Also known as: Tresiba · NN1250
| Parameter | Value | Source |
|---|---|---|
| Elimination Half-Life (SC) | ~25 hours | FDA NDA 203314[1] |
| Onset of Action | ~1 hour | FDA NDA 203314[1] |
| Time to Peak (Tmax) | ~9 hours | FDA NDA 203314[1] |
| Duration of Action | >42 hours | Heise T et al. 2012[2] |
| Bioavailability (SC) | ~91% | FDA NDA 203314[1] |
| Plasma Protein Binding | >99% (albumin) | FDA NDA 203314[1] |
| Time to Steady State | ~3–4 days (2–3 doses) | FDA NDA 203314[1] |
| Accumulation at Steady State | ~3–4× single dose | FDA NDA 203314[1] |
| Full Clearance (5 × t½) | ~125 hours (~5 days) | Calculated |
| Route of Administration | Subcutaneous injection only | — |
| Dosing Interval Flexibility | 8–40 hours between doses | FDA NDA 203314[1] |
| Standard Dosing Frequency | Once daily | FDA NDA 203314[1] |
| Data Quality | Human RCT — FDA NDA 203314; Heise T et al. Diabetes Obes Metab 2012 | |
Insulin degludec (Tresiba) has a subcutaneous elimination half-life of approximately 25 hours in adults — more than 3-fold longer than insulin detemir and approximately twice as long as insulin glargine.[1] This half-life supports a duration of blood-glucose-lowering action exceeding 42 hours, making degludec the longest-acting commercially available insulin analog. The ultra-long action is achieved through a dual mechanism: multihexamer depot formation at the subcutaneous injection site, and high-affinity albumin binding (>99%) in the systemic circulation.[2]
FDA approved Tresiba (insulin degludec injection) under NDA 203314, first approved in September 2015. Degludec is approved for improving glycaemic control in adults and paediatric patients (≥1 year) with type 1 diabetes, and in adults with type 2 diabetes.[1]
The pharmacokinetics of insulin degludec were characterized using euglycaemic glucose clamp methodology, the gold standard for insulin PK/PD studies. Heise et al. (2012) used a 26-hour euglycaemic clamp in subjects with type 1 diabetes to establish the >42-hour duration of action and quantify the flat, peakless glucose infusion rate (GIR) profile that distinguishes degludec from shorter-acting basal insulins.[2] Population pharmacokinetic modeling across the BEGIN clinical programme confirmed the ~25-hour half-life estimate.[1]
Three pharmacokinetic layers explain the complete picture for insulin degludec:
Even the plasma half-life alone exceeds the dosing interval of 24 hours, which is why degludec accumulates ~3–4-fold at steady state. The duration of action exceeds the plasma half-life because the SC multihexamer depot provides a sustained release source that adds to the circulating albumin-bound reservoir.[1]
After a single subcutaneous dose, insulin degludec follows first-order elimination with a half-life of approximately 25 hours:
| Half-Lives Elapsed | Time After Dose | % Remaining in Plasma | Clinical Note |
|---|---|---|---|
| 1 | ~25 hours | 50% | Still within active blood-glucose-lowering window |
| 2 | ~50 hours (~2 days) | 25% | End of single-dose activity (>42 h clamp duration) |
| 3 | ~75 hours (~3 days) | 12.5% | Near steady-state accumulation level after daily dosing |
| 4 | ~100 hours (~4 days) | 6.25% | Approaching full washout after last dose |
| 5 (clinical clearance) | ~125 hours (~5 days) | ~3% | Pharmacologically negligible; full washout |
After a single SC injection, degludec is absorbed slowly due to multihexamer depot dissolution, reaching Tmax at approximately 9 hours. The peak-to-trough concentration ratio is very flat — the GIR-time profile shows minimal peak, making degludec the most peakless commercially available basal insulin. Blood-glucose-lowering activity persists beyond 42 hours after a single dose in euglycaemic clamp conditions.[2]
With once-daily dosing and a 25-hour half-life, degludec accumulates approximately 3–4-fold before reaching steady state after 2–3 doses (~3–4 days). At steady state, the trough concentration is the dominant feature — the peak is barely distinguishable, producing a nearly constant plasma level throughout the 24-hour dosing interval. This pharmacokinetic flat-lining is the mechanistic basis for the reduced nocturnal hypoglycaemia rates observed in the BEGIN clinical programme.[1]
With a >42-hour duration of action and 25-hour half-life, insulin degludec can maintain adequate basal coverage even with dosing intervals as short as 8 hours or as long as 40 hours between consecutive injections. The FDA labeling explicitly states that the injection time can be varied from day to day when once-daily dosing is used, within the 8–40-hour window. This flexibility is clinically meaningful — shift workers, travelers crossing time zones, and patients with unpredictable schedules can maintain basal insulin therapy without strict adherence to a fixed daily injection time.[1]
