Insulin Degludec: A Comprehensive Monograph

Executive Summary

Insulin degludec is a second-generation, ultra-long-acting basal insulin analog developed and manufactured by Novo Nordisk. Marketed under the brand name Tresiba®, it is a cornerstone therapy for improving glycemic control in adult and pediatric patients (aged 1 year and older) with Type 1 and Type 2 diabetes mellitus.[1] Its development represents a significant evolution in insulin therapy, addressing the limitations of earlier long-acting analogs by offering a more stable and predictable glycemic profile.

The defining characteristic of insulin degludec is its novel protraction mechanism. Following subcutaneous injection, the drug is engineered to self-assemble into soluble, high-molecular-weight multi-hexamer chains. This assembly creates a depot from which active insulin monomers are slowly and continuously released into the circulation. The result is an exceptionally long duration of action, exceeding 42 hours, with a flat, peakless pharmacokinetic profile.[1] This mechanism is distinct from first-generation analogs like insulin glargine U100, which rely on microprecipitation in subcutaneous tissue.

The primary clinical advantage derived from this stable pharmacokinetic profile is a significantly reduced risk of hypoglycemia, particularly nocturnal hypoglycemia, when compared to first-generation basal insulins. This safety benefit has been consistently demonstrated across a robust clinical development program, including the pivotal BEGIN, SWITCH, and DEVOTE trials.[5] By mitigating the most feared adverse effect of insulin therapy, insulin degludec facilitates more confident dose titration, improves patient adherence, and offers greater dosing flexibility for adults. Its chemical stability at a neutral pH also permits co-formulation with other antidiabetic agents, such as the rapid-acting insulin aspart (Ryzodeg®) and the GLP-1 receptor agonist liraglutide (Xultophy®), offering simplified treatment regimens.[2]

Insulin degludec has secured global regulatory approval, including from the European Medicines Agency (EMA) in 2013 and the U.S. Food and Drug Administration (FDA) in 2015, and is included on the World Health Organization's List of Essential Medicines.[1] It has established a critical role in the modern diabetes treatment paradigm, shifting the therapeutic goal from merely achieving a long duration of action to optimizing the quality and safety of that duration.

Identification and Physicochemical Properties

Nomenclature and Identifiers

Insulin degludec is identified by a standardized set of names and codes used in chemical, pharmaceutical, and regulatory contexts.

• Generic Name: Insulin degludec [2]
• Brand Names: The standalone product is marketed globally as Tresiba®. It is also a component of two fixed-dose combination products: Ryzodeg®, which combines insulin degludec with the rapid-acting insulin aspart, and Xultophy®, which combines it with the GLP-1 receptor agonist liraglutide.[5]
• Chemical Name: The formal chemical name is 29B-[N6-[N-(15-carboxy-1-oxopentadecyl)-l-γ-glutamyl]-l-lysine]-(1A-21A) (1B-29B)-Insulin (human).[5] An alternative IUPAC name is B29N(ε)-ω-carboxypentadecanoyl-γ-L-glutamyl desB30 human insulin.[2]
• Key Identifiers: For unambiguous reference, the following identifiers are assigned:
• DrugBank ID: DB09564 [1]
• CAS Number: 844439-96-9.[1] A deprecated CAS number, 886983-20-6, is also noted in some databases.[1]
• FDA UNII: 54Q18076QB [1]
• ATC Code: A10AE06, classifying it as a long-acting insulin for injection.[2]

Molecular and Chemical Properties

Insulin degludec is a biologic drug, specifically a modified protein therapeutic.

• Drug Type: It is classified as a biotech product, a protein-based therapy, and an analog of human insulin.[1]
• Molecular Formula: C274H411N65O81S6 [4]
• Molecular Weight: The molecular weight is consistently reported as approximately 6104 Da.[4]
• Structural Modifications: Insulin degludec is produced via recombinant DNA technology in the yeast species Saccharomyces cerevisiae.[15] Its structure is derived from human insulin but features two critical, deliberate modifications that are fundamental to its unique pharmacokinetic properties:

1. Deletion: The terminal amino acid at position 30 of the B-chain, threonine (Thr-B30), is deleted. This is denoted by the term "desB30".[1]
2. Acylation: A fatty acid side-chain is covalently attached to the lysine residue at position B29 of the B-chain (Lys-B29). This side-chain consists of a C16 fatty diacid (hexadecanedioic acid) linked via a γ-L-glutamyl spacer.[1]

These specific chemical modifications are not arbitrary; they are the result of precise molecular engineering designed to confer the property of self-association upon subcutaneous injection. The deletion of Thr-B30 and the acylation at Lys-B29 are the lynchpins of its entire protraction mechanism. The fatty diacid side-chain provides a lipophilic "handle" that promotes intermolecular interactions once the stabilizing phenolic excipients diffuse away in the subcutaneous space. The glutamic acid spacer provides the appropriate spatial orientation and flexibility for these interactions to occur efficiently, leading to the formation of the multi-hexamer chains that define its mechanism of action.[4]

