Insulin Detemir (DB01307): A Comprehensive Monograph on its Molecular Design, Clinical Profile, and Therapeutic Standing

1.0 Introduction and Drug Profile

1.1 Overview of Basal Insulin Analogues in Diabetes Management

The management of diabetes mellitus aims to replicate the complex, dynamic secretion of insulin by a healthy pancreas. Physiologically, the pancreas provides a continuous, low-level (basal) secretion of insulin throughout the day and night. This basal insulin is critical for suppressing hepatic glucose production, thereby maintaining stable blood glucose levels between meals and during periods of fasting.[1] In individuals with diabetes, particularly type 1 diabetes (T1D) where pancreatic beta-cell function is absent, or in advanced type 2 diabetes (T2DM) where it is severely impaired, exogenous insulin therapy is required to replace this function.[1]

The therapeutic goal of basal insulin replacement is to establish a steady, peakless, and long-lasting insulin concentration in the bloodstream that mimics the natural physiological state.[1] For decades, Neutral Protamine Hagedorn (NPH) insulin served as the primary basal insulin. However, NPH has significant pharmacokinetic limitations, including a pronounced peak of action several hours after injection, a high degree of intra-patient variability in absorption, and a duration of action that is often insufficient to provide 24-hour coverage from a single injection. These characteristics contribute to an elevated risk of unpredictable hypoglycemia, especially nocturnal hypoglycemia, which is a major barrier to achieving optimal glycemic control.[3]

The development of long-acting insulin analogues in the early 21st century represented a major therapeutic advance. These molecules, created using recombinant DNA technology, were specifically engineered to overcome the shortcomings of NPH. Insulin detemir, the subject of this report, was one of the first-generation long-acting analogues designed to provide a more predictable and prolonged basal insulin profile, thereby reducing the risk of hypoglycemia and improving the safety and efficacy of diabetes management.[5]

1.2 Insulin Detemir: Identification and Classification

Insulin detemir is a long-acting, soluble human insulin analogue that has been a cornerstone of basal insulin therapy for nearly two decades.

1.2.1 Nomenclature and Identifiers

The compound is identified by a standardized set of chemical and regulatory codes essential for its classification in scientific literature, clinical practice, and pharmaceutical databases.

• Generic Name: Insulin detemir [3]
• Systematic Chemical Name: 29B-(N6-Myristoyl-L-lysine)-30B-de-L-threonineinsulin (human) [1]
• DrugBank ID: DB01307 [3]
• CAS Number: 169148-63-4 [3]
• ATC Code: A10AE05, under the classification A10AE (Insulins and analogues for injection, long-acting) [1]

1.2.2 Brand Names and Manufacturer

Insulin detemir is developed and manufactured by the global pharmaceutical company Novo Nordisk A/S.[1] It is marketed worldwide primarily under the brand name

Levemir®.[1] To facilitate patient use, it is supplied in multiple formats, including 10 mL multi-dose vials and pre-filled injection devices such as the

Levemir FlexPen®, Levemir FlexTouch®, and Levemir Penfill® cartridges.[9]

1.2.3 Regulatory Status and Market Discontinuation

Insulin detemir received its first major regulatory authorization from the European Medicines Agency (EMA) for use in the European Union on June 1, 2004.[1] This was followed by its approval in the United States by the Food and Drug Administration (FDA) on June 16, 2005.[3] Subsequent FDA approvals expanded its indication for use in children aged two to five years with T1D (May 22, 2012) and updated its pregnancy risk category (April 2, 2012), reflecting a robust post-approval clinical development program.[7]

However, the therapeutic landscape for basal insulins has continued to evolve. In a significant market development, Novo Nordisk announced the planned discontinuation of Levemir® in the United States. The Levemir® FlexPen® and vials are scheduled to be discontinued by December 31, 2024.[19] This decision can be understood as the commercial consequence of ongoing innovation in insulin analogue development. While detemir offered clear advantages over older insulins, the emergence of second-generation ultra-long-acting analogues, such as insulin degludec, with superior pharmacokinetic profiles and greater dosing flexibility, has rendered its therapeutic niche less competitive. The evolution from NPH to first-generation analogs like detemir, and subsequently to second-generation analogs, has been driven by the dual goals of minimizing hypoglycemia risk and reducing dosing frequency.[5] Comparative data demonstrate that newer agents like insulin degludec offer a longer duration of action and a lower risk of nocturnal hypoglycemia than insulin detemir.[22] Furthermore, insulin detemir's frequent requirement for twice-daily dosing to ensure full 24-hour coverage represents a clinical disadvantage compared to true once-daily options.[22] The discontinuation of Levemir® thus marks a pivotal moment, reflecting its role as a transitional but ultimately superseded therapy.

Property	Value	Source(s)
Generic Name	Insulin detemir	3
Common Brand Names	Levemir®, Levemir FlexPen®, Levemir FlexTouch®	1
Manufacturer	Novo Nordisk A/S	1
DrugBank ID	DB01307	3
CAS Number	169148-63-4	3
ATC Code	A10AE05	1
Molecular Formula	C267​H402​N64​O76​S6​	9
Molecular Weight	~5917 Da	9
Table 1.1: Key Identifiers and Properties of Insulin Detemir

1.3 Chemical Structure and Physical Properties

Insulin detemir is a biotech drug, classified as a recombinant human insulin analogue.[1] Its chemical structure is derived from human insulin but incorporates two specific modifications designed to prolong its duration of action.