Due to the 25-hour half-life and long duration, a missed dose of insulin degludec has a more gradual impact on blood glucose than with shorter-acting basal insulins. At steady state, a single missed dose leaves enough residual circulating degludec to provide partial basal coverage for an additional 24–48 hours. However, hyperglycaemia will eventually develop, particularly in type 1 diabetes. The next dose should be administered as soon as the missed dose is remembered, ensuring at least 8 hours elapse before the subsequent scheduled dose.[1]
| Compound | Half-Life (SC) | Duration of Action | Dosing Interval Flexibility | Approval Status |
|---|---|---|---|---|
| Insulin Degludec (Tresiba) | ~25 h | >42 h | 8–40 h between doses | FDA-approved NDA 203314 |
| Insulin Glargine (Lantus/Toujeo) | ~12–18 h | ~20–24 h | Fixed once-daily timing | FDA-approved NDA 021081 |
| Insulin Detemir (Levemir) | ~5–7 h (dose-dep.) | 16–24 h | Fixed timing; BID often needed | FDA-approved NDA 021536 |
| NPH Insulin (Humulin N / Novolin N) | ~4–6 h | 12–18 h | Twice-daily required | FDA-approved |
| Route | Half-Life | Bioavailability | Tmax | Notes |
|---|---|---|---|---|
| Subcutaneous (abdomen, thigh, upper arm) | ~25 h | ~91% | ~9 h | Only approved route; rotate injection sites |
| Intramuscular | No published data | No published data | No published data | Not approved; multihexamer depot mechanism may be disrupted by IM delivery |
| Intravenous | No published data | 100% (definitional) | Minutes | Not appropriate for degludec; IV regular or rapid-acting insulin used in acute settings |
Insulin degludec is a prescription medication and is not included in standard SAMHSA-5 workplace drug panels or routine forensic toxicology screens. Detection requires specialized immunoassay or LC-MS/MS methodology.[1]
WADA prohibits insulin analogs in competition without therapeutic use exemption (TUE). Due to degludec's long half-life of ~25 hours, it is detectable in urine for longer than most other insulin analogs — estimated detection window approximately 24–48 hours after the last dose using specialized immunoassay or LC-MS/MS. Athletes with insulin-dependent diabetes should obtain a TUE and disclose their insulin regimen to their sporting body before competition.[3]
Insulin degludec (NN1250) is a recombinant human insulin analogue produced by deletion of the B30 threonine residue and attachment of a C16 hexadecandioic fatty acid via a γ-glutamic acid and two mini-PEG (OEG, 8-amino-3,6-dioxaoctanoic acid) spacers at the epsilon-amino group of B29-lysine.[1] This linker-fatty acid construct confers an ultra-long half-life through two cooperating mechanisms that act at sequential phases of pharmacokinetics:
Mechanism 1 — Multihexamer depot formation (SC absorption phase): After SC injection, the formulation contains zinc and phenol. Monomers self-associate into hexamers and then into extended chains of dihexamers (multimers) stabilized by fatty acid-fatty acid interactions between adjacent hexamers. These multihexamer chains form a soluble depot that precipitates as a viscous aggregate at the injection site. Dissociation of monomers from the chain end is extremely slow — releasing a continuous, low-rate flux of insulin monomers into the interstitial space over more than 24 hours. This creates the flat absorption profile and explains the Tmax of ~9 hours.[2]
Mechanism 2 — Albumin binding in the systemic circulation (elimination phase): Once monomers reach the bloodstream, the C16 fatty acid chain binds non-covalently to serum albumin with very high affinity — greater than 99% of circulating degludec is albumin-bound. Only the unbound fraction (<1%) can engage insulin receptors or be cleared by proteolysis. The extremely high albumin occupancy creates a massive circulating reservoir that sustains insulin activity over the 25-hour terminal half-life. The C16 chain with γGlu-OEG-OEG spacer has higher albumin affinity than detemir's simpler C14 chain, contributing to the substantially longer t½ (25 h vs 5–7 h for detemir).[1]
The combination of both mechanisms — slow SC release over hours plus slow systemic clearance via albumin binding — produces a half-life of ~25 hours and duration of action exceeding 42 hours. No other currently marketed insulin analog achieves both effects simultaneously to this degree.[2]
Log once-daily degludec doses and visualize the ~25-hour half-life curve, steady-state accumulation after 3–4 days, and the >42-hour action window. Model how flexible dosing timing affects your trough concentrations. On-device. No account required.
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