Are We Moving ONWARDS and Upwards in the Treatment of Diabetes?

Ashley Meyer, PharmD, Mille Lacs Health System

Background: Insulin icodec is a once-weekly basal insulin that is currently under trial with an expected decision from the FDA in April of 2024. An article by Bajaj and Goldenberg describes insulin icodec as having an amino acid structure which is modified to irreversibly bind to albumin, thus prolonging its half-life to 196 hours, which is just over eight days. About 1 in 10 people in America have diabetes, with 90-95% being type 2 diabetes mellitus (T2DM). Patients with T2DM requiring daily insulin injections may struggle with adherence due to the inconvenience, pain, and/or stigma associated with insulin use according to an article by UT Southwestern Medical Center. The addition of a once-weekly insulin to the market could potentially increase patient adherence to insulin therapy and improve glycemic control.

Objective: To evaluate the safety and efficacy of once-weekly insulin icodec vs once-daily insulin degludec in insulin-naive patients with T2DM.

Study Design: ONWARDS is a phase 3a clinical trial program which consists of six separate trials investigating different clinical scenarios with insulin icodec. ONWARDS3 was a multi-center, double-blinded, double-dummy, treat-to-target, randomized controlled trial. Participants in this trial were insulin-naive adult patients with T2DM being treated with a non-insulin glucose-lowering medication with an A1c of 7.0-11.0%. Patients needed to be diagnosed with T2DM at least 180 days prior to screening and be on stable doses of an approved oral non insulin glucose-lowering agent for at least 90 days prior to screening. Approved regimens included any metformin formulation ≥1500 mg or maximum tolerated/effective dose, any metformin combination formulation ≥1500 mg or maximum tolerated/effective dose, or any of the following oral noninsulin glucose-lowering agent classes including combinations at least half of the maximum approved dose according to local label or maximum tolerated/effective dose (sulfonylureas, meglitinides, DPP-4 inhibitors, SGLT2 inhibitors, thiazolidinediones, alpha-glucosidase inhibitors, oral combination products, or oral or injectable GLP-1RAs). Notable exclusion criteria included if patients were pregnant or breast-feeding, had an episode of diabetic ketoacidosis within the last 90 days, had a myocardial infarction or stroke within 180 days or screening, NYHA class IV heart failure, an estimated glomerular filtration rate value <30 mL/min/1.73m², ALT ≥2.5 times or bilirubin >1.5 times upper normal limit, systolic blood pressure ≥180 mmHg or diastolic ≥110 mmHg, and uncontrolled diabetic retinopathy or maculopathy. If patients were being treated with a sulfonylurea or glinide, their dose was reduced by 50% at the investigator’s discretion. 588 study participants were randomized into two groups, the icodec group or the degludec group. The icodec group received once-weekly icodec and once-daily placebo while the degludec group received once-daily degludec and once-weekly placebo. Doses were titrated weekly based on specified pre-breakfast glucose readings using self-measured blood glucose values. The treatment period lasted for 26 weeks. The primary outcome for this study was change in A1c from baseline. The secondary efficacy endpoint was change in fasting plasma glucose (FBG) from baseline. Secondary safety endpoints included mean total weekly insulin dose in the last two weeks of treatment, change in body weight, and the number of level 2 and level 3 hypoglycemic events (plasma glucose <54 mg/dL and hypoglycemia with severe cognitive impairment, respectively). 

Results: 96% of participants completed the 26-week treatment period. Mean A1c levels decreased by 1.6% at 26 weeks in the icodec group and 1.3% in the degludec group (95% CI, -0.3% to -0.1%; P=0.002). The estimated change in FBG from baseline was -54 mg/dL in both groups with no statistically significant difference between groups (95% CI, -6 to 5; P=0.90). The estimated mean insulin dose in the last two weeks of treatment was 29 units/day in the icodec group and 27 units/day in the degludec group, which was not statistically significant (95% CI, 0.98 to 1.22; P=0.09). From baseline to week 26 the rate of level 2 hypoglycemia events was 8.2% in the icodec group and 4.4% in the degludec group. There were two level 3 hypoglycemic events in the degludec group and none in the icodec group. There was a statistical difference in combined level 2 and 3 hypoglycemic events between the two groups (95% CI, 1.3 to 7.5; P=0.01).

Conclusion: The results from this study demonstrate superiority of once-weekly insulin icodec compared to once-daily insulin degludec in reducing A1c in insulin-naive patients with T2DM. However, rates of hypoglycemia were higher in the icodec group compared to the degludec group. The small glycemic benefit on top of the once-weekly injection of insulin icodec may improve medication adherence. Limitations of this study include the inability to evaluate sustained effects of the drug after the 26-week treatment period, not using continuous glucose monitoring, and the study was only powered to detect the primary outcome and not the secondary outcomes. This means that any lack of statistical significance of secondary outcomes did not necessarily mean there was a lack of true clinical effect.

Key Point: Insulin icodec demonstrated superior A1c lowering in insulin-naive patients compared to insulin degludec. The use of once-weekly insulin icodec could play an important role in T2DM treatment by reducing the frequency of injections and increasing medication adherence. However, further analysis of safety endpoints with hypoglycemic events should be ongoing. 


  1. Bajaj HS, Goldenberg RM. Insulin icodec weekly: a basal insulin analogue for type 2 diabetes. touchREV Endocrinol. 2023;19(1):4-6. doi:10.17925/EE.2023.19.1.4
  2. Weekly insulin found safe, effective for type 2 diabetes. UT Southwestern Medical Center. Published July 12, 2023. Accessed August 18, 2023.
  3. 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. JAMA. 2023;330(3):228-237. doi:10.1001/jama.2023.11313