• Molecular Formula and Weight: The empirical formula of insulin detemir is C267​H402​N64​O76​S6​, and its molecular weight is approximately 5917 Da.[9]
• Key Structural Modifications:

1. Deletion: The terminal amino acid of the insulin B-chain, threonine, at position B30 is deleted. This precursor is referred to as des(B30) human insulin.[1]
2. Acylation: A 14-carbon saturated fatty acid, myristic acid (also known as tetradecanoic acid), is covalently attached via an amide linkage to the epsilon-amino (ϵ-amino) group of the lysine residue at position B29 of the B-chain.[1]

This fatty acid acylation is the defining structural feature of insulin detemir and is the cornerstone of its unique protraction mechanism, which relies on both subcutaneous self-association and systemic albumin binding.

2.0 Molecular Biology and Manufacturing

The production of insulin detemir is a sophisticated, multi-stage process that combines advanced biotechnological methods with precise chemical synthesis. This hybrid approach is necessary to create the molecule's unique structure, which cannot be fully assembled by biological systems alone.

2.1 Production via Recombinant DNA Technology in Saccharomyces cerevisiae

The polypeptide backbone of insulin detemir is produced using recombinant DNA technology.[1] The host organism selected for this process is the yeast

Saccharomyces cerevisiae.[9] The general manufacturing process begins with the insertion of a synthetic gene encoding the des(B30) human proinsulin precursor into a plasmid vector. This recombinant plasmid is then introduced into the yeast cells.[12]

The choice of S. cerevisiae, a eukaryotic organism, is significant. Compared to prokaryotic systems like Escherichia coli, yeast possesses the cellular machinery for more complex protein folding and post-translational modifications, which can lead to a higher yield of correctly folded, soluble proinsulin precursor.[12] The transformed yeast cells are then cultivated in large-scale industrial fermenters under tightly controlled environmental conditions (e.g., temperature, pH, nutrient supply) to maximize the expression and production of the precursor protein.[12] Following fermentation, the precursor is extracted from the yeast cells or the culture medium and subjected to extensive purification to isolate it from host cell proteins and other contaminants.[32]

2.2 Post-Translational Chemical Modification and Acylation

While S. cerevisiae is adept at producing the protein backbone, it cannot perform the specific fatty acid attachment required for insulin detemir. Therefore, after the des(B30) insulin precursor is purified, it undergoes a critical chemical modification step.[27] This step involves the selective acylation of the ε-amino group of the lysine residue at position B29.[35]

To achieve this with high specificity, an activated derivative of myristic acid (e.g., myristic acid succinimide ester) is reacted with the purified insulin precursor.[35] Patent literature reveals that the reaction conditions, particularly pH, are carefully controlled to ensure that the acylation occurs preferentially at the desired LysB29 ε-amino group rather than at the N-terminal amino groups of the A or B chains. By adjusting the pH to a specific alkaline range (e.g., pH 9.0-9.5), the target ε-amino group is deprotonated and becomes nucleophilic, while the N-terminal α-amino groups remain largely protonated and less reactive, thus directing the acylation to the correct site.[35] This hybrid manufacturing strategy—biotechnological synthesis of the peptide followed by targeted chemical modification—highlights the sophisticated engineering required to produce modern insulin analogues.

2.3 Pharmaceutical Formulation and Excipients

The final drug product, Levemir®, is formulated as a clear, colorless, neutral (pH approximately 7.4), sterile solution intended for subcutaneous injection.[9] The concentration is standardized to 100 units/mL. One unit of insulin detemir contains 0.142 mg of the salt-free anhydrous drug and is nominally equivalent in potency to one International Unit (IU) of human insulin.[9]

The formulation contains several critical excipients that are essential for the stability, safety, and unique action profile of the drug [9]:

• Zinc (as zinc acetate): Plays a crucial role in promoting the self-association of insulin detemir molecules into stable hexameric complexes within the vial.[9]
• Phenolic Preservatives (phenol and meta-cresol): Serve as antimicrobial agents to maintain sterility in the multi-dose vials and also contribute to the stabilization of the hexameric structure. Their rapid diffusion away from the injection site into the subcutaneous tissue is a key trigger for the formation of the drug depot.[9]
• Tonicity Agents (glycerol and sodium chloride): Added to ensure the solution is isotonic with bodily fluids, minimizing pain and irritation upon injection.[9]
• Buffer (dibasic sodium phosphate dihydrate): Maintains the solution at a stable, neutral pH, which is critical for the solubility and stability of the insulin analogue.[9]
• pH Adjusters (hydrochloric acid and sodium hydroxide): Used during the manufacturing process to precisely set the final pH of the solution.[9]
• Water for Injections: Serves as the sterile solvent vehicle for all other components.[9]

3.0 Clinical Pharmacology

The clinical utility of insulin detemir as a basal insulin is a direct consequence of its unique pharmacology. Its engineered chemical structure gives rise to a distinct mechanism of action that results in a prolonged and predictable pharmacodynamic profile.

3.1 Mechanism of Action: A Dual-Protraction Strategy

Like all insulins, the primary metabolic activity of insulin detemir is the regulation of glucose homeostasis. It achieves this by binding to insulin receptors on target cells, primarily in skeletal muscle and adipose tissue, which facilitates the cellular uptake of glucose. It also potently inhibits the output of glucose from the liver.[1]

The defining characteristic of insulin detemir is its prolonged duration of action, which is achieved through an innovative dual-protraction mechanism. This mechanism slows both the absorption of the drug from the injection site and its subsequent clearance from the bloodstream.[1]

3.1.1 Subcutaneous Depot Formation: Fatty Acid-Mediated Self-Association

The first level of protraction occurs at the subcutaneous injection site. In the pharmaceutical formulation, zinc and phenolic preservatives stabilize insulin detemir molecules in a hexameric state.[26] Upon subcutaneous injection, the small phenol and m-cresol molecules rapidly diffuse away into the surrounding tissue. This destabilizes the hexamers, allowing the myristic acid side chains on adjacent hexamers to engage in hydrophobic interactions. This fatty acid-mediated self-association leads to the formation of long di-hexamer and multi-hexamer chains, creating a large, soluble depot at the injection site.[26] From this depot, insulin monomers and dimers slowly dissociate and are gradually absorbed into the circulation, providing a sustained release over many hours.[26]

