Drug Monograph
Tresiba (Insulin Degludec)
insulin degludec
Pharmacokinetic Profile
Half-Life
~25 h (steady state)
Protein Binding
>99% (albumin)
Bioavailability
Dose-proportional (SC); absolute F not reported
Volume of Distribution
Not separately characterized (>99% albumin-bound)
Tmax
9 h (median)
Metabolism
Similar to human insulin
Clinical Information
Drug Class
Ultra-long-acting basal insulin analog
Available Doses
U-100 (pen, vial); U-200 (pen)
Route
Subcutaneous only
Renal Adjustment
No PK change; monitor closely
Hepatic Adjustment
No PK change; monitor closely
Pregnancy
No identified risk (limited data)
Lactation
No human data; present in rat milk
Schedule
Prescription only (Rx)
Generic Available
No; unbranded biologic available (Novo Nordisk)
Therapeutic Index
Narrow
Indications for Insulin Degludec
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Type 1 diabetes mellitus | Adults and pediatric patients ≥1 year | Basal component of basal-bolus regimen (must use with rapid-acting mealtime insulin) | FDA Approved |
| Type 2 diabetes mellitus | Adults and pediatric patients ≥1 year | Monotherapy or adjunctive with oral antidiabetic agents, GLP-1 RAs, or mealtime insulin | FDA Approved |
Insulin degludec is an ultra-long-acting basal insulin analog that received initial FDA approval in September 2015 for glycemic control in patients with type 1 and type 2 diabetes aged one year and older. In type 1 diabetes, it must always be combined with a rapid-acting mealtime insulin, as it provides only basal coverage. In type 2 diabetes, it may be used alone or combined with oral agents, GLP-1 receptor agonists, or bolus insulin depending on disease severity. It is not recommended for the treatment of diabetic ketoacidosis (FDA PI).
Off-Label Uses
Gestational diabetes: Limited data from a randomized trial of 91 pregnant women with type 1 diabetes showed no clear increase in maternal or fetal risk. Used off-label in pregnancy when the clinician judges the benefit outweighs potential risk. Evidence quality: Low.
Flexible dosing schedules: Clinical trials have evaluated thrice-weekly dosing in patients who cannot adhere to daily injection schedules, demonstrating non-inferior HbA1c reduction compared with daily glargine, though with a marginally smaller decrease. Evidence quality: Moderate.
Dosing of Insulin Degludec
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| T2DM — insulin-naïve, basal-only initiation | 10 units SC once daily | Titrate individually | No fixed ceiling | Adjust q3–4 days to fasting glucose target Inject at any time of day; ensure ≥8 h between doses |
| T2DM — switching from another basal insulin | Same total daily basal unit dose | Titrate to target | No fixed ceiling | Unit-for-unit conversion from glargine or detemir Increased monitoring during first 1–2 weeks after switch |
| T2DM — basal-bolus regimen | Same total daily basal unit dose | Titrate basal independently of bolus | No fixed ceiling | Mealtime insulin continues separately Consider reducing bolus doses by 10–20% if switching from twice-daily basal |
| T1DM — insulin-naïve, new diagnosis | ⅓ to ½ of total daily insulin dose | Titrate to fasting glucose target | No fixed ceiling | Remainder as rapid-acting insulin divided across meals Must always use with mealtime insulin in T1DM |
| T1DM — switching from another basal insulin | Same total daily basal unit dose | Titrate to target | No fixed ceiling | Unit-for-unit from once-daily glargine If switching from twice-daily basal, reduce initial degludec dose by 20% |
| High-dose requirement (>80 units/day) | Use U-200 formulation | Titrate individually | 160 units per single injection (U-200 pen) | U-200 delivers in 2-unit increments No dose conversion needed between U-100 and U-200 pens; the dose window shows units |
Pediatric Dosing (≥1 Year)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| T1DM — new to insulin | ⅓ to ½ of total daily insulin dose | Titrate individually | No fixed ceiling | Inject at the same time every day Use U-100 vial if <5 units/day required |
| T1DM or T2DM — switching from another basal insulin | 80% of current total daily basal dose | Titrate to target | No fixed ceiling | 20% dose reduction to minimize hypoglycemia risk on switch Must give at the same time each day (unlike adults) |
Clinical Pearl: Dosing Flexibility in Adults
Unlike other basal insulins, insulin degludec allows flexible injection timing in adults — the dose may be given at any time of day as long as at least 8 hours separate consecutive injections. This flexibility, supported by its ultra-long half-life, is particularly advantageous for patients with shift work, travel schedules, or inconsistent routines. Note that this flexibility does NOT apply to pediatric patients, who should inject at the same time each day (FDA PI).
