Insulin degludec

Insulin degludec is an Antidiabetic Agent belonging to the pharmacological class of long-acting Insulin.

Insulin degludec is approved for treating diabetes mellitus in adults, adolescents, and children aged one year and above. It improves glycemic control in patients with type 1 or type 2 diabetes.

Insulin degludec, when administered, forms multiple hexamers upon injection, providing a consistent, slow, and steady insulin release into the bloodstream. The half-life is approximately 25 hours, primarily cleared by the kidneys.

Low blood sugar (hypoglycemia) is Insulin degludec's most common side effect. Other side effects include injection site responses, including redness, swelling, or hard lumps (lipohypertrophy). Some individuals who use Insulin may also gain weight.

Insulin degludec is available as an injectable solution (prefilled pen).

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Insulin degludec is an Antidiabetic Agent belonging to the pharmacological class of long-acting Insulin.

Regulation of glucose metabolism is the primary function of Insulin, including Insulin Degludec. Insulin and its analogues reduce blood sugar by blocking hepatic glucose synthesis and boosting peripheral glucose absorption, particularly by skeletal muscle and fat. In addition, Insulin blocks lipolysis and proteolysis while promoting protein synthesis. A subcutaneous insulin degludec depot is created when insulin degludec is injected into the subcutaneous tissue and generates multi-hexamers. Insulin Degludec has a prolonged period of action, mainly caused by delayed absorption into the bloodstream from subcutaneous tissue and, to a lesser extent, by binding to circulating albumin.

Data duration of Insulin degludec action for up to 42 hours after administration.

The Data of Tmax of Insulin degludec 1 to 3 hours after subcutaneous administration.

The Data of Cmax of Insulin degludec needs to be established.

Insulin degludec is available as an injectable solution (prefilled pen).

Injectable solution: To be administered parenterally, as applicable.

To use the Insulin degludec injectable solution, prepare the dose, identify an injection site, disinfect it, prepare the pen, dial the quantity, administer the Insulin subcutaneously, and cautiously dispose of the needle. For proper use, adhere to the doctor's recommendations.

Diabetes

• It is used to enhance blood sugar management in type 1 diabetic people and children (aged one and older). It provides long-acting insulin coverage, maintaining blood sugar levels throughout the night and between meals.
• Adults with type 2 diabetes may also use it. Supplying a steady supply of basal Insulin, lowering blood glucose levels, and managing hyperglycemia helps regulate blood sugar.

In Treatment of diabetes mellitus

Insulin degludec is an ultra-long-acting type of Insulin that provides a consistent basal insulin supply, helping maintain stable blood sugar levels and lowering the risk of high or low blood sugar episodes. It replaces the Insulin that is typically produced in the body. It helps regulate blood sugar levels and synthesises energy from sugar by promoting glucose entry into cells.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine. Thus, by stabilizing blood sugar levels and reducing the risk of hypoglycemia, insulin degludec contributes to an improved quality of life for those with diabetes.

• Children and adolescents with diabetes mellitus type 1 between aged 1 to 17 are indicated to use long-acting basal Insulin to enhance their glycemic control.
• Long-acting basal Insulin is indicated for people with type 1 and 2 diabetes mellitus to enhance glycemic control.

Parenterally: Insulin degludec is an injectable solution (prefilled pen) that can be taken parenterally. Administer a subcutaneous injection once daily at any time. Rotate injection sites within the upper arm, the thigh, or abdomen to lower the risk of lipodystrophy. Do not administer through IV, IM, or an insulin pump. Consider increasing the dose after three to four days and adjusting it based on metabolic requirements, blood glucose monitoring, and glycemic targets. To avoid hypo- or hyperglycemia, adjustments may be required when activities, eating habits, or health conditions change. Encourage patients to take any missed doses as soon as they remember and wait at least 8 hours between each subsequent injection.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injectable solution (Prefilled pen): 100 units/mL or 200 units/mL

Insulin degludec is available as an injectable solution (prefilled pen).

