Insulin Degludec

Introduction Overview

Generic Name

insulin degludec

Brand Name

Tresiba

Dosage Form

injection, solution

Drug Class

Insulin

Pharmacokinetics

Absorption:
Insulin degludec (Tresiba) exhibits a protracted and ultra-long duration of action owing to its unique pharmacokinetic properties. After subcutaneous administration, insulin degludec forms soluble multihexamers in the subcutaneous tissue, creating an insulin depot that slowly and continuously releases monomers into the circulation. In patients with type 1 diabetes, following 8 days of once-daily dosing at 0.4 units/kg, maximum plasma concentrations (Cmax) of approximately 4472 pmol/L are attained at a median time (Tmax) of 9 hours. The onset of appearance post-injection is around one hour. Absorption is dose-proportional for doses ranging from 0.4 to 0.8 units/kg. Steady-state insulin concentrations are typically reached after 3 to 4 days of daily dosing.

Distribution:
Insulin degludec binds extensively (>99%) to serum albumin, a binding that is reversible and responsible in part for the prolonged duration of effect through systemic depot storage. The drug’s plasma protein binding is high and uniform with no clinically relevant displacement interactions with other protein-bound drugs. Insulin degludec’s volume of distribution is consistent with extracellular fluid distribution. Pharmacokinetic studies demonstrate no significant differences in distribution between genders or across ethnicities.

Metabolism:
Insulin degludec is metabolized similarly to endogenous human insulin. Following absorption, it is degraded enzymatically to inactive metabolites in liver, kidney, and muscle tissues via proteolytic cleavage. The structural modifications (omission of B30 threonine and addition of hexadecanedioyl-γ-glutamic acid side-chain) do not alter its metabolic pathway but impart the protracted pharmacokinetic profile.

Elimination:
The elimination half-life of insulin degludec after subcutaneous administration is approximately 25 hours at steady state, independent of dose, contributing to its ultra-long activity duration exceeding 42 hours. Clearance is approximately 0.03 L/kg/h (or 2.1 L/h in a 70 kg patient) following a 0.4 units/kg single SC dose. The rate-limiting step for elimination is absorption from the subcutaneous depot rather than metabolic degradation or renal clearance. Hepatic or renal impairment does not significantly affect pharmacokinetics, although clinical monitoring and dose adjustments are advised.

Specific Populations:
Pharmacokinetics are consistent across pediatric (1 year and older), adult, and geriatric populations. Body weight influences clearance, with higher body weight associated with increased clearance; however, exposure is generally dose-proportional after adjustment for weight. No significant clinically relevant pharmacokinetic differences have been observed based on gender, renal or hepatic impairment, or ethnic background.

Dosage Forms

Available Dosage Forms:
Tresiba is formulated as a sterile, aqueous, clear, and colorless solution for subcutaneous injection available in two concentrations: 100 units/mL (U-100) and 200 units/mL (U-200). Specific dosage presentations include:
- 100 units/mL (U-100): 3 mL single-patient-use FlexTouch® prefilled pen delivering doses in 1 unit increments, maximum 80 units per injection.
- 100 units/mL (U-100): 10 mL multiple-dose vial intended for use with U-100 insulin syringes.
- 200 units/mL (U-200): 3 mL single-patient-use FlexTouch® prefilled pen delivering doses in 2 unit increments, maximum 160 units per injection.

Dosages for Adults and Adolescents:
- In adults, Tresiba is administered once daily subcutaneously at any time of day.
- Dose titration is individualized based on type of diabetes, blood glucose monitoring, and glycemic targets; adjustments in dose usually made every 3 to 4 days.
- Initial doses for insulin-naïve patients with type 2 diabetes generally start at 10 units once daily.
- In type 1 diabetes adults, Tresiba dose is typically one-third to one-half of total daily insulin dose, with remaining basal and bolus insulin doses divided accordingly.

Specific Patient Populations:
- Pediatric use established for patients aged 1 year and older. Pediatric patients should be dosed once daily at the same time each day.
- For pediatric patients requiring less than 5 units daily, the U-100 vial formulation is recommended due to dose precision.
- Geriatric patients require cautious dosing, with conservative titration to reduce hypoglycemia risk.
- No dose adjustments are specifically required based on renal or hepatic impairment, but closer monitoring is advised.
- Dose adjustments should be considered with changes in physical activity, meal patterns, or concomitant medications.

Mechanism Of Action

Insulin degludec, the active ingredient in Tresiba, is a long-acting basal insulin analog designed to regulate glucose metabolism by mimicking endogenous insulin's physiological effects. On molecular level, it binds to insulin receptors on target cells, primarily skeletal muscle and adipocytes, promoting glucose uptake by facilitating translocation of glucose transporter type 4 (GLUT4) to the cell membrane. This enhances peripheral utilization of glucose and storage as glycogen.

