Awiqli (insulin icodec) became the first once-weekly basal insulin approved by the FDA on March 26, 2026. Manufactured by Novo Nordisk and approved for adults with type 2 diabetes, Awiqli is delivered via a 700 units/mL pre-filled FlexTouch pen, reducing injection frequency from daily to just once per week. The ONWARDS clinical trial program — comprising six Phase 3 trials with over 4,000 participants — provides the most comprehensive safety data available. This guide covers what patients and providers need to know about Awiqli's side effects, safety considerations, and contraindications.
The ONWARDS Clinical Trial Program
The ONWARDS program consisted of six randomized controlled trials (ONWARDS 1–6) evaluating insulin icodec across different type 2 diabetes populations:
- ONWARDS 1: Insulin-naive patients, compared to insulin glargine U-100 (Lantus) over 78 weeks
- ONWARDS 2: Insulin-naive patients, compared to insulin degludec (Tresiba) over 26 weeks
- ONWARDS 3: Patients previously on basal insulin, switching to icodec vs. continuing daily insulin over 26 weeks
- ONWARDS 5: Patients with type 2 diabetes on basal-bolus regimen over 52 weeks
- ONWARDS 6: Patients with type 1 diabetes (studied for T1D data, though Awiqli is NOT approved for type 1)
Across these trials, insulin icodec demonstrated non-inferior A1C reduction compared to daily basal insulins, with a safety profile broadly consistent with the insulin class.
Hypoglycemia: The Primary Concern
Hypoglycemia (low blood sugar) is the most clinically significant side effect of any insulin therapy. The ONWARDS trials showed a nuanced picture:
- ONWARDS 1: Rates of clinically significant hypoglycemia (blood glucose <54 mg/dL) were slightly higher with icodec vs. glargine U-100 — 0.30 vs. 0.16 events per patient-year of exposure. The difference was statistically significant but clinically modest.
- ONWARDS 2: Hypoglycemia rates were comparable between icodec and degludec (Tresiba), suggesting the difference in ONWARDS 1 may reflect the comparator rather than an inherent icodec risk.
- ONWARDS 3: Patients switching from daily basal insulin to icodec showed no significant increase in hypoglycemia during or after the transition period.
The slightly elevated hypoglycemia rate in some trials is likely related to icodec's long 7-day half-life. Unlike daily insulins, which can be adjusted day-to-day, icodec's effects persist for roughly a week after each dose. This means dose adjustments take longer to fully take effect, and overcorrection carries risk over a longer window. Patients and providers should approach dose titration carefully, especially during the initial weeks.
Side Effects Comparison: Awiqli vs. Daily Insulin
| Side Effect | Awiqli (Insulin Icodec) | Lantus (Glargine U-100) | Tresiba (Degludec) |
|---|---|---|---|
| Clinically Significant Hypoglycemia | 0.30 events/patient-year | 0.16 events/patient-year | ~0.25 events/patient-year |
| Severe Hypoglycemia | Rare (<1%) | Rare (<1%) | Rare (<1%) |
| Weight Change | +1.5 to +2.5 kg | +1.0 to +2.0 kg | +1.0 to +2.0 kg |
| Injection Site Reactions | Uncommon (52 injections/yr) | Uncommon (365 injections/yr) | Uncommon (365 injections/yr) |
| Nausea | Not typical | Not typical | Not typical |
| Allergic Reactions | Rare | Rare | Rare |
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Browse All Guides →Weight Changes
Insulin therapy is commonly associated with modest weight gain, and Awiqli is no exception. Across the ONWARDS trials, patients on icodec experienced an average weight gain of 1.5 to 2.5 kg over 26–78 weeks, which was comparable to or slightly higher than daily insulin comparators. The weight gain is attributed to insulin's anabolic effects and improved glycemic control reducing glucosuria (glucose lost in urine). Patients concerned about weight should discuss lifestyle modifications and the potential role of GLP-1 combination therapy with their provider.