Physical and Formulation Properties

• Appearance: Insulin degludec is supplied as a sterile, clear, colorless, aqueous solution for subcutaneous injection.[3]
• Formulation: It is formulated to be soluble and stable at a neutral, physiologic pH. This is a key distinction from first-generation insulin glargine, which is formulated at an acidic pH and relies on precipitation upon injection into the neutral pH of subcutaneous tissue.[2] The formulation contains zinc, m-cresol, and phenol, which are essential for stabilizing the insulin in a di-hexameric state within the vial and pen. Upon injection, these excipients diffuse away, triggering the formation of the therapeutic depot.[4] This neutral pH stability is what enables its co-formulation with other neutral-pH stable molecules like insulin aspart and liraglutide, a significant clinical advantage not shared by insulin glargine.[2]
• Storage and Handling: Unopened vials and pens should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). Once in use, a vial or pen can be kept at room temperature (below 30°C or 86°F) or refrigerated for up to 56 days (8 weeks). This extended in-use stability is longer than that of many other insulin products and offers greater convenience for patients.[18]

Table 2.1: Summary of Physicochemical and Identification Data for Insulin Degludec
Parameter	Value / Description
Generic Name	Insulin degludec
Brand Names	Tresiba®, Ryzodeg®, Xultophy®
DrugBank ID	DB09564
CAS Number	844439-96-9
FDA UNII	54Q18076QB
ATC Code	A10AE06
Molecular Formula	C274​H411​N65​O81​S6​
Molecular Weight	~6104 Da
Drug Type	Biotech, Protein-Based Therapy, Insulin Analog
Structural Modifications	desB30 human insulin acylated at LysB29 with hexadecanedioic acid via a γ-L-glutamyl spacer

Molecular Pharmacology and Mechanism of Action

Primary Pharmacodynamic Effect: Insulin Receptor Agonism

Like endogenous human insulin, insulin degludec exerts its metabolic effects by acting as an agonist at the insulin receptor (INSR).[12] The INSR is a transmembrane heterotetrameric protein composed of two extracellular alpha subunits and two transmembrane beta subunits, located on the surface of primary target cells in the liver, adipose tissue, and skeletal muscle.[12]

The binding of an insulin degludec monomer to the alpha subunit of the INSR induces a conformational change that activates the intrinsic tyrosine kinase domain of the beta subunit. This activation leads to receptor autophosphorylation and the subsequent phosphorylation of a cascade of intracellular signaling molecules, most notably the Insulin Receptor Substrate (IRS) proteins (e.g., IRS-1, IRS-2).[12] Phosphorylation of IRS proteins creates docking sites for other signaling molecules, propagating the signal downstream, primarily through the PI3K/Akt pathway.[12] This signaling cascade culminates in the primary metabolic actions of insulin:

1. Stimulation of Glucose Uptake: In muscle and fat cells, the Akt pathway promotes the translocation of GLUT4 glucose transporters from intracellular vesicles to the plasma membrane, facilitating the uptake of glucose from the bloodstream.[1]
2. Regulation of Hepatic Glucose Metabolism: Insulin inhibits hepatic glucose production (gluconeogenesis) and promotes the conversion of glucose into its storage form, glycogen (glycogenesis).[1]
3. Anabolic Effects: Insulin inhibits the breakdown of fats (lipolysis) and proteins (proteolysis) while promoting protein synthesis through increased amino acid uptake.[1]

In vitro studies have demonstrated that insulin degludec binds to the human insulin receptor with high efficiency, showing an IC50​ value of 19.59 nM.[21] Its metabolites are inactive, confirming that the parent molecule is solely responsible for the observed pharmacologic activity.[12]

The Ultra-Long-Acting Profile: A Novel Protraction Mechanism

The defining feature of insulin degludec is its unique mechanism of protraction, which creates an ultra-long and stable duration of action. This process occurs entirely within the subcutaneous tissue post-injection.[4]

1. Formulation State: In the pharmaceutical preparation (vial or pen), insulin degludec is formulated at a neutral pH and exists as stable, soluble di-hexamers. These structures are held together by zinc ions and are further stabilized by the presence of phenolic excipients (phenol and m-cresol).[4]
2. Post-Injection Transformation: When injected into the subcutaneous space, the small phenolic molecules rapidly diffuse away from the di-hexamers into the surrounding tissue.[4]
3. Multi-Hexamers Formation: The loss of the stabilizing phenols triggers a conformational change that allows the fatty diacid side-chains on adjacent insulin molecules to interact. In the continued presence of zinc, this leads to the rapid self-assembly of the di-hexamers into extremely large, but still soluble, multi-hexameric chains. This process effectively creates a liquid depot of insulin at the injection site.[1]
4. Slow Monomer Dissociation: From this large subcutaneous depot, zinc ions begin to slowly dissociate from the multi-hexamer chains. This gradual loss of zinc leads to the slow and progressive disassembly of the chains, first into di-hexamers, then dimers, and finally into individual, biologically active insulin degludec monomers.[4]
5. Sustained Absorption: These monomers are then slowly and continuously absorbed from the subcutaneous tissue into the systemic circulation. It is this slow, rate-limiting step of monomer release from the depot that results in the flat, peakless, and exceptionally prolonged glucose-lowering effect of the drug.[1]