Dose Adjustment in Adult Patients:

Type 1 Diabetes Mellitus

Initial dose for insulin-naïve patients

Start with 1/3-1/2 of the daily insulin dose; split the remaining portion between each meal.

0.2 to 0.4 units/kg is the recommended initial dosage range.

Type 2 Diabetes Mellitus

Initial dose for insulin-naïve patients

Start ten units SC qDay

Dosing Considerations

Patients who may depend on auditory clicks to dial their dose of insulin degludec should be used with caution if they have vision impairment.

Starting dosage for those who are currently on insulin treatment

Type 1 or Type 2 diabetes mellitus: Begin insulin degludec at the same dose as the daily long-acting or intermediate-acting insulin unit dose.

Insulin degludec should be used in treating Diabetes Mellitus, along with appropriate nutritional limits.

While taking Insulin degludec, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages, as they can lead to rapid spikes in blood glucose. In case of hypoglycemia, always carry a source of fast-acting glucose (like glucose tablets or gel) to treat promptly.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Insulin degludec may be contraindicated in the following conditions:-

• Documented hypersensitivity to Insulin degludec or any of the excipients in Insulin Degludec
• During episodes of hypoglycemia.

• Even though the needle is replaced, sharing disposable prefilled insulin pens between patients is never advisable. Never share needles or syringes with any individual when using Insulin Degludec vials. Blood-borne infections may be transmitted through sharing.
• Adjustments in the amount, type, or manner of insulin delivery may impact glycemic control and raise the risk of hypoglycemia or hyperglycemia. These adjustments should only be conducted under medical supervision and blood glucose testing should be done more often.
• Anaphylaxis, a severe, perhaps fatal, generalised allergy, can develop; if this happens, stop taking your medication, treat it as usual, and monitor the signs until they disappear.
• A shift in potassium from the extracellular to the intracellular space is a common effect of all insulin products and may result in hypokalemia. When patients are at risk for hypokalemia, whether taking a prescription that lowers their potassium levels or affects how much potassium is in their blood, their potassium levels should be monitored and treated as necessary.
• Never withdraw a medicine from a pen injector into a syringe using a syringe to prevent dosage mistakes and possible overdose.
• When combined with Insulin, the peroxisome proliferator-activated receptor (PPAR)-gamma agonist thiazolidinediones can produce dose-related fluid retention, which can cause or aggravate heart failure.
• Hypoglycemia or Hyperglycemia Associated with Changes in Insulin Regimen: Changes to an insulin regimen (such as insulin strength, manufacturer, type, injection location, or administration technique) may impact glycemic control and increase the risk of hypoglycemia Or diabetes mellitus. A quick shift in the injection location (to an unaffected region) has been observed to cause hypoglycemia. In contrast, repeated insulin injections into areas of lipodystrophy or localised cutaneous amyloidosis have been documented to cause hyperglycemia. Any adjustments to a patient's insulin regimen should be made under intensive physician supervision with more frequent blood glucose testing. Recommend to patients who have been injected into regions of lipodystrophy or localised cutaneous amyloidosis that they should alter the injection site and monitor out for hypoglycemia. Regulating concurrent antidiabetic therapy may be required for people with type 2 diabetes.

It is unsafe to consume Insulin degludec with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Insulin degludec in breastfeeding.

Safe to use during pregnancy but only if the possible benefit outweighs the potential risk to the foetus.

Limit Alcohol consumption and reduce sugary and high-glycemic-index foods and beverages.

The adverse reactions related to Insulin degludec can be categorized as

• Common Adverse Effects: Nasopharyngitis, severe hypoglycemic episode, upper respiratory tract infection, headache
• Less Common Adverse Effects: Diarrhea, sinusitis, gastroenteritis, injection site reactions, peripheral oedema.
• Rare Adverse Effects: Lipodystrophy (changes in fat tissue)

Reports on Postmarketing

Localized cutaneous amyloidosis at the injection

The clinically relevant drug interactions of Insulin degludec are briefly summarized here.