The ultra-long pharmacodynamic profile of insulin degludec is achieved through structural modification from human insulin: deletion of the ThrB30 residue and conjugation of a fatty acid moiety (hexadecanedioyl-glutamic acid) to LysB29. Upon subcutaneous injection, this modification promotes multi-hexamer formation, creating a subcutaneous depot that releases insulin monomers slowly and steadily over an extended period, resulting in a flat and stable insulin action profile with a duration exceeding 42 hours.

Insulin degludec also inhibits hepatic glucose production by suppressing gluconeogenesis and glycogenolysis in liver cells, contributing further to lowering fasting plasma glucose. Additionally, insulin suppresses lipolysis and proteolysis, and promotes protein synthesis, supporting an anabolic metabolic state.

Compared to other long-acting insulins such as insulin glargine and insulin detemir, insulin degludec exhibits lower within-subject variability and greater flexibility in dosing time without compromising efficacy or safety. Clinical evidence demonstrates that Tresiba achieves similar or superior glycemic control with a reduced risk of hypoglycemia, particularly nocturnal hypoglycemia, due to its stable pharmacokinetic and pharmacodynamic properties.

Collectively, insulin degludec’s mechanism allows sustained basal insulin coverage with minimal peak effects, providing consistent blood glucose management and enhanced patient convenience through flexible dosing schedules.

Pharmacological Actions

Ultra-long-acting basal insulin analog providing steady insulin release over 42+ hours.
Stimulates peripheral glucose uptake in skeletal muscle and adipocytes via GLUT4 translocation.
Suppresses hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
Inhibits lipolysis and proteolysis, promoting anabolic metabolic effects.
Forms multihexamer complexes after subcutaneous injection to provide prolonged absorption.
Binds extensively (>99%) to serum albumin in circulation, contributing to prolonged half-life.
Facilitates protein synthesis and fat storage enhancing metabolic homeostasis.
Lower within-subject variability in glucose lowering effect compared to other basal insulins.
Provides glycemic control with reduced risk of hypoglycemia, especially nocturnal episodes.
Allows once-daily flexible dosing supporting improved adherence and patient convenience.
Demonstrates linear, dose-proportional pharmacokinetics across therapeutic dosing range.
Effective in pediatric, adult, and geriatric patients with dose individualization.

Therapeutic Or Clinical Uses

Basal insulin therapy to improve glycemic control in patients with type 1 diabetes mellitus aged 1 year and older.
Basal insulin therapy for glycemic management in adults with type 2 diabetes mellitus.
Used in combination with mealtime rapid-acting insulin analogs in type 1 diabetes.
Adjunct to oral antidiabetic agents in insulin-naïve or previously treated type 2 diabetic patients.
Provides flexibility in dosing time without compromising glycemic control.
To achieve targeted HbA1c reduction and fasting plasma glucose control.
Management of diabetes mellitus requiring basal insulin supplementation.
Alternative basal insulin for patients with prior insulin therapy with intermediate or long-acting insulins.
Potential to reduce incidence of hypoglycemia, especially nocturnal hypoglycemia.
Applicable for pediatric patients 1 year and older requiring basal insulin therapy.
Integration in comprehensive diabetes care plans with individualized dose titration.
To maintain steady-state insulin levels minimizing glycemic excursions.
Preferred option for patients desiring flexible basal insulin administration schedules.
Can be part of regimen in patients with renal or hepatic impairments with cautious monitoring.

Side Or Adverse Effects

Hypoglycemia, including severe episodes requiring assistance, is the most common adverse reaction.
Injection site reactions such as hematoma, pain, erythema, swelling, nodules, pruritus, and discoloration.
Localized lipodystrophy including lipohypertrophy and lipoatrophy at injection sites.
Allergic reactions ranging from mild hypersensitivity to severe anaphylaxis.
Weight gain due to anabolic effects of insulin therapy.
Peripheral edema possibly linked to sodium retention.
Localized cutaneous amyloidosis at repeated injection sites.
Nasopharyngitis and upper respiratory tract infections reported in clinical trials.
Occasional headaches and sinusitis reported with insulin degludec use.
Gastroenteritis and diarrhea in some patients during clinical studies.
Hypokalemia as a result of insulin-induced potassium shift into cells.
Rare events of skin rash and pruritus noted in some patients.
Potential for injection site amyloidosis leading to altered insulin absorption.
Infrequent reports of severe systemic allergic reactions including angioedema, bronchospasm.
Possibility of fluctuations in blood glucose leading to hyperglycemia if dosing is inconsistent.