3.1.2 Systemic Protraction: Reversible Albumin Binding

The second level of protraction occurs once insulin detemir enters the bloodstream. The same myristic acid side chain that mediates self-association also confers a high binding affinity for circulating serum albumin.[1] More than 98% of insulin detemir in the circulation is reversibly bound to albumin.[1]

This extensive protein binding has two major consequences:

1. Creation of a Circulating Buffer: The albumin-bound insulin acts as a large circulating reservoir. This buffers the concentration of free, biologically active insulin, which constitutes only about 2% of the total circulating drug. As free insulin is taken up by tissues or cleared, it is steadily replenished by dissociation from this albumin reservoir, smoothing out fluctuations in insulin availability.[26]
2. Delayed Clearance: The large size of the albumin-insulin detemir complex prevents it from being filtered by the kidneys. Furthermore, binding to albumin slows its clearance by receptor-mediated pathways. This significantly prolongs its overall residence time in the body.[26]

3.2 Pharmacodynamics (PD)

The dual-protraction mechanism translates into a distinct pharmacodynamic profile that is well-suited for basal insulin therapy.

• Onset, Profile, and Duration of Action:
• Onset of Action: The glucose-lowering effect begins approximately 1 to 2 hours after subcutaneous injection.[38]
• Action Profile: Insulin detemir is characterized by a relatively flat and predictable time-action profile, with a less pronounced peak of activity compared to NPH insulin.[4] This profile is a direct result of the continuous, slow release from the subcutaneous depot and the buffering effect of albumin binding.
• Duration of Action: The duration is dose-dependent. Studies have shown it can range from approximately 6 hours at very low doses to up to 24 hours at higher therapeutic doses.[1] However, head-to-head euglycemic clamp studies suggest that for many patients, the clinically effective duration is shorter than 24 hours, often in the range of 17.5 to 20 hours, which is less than that of insulin glargine in the same studies.[40] This pharmacokinetic property is a key reason why twice-daily dosing is frequently required for optimal glycemic control.[22]
• Peak Effect: While there is a pharmacokinetic peak in serum concentration (Cmax) occurring 6 to 8 hours post-injection, the corresponding pharmacodynamic (glucose-lowering) effect is much flatter.[1] The potent buffering effect of albumin binding effectively uncouples the peak in total drug concentration from the metabolic activity. As free insulin is used, it is rapidly replenished from the large albumin-bound pool, maintaining a relatively steady glucose infusion rate in clamp studies. This distinction is crucial for understanding why insulin detemir is described as having a "peakless" profile in a functional sense and why it reduces the risk of nocturnal hypoglycemia despite having a Cmax that may occur overnight.
• Glucose-Lowering Effects and Receptor Affinity:
• Insulin detemir exerts its glucose-lowering effect through the canonical insulin signaling pathway.[2]
• An interesting molecular feature is its reduced binding affinity for the human insulin receptor, which is approximately 30% of that of native human insulin.[38] It also exhibits reduced affinity for the related insulin-like growth factor-1 (IGF-1) receptor.[9] The clinical implications of this reduced affinity have not been fully established but may contribute to its overall pharmacodynamic characteristics, including its association with less weight gain.

3.3 Pharmacokinetics (PK)

The movement of insulin detemir through the body is defined by its slow absorption, high protein binding, and consequent prolonged half-life.

• Absorption: Absorption from the subcutaneous tissue is slow and protracted. The absolute bioavailability is approximately 60%.[3] The injection site can influence the rate of absorption; administration into the thigh results in slower absorption compared to the abdomen or deltoid region.[6]
• Distribution: The apparent volume of distribution is low (approximately 0.1 L/kg), which is consistent with its extensive confinement to the vascular space due to high protein binding.[38] The binding to albumin exceeds 98% and is the key pharmacokinetic feature responsible for limiting its distribution to peripheral tissues and slowing its clearance.[1]
• Metabolism: Degradation pathways are similar to those of human insulin, with metabolism occurring primarily in the liver and kidneys. The resulting metabolites are inactive.[9]
• Elimination: The terminal half-life following subcutaneous administration is dose-dependent and ranges from 5 to 7 hours.[3]

Parameter	Value / Description	Source(s)
Onset of Action	1–2 hours	38
Time to Cmax (PK Peak)	6–8 hours	1
Duration of Action	Dose-dependent; up to 24 hours	1
Action Profile	Relatively flat, predictable, "peakless" (pharmacodynamically)	4
Absolute Bioavailability	~60%	3
Volume of Distribution	~0.1 L/kg	38
Protein Binding (Albumin)	>98%	1
Terminal Half-Life	5–7 hours (dose-dependent)	3
Table 3.1: Summary of Pharmacokinetic and Pharmacodynamic Parameters

4.0 Clinical Application and Dosing Regimens

The pharmacological properties of insulin detemir directly inform its clinical use. The following section outlines its approved indications, recommended dosing strategies, and essential administration guidelines for safe and effective therapy.

