Once-Weekly Insulin Icodec (AWIQLI): Do Not Use for Seven Years

In March 2026 the Food and Drug Administration (FDA) approved the first very-long-acting insulin — which differs in certain chemical aspects from human insulin — as an add-on to diet and exercise to manage high blood sugar in adults with type 2 diabetes.[1]

Called insulin icodec (AWIQLI), the bioengineered drug is injected once weekly (on the same day each week) under the skin as an alternative to proven daily (basal, long-acting) insulins, which control steady (background) blood sugar throughout the day and night. This new drug, however, does not replace the rapid-acting (bolus) insulins, such as insulin aspart (KIRSTY, other brands and generics), needed in some diabetic individuals to manage mealtime spikes in blood sugar levels.

Insulin icodec comes in prefilled pen injectors (with a dose selector and disposable needles for multiple use) that contain either 700, 1,050 or 2,100 units of the drug. According to the manufacturer, one unit of insulin icodec corresponds to one international unit of human insulin.

Public Citizen’s Health Research Group has designated insulin icodec as Do Not Use for Seven Years to allow time for better evidence to emerge about its net benefit-risk profile.[2] The current evidence, which is limited to one year of use, shows that insulin icodec does not offer a clinically meaningful benefit over daily basal insulins. Overall, the convenience of once-weekly administration of this drug does not outweigh uncertainties about its dosage schedule and potential related risks, especially hypoglycemia (blood glucose levels below 70 milligrams per deciliter [mg/dL]).

Long-term studies assessing insulin icodec’s clinical outcomes, including rates of diabetes complications, are needed before the drug can be accepted as a standard therapy.

As of early August 2026, the annual U.S. cost of insulin icodec was unknown because the drug was not yet available. The annual price for this drug in Canada is close to that of the once-daily insulin degludec (TRESIBA),[3] whose annual wholesale acquisition cost (for 40 units daily) in the United States ranges from approximately $5,880 to $6,480.

Limited effectiveness over daily insulins

The FDA approved insulin icodec based on four randomized, active-controlled clinical trials involving adults with type 2 diabetes.

The first two trials enrolled participants who had never used insulin and whose blood sugar levels were not adequately managed with one or more common oral diabetic drugs (such as metformin [generics only]) or glucagon-like peptide-1 receptor agonists.

In the first trial, 492 participants received insulin icodec once weekly and an equivalent number received insulin glargine (100 units) once daily for 52 weeks. In the second trial, 294 participants received insulin icodec once weekly and an equal number received insulin degludec (100 units) once daily for 26 weeks. Participants continued to use most of their previous diabetes medications during the trials.

At the end of follow-up of both trials, participants who received insulin icodec had a statistically significant slighter reduction (approximately 0.2%) in their hemoglobin A1c (HbA1c) blood levels than those who received the comparator daily basal insulins. HbA1c is a test of average blood sugar levels over time, with values below 5.7% considered normal.

Overall, the design of the third and fourth trials was largely similar to that of the earlier two trials, except that they lasted for 26 weeks and their participants had previously received basal insulin.

In the third trial, 263 participants received insulin icodec once weekly and a comparable number received insulin degludec (100 units) once daily. Participants in both groups also continued taking most of their previous diabetes drugs. In the fourth trial, 291 participants received insulin icodec once weekly and the same number received insulin glargine (100 units) once daily, both in combination with insulin aspart before meals and most of their previous diabetes drugs.
Overall, insulin icodec users had a statistically significant smaller reduction (0.19%) in HbA1c levels in the third trial, but the drug users in the fourth trial had a similar reduction in HbA1c levels compared with those who received daily basal insulins.

In all but the second trial, participants and researchers knew what treatment was given, which likely biased the results in favor of insulin icodec.

Risks and other considerations

Hypoglycemia is a potential concern for insulin icodec because half of the dose remains in the body for approximately 196 hours after injection.[4]

According to insulin icodec’s labeling, level 2 hypoglycemia (blood sugar levels below 54 mg/dL) was reported in fewer than 10% of users in the first two trials. In contrast, 14% and 51% of the drug’s users reported this adverse effect in the third and fourth trials, respectively. The labeling does not report hypoglycemia rates in the comparison groups.

However, a published article based on the open-label trial indicates that the combined rates of reported level 2 or 3 hypoglycemia were statistically significantly higher in the insulin icodec group than in the comparison group (0.35 versus 0.12 events per participant-year exposure, respectively).[5] Level 3 hypoglycemia refers to episodes of low blood sugar with severe cognitive impairment that require assistance.