The Role of Albumin Binding

In addition to the primary depot mechanism, insulin degludec employs a secondary protraction strategy once in the systemic circulation. The C16 fatty diacid side-chain imparts a high affinity for serum albumin, leading to extensive plasma protein binding of over 99%.[1] This reversible binding to albumin serves as a circulating reservoir for the drug. It buffers fluctuations in the concentration of free insulin monomers, further smoothing the pharmacodynamic profile. This binding also slows the rate of diffusion into peripheral tissues and reduces the rate of clearance by both the kidneys and receptor-mediated pathways, contributing to the overall protracted action and low variability of insulin degludec.[4]

The combination of these two distinct but complementary mechanisms—a primary subcutaneous depot formation and a secondary circulatory albumin binding—creates a highly resilient and stable pharmacokinetic profile. A single mechanism of protraction can be subject to variability; for instance, the precipitation of insulin glargine can be influenced by local blood flow and tissue characteristics. Insulin degludec's dual-protraction system provides redundancy. Even if minor variations occur in the rate of absorption from the subcutaneous depot, the large fraction of albumin-bound drug in the bloodstream acts as a buffer, dampening these fluctuations. This "belt and suspenders" approach results in lower within-subject variability compared to insulins that rely on a single mechanism. This lower variability translates directly into a more predictable and stable glucose-lowering effect, particularly during the overnight period, which is the biological basis for its observed clinical advantage in reducing the risk of nocturnal hypoglycemia.[7]

Pharmacokinetic Profile (ADME)

The unique molecular structure and formulation of insulin degludec give rise to a distinct pharmacokinetic profile characterized by slow absorption, extensive distribution, and a very long half-life.

Absorption

• Onset and Duration: Following subcutaneous injection, the onset of action is approximately 30 to 90 minutes.[2] The glucose-lowering effect is profoundly prolonged, with a duration of action that extends beyond 42 hours after a single dose, significantly longer than first-generation basal insulins like insulin glargine and insulin detemir, which typically last 20-24 hours.[1]
• Peak and Trough: A hallmark of insulin degludec is its flat, "peakless" pharmacokinetic profile. The slow and continuous absorption from the multi-hexamer depot prevents the sharp peaks in plasma concentration seen with shorter-acting insulins. This results in a very low peak-to-trough ratio, which is fundamental to its stable and predictable glycemic effect over a 24-hour period.[1] The median time to maximum concentration ( Tmax​) after a single dose is approximately 9 hours.[12]
• Steady State: Due to its long half-life, steady-state plasma concentrations of insulin degludec are achieved after 3 to 4 days of consistent once-daily administration.[5]

Distribution

• Volume of Distribution: The apparent volume of distribution (Vd​) in adults is estimated to be approximately 13.9 L.[12]
• Plasma Protein Binding: As previously noted, insulin degludec is extensively bound to plasma proteins, with over 99% bound to serum albumin.[1] In vitro studies have confirmed that this binding is not subject to clinically relevant displacement interactions with other highly protein-bound drugs, ensuring its pharmacokinetic profile remains stable even when co-administered with such agents.[1]

Metabolism

The metabolic pathway of insulin degludec is analogous to that of human insulin. Degradation occurs primarily in the liver and kidneys through proteolytic cleavage.[12] All resulting metabolites are inactive, meaning the pharmacologic activity is attributable entirely to the parent compound.[12]

Elimination

• Half-Life: The terminal elimination half-life (T1/2​) at steady state is approximately 25 hours.[2] This half-life is independent of the dose administered. Critically, the long half-life is not a function of slow systemic clearance but is instead determined by the very slow rate of absorption from the subcutaneous depot, making absorption the rate-limiting step in its elimination.[5]
• Clearance: The mean apparent clearance after a single subcutaneous dose is approximately 0.03 L/kg.[12] Like other insulins, a substantial portion (30-80%) of the circulating drug is cleared by the kidneys.[12]

The combination of a 25-hour half-life and a duration of action exceeding 42 hours creates a unique pharmacokinetic "stacking" effect. When administered once daily, there is a significant overlap in the action profiles of consecutive doses. This overlap is what allows the drug to reach a stable steady-state concentration after 3-4 days, where the amount of insulin absorbed from the depot over a 24-hour period is approximately equal to the amount cleared from the body. This stable plateau is the foundation for its clinical dosing flexibility in adults. Shifting a single dose by several hours does not cause a clinically significant peak or trough in the overall insulin level, in contrast to an insulin with a duration closer to 24 hours, where a delayed dose could create a period of insufficient basal coverage.[2] This pharmacokinetic rationale directly supports the FDA-approved guidance for flexible dosing in adults.