• Hypoglycemic Agents: When used with other antidiabetic medications like sulfonylureas, meglitinides, or Insulin, there's an increased risk of hypoglycemia (low blood sugar). Dosage adjustments may be needed.
• Thiazolidinediones (TZDs): Combining TZDs with insulin degludec may increase the risk of heart failure. Careful monitoring is essential when using both.
• Beta-Blockers: Beta-blockers may mask some of the symptoms of hypoglycemia (e.g., tachycardia). Dosage adjustment and increased frequency of glucose monitoring may be required when Insulin Degludec is co-administered with these drugs.
• Other Medications: Certain medications, like corticosteroids, thyroid hormones, and sympathomimetic agents, may alter glucose metabolism and require dose adjustments of insulin degludec.

The most common side effects of Insulin degludec include:

• Low blood sugar is commonly referred to as hypoglycemia.
• Swelling, pain and redness at the site where the injection was administered.

• Pregnancy

Pregnancy Category C; Use with caution if benefits outweigh risks.

Pregnancy-related drug use has not been associated with a substantially increased risk of significant birth abnormalities, miscarriages, or other adverse maternal or foetal outcomes, according to information from one unpublished experiment and published research.

No obvious indication of harm to the mother or foetus was shown in a clinical investigation in which pregnant women with type 1 diabetes were given this medication once daily along with insulin aspart, starting in gestational weeks 8 to 13 or before conception.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Patients with pre-gestational diabetes are more likely to experience hypo- and hyperglycemia throughout pregnancy. Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, premature birth, and other problems. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Human data

In an open-label clinical research, 185 type 1 diabetic pregnant women were administered insulin part 2 to 4 times daily with meals in either the Insulin Degludec (once daily) or Insulin Detemir (once or twice daily) group. There were no appreciable drug-related variations between the two groups regarding pregnancy outcomes or the well-being of the foetus and baby. Regarding the severe hypoglycemia and hypoglycemia criteria in this trial, see Adverse Reactions (6.1) for a comparison of the proportion of individuals in each treatment arm. The study was limited by poor glycemic management throughout pregnancy in both groups and a small sample size.

About two-thirds of newborns had levels of insulin degludec in their cord blood that were over the lower limit of quantification of the assay.

Animal Data

Studies on fertility, embryo-fetal development, pre-and postnatal development, and insulin degludec were conducted in rats and rabbits throughout the embryo-fetal development stage. A comparator was used, which was human Insulin (NPH insulin). In these studies, subcutaneous administration of insulin degludec at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits resulted in 5 times (for the rats) and ten times (for the rabbits) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. These subcutaneous administration doses also resulted in pre- and post-implantation losses and visceral/skeletal abnormalities. The effects of insulin degludec were generally comparable to those of human Insulin and were most likely caused by maternal hypoglycemia.

• Nursing Mothers

There is no data regarding the presence of insulin degludec in human milk, its effects on breastfed children, or its impact on milk production.

Rat milk contains insulin degludec.

Consider the developmental and health advantages of nursing, the mother's clinical need for the medication, and any potential adverse effects on the breastfed newborn from the medicine or the underlying maternal disease

• Pediatric Use

Insulin Degludec has been proven to be safe and effective for treating paediatric patients with diabetes mellitus one year of age or older to enhance glycemic control. Evidence from a sufficient and well-controlled trial and pharmacokinetic research, which included paediatric patients with type 1 diabetes mellitus aged one year and older, support the use of Insulin Degludec for this indication. Evidence from appropriate and well-controlled studies in adults with type 2 diabetes mellitus also supports the use of Insulin Degludec in paediatric patients aged one year and older.

Initiate Insulin Degludec at a lower dose in children one year of age and older who are already receiving insulin treatment to lessen the risk of hypoglycemia.

Paediatric patients under one have not yet been subject to Insulin Degludec safety and efficacy studies.