Importantly, hypoglycemia was not studied as a primary outcome in the preapproval trials.[6] Therefore, the absence of statistically significant differences in hypoglycemia in these trials does not rule out the possibility that insulin icodec is associated with higher rates of this adverse effect.

Moreover, numerous factors (such as fasting, exercise, illness, infections, menstruation and surgery) pose challenges for insulin icodec dosing and affect the frequency and intensity of hypoglycemia. These factors were not investigated in the clinical trials.

In 2024, FDA scientists who evaluated insulin icodec’s evidence in type 1 diabetes patients cautioned that the drug’s glucose-lowering effect is not “peakless” throughout the week.[7] Rather, its maximum effect occurs on days 2 to 4 after injection, suggesting that the risk of hypoglycemia is likely the highest at this time. The scientists also noted that the higher icodec-induced hypoglycemia rate is not exclusively associated with the loading dose or limited to the titration phase at start of treatment.

To our knowledge, insulin icodec’s dosing was not based on a well-evidenced titration regimen. Instead, the dosing seems to have been extrapolated from once-daily insulin regimens.

Increased risk of hypersensitivity (swelling of face and lips, as well as hives), modest weight gain and diabetic retinopathy (damage to blood vessels in the retina) were reported among icodec users in some of the preapproval trials.[8],[9]

No studies were conducted regarding the use of insulin icodec during pregnancy and in individuals aged 75 or older.

Notably, in July 2024 the FDA declined to approve the use of insulin icodec in type 1 diabetes due to issues with the manufacturing process as well as concerns about the increased risk of clinically meaningful hypoglycemia with its use “without evidence of any additional glycemic control or other benefit” in this patient population.[10],[11]

What You Can Do

Individuals with type 2 diabetes should modify their diet (such as by replacing white bread with complex carbohydrates and filling half of their plates with non-starchy vegetables) and increase their physical activity (including taking a 10-minute walk after meals). Those who need to take insulin can use a daily basal insulin because these are older, proven drugs. Unless further research establishes the long-term benefits and safety of insulin icodec, it is best not to use this drug.
 

References

[1] Novo Nordisk. Label: insulin icodec (AWIQLI). March 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761326Orig2s000lbl.pdf. Accessed August 5, 2026. 

[2] Editorial: The seven-year rule for safer prescribing. Worst Pills, Best Pills News. October 2012. https://www.worstpills.org/newsletters/view/816. Accessed August 5, 2026. 

[3] Meier M, Hagans J, Brackett C. Once-weekly basal insulin therapy in type 1 diabetes: A paradigm shift or a work in progress? Am J Heal Syst Pharm. 2025;82(22):1220-1227. 

[4] Pieber TR, Arfelt KN, Cailleteau R, et al. Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial. Diabetologia. 2023;66(8):1413-1430. 

[5] Lingvay I, Asong M, Desouza C, et al. Once-weekly insulin icodec vs once-daily insulin degludec in adults with insulin-naive type 2 diabetes: The ONWARDS 3 randomized clinical trial. JAMA. 2023;330(3):228-237. 

[6] Public Citizen. Testimony before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee regarding insulin icodec. May 24, 2024. https://www.citizen.org/article/testimony-before-the-fdas-endocrinologic-and-metabolic-drugs-advisory-committee-regarding-insulin-icodec/. Accessed August 5, 2026. 

[7] Food and Drug Administration. FDA briefing document, the safety and efficacy of biologics license application 761326 for NNC0148-0287 injection (insulin icodec); Endocrinologic and Metabolic Drugs Advisory Committee Meeting. https://www.fda.gov/media/178821/download. Accessed August 5, 2026. 

[8] 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, randomised, open label, multicentre, treat-to-target trial. Lancet Diabetes Endocrinol. 2023;11(6):414-425. 

[9] Lingvay I, Asong M, Desouza C, et al. Once-weekly insulin icodec vs once-daily insulin degludec in adults with insulin-naive type 2 diabetes: The ONWARDS 3 randomized clinical trial. JAMA. 2023;330(3):228-237. 

[10] Food and Drug Administration. Risk assessment and risk mitigation reviews for insulin icodec. Application number: 761326O rig2s000, BLA number: 761326. July 3, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/761326Orig2s000RiskR.pdf. Accessed August 5, 2026. 

[11] Novo Nordisk. Company announcement. Novo Nordisk receives complete response letter in the US for once-weekly basal insulin icodec. July 10, 2024. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=168532. Accessed August 5, 2026.