Table 4.1: Key Pharmacokinetic Parameters of Insulin Degludec
Parameter	Value (Adults)
Onset of Action	30–90 minutes
Time to Steady State	3–4 days
Duration of Action	>42 hours
Terminal Half-Life (T1/2​)	~25 hours
Volume of Distribution (Vd​)	~13.9 L
Plasma Protein Binding	>99% (to albumin)

Clinical Application and Therapeutic Use

Approved Indications and Patient Populations

Insulin degludec is a long-acting human insulin analog indicated to improve glycemic control in patients with diabetes mellitus.[1]

• Approved Populations: Its use is approved for both adults and pediatric patients aged 1 year and older who have either Type 1 or Type 2 diabetes.[3]
• Limitations of Use: Insulin degludec is not recommended for the treatment of diabetic ketoacidosis (DKA). DKA is a medical emergency that requires the use of intravenous, short-acting insulins (e.g., regular insulin) for rapid correction of hyperglycemia and acidosis.[3]

Dosage Forms and Strengths

Insulin degludec is available as a clear, colorless solution for subcutaneous injection, provided in several formats to meet diverse patient needs [3]:

• Tresiba® FlexTouch® Prefilled Pen: This disposable pen injector is available in two concentrations:
• 100 units/mL (U-100)
• 200 units/mL (U-200)
• Tresiba® Multi-dose Vial: A 10 mL vial is available at a concentration of 100 units/mL (U-100) for use with conventional insulin syringes.

The U-100 and U-200 formulations are pharmacokinetically and pharmacodynamically bioequivalent. The dose counter on both the U-100 and U-200 FlexTouch® pens displays the number of insulin units to be delivered. Therefore, no dose conversion is necessary when switching a patient between the two concentrations.[3] The higher concentration U-200 pen allows for the delivery of larger doses in a smaller injection volume, which can improve comfort for patients requiring high doses of basal insulin.

Administration and Storage

• Administration Route: Insulin degludec must be administered by subcutaneous injection only. It should never be administered intravenously (IV) or intramuscularly (IM), nor should it be used in insulin infusion pumps.[5]
• Injection Sites: Recommended injection sites are the abdomen, thigh, or upper arm. To reduce the risk of local complications such as lipodystrophy (pitting or thickening of the skin) and localized cutaneous amyloidosis (lumps under the skin), patients must be instructed to rotate injection sites within the chosen area with each dose.[3]
• Storage: Proper storage is critical to maintain the drug's potency. Unopened pens and vials must be stored in a refrigerator (2°C to 8°C / 36°F to 46°F). Once a pen or vial is in use, it can be kept at room temperature (up to 30°C / 86°F) or refrigerated for a maximum of 56 days (8 weeks), after which it must be discarded.[18]

Dosing and Titration Strategies

Dosing of insulin degludec must be individualized based on the patient's type of diabetes, metabolic needs, blood glucose monitoring results, and glycemic control goals. To allow the drug to approach its steady-state concentration, dose increases should be made no more frequently than every 3 to 4 days.[5]

• Dosing Time:
• Adults: May administer their once-daily dose at any time of day, offering significant flexibility. However, a minimum of 8 hours must elapse between consecutive doses.[2]
• Pediatric Patients: Must administer their dose at the same time each day to ensure consistency.[3]
• Starting Dose for Insulin-Naïve Patients:
• Type 2 Diabetes: The recommended starting dose is 10 units injected subcutaneously once daily.[26]
• Type 1 Diabetes: The recommended starting dose of basal insulin is approximately one-third to one-half of the total daily insulin requirement. The total daily dose is typically calculated as 0.2 to 0.4 units/kg of body weight. The remainder of the total daily insulin dose should be administered as a rapid-acting (bolus) insulin divided among meals.[26]
• Switching from Other Insulin Therapies:
• Adults (Type 1 or 2): When switching from another long- or intermediate-acting insulin, the recommended starting dose of insulin degludec is the same as the total daily unit dose of the previous basal insulin (a 1:1 unit conversion).[30]
• Pediatric Patients (Type 1 or 2): To minimize the risk of hypoglycemia, the recommended starting dose of insulin degludec is 80% of the total daily unit dose of the previous long- or intermediate-acting insulin.[5]

The different dosing rules for adults (flexible timing) versus children (fixed timing) reflect a cautious, evidence-based regulatory approach. The flexibility for adults is supported by the drug's robust pharmacokinetic profile, which establishes a stable steady-state plateau. In contrast, pediatric patients exhibit greater metabolic variability and insulin sensitivity. Clinical trials in this population likely employed a fixed-time protocol to minimize variables and ensure safety, a practice that regulators carried into the final approved labeling.[3] The specific recommendation to start pediatric patients at 80% of their previous basal dose is not arbitrary; it suggests that clinical trial data showed that a direct 1:1 switch resulted in an unacceptable rate of hypoglycemia. This highlights the potency and stability of insulin degludec, which may be more pronounced than that of older, more variable insulins, thus necessitating a prophylactic dose reduction as a critical safety measure for this vulnerable population.