Pharmacology of Insulin Degludec
Mechanism of Action
Insulin degludec is a recombinant human insulin analog that differs from human insulin by deletion of threonine at position B30 and conjugation of a 16-carbon fatty diacid chain to lysine at position B29 via a gamma-glutamic acid linker. This acylation allows insulin degludec to self-associate into stable dihexamers upon injection into the subcutaneous space. These dihexamers form soluble multi-hexamer chains that create a slow-release depot. Zinc gradually dissociates, releasing insulin degludec monomers into the circulation at a constant rate over more than 42 hours. Once circulating, insulin degludec binds to the insulin receptor on skeletal muscle and adipose tissue, activating intracellular signaling cascades that stimulate glucose uptake, promote glycogen synthesis, and suppress hepatic glucose production — the same primary actions as endogenous human insulin. Its extremely flat and stable pharmacodynamic profile provides nearly peakless basal insulin coverage with four-fold lower day-to-day variability compared with insulin glargine U-100.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Onset ~1 h; Tmax ~9 h (median); dose-proportional exposure (absolute bioavailability not separately reported); steady state in 3–4 days | Slow, continuous absorption from SC multi-hexamer depot; full therapeutic effect not reached until day 3–4 of dosing |
| Distribution | Protein binding >99% (albumin); circulates primarily bound in blood | Albumin binding prolongs residence time; no clinically relevant displacement interactions with other protein-bound drugs |
| Metabolism | Degraded similarly to human insulin; all metabolites inactive | No CYP-mediated metabolism; no hepatic drug-drug interactions via enzyme pathways |
| Elimination | t½ ~25 h (steady state, dose-independent); CL ~0.03 L/kg (2.1 L/h in 70 kg); duration of action >42 h | Ultra-long half-life supports once-daily dosing at any time of day; residual activity persists for >42 h, allowing flexible dosing intervals |
Side Effects of Insulin Degludec
≥10%
Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nasopharyngitis | 23.9% | Most common non-hypoglycemic adverse event across clinical trials; not dose-related |
| Upper respiratory tract infection | 11.9% | Comparable to rates observed with insulin glargine in head-to-head trials |
| Headache | 11.3% | Generally transient; similar frequency to comparator insulins |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site reactions | 3–5% | Includes redness, swelling, itching at injection site; mitigated by rotating sites |
| Peripheral edema | ~5% | Insulin-mediated sodium retention; usually mild and self-limiting |
| Weight gain | ~3–5% | Typical of insulin therapy; generally 1–2 kg over 26–52 weeks in trials |
| Lipodystrophy | 1–2% | Lipohypertrophy or lipoatrophy at injection sites; rotation of sites is preventive |
| Pruritus | 1–3% | May be localized or generalized; usually mild |
| Rash | 1–2% | Consider allergy evaluation if persistent or worsening |
Serious
Serious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hypoglycemia | 0–4.5% of T2DM patients; higher in T1DM (variable by regimen) | Any time; peak risk 10–16 h post-dose | Immediate oral glucose or glucagon; assess for precipitating factors; adjust dose |
| Anaphylaxis / severe allergic reaction | Rare | Minutes to hours after injection | Emergency treatment; permanent discontinuation of insulin degludec |
| Hypokalemia | Uncommon | Hours after large doses or in combination with potassium-lowering drugs | Monitor potassium in at-risk patients; supplement if needed |
| Heart failure exacerbation (with TZDs) | Uncommon | Weeks to months | Monitor for fluid retention; reduce or stop TZD if signs develop |