Injection Site Reactions
Injection site reactions — redness, swelling, itching, or pain at the injection site — were uncommon in the ONWARDS trials and occurred at rates similar to daily insulins. A practical advantage of once-weekly dosing is that patients inject 52 times per year rather than 365, which dramatically reduces cumulative injection site exposure. This can be particularly beneficial for patients who develop lipodystrophy (changes in fat tissue) at frequently used injection sites — a common concern with daily insulin use over years.
Rare and Serious Risks
As with all insulins, rare but serious risks include:
- Severe hypoglycemia: Can cause loss of consciousness, seizures, or death. Occurred in <1% of trial participants. Patients should always carry fast-acting glucose.
- Hypokalemia: Insulin shifts potassium into cells. Patients on potassium-lowering medications (e.g., diuretics) should have electrolytes monitored.
- Allergic reactions: Generalized allergic reactions including anaphylaxis are extremely rare but possible with any insulin product.
- Fluid retention and heart failure: Insulin can cause sodium retention and edema, particularly when combined with thiazolidinediones (pioglitazone, rosiglitazone). Use caution in patients with congestive heart failure.
Drug Interactions
Awiqli shares the same drug interaction profile as other insulins. Medications that may increase hypoglycemia risk when combined with Awiqli include:
- Sulfonylureas (glipizide, glyburide, glimepiride)
- GLP-1 receptor agonists (when used for diabetes, not weight loss alone)
- ACE inhibitors and ARBs
- MAO inhibitors and salicylates at high doses
Medications that may reduce insulin effectiveness include corticosteroids, thyroid hormones, oral contraceptives, and certain antipsychotics. Dose adjustments may be needed when starting or stopping these medications.
Who Should NOT Take Awiqli
Awiqli is not approved for and should not be used in the following situations:
- Type 1 diabetes: Awiqli is approved only for type 2 diabetes. While ONWARDS 6 studied icodec in type 1 diabetes, the FDA did not grant approval for this indication due to higher hypoglycemia rates.
- Diabetic ketoacidosis (DKA): Awiqli is a basal insulin and is not appropriate for treating DKA, which requires rapid-acting insulin and intensive monitoring.
- Known hypersensitivity: Patients with a documented allergy to insulin icodec or any excipient in the Awiqli formulation.
- During episodes of hypoglycemia: Do not administer any insulin during active hypoglycemia.
Special Populations
- Elderly patients (≥65 years): No dose adjustment required, but more conservative titration is recommended due to higher hypoglycemia risk and potential for impaired counter-regulatory responses.
- Renal impairment: Insulin clearance may be reduced in patients with kidney disease, increasing hypoglycemia risk. More frequent blood glucose monitoring and careful dose titration are advised. Severe renal impairment (eGFR <15) warrants particularly close monitoring.
- Hepatic impairment: Liver disease can impair gluconeogenesis and reduce insulin clearance. Lower doses and closer monitoring may be necessary.
- Pregnancy and lactation: Insufficient data. Awiqli is not recommended during pregnancy; patients should switch to a daily insulin with established pregnancy safety data.
When to Call Your Doctor
Contact your healthcare provider immediately if you experience:
- Repeated episodes of blood glucose below 70 mg/dL
- Any episode of severe hypoglycemia (confusion, loss of consciousness, seizures)
- Signs of allergic reaction (rash, swelling, difficulty breathing)
- Unexplained swelling in legs or feet
- Persistent injection site changes (hard lumps, dimpling, or skin thickening)
- Blood glucose consistently above target despite proper dosing
The Bottom Line
Awiqli's side effect profile is broadly consistent with existing basal insulins, with the important caveat that its long half-life requires more thoughtful dose titration and a wider lens on hypoglycemia management. For most type 2 diabetes patients, the trade-off of slightly more careful monitoring in exchange for just 52 injections per year is well worth it. For a comprehensive look at how Awiqli compares to daily insulin clinically, see our Awiqli vs. daily insulin comparison. If you're considering the switch, our switching guide walks through the transition step by step.
Medical Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult your healthcare provider before starting, stopping, or changing any medication.