Combination Therapies

Insulin degludec can be used as a standalone basal insulin or as part of a comprehensive regimen in combination with other antidiabetic medications, including oral agents, GLP-1 receptor agonists, and rapid-acting (bolus) insulins.[6]

• Fixed-Dose Combinations: The unique neutral-pH stability of insulin degludec allows for its co-formulation with other agents, simplifying treatment regimens:
• Xultophy® 100/3.6: A once-daily injectable combining 100 units/mL of insulin degludec with 3.6 mg/mL of the GLP-1 receptor agonist liraglutide. It is indicated for adults with Type 2 diabetes. The maximum daily dose is 50 units of insulin degludec and 1.8 mg of liraglutide.[5]
• Ryzodeg® 70/30: A once- or twice-daily injectable combining 70% insulin degludec with 30% of the rapid-acting insulin aspart. This formulation provides both basal and prandial (mealtime) coverage in a single injection.[12]

Safety Profile, Contraindications, and Adverse Events

The safety profile of insulin degludec has been extensively characterized in a large clinical development program. While it shares many class-specific risks with other insulins, its primary safety advantage is a reduced incidence of hypoglycemia.

Contraindications

Insulin degludec is contraindicated in the following situations:

• During episodes of hypoglycemia.[3]
• In patients with a history of serious hypersensitivity reaction to insulin degludec or any of its excipients.[3]

Warnings and Precautions

The FDA-approved prescribing information includes several important warnings and precautions for the safe use of insulin degludec:

• Hypoglycemia: This is the most common and potentially dangerous adverse reaction associated with all insulin therapies. The risk of hypoglycemia is increased by changes in insulin regimen, meal patterns, or physical activity levels. Patients with renal or hepatic impairment, or those with hypoglycemia unawareness, are at higher risk. Severe hypoglycemia can be life-threatening, leading to seizures, coma, or death.[3]
• Hyperglycemia and Diabetic Ketoacidosis (DKA): Errors in dosing, missed doses, or illness can lead to hyperglycemia and, in patients with Type 1 diabetes, DKA.[3]
• Medication Errors: To prevent accidental overdose and transmission of blood-borne pathogens, patients must be instructed to never share a FlexTouch® pen, even if the needle is changed. Insulin should not be transferred from the pen into a syringe, as the markings on a standard syringe will not measure the dose correctly and can lead to severe hypoglycemia.[3]
• Fluid Retention and Heart Failure with TZDs: Co-administration of insulin degludec with thiazolidinediones (TZDs), a class of oral antidiabetic drugs, can cause dose-related fluid retention. This may lead to or exacerbate heart failure. Patients should be closely monitored for signs and symptoms such as rapid weight gain, shortness of breath, and edema.[3] This is a class effect for insulins, but the continuous, stable effect of degludec might lead to a more sustained state of fluid retention when combined with a TZD, warranting heightened clinical vigilance.
• Hypokalemia: All insulins facilitate the shift of potassium from the extracellular to the intracellular space. If left untreated, the resulting hypokalemia can lead to respiratory paralysis, ventricular arrhythmias, and death.[23]
• Injection Site Reactions: To minimize the risk of lipodystrophy and localized cutaneous amyloidosis, it is imperative that patients rotate their injection sites with each dose.[3]

Adverse Reactions

• Common Adverse Reactions: The most frequently reported adverse reactions (occurring in ≥5% of patients in clinical trials) include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus (itching), rash, edema (swelling), and weight gain.[3] Other commonly reported events include upper respiratory tract infections and headache.[37]
• Serious Adverse Reactions: The most significant serious adverse reactions are severe hypoglycemia, systemic allergic reactions (anaphylaxis), and severe hypokalemia.[3]

Management of Overdose

An overdose of insulin degludec can cause severe, and due to its ultra-long duration of action, prolonged hypoglycemia. Management depends on the severity of the episode. Mild hypoglycemia can be treated with oral administration of glucose or sugar-containing products. Severe episodes, where the patient is unable to self-treat, may require intramuscular or subcutaneous injection of glucagon, or intravenous administration of concentrated glucose by a healthcare professional. Due to the protracted nature of insulin degludec, prolonged observation and repeated carbohydrate administration may be necessary to prevent relapse.[9]

Drug and Disease State Interactions

The therapeutic effect of insulin degludec can be modified by numerous drugs and certain underlying disease states, primarily by altering glucose metabolism or by masking the symptoms of hypoglycemia.

Pharmacodynamic Interactions Increasing Hypoglycemia Risk

A number of medications can enhance the glucose-lowering effect of insulin degludec, increasing the risk of hypoglycemia. When these drugs are co-administered, more frequent blood glucose monitoring and potential dose reductions of insulin degludec may be necessary. These drugs include:

• Other Antidiabetic Agents: Oral hypoglycemic agents (e.g., sulfonylureas), GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, and pramlintide.[27]
• Cardiovascular Drugs: ACE inhibitors and Angiotensin II Receptor Blockers (ARBs).[27]
• Lipid-Lowering Agents: Fibrates.[36]
• Antidepressants and Psychiatric Medications: Fluoxetine and Monoamine Oxidase Inhibitors (MAOIs).[36]
• Analgesics and Anti-inflammatory Drugs: Salicylates (e.g., aspirin).[27]
• Other Agents: Somatostatin analogs (e.g., octreotide) and sulfonamide antibiotics.[27]