| Localized cutaneous amyloidosis | Rare (post-marketing) | Months to years with repeated injections at same site | Switch injection site; do not inject into affected areas |
Discontinuation
Discontinuation Rates
Adults (T1DM + T2DM pooled)
3.7 events/100 PYE vs 4.0 events/100 PYE glargine
Top reasons: Adverse events, hyperglycemia, patient preference
DEVOTE Trial (T2DM, high CV risk)
Similar to glargine no significant difference
Top reasons: Adverse events, investigator decision
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Adverse events (any) | ~3.7% | Comparable to insulin glargine in BEGIN and DEVOTE programs |
| Hypoglycemia | <1% | Severe hypoglycemia rarely leads to permanent discontinuation |
| Injection site reactions | <1% | Typically mild; seldom necessitates stopping therapy |
Managing Hypoglycemia
Hypoglycemia is the most clinically important adverse effect of all insulins including insulin degludec. Because of its ultra-long half-life, recovery from hypoglycemia may be delayed compared with shorter-acting insulins. The DEVOTE trial demonstrated that insulin degludec was associated with significantly lower rates of severe hypoglycemia compared with insulin glargine U-100 in patients with type 2 diabetes at high cardiovascular risk (rate ratio 0.60; p < 0.001). Nocturnal hypoglycemia rates were also consistently lower across the BEGIN trial program, particularly during the maintenance phase.
Drug Interactions with Insulin Degludec
Insulin degludec is not metabolized by cytochrome P450 enzymes and does not clinically displace other protein-bound drugs despite its >99% albumin binding. Interactions are primarily pharmacodynamic, involving drugs that alter glucose metabolism or mask hypoglycemia symptoms.
Major
Beta-Blockers
MechanismBlunted adrenergic counter-regulation; impaired glycogenolysis
EffectMasking of hypoglycemic symptoms (tachycardia, tremor); may prolong hypoglycemia duration
ManagementIncreased blood glucose monitoring; educate patient on non-adrenergic hypoglycemia signs (sweating, hunger); consider cardioselective beta-blockers
FDA PI
Major
Thiazolidinediones (TZDs)
MechanismPPAR-gamma-mediated sodium and fluid retention; additive glucose lowering
EffectIncreased risk of peripheral edema and congestive heart failure; amplified hypoglycemia risk
ManagementMonitor for heart failure symptoms; reduce or discontinue TZD if edema or dyspnea develops
FDA PI
Moderate
GLP-1 Receptor Agonists
MechanismAdditive glucose-lowering via pharmacodynamic synergism
EffectIncreased hypoglycemia risk when combined with insulin
ManagementReduce insulin degludec dose by 10–20% when initiating GLP-1 RA; intensify monitoring
FDA PI / Medscape
Moderate
Corticosteroids (systemic)
MechanismGlucocorticoid-induced insulin resistance and hepatic gluconeogenesis
EffectHyperglycemia; insulin requirements may increase substantially
ManagementAnticipatory insulin dose increase when starting steroids; frequent glucose monitoring; taper insulin when steroids are discontinued
FDA PI
Moderate
Alcohol
MechanismInhibition of hepatic gluconeogenesis; unpredictable glycemic effects
EffectIncreased or decreased blood glucose; risk of severe hypoglycemia especially with heavy intake
ManagementAdvise moderate consumption with food; never drink on an empty stomach; increased monitoring
FDA PI / Medscape
Moderate
ACE Inhibitors / ARBs
MechanismIncreased insulin sensitivity via improved peripheral glucose uptake
EffectModestly increased hypoglycemia risk
ManagementMonitor blood glucose when initiating or titrating ACEI/ARB; adjust insulin if needed
FDA PI
Moderate
Atypical Antipsychotics
MechanismDrug-induced insulin resistance and metabolic syndrome