4.1 Approved Indications for Use

Insulin detemir is indicated to improve glycemic control in adults and children with diabetes mellitus.[1]

• Type 1 Diabetes Mellitus (T1DM): It is approved for use in adults, adolescents, and children. The specific age for pediatric approval varies by region, being from one year of age in the European Union and from two years of age in the United States.[1] In the management of T1DM, insulin detemir must be used as the basal component of a basal-bolus insulin regimen, in combination with a separate rapid- or short-acting insulin administered at mealtimes to cover prandial glucose excursions.[13]
• Type 2 Diabetes Mellitus (T2DM): It is approved for use in adults with T2DM.[1] It can be incorporated into various treatment regimens, including as an initial insulin therapy added to oral antidiabetic drugs (OADs), in combination with glucagon-like peptide-1 (GLP-1) receptor agonists, or as part of a more intensive basal-bolus regimen with mealtime insulin.[18]
• Important Limitation of Use: Insulin detemir is not recommended for the treatment of diabetic ketoacidosis (DKA). The standard of care for this acute, life-threatening condition is the intravenous administration of a rapid- or short-acting insulin.[13]

4.2 Dosing and Administration

The dosing of insulin detemir must be individualized for each patient based on their metabolic needs, blood glucose monitoring results, and glycemic targets.

4.2.1 Initiation of Therapy in Insulin-Naïve Patients

• T1DM: For patients newly diagnosed with T1DM, the recommended starting dose of insulin detemir is approximately one-third of the total daily insulin requirement (TDIR). The TDIR is often initially estimated based on body weight, typically in the range of 0.2 to 0.4 units/kg per day. The remaining two-thirds of the TDIR should be administered as a rapid- or short-acting bolus insulin, divided among meals.[15]
• T2DM: For patients with T2DM who are new to insulin, a common starting dose is 10 units once daily, or a weight-based dose of 0.1 to 0.2 units/kg. This initial dose is typically administered in the evening, either with the evening meal or at bedtime.[19]

4.2.2 Conversion from Other Insulin Therapies

• From Insulin Glargine: When switching from another long-acting analogue like insulin glargine (100 U/mL), the conversion to insulin detemir can generally be done on a unit-for-unit basis. The dose should then be titrated based on subsequent blood glucose measurements.[16]
• From NPH Insulin: Conversion from NPH insulin can also be initiated on a unit-for-unit basis. However, clinicians should be aware that some patients may ultimately require a higher total daily dose of insulin detemir to achieve the same level of glycemic control as with NPH. Close and frequent blood glucose monitoring is essential during the transition period and in the initial weeks thereafter.[43]

4.2.3 Once-Daily vs. Twice-Daily Dosing Strategies

The dosing frequency of insulin detemir must be tailored to the individual patient's needs to ensure consistent 24-hour basal coverage.[9] This reveals a key clinical aspect of the drug. While it is often initiated as a simple once-daily injection, its pharmacokinetic profile, with a duration of action that may not reliably extend to 24 hours, frequently necessitates a more complex regimen.[40] Clinicians must be vigilant for patterns of waning insulin effect, such as pre-dinner or next-day fasting hyperglycemia, which indicate the need to split the dose.

• Once-Daily Dosing: When used once daily, the dose should be administered with the evening meal or at bedtime to provide crucial overnight basal insulin coverage and control fasting plasma glucose.[20]
• Twice-Daily Dosing: For patients who do not achieve adequate glycemic control over a full 24-hour period, the total daily dose should be divided and administered as two separate injections. These are typically given approximately 12 hours apart, for example, with the morning and evening meals, or with the morning meal and at bedtime.[9]

4.2.4 Administration Technique and Patient Counseling

Proper administration technique is critical for the safety and efficacy of insulin detemir.

• Route of Administration: Insulin detemir must be administered by subcutaneous (SC) injection only. It must never be administered intravenously (IV) or intramuscularly (IM), as this would lead to rapid absorption and could cause severe hypoglycemia. It is also not approved for use in insulin infusion pumps.[14]
• Injection Sites: Recommended injection sites include the abdomen, the thigh, or the deltoid region of the upper arm.[42]
• Site Rotation: Patients must be counseled on the critical importance of rotating injection sites within the same anatomical region with each injection. This practice is essential to reduce the risk of developing lipodystrophy (either lipohypertrophy, a thickening of subcutaneous fat, or lipoatrophy, a thinning of fat) and localized cutaneous amyloidosis (lumps under the skin).[14] Injecting insulin into these affected areas can impair its absorption, leading to unpredictable glycemic control and hyperglycemia.[14]
• Safety Precautions: Patients must be instructed to never share insulin pens (e.g., Levemir FlexPen®) or needles with another person, even if the needle has been changed. Sharing poses a significant risk for the transmission of blood-borne pathogens.[14]

5.0 Safety Profile and Tolerability

The safety and tolerability profile of insulin detemir has been well-characterized through an extensive program of clinical trials and years of post-marketing surveillance. The most significant risk is hypoglycemia, a class effect of all insulins, but its profile also includes unique characteristics related to weight change and local tolerability.

5.1 Comprehensive Review of Adverse Reactions from Clinical Trials

Data from large, pooled analyses of clinical trials provide quantitative insight into the most common adverse events associated with insulin detemir therapy. The tables below summarize adverse reactions (excluding hypoglycemia) with an incidence of ≥5% in pivotal trials comparing insulin detemir to NPH or insulin glargine in various patient populations.[45]

A meta-analysis of studies in patients with T2DM noted a clinically relevant difference in tolerability, finding that patients treated with insulin detemir had a higher rate of withdrawal due to adverse events when compared to those treated with insulin glargine.[23]

Adverse Reaction	LEVEMIR® % (n=767)	NPH % (n=388)
Upper respiratory tract infection	26.1	21.4
Headache	22.6	22.7
Pharyngitis	9.5	8.0
Influenza-like illness	7.8	7.0
Abdominal Pain	6.0	2.6
Table 5.1: Adverse Reactions in Pooled Trials (16-24 weeks) in Adults with Type 1 Diabetes 45

Adverse Reaction	LEVEMIR® % (n=432)	NPH % (n=437)
Upper respiratory tract infection	12.5	11.2
Headache	6.5	5.3
Table 5.2: Adverse Reactions in Pooled Trials (22-24 weeks) in Adults with Type 2 Diabetes 52