Pharmacodynamic Interactions Increasing Hyperglycemia Risk

Conversely, some drugs can antagonize the effect of insulin degludec, leading to hyperglycemia and a potential need to increase the insulin dose. These include:

• Hormonal Therapies: Corticosteroids, estrogens, progestogens, danazol, and thyroid hormones.[27]
• Antipsychotics: Atypical antipsychotics (e.g., olanzapine, clozapine) are known to be associated with hyperglycemia and may impair glycemic control.[27]
• Diuretics: Thiazide and loop diuretics can increase blood glucose, possibly through diuretic-induced hypokalemia.[27]
• Other Agents: Sympathomimetic agents (e.g., epinephrine, pseudoephedrine), protease inhibitors (used in HIV treatment), niacin, and glucagon.[27]

Interactions with Variable Effects on Glycemic Control

Certain substances have unpredictable effects on blood glucose and require particular caution:

• Alcohol: Can both increase and decrease the glucose-lowering effect of insulin. It impairs hepatic gluconeogenesis, which significantly increases the risk of hypoglycemia, but it also provides calories that can lead to hyperglycemia.[27]
• Beta-Blockers: These drugs can have a dual effect. They may increase or decrease the blood glucose-lowering effect of insulin. More importantly, they can mask the adrenergic warning signs of hypoglycemia, such as tachycardia and tremors, making it difficult for a patient to recognize a hypoglycemic event until it becomes severe.[27] This interaction is of paramount clinical importance because it is not merely pharmacodynamic but also diagnostic. By silencing the body's early warning system, beta-blockers can transform a manageable low blood sugar episode into a severe neuroglycopenic event. This requires intensive patient education to focus on non-adrenergic symptoms (like sweating, which is cholinergic) and to rely more heavily on frequent blood glucose monitoring.
• Clonidine and Lithium Salts: These agents may also either potentiate or reduce the hypoglycemic effect of insulin.[36]

Special Considerations in Disease States

• Renal and Hepatic Impairment: Patients with impaired kidney or liver function may have decreased insulin clearance, leading to reduced insulin requirements and an increased risk of hypoglycemia. While pharmacokinetic studies showed no major differences in patients with hepatic impairment, close glucose monitoring and careful dose adjustments are warranted in both conditions.[3]
• Hypokalemia: As insulin promotes the cellular uptake of potassium, it can cause or worsen hypokalemia. Caution is necessary in patients predisposed to low potassium levels.[23]

Evidence from Clinical Development: Efficacy and Safety Trials

The clinical development program for insulin degludec was extensive, strategically designed not only to establish efficacy but to demonstrate a superior safety profile compared to existing standards of care.

The BEGIN Program: Foundational Evidence

The BEGIN (Basal-bolus Effect of Insulin Degludec in Normalisation of Glycaemia) program comprised a series of large, randomized, open-label, treat-to-target trials that provided the foundational evidence for insulin degludec's approval.[6]

• Primary Efficacy: Across multiple studies in diverse populations (insulin-naïve, insulin-experienced, Type 1 and Type 2 diabetes), insulin degludec consistently demonstrated non-inferiority in lowering hemoglobin A1c (HbA1c) compared to the then-standard-of-care, insulin glargine U100.[40]
• Key Safety Finding: The most consistent and significant finding from the BEGIN program was a lower rate of confirmed nocturnal hypoglycemia with insulin degludec versus insulin glargine U100. This benefit was observed in patients with both Type 1 and Type 2 diabetes.[40] Rates of overall hypoglycemia were also often numerically or statistically lower.[40]
• Exploration of Dosing Regimens: The program also explored alternative dosing strategies. The BEGIN Easy AM/PM trials tested a three-times-weekly dosing regimen, which was found to be inferior for glycemic control and was associated with an increased risk of hypoglycemia. This led to the conclusion that a once-daily regimen is optimal.[40]

The SWITCH and DEVOTE Trials: Confirming Safety and Superiority

Following the initial signals from the BEGIN program, subsequent trials were designed to robustly confirm the safety benefits of insulin degludec.

• SWITCH Trials: These were Phase 3b, double-blind, crossover trials specifically designed to compare rates of hypoglycemia in patients at high risk for such events. The SWITCH 2 trial, for example, enrolled patients with Type 2 diabetes and at least one risk factor for hypoglycemia. The results definitively confirmed that treatment with insulin degludec was associated with significantly lower rates of overall symptomatic, nocturnal symptomatic, and severe hypoglycemia when compared directly to insulin glargine U100, all while achieving similar levels of glycemic control.[8]
• DEVOTE Trial: This was a large-scale, randomized, double-blind cardiovascular outcomes trial (CVOT) conducted to satisfy the FDA's requirement to rule out excess cardiovascular risk. The trial successfully demonstrated that insulin degludec was non-inferior to insulin glargine U100 regarding the risk of major adverse cardiovascular events (MACE).[6] A crucial secondary endpoint of the trial was the rate of severe hypoglycemia. The DEVOTE trial found that patients treated with insulin degludec experienced a 40% reduction in the rate of severe hypoglycemic events compared to those treated with insulin glargine U100, providing powerful evidence of its superior safety profile.[6]

This clinical development pathway illustrates a sophisticated strategy. In a mature therapeutic area like basal insulins, simply matching the efficacy (HbA1c reduction) of the standard of care is insufficient for differentiation. Novo Nordisk identified the primary clinical barrier to insulin therapy—the fear and risk of hypoglycemia—and pivoted its trial program accordingly. After establishing non-inferiority on efficacy in the BEGIN program, the company invested in large, methodologically rigorous trials like SWITCH and DEVOTE to prove superiority on the safety outcomes that are most meaningful to patients and clinicians.

