, and superior in terms of reduced frequency of hypoglycemic episodes and reduced body weight gain. [16]

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