Adverse Reaction	LEVEMIR® % (n=232)	NPH % (n=115)
Upper respiratory tract infection	35.8	42.6
Headache	31.0	32.2
Pharyngitis	17.2	20.9
Gastroenteritis	16.8	11.3
Influenza-like illness	13.8	20.9
Abdominal pain	13.4	13.0
Pyrexia (Fever)	10.3	6.1
Table 5.3: Adverse Reactions in a 26-week Trial in Pediatric Patients (ages 6-17) with Type 1 Diabetes 53

5.2 Hypoglycemia: Incidence, Risk Factors, and Management

• Incidence and Severity: Hypoglycemia (low blood sugar) is the most common and most serious adverse reaction associated with all insulin therapies, including detemir.[3] Severe hypoglycemia can be life-threatening, potentially leading to seizures, convulsions, temporary or permanent neurological impairment, coma, and death.[14]
• Risk Profile vs. Comparators: A key therapeutic advantage of insulin detemir is its favorable hypoglycemia profile compared to older basal insulins. Clinical trials have consistently demonstrated that treatment with insulin detemir is associated with a significantly lower risk of overall and, most notably, nocturnal hypoglycemia when compared to NPH insulin in patients with both T1DM and T2DM.[4] When compared to its first-generation contemporary, insulin glargine, the risk of hypoglycemia is generally similar, with some studies showing minor or no significant differences.[6] However, the newer, second-generation basal analogue, insulin degludec, has demonstrated a superior safety profile, with a significantly lower risk of nocturnal hypoglycemia compared to both insulin detemir and insulin glargine.[23]
• Management: Patient education is paramount. All patients must be trained to recognize the signs and symptoms of hypoglycemia, which include dizziness, light-headedness, shakiness, sweating, confusion, headache, blurred vision, slurred speech, rapid heartbeat, anxiety, irritability, and hunger.[14] They should also be instructed on how to manage mild to moderate episodes, for example, by following the "15-15 rule," which involves consuming 15 grams of a fast-acting carbohydrate and re-checking blood glucose after 15 minutes.[44]

5.3 Hypersensitivity and Injection Site Reactions

• Local Reactions: Reactions at the injection site, such as pain, redness, hives, inflammation, swelling, and itching, are common adverse events with any insulin therapy.[3] Some comparative studies have suggested a higher incidence of injection site reactions with insulin detemir compared to insulin glargine, a finding that may be related to its unique fatty acid component.[6] Consistent rotation of injection sites is crucial for minimizing these reactions.[47]
• Systemic Reactions: Severe, life-threatening, generalized allergic reactions, including anaphylaxis, are rare but can occur. Insulin detemir is contraindicated in any patient with a history of hypersensitivity to the drug or any of its excipients.[15]

5.4 Other Clinically Significant Adverse Events

The safety profile of insulin detemir is notable for several other clinically relevant effects, particularly concerning weight.

• Weight Gain: While weight gain is a well-known anabolic effect of insulin therapy, a defining and advantageous feature of insulin detemir is its association with attenuated weight gain. Numerous clinical trials have shown that patients treated with insulin detemir experience significantly less weight gain—and in some cases, slight weight loss—compared to those treated with NPH insulin, insulin glargine, and insulin degludec.[3] This makes it a potentially favorable option for patients for whom weight management is a primary concern.
• Lipodystrophy: As with all insulins, long-term, repeated injections into the same site can lead to lipodystrophy, which can manifest as either lipohypertrophy (a thickening of fatty tissue) or lipoatrophy (a thinning of fatty tissue). This can be effectively prevented by adhering to a strict injection site rotation schedule.[14]
• Peripheral Edema: Insulin can cause sodium retention and subsequent fluid accumulation (edema), particularly in patients who experience a rapid improvement in metabolic control after a period of poor control.[15]
• Hypokalemia: All insulins, including detemir, promote the shift of potassium from the extracellular to the intracellular space. This can potentially lead to hypokalemia, which can be serious. Caution is advised, especially in patients taking other potassium-lowering medications.[15]

5.5 Contraindications and Critical Warnings

• Contraindications:
• Levemir® is contraindicated during episodes of hypoglycemia.[19]
• It is contraindicated in patients with a known hypersensitivity to insulin detemir or any of its excipients.[19]
• Warnings and Precautions:
• Medication Errors: Accidental mix-ups between different insulin products have been reported. Patients must be instructed to always check the insulin label before each injection to prevent errors.[45]
• Regimen Changes: Any changes to an insulin regimen (e.g., strength, manufacturer, type, or method of administration) must be made under close medical supervision with increased frequency of blood glucose monitoring, as they can predispose the patient to hyperglycemia or hypoglycemia.[15]
• Shared Use: Insulin pens and needles must never be shared between patients, as this practice carries a high risk of transmitting blood-borne pathogens.[14]

The overall safety profile of insulin detemir presents a clinical trade-off. Its significant advantages—a reduced risk of nocturnal hypoglycemia compared to NPH and attenuated weight gain compared to other basal insulins—address major barriers in diabetes care. These benefits, however, are balanced by potential drawbacks, including a higher incidence of local injection site reactions and higher rates of treatment discontinuation due to adverse events in some T2DM trials when compared to insulin glargine.[23] The very molecular feature responsible for its unique benefits, the myristic acid side chain, is also the most probable cause of its local tolerability issues, as it introduces a novel chemical moiety at the injection site. This creates a nuanced clinical decision, where detemir might be an excellent choice for a patient highly concerned with hypoglycemia and weight gain, but another analog may be preferable for a patient with sensitive skin or a history of injection site problems.