EffectHyperglycemia; increased insulin dose requirements
ManagementIncreased frequency of glucose monitoring; consider insulin dose adjustment
Medscape
Minor
Clonidine / Reserpine
MechanismCentral sympatholytic action
EffectMay reduce or eliminate adrenergic warning symptoms of hypoglycemia
ManagementEducate patient on neuroglycopenic symptoms; consider more frequent self-monitoring
FDA PIMonitoring for Insulin Degludec
-
Blood Glucose
Daily (fasting) during titration; per ADA targets at maintenance
Routine Fasting blood glucose is the primary titration target. Increase monitoring frequency during illness, dose changes, or regimen switches. CGM is recommended when available, particularly in T1DM. -
HbA1c
Every 3 months until stable, then every 6 months
Routine Individualized glycemic targets per ADA/EASD 2025 Standards of Care. Consider more frequent testing if regimen changes are made. -
Potassium
Baseline; periodically in at-risk patients
Trigger-based All insulins drive potassium intracellularly. Check potassium in patients on diuretics, digoxin, or other potassium-lowering agents. Especially important with high insulin doses. -
Renal Function
Baseline, then annually (or per ADA)
Routine No pharmacokinetic change in renal impairment including ESRD, but glucose counter-regulation may be blunted. Insulin requirements often decrease in advancing CKD; dose reduction may be needed. -
Hepatic Function
Baseline; as clinically indicated
Trigger-based No pharmacokinetic change in hepatic impairment, but hepatic gluconeogenesis capacity may be diminished, increasing hypoglycemia risk. Monitor glucose more closely. -
Injection Sites
Every visit
Routine Inspect for lipodystrophy and localized cutaneous amyloidosis. Repeated injections into affected areas alter insulin absorption, causing erratic glucose control. -
Weight
Every visit
Routine Insulin therapy can promote weight gain. Track trends and reinforce lifestyle counseling, particularly in T2DM patients. -
Hypoglycemia Episodes
Every visit; patient diary or CGM data review
Routine Assess frequency, severity, and timing (especially nocturnal events). Evaluate for hypoglycemia unawareness. Recovery from insulin degludec-induced hypoglycemia may be prolonged due to its long duration of action.
Contraindications & Cautions for Insulin Degludec
Absolute Contraindications
- During episodes of hypoglycemia — do not administer insulin degludec while blood glucose is below normal range.
- Hypersensitivity to insulin degludec or any excipient (glycerin, metacresol, phenol, zinc) — severe life-threatening generalized allergy including anaphylaxis has been reported.
Relative Contraindications (Specialist Input Recommended)
- Hypoglycemia unawareness — patients who cannot recognize early warning signs require intensified monitoring (CGM strongly recommended) and may need higher glucose targets, making any insulin selection a specialist decision.
- Diabetic ketoacidosis (DKA) — insulin degludec is not recommended for treatment of DKA. Rapid-acting IV insulin is the standard of care for acute DKA management.
- Significant heart failure (NYHA Class III–IV) when combined with TZDs — the combination increases fluid retention risk, and concomitant use in advanced heart failure requires careful risk-benefit assessment.
Use with Caution
- Renal impairment (including ESRD) — no pharmacokinetic change, but insulin requirements frequently decrease. Increased glucose monitoring is essential.
- Hepatic impairment — reduced gluconeogenic reserve may amplify hypoglycemia risk. Increase monitoring frequency.
- Elderly patients (≥65 years) — greater between-subject pharmacokinetic variability has been observed. Careful titration and avoidance of aggressive glucose targets are recommended (ADA 2025).
