Once-weekly insulin: a spotlight on insulin icodec

Insulin icodec was marketed in Canada in June 2024 for use in patients with type 1 and type 2 diabetes.1 It is a basal insulin analogue with a pharmacokinetic and pharmacodynamic profile allowing for once-weekly injection.2How does it work?Icodec is a modified human insulin with three amino acid substitutions and a 20-carbon icosane fatty diacid chain. The substitutions provide molecular stability, minimize enzymatic breakdown and reduce receptor-mediated clearance. It takes 16 hours to achieve the maximum concentration and the half-life is approximately seven days.3Icodec binds reversibly to albumin to form an inactive depot allowing for slow release. There is little cause for concern regarding icodec’s plasma concentrations in patients with hypoalbuminuria or in those using other competitive protein-binding agents, as the maximum serum concentration of icodec at steady state is significantly lower than the serum concentration of albumin.4How is it dosed?For insulin-naïve patients, dosing starts at 70 units weekly (equivalent to a daily dose of 10 units of intermediate or long-acting basal insulin). Ideally, icodec should be given on the same day each week; however, it does not need to be taken at the same time each day. Dose titrations are made in 10–20 unit increments weekly. If needed, the injection date may be changed by up to three days (provided there is a minimum interval of 4 days between doses). If a dose is missed, it may be given if within three days of the scheduled dose. If more than three days have passed since the missed dose, continue with the next scheduled dose.4If the patient has been using another basal insulin (dosed once or twice daily) and is transitioning to icodec, the initial dosing regimen involves multiplying the current daily basal insulin dose by seven to determine the weekly icodec dose. One unit of icodec has glucose lowering equivalent to that of one unit of any standard basal insulin. As it takes three to four weeks for icodec to reach steady state, the patient may experience suboptimal glycemic control while icodec takes effect. A one-time supplemental dose of an additional 50% of icodec may be given to help facilitate the transition.1,4What were the key findings in trials?The ONWARDS clinical trial program was a combination of phase 2 and phase 3a trials conducted in adults with type 2 diabetes who were either insulin-naïve or previously treated with insulin. One phase 3a trial was conducted in adults with type 1 diabetes.4ONWARDS 1, focused on insulin-naïve patients with type 2 diabetes, who were randomly assigned to receive either icodec weekly or glargine daily.5 ONWARDS 2 looked at patients not controlled on their current basal insulin regimen, randomizing them to either daily degludec or weekly icodec.6 Similarly, ONWARDS 3 compared insulin icodec with insulin degludec in insulin-naïve patients with type 2 diabetes.7 ONWARDS 4 included patients with a longer duration of type 2 diabetes and who had been receiving a basal bolus regimen; icodec was compared to glargine insulin and use of bolus insulin continued.8 ONWARDS 5 compared insulin-naïve type 2 patients using icodec (dosed and titrated with an app) to daily basal insulin (dosed as per standard practice).9In all ONWARDS trials focusing on patients with type 2 diabetes, icodec was deemed noninferior to its comparators and showed a statistically significant reduction in glycated hemoglobin (A1C). The only trial that studied patients with type 1 diabetes (ONWARDS 6) looked at the change in A1C from baseline in patients assigned either to icodec or degludec. With regards to A1C lowering, icodec was deemed noninferior to degludec; however, there were statistically higher rates of hypoglycemia with icodec.10Overall, the trials showed improved glycemic control with icodec and the potential for improved treatment adherence through reducing insulin injection burden.1,4What are common side effects?Patients using icodec tend to have a higher incidence of hypoglycemic events compared to glargine or degludec, especially on days 2–4 of the weekly dosing cycle. They should be advised to carry treatment for hypoglycemia with them, especially if they are planning activity.1,2How is icodec supplied?Icodec (brand name Awiqli) is available in a concentration of 700 units/mL in either 1.5 mL or 3 mL prefilled pens. The higher concentration ensures that the injection volume is similar to once-daily basal insulin. Icodec should be stored in the fridge before use. Once opened, it can be kept at room temperature for up to 12 weeks.1,11What are the advantages of icodec?The biggest advantage of icodec is its weekly administration, which helps to reduce the injection burden for patients. As well, prescribers may be more likely to prescribe insulin for patients that need to have their diabetes treatment augmented, if the insulin has to be given only once weekly.2 In addition, there may be an environmental benefit due to fewer pens being used.11Which patients will benefit most?Although icodec has been approved for use in patients with type 1 or type 2 diabetes, very few trials have looked at patients with type 1 diabetes. Until more information is available regarding how patients with type 1 diabetes will respond to it, icodec will likely be used more in those with type 2 diabetes.Final thoughtsAs with any new medication, there are many unanswered questions. For example, consideration will need to be made as to timing for patients needing to do fasting blood work or having medical procedures completed. As icodec is used more post-market, valuable experience will be gained to help answer such questions.Rhonda Roedler is a pharmacist in Calgary, AB. She maintains an ambulatory clinical practice in diabetes.ReferencesNovo Nordisk Canada Inc. Awiqli (insulin icodec injection) product monograph. Mississauga, ON; March 12, 2024. 00074917.PDF (accessed November 29, 2024).Rosenstock J, Bajaj HS, Janez A, et al. Once-weekly insulin for type 2 diabetes without previous insulin treatment. N Engl J Med 2020;383:2107-16.Nishimura E, Pridal L, Glendorf T, et al. Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once weekly dosing. BMJ Open Diab Res Care 2021:9:e002301. doi:10.1136/ bmjdrc-2021-002301.Morales J, King A, Oser S et al. Advances in insulin: a review of icodec as a novel once-weekly treatment for type 2 diabetes. Postgrad Med 2024;136(8):791-800. DOI: 10.1080/00325481.2024.2410694.Rosenstock J, Bain SC, Gowda A, et al. Weekly icodec versus daily glargine U100 in type 2 diabetes without previous insulin. N Engl J Med 2023;389:297-308.Philis-Tsimikas A, Asong M, Franek E, et al. Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomized, open-label, multicentre, treat-to-target trial. Lancet Diabetes Endocrinol 2023;11(6):414-25.Lingvay I, Asong M, Desouza C, et al. Once-weekly insulin icodec vs once-daily insulin degludec in adults with insulin-naïve type 2 diabetes. JAMA 2023:330(3):228-37.Mathieu C, Asbjornsdottir B, Bajaj HS, et al. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet 2023;401:1929-40.Bajaj HS, Aberle J, Davies M, et al. Once-weekly insulin icodec with dosing guide app versus one-daily basal insulin analogues in insulin naïve type 2 diabetes (ONWARDS 5): a randomized trial. Ann Intern Med 2023;176(11):1476-85.Russell-Jones D, Babazono T, Cailleteau R, et al. Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial. Lancet 2023;402:1636-47.Novo Nordisk. Insulin icodec explained. September 2022. 1232966_NovoNordisk_InsulinIcodecBackgrounder_V11 (accessed November 22, 2024).

Once-weekly insulin: a spotlight on insulin icodec

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RHONDA LYNN ROEDLER

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