Dose Adjustment in Pediatric Patient

<1 year: Safety and efficacy not established

Type 1 Diabetes Mellitus

Children and adolescents aged 1 to 17

Initial dosage for patients who are insulin-naive

Start with 1/3 to 1/2 of the daily insulin dose; split the remaining portion between each meal.

0.2 to 0.4 units/kg is the typical initial dosage range.

Type 2 Diabetes Mellitus

Children and adolescents aged 1 to 17

Ten units SC qDay is the first dose for insulin-naive individuals.

Dosing Considerations

Use Restrictions

It is not recommended for diabetic ketoacidosis.

Paediatric patients requiring less than five units of insulin degludec are not advised.

• Geriatric Use

Of the 1102 type 1 diabetes patients treated with Insulin Degludec in controlled clinical studies, 77 (7%) were 65 or older, and 9 (1%) were 75 or older. Of the 2713 type 2 diabetes patients who received Insulin Degludec treatment, 670 (25%) and 80 (3%) were 75 or older, respectively. Subgroup studies contrasting patients over 65 with younger subjects failed to identify differences in safety or efficacy.

Of the 3818 type 2 diabetic patients who received Insulin Degludec treatment in the safety outcomes study (DEVOTE), a total of 1983 (52%) and 381 (10%) were 75 years of age or older. There were no variations in these subgroups in terms of safety or efficacy.

However, caution should be used while administering Insulin Degludec to geriatric patients because certain elderly people may be more sensitive to its effects. The initial dosage, dose increases, and maintenance dosage should all be cautious to prevent hypoglycemia. In elderly people, hypoglycemia could be more challenging to determine.

Dose Adjustment in Kidney Impairment Patients:

In research comparing healthy people with subjects with renal impairment, including issues with end-stage renal disease, no clinically significant variation in the pharmacokinetics of insulin degludec was observed.

Dose Adjustment in Hepatic Impairment Patients:

In research comparing healthy people with those with hepatic impairment (mild, moderate, and severe), no differences in the pharmacokinetics of insulin degludec were observed.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Insulin degludec.

Overconsumption of Insulin degludec could lead to hypoglycemia symptoms such as sweating, confusion, tremors, and palpitations. Severe cases may lead to life-threatening hypokalemia, seizures or coma.

Management

There is no specific antidote or treatment for excessive intake of Insulin degludec. However, immediate medical attention is essential. Insulin degludec should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Mild hypoglycemia can often be managed with oral glucose and potential adjustments in insulin dosage, meal timing, or exercise. Severe hypoglycemia may require emergency measures like glucagon or intravenous glucose. After recovery, ongoing monitoring and additional carbohydrate intake may be needed to prevent recurrence. Additionally, hypokalemia should be treated as necessary.

Modifying the medicine dose, eating habits, or exercise routine may be necessary.

Management typically involves supportive measures and symptomatic treatment. The patient will continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

The beta cells in the pancreas produce the hormone insulin regularly. The pancreas continuously generates low amounts of basal Insulin in non-diabetics and increases insulin levels after meals. The metabolic alterations that occur as the body shifts from a postabsorptive to an absorptive state are brought on by increased insulin secretion after meals. Insulin encourages cellular uptake of glucose, especially in muscle and fatty tissues, enhances energy storage via glycogenesis, increases DNA replication, and fights against the catabolism of energy stores and protein synthesis by increasing the amino acid uptake by the liver, muscle and adipose tissue, and changes the activity of many enzymes involved in glycogen synthesis and glycolysis. The effects of growth hormone, including protein synthesis, cell division, and DNA synthesis, require Insulin, which also stimulates growth. With an unaltered and predictable action profile, insulin detemir is a long-acting insulin analogue. The basal insulin levels in people with diabetes are mimicked by it. Insulin detemir takes up to 24 hours to start working and 1 to 2 hours to finish. Weirdly, compared to human Insulin, it has a lesser affinity for the insulin receptor (30%).