- Visual impairment — patients relying on audible clicks for dose selection should use FlexTouch pens with caution.
- Switching from twice-daily basal insulin — risk of hypoglycemia during transition. Reduce initial dose by approximately 20% and monitor closely.
FDA Class-Wide Regulatory Warning
Insulin Medication Errors and Never Share Pens
Accidental mix-ups between insulin products have caused medication errors. Patients must always verify the insulin label before each injection. Do NOT transfer insulin degludec from the FlexTouch pen into a syringe, as overdosage and severe hypoglycemia can result due to concentration differences. Never share a FlexTouch pen, insulin syringe, or needle between patients, even if the needle is changed, due to the risk of transmitting blood-borne pathogens (FDA PI).
Patient Counselling for Insulin Degludec
Purpose of Therapy
Insulin degludec is a long-acting basal insulin that works in the background throughout the day and night to help control blood sugar levels between meals and overnight. In type 1 diabetes, it is always used together with a rapid-acting mealtime insulin. In type 2 diabetes, it may be used alone or alongside other diabetes medications. It does not replace the need for a healthy diet, regular physical activity, and ongoing blood glucose monitoring.
How to Take
Inject insulin degludec once daily under the skin of the thigh, upper arm, or abdomen. Rotate the injection site with each dose to prevent skin changes. Adults may inject at any time of day, but there must be at least 8 hours between injections. Children should inject at the same time each day. Never mix insulin degludec with other insulins, and never transfer it from a FlexTouch pen into a syringe. Store unopened pens and vials in the refrigerator; once in use, store at room temperature (below 30°C / 86°F) for up to 56 days.
Hypoglycemia (Low Blood Sugar)
Tell patient
Know the symptoms of low blood sugar: shakiness, sweating, confusion, fast heartbeat, dizziness, hunger, and blurred vision. Always carry a fast-acting sugar source (glucose tablets, juice). Because insulin degludec works for a very long time, recovery from a low blood sugar episode may take longer than with other insulins.
Call prescriber
If you experience a severe low blood sugar episode requiring help from another person, if you lose consciousness, or if low blood sugar episodes are happening frequently or worsening.
Injection Technique & Site Rotation
Tell patient
Rotate your injection site within the same body region each time. Do not inject into lumps, hard spots, or pitted areas. Never reuse needles. The solution should appear clear and colorless; do not use if it looks cloudy, thickened, or discolored.
Call prescriber
If you notice lumps, indentations, or thickened skin at injection sites, as these changes can affect how your insulin is absorbed.
Missed Dose
Tell patient
If you miss a dose, take it as soon as you remember during waking hours, ensuring at least 8 hours have passed since your last injection. Then return to your usual once-daily schedule. Do not take two doses at the same time to make up for a missed dose. For children, contact your prescriber for guidance on missed doses.
Call prescriber
If you miss more than one dose or are unsure how to get back on schedule.
Pen Safety & Sharing
Tell patient
Never share your FlexTouch pen, needles, or syringes with another person, even if the needle is changed. Sharing can spread serious blood-borne infections. Always check the insulin label before injecting to confirm you are using the correct product. Do not transfer from the pen to a syringe.
Call prescriber
If you suspect you injected the wrong insulin product or the wrong dose.
Allergic Reactions
Tell patient
Seek emergency help immediately if you develop a whole-body rash, difficulty breathing, swelling of the face or throat, or rapid heartbeat after injection. These may indicate a severe allergic reaction.
Call prescriber
For any skin rash, itching, or swelling at the injection site that does not resolve within a few days.
Driving & Machinery
Tell patient
Low blood sugar can impair concentration and reaction time. Do not drive or operate heavy machinery until you know how insulin degludec affects your blood sugar levels. Always check blood glucose before driving and keep a fast-acting sugar source accessible in your vehicle.
Call prescriber
If you have had a hypoglycemic episode while driving or if you are experiencing frequent low blood sugar that affects your ability to drive safely.