Long-Term and Pediatric Studies

• Long-term extension studies of the BEGIN trials, lasting up to two years, confirmed that the efficacy and safety benefits of insulin degludec, particularly the reduction in nocturnal hypoglycemia, were sustained over time.[40]
• The efficacy and safety in pediatric populations were established in dedicated trials, such as the BEGIN™ Young 1 trial (NCT01513473), which evaluated insulin degludec in children and adolescents (aged 1 to <18 years) with Type 1 diabetes. The positive results from this trial led to the expansion of its indication to include this patient group.[32]

Comparative Analysis with Other Basal Insulins

Insulin degludec's place in therapy is best understood by comparing it to other available long-acting basal insulins.

Insulin Degludec vs. Insulin Glargine (U100 & U300)

• Versus Insulin Glargine U100 (Lantus®, Basaglar®): Insulin degludec possesses a longer, flatter, and more stable pharmacokinetic and pharmacodynamic profile.[1] Clinically, this translates into similar HbA1c reduction but with a clear and consistent advantage for insulin degludec in reducing the rates of nocturnal and severe hypoglycemia, as demonstrated across the BEGIN, SWITCH, and DEVOTE trials.[6]
• Versus Insulin Glargine U300 (Toujeo®): This comparison is more complex, as both are second-generation insulins with improved profiles over U100.[42]
• Efficacy: Meta-analyses generally show comparable efficacy in HbA1c reduction between degludec and glargine U300.[42] Some evidence suggests degludec may achieve a greater reduction in fasting plasma glucose (FPG).[7]
• Hypoglycemia: The evidence on hypoglycemia is conflicting. Several studies and meta-analyses have reported lower rates of nocturnal and/or severe hypoglycemia with degludec.[7] However, other analyses have found no significant difference in overall hypoglycemia rates, and at least one trial reported a lower rate of hypoglycemia with glargine U300 during the initial titration period.[42] This suggests that on a population level, their safety profiles may be very similar. One intriguing study in patients with Type 1 diabetes found that switching from degludec to glargine U300 improved glycemic variability and reduced nocturnal hypoglycemia specifically in patients with low serum albumin levels.[43] This points toward a potential patient-specific factor that could guide therapy choice, as degludec's albumin-binding mechanism may be less stable in patients with hypoalbuminemia.
• Formulation: A key practical difference is that insulin degludec's neutral-pH formulation allows it to be co-formulated in a single injection with other insulins (e.g., Ryzodeg®), a capability that the acidic formulation of insulin glargine lacks.[2]

Insulin Degludec vs. Insulin Detemir (Levemir®)

• Duration and Dosing: Insulin degludec has a substantially longer duration of action (>42 hours) compared to insulin detemir (approximately 20-24 hours).[1] This allows for true once-daily dosing in virtually all patients, whereas a subset of patients using insulin detemir may require twice-daily injections to achieve adequate 24-hour basal coverage.[4]
• Variability: The unique multi-hexamer depot mechanism of insulin degludec results in lower day-to-day pharmacodynamic variability compared to insulin detemir.[17]
• Clinical Outcomes: Head-to-head clinical trials have demonstrated comparable glycemic control between the two, but with significantly lower rates of nocturnal hypoglycemia for patients treated with insulin degludec.[32]

Table 9.1: Comparative Profile of Long-Acting Basal Insulins
Feature	Insulin Degludec	Insulin Glargine U100	Insulin Glargine U300	Insulin Detemir
Mechanism of Protraction	Subcutaneous multi-hexamer depot; Albumin binding	Subcutaneous microprecipitation at neutral pH	Subcutaneous microprecipitation (more compact)	Albumin binding; Self-association
Duration of Action	>42 hours	~24 hours	>24 hours (up to 36)	~20-24 hours
PK Profile (Peak)	Peakless	Relatively flat with slight peak	Flatter than U100	Relatively flat with slight peak
Dosing Frequency	Once daily	Once daily	Once daily	Once or twice daily
Dosing Flexibility (Adults)	Yes (any time of day)	No (same time recommended)	No (same time recommended)	No (same time recommended)
Nocturnal Hypoglycemia Risk	Lower vs. U100 & Detemir	Baseline	Lower vs. U100	Higher vs. Degludec
Severe Hypoglycemia Risk	Lower vs. U100	Baseline	Lower vs. U100	Comparable to U100
Ability to be Co-formulated	Yes (e.g., with Aspart)	No	No	No
Pediatric Indication (Age)	≥1 year	≥6 years (Lantus)	≥6 years	≥2 years

Regulatory and Manufacturing Overview

Manufacturing Process

Insulin degludec is a product of modern biotechnology, manufactured using recombinant DNA (rDNA) technology.[1] The process begins with the genetic engineering of the yeast species

Saccharomyces cerevisiae, which serves as the host organism for expression of the insulin precursor protein.[15] Following fermentation and purification of the recombinant protein, a subsequent chemical modification step is performed. In this step, the hexadecanedioic acid side-chain is covalently attached via a glutamic acid spacer to the ε-amino group of the lysine residue at position B29 of the insulin molecule, yielding the final active drug substance.[15]

Global Regulatory History

The regulatory journey of insulin degludec varied significantly between major global agencies, highlighting different regulatory philosophies regarding cardiovascular safety for diabetes drugs.