Pharmacokinetics:

Absorption

Maximum insulin degludec concentrations of 4472 pmol/L were achieved in individuals with type 1 diabetes following eight days of once-daily subcutaneous treatment with 0.4 U/kg (tmax). The median appearance after the first dose began around an hour later. The final of eight once-daily injections had a glucose-lowering impact for at least 42 hours. It takes 3–4 days for the concentration of insulin degludec to stabilise.

Peak plasma time: 9 hr

Peak plasma concentration: 4472 pmol/L

Steady-state: 3-4 days

Distribution

A plasma protein binding of more than 99% in human plasma is consistent with the affinity of insulin degludec to serum albumin. According to the findings of the in vitro protein binding studies, there is no clinically significant interaction between insulin degludec and other protein-bound medications.

The apparent volume of distribution was calculated to be 10.6 L for paediatric patients and 13.9 L for adults using a one-compartment pharmacokinetics model.

Protein-bound: >99% to albumin

Metabolism

The metabolites of insulin degludec are all inert. The liver and kidney mostly carry out insulin metabolism. However, although exogenous Insulin is metabolised mainly through the kidney since it is not immediately transported into the portal system, endogenous Insulin is primarily metabolised by the liver.

Metabolites: Inactive

Elimination

Following subcutaneous administration, the rate at which insulin degludec is absorbed from subcutaneous tissue significantly impacts its half-life. No matter the dosage, the half-life is typically constant in a steady state at around 25 hours. The kidneys eliminate between 30 and 80 per cent of the Insulin in circulation. Following a single 0.4 unit/kg subcutaneous injection, the apparent elimination of insulin degludec averages 0.03 L/kg (corresponding to 2.1 L/h in people weighing 70 kg).

Half-life: ~25 hr

Clearance: 0.03 L/kg

• Kalra, Sanjay, and Yashdeep Gupta. “Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions.” North American Journal of medical sciences vol. 7,3 (2015): 81-5. doi:10.4103/1947-2714.153918
• Philis-Tsimikas, A., Klonoff, D.C., Khunti, K. et al. Risk of hypoglycaemia with insulin degludec versus Insulin degludecU300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial. Diabetologia 63, 698–710 (2020). https://doi.org/10.1007/s00125-019-05080-9
• Lane W, Bailey TS, Gerety G, et al. Effect of the Insulin Degludec vs Insulin degludecU100 on Hypoglycemia in the Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial. JAMA. 2017;318(1):33–44. doi:10.1001/jama.2017.7115
• Wei Liu, Xiaojie Yang, Jing Huang, "Efficacy and Safety of Insulin Degludec versus Insulin Glargine: A Systematic Review and Meta-Analysis of Fifteen Clinical Trials", International Journal of Endocrinology, vol. 2018, Article ID 8726046, 10 pages, 2018. https://doi.org/10.1155/2018/8726046
• Dawn Battise; A New Basal Insulin Option: The BEGIN Trials in the Patients With Type 2 Diabetes. Clin Diabetes 1 October 2013; 31 (4): 166–170. https://doi.org/10.2337/diaclin.31.4.166

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies on the carcinogenicity of insulin degludec administered for over two years have yet to be done. In a 52-week study with Sprague-Dawley rats, subcutaneous administration of insulin degludec at doses of 3.3, 6.7, and 10 units/kg/day led to exposures (AUC) 5 times higher than those associated with human subcutaneous doses of 0.75 units/kg/day. Human Insulin was administered at 6.7 units/kg/day. In female mammary glands of rats receiving insulin degludec, neither significant alterations in cell proliferation nor increases in hyperplasia, benign or malignant tumours, were shown to be treatment-related. In addition, compared to animals receiving the vehicle or human Insulin, there were no treatment-related differences in the frequency of hyperplastic or neoplastic lesions in other tissues in the animals receiving insulin degludec.

Insulin degludec was not tested for genotoxicity testing.

Treatment with insulin degludec up to 21 units/kg/day (roughly five times the human subcutaneous dose of 0.75 units/kg/day, based on units/body surface area) before mating and in female rats during gestation had no impact on mating performance or fertility in a combined fertility and embryo-fetal study in male and female rats.

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