6.0 Drug Interactions

The glucose-lowering effect of insulin detemir can be modified by numerous concomitant medications. These interactions can either increase the risk of hypoglycemia or decrease the efficacy of insulin detemir, leading to hyperglycemia. Careful monitoring and potential dose adjustments are necessary when these drugs are co-administered.

6.1 Drugs that Potentiate the Hypoglycemic Effect

Several classes of drugs can enhance the glucose-lowering action of insulin detemir, increasing the risk of hypoglycemia. Dose reduction of insulin detemir and more frequent blood glucose monitoring may be required.

• Other Antidiabetic Agents: Co-administration with oral antidiabetics (e.g., sulfonylureas like glipizide), GLP-1 receptor agonists (e.g., semaglutide), SGLT2 inhibitors (e.g., dapagliflozin), or other insulins will have an additive hypoglycemic effect.[56]
• ACE Inhibitors: Drugs such as lisinopril and captopril can increase insulin sensitivity.[20]
• Angiotensin II Receptor Blockers (ARBs): Agents like losartan and azilsartan may enhance the hypoglycemic effect.[20]
• Salicylates: High doses of aspirin and other salicylates can lower blood glucose.[15]
• Monoamine Oxidase Inhibitors (MAOIs): This class of antidepressants can increase insulin's effect.[56]
• Fibrates: Used to treat hyperlipidemia, fibrates like fenofibrate can increase insulin sensitivity.[56]
• Certain Antibiotics: Sulfonamide antibiotics (e.g., acetyl sulfisoxazole) and clarithromycin can increase hypoglycemia risk.[38]
• Other Agents: Disopyramide, fluoxetine, and the supplement chromium have also been associated with an increased risk of hypoglycemia when used with insulin.[56]

6.2 Drugs that Diminish the Hypoglycemic Effect

Conversely, several medications can counteract the effect of insulin detemir, leading to hyperglycemia and a potential loss of glycemic control. An increase in the insulin detemir dose may be necessary.

• Corticosteroids: Systemic corticosteroids like prednisone and dexamethasone are well-known to increase blood glucose levels.[56]
• Atypical Antipsychotics: Drugs such as olanzapine, clozapine, and aripiprazole can cause hyperglycemia and insulin resistance.[20]
• Sympathomimetic Agents: Decongestants like pseudoephedrine and bronchodilators like albuterol can raise blood glucose.[56]
• Thyroid Hormones: Thyroid hormone replacement therapy (e.g., levothyroxine) can increase insulin requirements.[57]
• Protease Inhibitors: Certain HIV medications, such as atazanavir and ritonavir, can induce insulin resistance.[20]
• Diuretics: Thiazide and loop diuretics (e.g., hydrochlorothiazide, furosemide) can increase blood glucose.[58]
• Hormonal Contraceptives: Estrogen- and progestogen-containing products may decrease insulin sensitivity.[57]
• Other Agents: Danazol and niacin can also antagonize the effects of insulin.[58]

6.3 Drugs with Variable or Masking Effects

Some drugs have unpredictable effects on blood glucose or can mask the warning signs of hypoglycemia, requiring heightened patient awareness and monitoring.

• Beta-Blockers: Agents like metoprolol and propranolol can have variable effects, sometimes potentiating hypoglycemia and at other times causing hyperglycemia. Critically, they can also blunt the adrenergic warning symptoms of hypoglycemia, such as tremor and tachycardia, making it difficult for patients to recognize a low blood sugar event.[45]
• Alcohol: Ethanol consumption can have a dual effect. It can initially cause hyperglycemia but can also lead to delayed hypoglycemia, particularly when consumed without food, by inhibiting hepatic gluconeogenesis. Patients should be counseled on the risks of alcohol use.[14]
• Lithium: This mood stabilizer can unpredictably increase or decrease blood glucose levels.[56]
• Clonidine and Reserpine: These antihypertensive agents can also reduce or mask the warning signs of hypoglycemia.[45]

6.4 Other Clinically Significant Interactions

• Thiazolidinediones (TZDs): Co-administration of insulin detemir with TZD medications (e.g., pioglitazone, rosiglitazone) can cause dose-related fluid retention, which may lead to or exacerbate heart failure. Patients should be monitored for signs and symptoms of heart failure, and dose reduction or discontinuation of the TZD may be necessary.[15]
• Potassium-Lowering Drugs: The risk of hypokalemia may be increased when insulin detemir is used with other drugs that lower serum potassium, such as loop or thiazide diuretics.[15]

Interacting Agent/Class	Effect on Glycemic Control	Clinical Management
Increase Hypoglycemia Risk
Other Antidiabetics (Sulfonylureas, GLP-1 RAs, SGLT2i)	Potentiate hypoglycemic effect	Lower insulin dose may be needed; increase glucose monitoring.
ACE Inhibitors, ARBs, Fibrates, Salicylates, MAOIs	Increase insulin sensitivity	Increase glucose monitoring; consider insulin dose reduction.
Decrease Hypoglycemic Effect
Corticosteroids, Atypical Antipsychotics	Cause hyperglycemia/insulin resistance	Increase glucose monitoring; insulin dose increase may be needed.
Sympathomimetics, Thyroid Hormones, Protease Inhibitors	Antagonize insulin effect	Increase glucose monitoring; anticipate need for higher insulin doses.
Variable or Masking Effects
Beta-Blockers, Clonidine, Reserpine	Variable effect on glucose; mask hypoglycemia symptoms	Counsel patient on atypical symptoms of hypoglycemia; increase glucose monitoring.
Alcohol	Potentiates hypoglycemia (especially delayed)	Counsel patient on risks and moderation; advise against drinking on an empty stomach.
Other Significant Interactions
Thiazolidinediones (TZDs)	Increased risk of fluid retention and heart failure	Monitor for signs of heart failure (e.g., edema, dyspnea, weight gain).
Table 6.1: Summary of Key Drug Interactions with Insulin Detemir 15

7.0 Use in Special Populations

The safety and efficacy of insulin detemir must be carefully considered in specific patient populations where physiological changes can alter insulin requirements and increase the risk of adverse events.