Sources
Regulatory (PI / SmPC)
- Novo Nordisk. Tresiba (insulin degludec) injection, for subcutaneous use. Full Prescribing Information. Plainsboro, NJ; Revised July 2022. FDA Label (PDF) Primary regulatory reference for all dosing, indications, contraindications, adverse effects, and pharmacokinetic data in this monograph.
- Novo Nordisk. Insulin Degludec injection prescribing information. DailyMed/NLM. Updated 2024. DailyMed Label NLM-hosted version of the most current labeling including administration instructions and patient information.
Key Clinical Trials
- Marso SP, McGuire DK, Zinman B, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes (DEVOTE). N Engl J Med. 2017;377:723-732. doi:10.1056/NEJMoa1615692 Landmark cardiovascular outcomes trial (n=7637) demonstrating cardiovascular safety and significantly lower severe hypoglycemia rates with insulin degludec vs glargine U-100.
- Wysham C, Bhargava A, Chaykin L, et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA. 2017;318(1):45-56. doi:10.1001/jama.2017.7117 Double-blind crossover trial in T2DM patients at high hypoglycemia risk, showing lower rates of overall symptomatic and nocturnal hypoglycemia with degludec.
- Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2). Lancet. 2012;379:1498-1507. doi:10.1016/S0140-6736(12)60205-0 Pivotal phase 3 non-inferiority trial establishing equivalent HbA1c reduction with lower nocturnal hypoglycemia in a basal-bolus T2DM regimen.
- Thalange N, Deeb L, Iotova V, et al. Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2015;16:164-176. doi:10.1111/pedi.12263 Pediatric trial supporting the safety and efficacy of insulin degludec in children ≥1 year with type 1 diabetes.
Guidelines
- American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025. Diabetes Care. 2025;48(Suppl 1):S181-S206. doi:10.2337/dc25-S009 Current ADA guidelines for basal insulin selection and titration, including positioning of ultra-long-acting insulin analogs.
- Samson SL, Vellanki P, Blonde L, et al. American Association of Clinical Endocrinology Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm—2023 Update. Endocr Pract. 2023;29(5):305-340. doi:10.1016/j.eprac.2023.02.001 AACE treatment algorithm positioning insulin degludec among preferred basal insulins for patients requiring injectable therapy.
Mechanistic / Basic Science
- Steensgaard DB, Schluckebier G, Strauss HM, et al. Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec. Biochemistry. 2013;52:295-309. doi:10.1021/bi3008609 Foundational structural biology study elucidating the unique multi-hexamer depot formation mechanism that underlies degludec’s ultra-long pharmacokinetic profile.
- Jonassen I, Havelund S, Hoeg-Jensen T, et al. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29:2104-2114. doi:10.1007/s11095-012-0739-z Describes the fatty-diacid acylation chemistry and the rationale for the B29 lysine linkage enabling albumin binding and depot formation.
Pharmacokinetics / Special Populations
- Haahr H, Heise T. A Review of the Pharmacological Properties of Insulin Degludec and Their Clinical Relevance. Clin Pharmacokinet. 2014;53:787-800. doi:10.1007/s40262-014-0165-y Comprehensive pharmacokinetic and pharmacodynamic review establishing the >25 h half-life, flat steady-state profile, and 4-fold lower day-to-day variability compared with glargine.
- Heise T, Nosek L, Bøttcher SG, et al. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14:944-950. doi:10.1111/j.1463-1326.2012.01638.x Euglycemic clamp study demonstrating peakless, evenly distributed glucose-lowering effect across a 24-h dosing interval in T2DM patients.
- Korsatko S, Deller S, Koehler G, et al. A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec. Clin Drug Investig. 2013;33:515-521. doi:10.1007/s40261-013-0096-7 Bioequivalence study confirming equivalent pharmacokinetic and pharmacodynamic profiles between U-100 and U-200 formulations at same unit/kg dose.