Precautions

Do not use during episodes of hypoglycemia.
Rotate injection sites within the same region to reduce risk of lipodystrophy and cutaneous amyloidosis.
Closely monitor blood glucose during insulin regimen changes to avoid hyper- or hypoglycemia.
Avoid intravenous administration or use in insulin infusion pumps.
Do not dilute or mix Tresiba with any other insulin or solution.
Use caution and individualized dose titration in patients with renal or hepatic impairment.
Advise patients with visual impairment on proper device usage.
Monitor potassium levels in patients at risk of hypokalemia, especially if on medications influencing potassium.
Exercise caution when combined with thiazolidinediones due to risk of fluid retention and heart failure.
Educate patients about symptoms and management of hypoglycemia.
Ensure patients understand not to share insulin pens, needles, or syringes to prevent infections.
In patients with reduced hypoglycemia awareness, increase glucose monitoring frequency.
Avoid syringe removal of insulin from FlexTouch pen to prevent dosing errors.
Adjust dose cautiously in the elderly due to increased hypoglycemia risk.
Changes in physical activity, diet, or concomitant medications may require dosage adjustments.

Warnings

Never share Tresiba FlexTouch pens, needles, or insulin syringes between patients to prevent transmission of blood-borne pathogens.
Hypoglycemia may be life-threatening; monitor frequently, especially after dose changes or in patients with renal or hepatic impairment.
Medication errors including accidental mix-ups between insulin products can lead to hypoglycemia or hyperglycemia.
Do not administer Tresiba intravenously or via insulin pump.
Severe hypersensitivity reactions including anaphylaxis have been reported; discontinue therapy immediately if suspected.
Risk of fluid retention and heart failure when combined with thiazolidinediones (TZDs); monitor for signs of heart failure.
Do not use during episodes of hypoglycemia.
Instruct patients to inspect insulin for particulate matter or discoloration before use; only clear and colorless solution should be used.
Sudden changes in injection site can precipitate hypoglycemia.
Hypoglycemia symptoms may be masked by concomitant medications such as beta-blockers.
Educate patients on proper administration techniques and dose selection to avoid overdose.
Advise patients to inform healthcare providers about all concomitant medications to manage interactions affecting glucose control.
Closely supervise dose conversions from other insulin types to Tresiba to minimize hypoglycemia risk.
Hypokalemia may be life-threatening; monitor and treat as necessary.
Hypoglycemia due to medication errors may require urgent intervention including glucose or glucagon administration.

Contraindication

During episodes of hypoglycemia.
Hypersensitivity to insulin degludec or any excipients in Tresiba.
Do not use if insulin appears cloudy, discolored, or contains particles.
Contraindicated to be administered intravenously or by insulin infusion pump.
Use is contraindicated if patient exhibits signs of severe allergic reaction to insulin degludec.
Do not share insulin pens or syringes with other individuals due to infection risk.

Drug Interactions

Antidiabetic agents (e.g., sulfonylureas, metformin): May increase hypoglycemia risk; dose adjustments necessary.
ACE inhibitors and angiotensin II receptor blockers: Potential to enhance hypoglycemic effect.
Beta-blockers, clonidine, guanethidine, and reserpine: May blunt symptoms of hypoglycemia making recognition difficult.
Corticosteroids, atypical antipsychotics (e.g., olanzapine), estrogen, thyroid hormones: May reduce insulin effectiveness requiring dose increases.
Disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, and pentoxifylline: May potentiate hypoglycemic effects.
Pramlintide, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics: May increase risk of hypoglycemia.
DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors: Require glucose monitoring and possible insulin dose adjustments.
Diuretics, danazol, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens: May decrease insulin’s glucose-lowering effects.
Alcohol: Can unpredictably potentiate or reduce hypoglycemic effects.
Sympathomimetic agents (e.g., albuterol, epinephrine): May decrease insulin action.
Lithium salts: May either increase or decrease blood glucose levels requiring dose adjustments.
Pentamidine: May cause initial hypoglycemia followed by hyperglycemia.

Preparations Of The Drug

TRESIBA U-100 FlexTouch pen: 3 mL single-patient-use prefilled pen, 100 units/mL concentration, delivers doses in 1 unit increments, max 80 units per injection, packaged 5 pens per carton.
TRESIBA U-100 multiple-dose vial: 10 mL vial, 100 units/mL concentration, for use with U-100 insulin syringes, single vial per package.
TRESIBA U-200 FlexTouch pen: 3 mL single-patient-use prefilled pen, 200 units/mL concentration, delivers doses in 2 unit increments, max 160 units per injection, packaged 3 pens per carton.
Inactive ingredients include glycerin, metacresol, phenol, zinc, water for injection, with pH adjusted by hydrochloric acid or sodium hydroxide.
Products are supplied in sealed cartons with patient instructions for use included.
Storage conditions: Unopened vials and pens should be refrigerated (2°C to 8°C), not frozen; in-use pens and vials can be stored at room temperature (up to 30°C) for up to 56 days.
Disposable pen needles recommended: NovoFine, NovoFine Plus, or NovoTwist disposable needles.
Packaging details include product NDC codes and lot-specific labeling for traceability.
Patient instructions emphasize single-patient use to prevent cross-contamination.
The product is manufactured by Novo Nordisk Inc., Plainsboro, NJ.