7.1 Pregnancy and Lactation

• Pregnancy: Insulin detemir is considered safe for use during pregnancy. It is assigned FDA Pregnancy Category B and Australian TGA Pregnancy Category B3.[3] These categories indicate that while there are no adequate and well-controlled studies in pregnant women, animal reproduction studies have not demonstrated a fetal risk, or that animal studies have shown some risk but it is considered of uncertain significance in humans.[61] An open-label trial comparing insulin detemir to NPH insulin in pregnant women with T1D found no increase in the risk of fetal abnormalities with detemir.[61] Maintaining good glycemic control is crucial during pregnancy, as uncontrolled hyperglycemia poses significant risks to both the mother and fetus, including birth defects and pregnancy loss.[61] Insulin requirements typically change throughout gestation, often decreasing in the first trimester and increasing during the second and third trimesters, before declining rapidly postpartum. Therefore, frequent glucose monitoring and dose adjustments are essential.[61]
• Lactation: Insulin detemir is considered acceptable for use during breastfeeding.[61] While exogenous insulins are excreted into breast milk, insulin is a large protein that is inactivated in the infant's digestive tract if ingested and is therefore unlikely to cause harm.[61] Insulin is a normal component of human milk and may even play a role in the infant's gut maturation.[63] Breastfeeding mothers may require adjustments to their insulin dose and diet, as insulin requirements are often lower during lactation due to glucose utilization for milk production.[61]

7.2 Pediatric Use

Insulin detemir is approved for improving glycemic control in pediatric patients with T1D. The approved age varies by jurisdiction, with the EMA authorizing use from the age of 1 year and the FDA from the age of 2 years.[1] Safety and efficacy have not been established in children younger than these ages, nor have they been established for children with T2DM.[16] As in adults, it must be used in a basal-bolus regimen. Dosing must be carefully individualized and adjusted, particularly during growth spurts when insulin needs can change rapidly.[20]

7.3 Geriatric Use

The management of diabetes in elderly patients requires a careful balance between achieving glycemic control and avoiding hypoglycemia, to which this population is particularly vulnerable due to factors like comorbidities, cognitive impairment, and polypharmacy.[21] Long-acting insulin analogs like detemir are generally recommended over NPH for older adults because of their lower risk of hypoglycemia.[21]

A large observational sub-analysis of the SOLVE study specifically evaluated the initiation of once-daily insulin detemir in patients aged 75 years or older.[64] The study found that detemir was both effective and safe in this population. It produced significant improvements in HbA1c that were comparable to those seen in younger patients, without increasing the risk of severe hypoglycemia or causing weight gain.[64] However, some practical considerations may limit its suitability for all elderly patients. The frequent need for a twice-daily injection regimen to achieve full 24-hour coverage can be burdensome and may pose a challenge for individuals with impaired manual dexterity or cognitive function.[25] The higher cost of insulin detemir compared to older insulins like NPH may also be a factor.[25]

7.4 Renal Impairment

Patients with renal impairment may have altered insulin requirements. As kidney function declines, the metabolism and clearance of insulin are reduced, which can lead to increased circulating insulin levels and a higher risk of hypoglycemia.[55] Therefore, the prescribing information for insulin detemir recommends that patients with renal impairment may require a dose reduction and should undergo more frequent glucose monitoring.[15]

An observational study found a strong positive correlation between insulin detemir dosage and renal function (as measured by estimated glomerular filtration rate, or eGFR). Patients with an eGFR below 60 mL/min required a daily dose of insulin detemir that was approximately 27.3% lower than that required by patients with normal renal function (eGFR > 90 mL/min).[67] This highlights the critical need to adjust insulin therapy in parallel with the progression of diabetic nephropathy to maintain safety.

7.5 Hepatic Impairment

Similar to renal impairment, hepatic impairment can reduce a patient's insulin requirements. This is due to both reduced clearance of insulin and impaired capacity for gluconeogenesis in the liver.[55] Consequently, patients with liver disease may be at an increased risk of hypoglycemia. Cautious dosing, starting with lower initial doses, and frequent glucose monitoring are recommended for patients with hepatic impairment using insulin detemir.[15]

Furthermore, some clinical evidence suggests that the efficacy of insulin detemir may be reduced in patients with significant nonalcoholic fatty liver disease (NAFLD) and associated hypertriglyceridemia. Case reports have described a relative lack of effectiveness and the need for very high doses of detemir in such patients, with better glycemic control achieved upon switching to a different insulin like NPH.[68] The proposed mechanisms include altered hepatic insulin clearance or direct impairment of insulin signaling in fat-infiltrated hepatocytes. While not a universal finding, this suggests that in patients with severe NAFLD, the hepatoselective properties of insulin detemir may be a disadvantage, and alternative insulin choices should be considered if glycemic targets are not met with escalating doses.[68]

8.0 Comparative Efficacy and Safety Analysis

The clinical value of insulin detemir is best understood in the context of its therapeutic alternatives. Head-to-head clinical trials and meta-analyses have established its relative strengths and weaknesses compared to other basal insulins, from the older NPH insulin to its first- and second-generation analogue counterparts.