• European Medicines Agency (EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2012, the European Commission granted full marketing authorization for Tresiba® on January 21, 2013.[2]
• U.S. Food and Drug Administration (FDA): The path to approval in the United States was more protracted. In the wake of the controversy surrounding the cardiovascular safety of rosiglitazone, the FDA had implemented stricter guidance in 2008 requiring rigorous cardiovascular safety assessment for all new Type 2 diabetes therapies. After an initial submission, the FDA issued a complete response letter in February 2013, requesting additional cardiovascular outcomes data to rule out any potential excess risk.[2] After Novo Nordisk provided additional data and committed to conducting the large-scale DEVOTE cardiovascular outcomes trial, the FDA ultimately granted approval for Tresiba® on September 25, 2015. Marketing in the U.S. commenced in January 2016.[2] This 2.5-year delay between EMA and FDA approval demonstrates how a significant regulatory precedent can profoundly impact the development timeline of subsequent drugs within the same therapeutic class.
• Other Regulatory Bodies: Insulin degludec is approved for use in over 100 countries worldwide, including Japan and Canada. Health Canada further approved a label update in November 2022 for its use in pregnant women with diabetes.[6]

Expert Synthesis and Clinical Recommendations

Defining the Role of Insulin Degludec in Diabetes Management

Insulin degludec represents a significant advancement in basal insulin therapy. Its ultra-long, stable, and predictable pharmacokinetic and pharmacodynamic profile positions it as a first-line option for basal insulin replacement. Its primary value lies not just in its ability to lower HbA1c, but in its capacity to do so with a demonstrably lower risk of hypoglycemia—particularly severe and nocturnal events—compared to first-generation analogs. This enhanced safety profile is the key differentiator that should guide its clinical use. It is an excellent choice for insulin-naïve patients with Type 2 diabetes initiating basal insulin and is a superior option for any patient with Type 1 or Type 2 diabetes who experiences problematic hypoglycemia or significant glycemic variability on older basal insulin formulations.

The Ideal Patient Profile

While beneficial for a broad range of patients with diabetes, certain profiles are particularly well-suited for treatment with insulin degludec:

• Strong Candidates:
• Patients with a pronounced fear of or a documented history of hypoglycemia, especially nocturnal episodes. The robust evidence for its safety in this regard can help overcome a major barrier to treatment.
• Adult patients with demanding or unpredictable lifestyles (e.g., shift workers, frequent travelers) who would benefit from the approved dosing flexibility.
• Patients requiring high doses of basal insulin (>80 units/day), where the concentrated U-200 formulation can reduce injection volume and discomfort.
• Patients who could benefit from a simplified regimen that combines basal and prandial coverage, making the fixed-ratio co-formulation Ryzodeg® (degludec/aspart) an attractive option.
• Candidates Requiring Caution:
• Patients with severe renal or hepatic impairment, who will require careful dose titration and more frequent glucose monitoring due to the potential for altered insulin clearance.
• Patients on concurrent beta-blocker therapy, who need intensive education on recognizing the atypical (non-adrenergic) symptoms of hypoglycemia.
• A potential consideration for patients with Type 1 diabetes and very low serum albumin (e.g., due to nephrotic syndrome), where the alternative second-generation basal insulin, glargine U300, might offer a more predictable profile, as suggested by limited evidence.[43]

Future Perspectives and Unanswered Questions

The development of insulin degludec has fundamentally shifted the risk-benefit calculation of insulin therapy. By "de-risking" the initiation and intensification of insulin, it empowers clinicians to titrate doses more confidently to achieve glycemic targets and enables patients to manage their disease with greater safety and flexibility. This can lead to improved treatment adherence and long-term quality of life.

Future research will likely focus on several key areas. The ultra-stable and predictable profile of insulin degludec makes it a highly promising candidate for use in advanced hybrid closed-loop "artificial pancreas" systems, where a consistent basal rate is critical for algorithm performance.[43] Further head-to-head trials against insulin glargine U300 are needed to clarify the nuances of their comparative profiles, particularly in specific subpopulations, to better guide personalized treatment decisions. Finally, long-term, real-world evidence will continue to elucidate its impact on patient-reported outcomes, treatment satisfaction, and overall diabetes management.[48] Insulin degludec is not merely another long-acting insulin; it is a tool that helps make insulin therapy safer, more predictable, and more adaptable to the lives of people with diabetes.

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