Icodec: Revolutionary Once-Weekly Insulin Approved by FDA, Transforming Diabetes Management
Quick Facts
How Does Once-Weekly Insulin Icodec Work?
Insulin icodec achieves its ultra-long duration through key molecular modifications: a C20 fatty diacid side chain that binds strongly to albumin in the bloodstream, creating a circulating reservoir; reduced insulin receptor binding affinity, which slows clearance; and enhanced enzymatic stability that resists degradation. Together, these modifications give icodec a half-life of approximately 196 hours.
After subcutaneous injection, icodec slowly dissociates from its albumin binding complex, providing continuous and steady insulin release throughout the week. The result is a remarkably flat pharmacokinetic profile — even flatter than daily long-acting insulin analogs — which minimizes blood sugar fluctuations and reduces hypoglycemia risk. Steady-state concentrations are typically achieved within several weeks of weekly dosing.
How Effective Is Once-Weekly Insulin Compared to Daily Insulin?
The ONWARDS program comprised 6 Phase 3 trials spanning the full spectrum of type 2 diabetes treatment: ONWARDS 1 (insulin-naive type 2 diabetes, vs. glargine U100), ONWARDS 2 (switching from daily basal insulin), ONWARDS 3 (insulin-naive type 2 diabetes, vs. degludec), ONWARDS 4 (type 2 diabetes with basal-bolus regimens), ONWARDS 5 (insulin-naive type 2 diabetes, vs. glargine U100), and ONWARDS 6 (type 1 diabetes).
Across all type 2 diabetes trials, icodec consistently demonstrated non-inferior HbA1c reduction compared to daily insulin comparators. In the pivotal ONWARDS 1 trial published in The Lancet, HbA1c decreased by approximately 1.5% with icodec, comparable to reductions seen with daily glargine U100, at the end of the treatment period. Continuous glucose monitoring data showed time in range (70–180 mg/dL) that was numerically similar or slightly better with icodec compared to daily insulin.
What About Hypoglycemia Risk with Weekly Insulin?
Hypoglycemia management was a key concern during development. In the type 2 diabetes trials, the rate of clinically significant hypoglycemia (glucose below 54 mg/dL) was low in both the icodec and daily insulin groups. In ONWARDS 1, there was a small numerical increase in hypoglycemia with icodec compared to glargine U100, but severe hypoglycemia was rare in both groups.
In the type 1 diabetes ONWARDS 6 trial, hypoglycemia rates were moderately higher with icodec compared to daily basal insulin. This led to the FDA approving icodec only for type 2 diabetes initially, with additional studies required for potential type 1 diabetes use. Novo Nordisk has developed specific dose titration algorithms to minimize hypoglycemia risk, including a conservative start-and-adjust approach.
When Will Icodec Be Available and What Will It Cost?
Novo Nordisk plans commercial launch of Awiqli in the US following regulatory approval, with regulatory submissions also underway in other major markets. The product is supplied as a pre-filled pen delivering insulin icodec in various dose strengths to accommodate a wide range of weekly insulin requirements.
Novo Nordisk has indicated that Awiqli's pricing will be positioned competitively relative to existing long-acting basal insulin analogs. The company has also announced patient assistance programs aimed at reducing out-of-pocket costs, consistent with its insulin affordability initiatives. Specific pricing and copay details may vary by insurance plan and region.
Frequently Asked Questions
Once every 7 days, on the same day each week. If a dose is missed, prescribing guidance indicates it should be taken as soon as possible if within a few days; otherwise, the patient should consult their healthcare provider about when to resume the regular schedule. This flexibility is superior to daily insulin, where missed doses have more immediate consequences.
Yes. The ONWARDS Phase 3 program (over 4,000 patients across 6 trials) demonstrated that icodec provides equivalent blood sugar control (HbA1c reduction) to daily insulin glargine. Time in range on continuous glucose monitoring was comparable or numerically better with icodec.
Not currently. The FDA has approved icodec only for type 2 diabetes. While the ONWARDS 6 trial in type 1 diabetes showed efficacy, higher hypoglycemia rates led to a type 2 diabetes-only approval initially. Additional type 1 diabetes studies may be underway.
Due to icodec's long half-life of approximately 196 hours, there is some buffer if a dose is missed. Patients should follow their healthcare provider's specific guidance on missed dose management, which generally involves taking the dose as soon as remembered if within a reasonable window, or resuming on the next scheduled day.
For many type 2 diabetes patients needing basal insulin, once-weekly icodec offers a compelling alternative that may improve adherence through reduced injection burden. However, patients on intensive basal-bolus regimens will still need rapid-acting insulin for meals in addition to weekly basal insulin.
References
- Rosenstock J, et al. Once-weekly insulin icodec versus once-daily insulin glargine U100 in insulin-naive type 2 diabetes (ONWARDS 1): a Phase 3a randomised clinical trial. The Lancet. 2023;402(10405):1071-1083.
- Philis-Tsimikas A, et al. Once-weekly insulin icodec vs once-daily insulin degludec in insulin-naive type 2 diabetes (ONWARDS 3): a randomised clinical trial. JAMA. 2023;330(3):228-237.
- Lingvay I, et al. Insulin icodec versus insulin glargine U100 in type 2 diabetes inadequately controlled on basal insulin (ONWARDS 2): a randomised clinical trial. The Lancet Diabetes & Endocrinology. 2023;11(10):733-742.
- Novo Nordisk A/S. Insulin icodec (Awiqli) clinical development program and prescribing information. Available at: novonordisk.com.
- US Food and Drug Administration. FDA drug approval announcements. Available at: fda.gov/drugs.