8.1 Comparison with NPH Insulin

Compared to NPH insulin, insulin detemir represents a significant therapeutic improvement. Numerous studies have shown that while both insulins provide equivalent glycemic control (as measured by reductions in HbA1c), insulin detemir does so with a more favorable safety profile.[3] The key advantages of insulin detemir over NPH are:

• Reduced Risk of Hypoglycemia: The flatter, more predictable action profile of insulin detemir leads to a significantly lower incidence of overall and, particularly, nocturnal hypoglycemic events.[6]
• Less Weight Gain: Treatment with insulin detemir is consistently associated with less weight gain than treatment with NPH insulin.[49]
• Lower Glycemic Variability: Insulin detemir demonstrates lower day-to-day variability in fasting plasma glucose levels, contributing to more stable and predictable glycemic control.[9]

8.2 Comparison with Insulin Glargine (First-Generation Analog)

Insulin glargine (100 U/mL, brand name Lantus®) was the other major first-generation long-acting analogue launched in a similar timeframe as insulin detemir. Head-to-head comparisons have generally shown more similarities than differences:

• Glycemic Control: Both insulin detemir and insulin glargine provide similar efficacy in terms of HbA1c reduction.[6]
• Hypoglycemia: The rates of hypoglycemia are broadly comparable between the two, although some studies have reported minor differences, often favoring one or the other depending on the specific patient population and study design.[6]
• Duration of Action: Some euglycemic clamp studies suggest that insulin glargine may have a slightly longer and more consistent 24-hour duration of action compared to insulin detemir, whose effects can wane before 24 hours in some individuals, often necessitating twice-daily dosing.[40]
• Weight Gain: Insulin detemir consistently demonstrates an advantage, being associated with significantly less weight gain than insulin glargine.[23]
• Tolerability: Some evidence suggests that insulin detemir may be associated with a higher incidence of injection site reactions and higher rates of discontinuation due to adverse events in patients with T2DM compared to insulin glargine.[23]

8.3 Comparison with Insulin Degludec (Second-Generation Analog)

Insulin degludec (brand name Tresiba®) is an ultra-long-acting second-generation basal analogue that was engineered for an even flatter and more prolonged action profile. Comparative studies have established a clear hierarchy in pharmacokinetic and some safety outcomes:

• Glycemic Control: Meta-analyses show no statistically significant difference in HbA1c reduction between insulin degludec, detemir, and glargine, indicating all are similarly effective at lowering average blood glucose.[23]
• Duration of Action and Dosing Flexibility: Insulin degludec has a clear advantage with a duration of action extending up to 42 hours. This allows for true once-daily dosing with significant flexibility in the timing of administration (as long as there are at least 8 hours between doses), a benefit not offered by insulin detemir.[22]
• Hypoglycemia: Insulin degludec demonstrates a superior safety profile, with a significantly lower risk of overall and nocturnal hypoglycemia compared to both insulin glargine and insulin detemir.[22]
• Weight Gain: Insulin detemir retains its advantage in this domain, with studies showing that patients taking detemir gain approximately 1 kg less body weight than those taking degludec (in T1DM).[23]

Parameter	Insulin Detemir	Insulin Glargine (U-100)	Insulin Degludec (U-100)
Glycemic Control (HbA1c)	Equivalent	Equivalent	Equivalent
Duration of Action	Up to 24 hours (often <24h)	~24 hours	Up to 42 hours
Dosing Frequency	Once or twice daily	Once daily	Once daily (flexible timing)
Nocturnal Hypoglycemia Risk	Lower than NPH; similar to Glargine	Lower than NPH; similar to Detemir	Lower than Glargine and Detemir
Weight Gain	Less than Glargine and Degludec	More than Detemir	More than Detemir
Injection Site Reactions	Higher than Glargine	Lower than Detemir	Similar to Glargine
Table 8.1: Comparative Profile of Long-Acting Insulin Analogues 6

9.0 Conclusion

Insulin detemir (Levemir®) represents a pivotal milestone in the evolution of diabetes therapy. Through a sophisticated manufacturing process combining recombinant DNA technology in Saccharomyces cerevisiae with subsequent chemical acylation, a unique insulin analogue was created. Its defining feature—a myristic acid chain attached to the lysine B29 residue—enabled a novel dual-protraction mechanism involving both subcutaneous self-association and extensive reversible binding to circulating albumin.

This molecular design successfully translated into a clinically meaningful improvement over older basal insulins like NPH. The resulting pharmacodynamic profile was flatter, more predictable, and associated with significantly lower intra-patient variability. For patients, this meant a reduced risk of hypoglycemia, particularly feared nocturnal episodes, and the notable ancillary benefit of attenuated weight gain. These advantages directly addressed major clinical barriers to insulin initiation and intensification, improving the safety and tolerability of basal insulin therapy for millions of people with type 1 and type 2 diabetes worldwide.

However, the clinical profile of insulin detemir also presented inherent limitations that ultimately defined its role as a transitional, rather than a definitive, basal insulin. Its dose-dependent duration of action, which often falls short of a full 24 hours, frequently necessitates a more complex twice-daily dosing regimen to maintain optimal glycemic control. This contrasts with the greater convenience of a true once-daily insulin. Furthermore, its unique chemical structure, while beneficial for protraction, was associated with a higher incidence of local injection site reactions and higher rates of discontinuation in some patient populations compared to its contemporary, insulin glargine.

The continued pursuit of an ideal basal insulin—one with an even flatter, longer, and more predictable profile—led to the development of second-generation analogues like insulin degludec. With a duration of action exceeding 42 hours, greater dosing flexibility, and a superior hypoglycemia risk profile, these newer agents have raised the standard of care for basal insulin therapy. The planned market discontinuation of Levemir® in major markets like the United States is a direct and logical consequence of this therapeutic progress. While its time as a frontline therapy is concluding, the legacy of insulin detemir is secure. It served as a critical bridge from the unpredictable era of NPH insulin to the modern age of highly engineered, ultra-long-acting analogues, demonstrating the profound clinical benefits that could be achieved through rational drug design.

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