Insulin Degludec (Tresiba) - a Long-acting Insulin analog

Insulin Degludec (Tresiba) is long-acting insulin with a half-life elimination of about 25 hours. Compared to Insulin glargine and insulin detemir, other long-acting insulin formulations, it may be administered as a once-daily injection at any time of the day. It is used for the treatment of hyperglycemia in patients aged one year or older with type-1 or type-2 diabetes mellitus.

Insulin Degludec Dose in Adults

Insulin Degludec Dose in the treatment of type 1 Diabetes mellitus: 

Note:

  • Patients with type 1 Diabetes mellitus should be advised insulin Degludec as basal insulin and rapid or short-acting insulins as prandial insulins (multiple daily injections are required).
  • The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

Insulin Degludec General insulin dosing:

  • Initial TDD (total daily dose):
    • 0.2 - 0.4 units /kg/day initially to avoid hypoglycemia. The dose is adjusted according to the blood glucose levels.
    • Obese patients may be initiated at a dose of about 0.4 - 0.5 units/kg/day.
  • The usual maintenance (total daily dose) ranges between 0.4 - 1 unit/kg/day that is administered in divided doses.

The total daily dose may be divided into multiple daily injections as follows:

  • Basal insulin (insulin degludec):

    • 40% - 50% of the total daily dose is administered as basal insulin once daily.
  • Prandial insulin:

    • The remaining portion is divided and administered before meals. Premeals insulins comprise mostly of rapid (Aspart, lispro, and glulisine) and short-acting (regular) insulins.

The dose of insulin Degludec should be adjusted at 3 - 7 days interval to minimize the risk of hypoglycemia.


Insulin Degludec Dose in the treatment of type 2 Diabetes mellitus:

  • Basal insulin may be added to oral therapy if the patients' glycemic control is inadequate.
  • Furthermore, if the glycated hemoglobin is greater than 10%, the blood glucose is more than 300 mg/dl and the patient is symptomatic, insulin may be considered as a part of initial treatment.
  • Long-acting insulins may be preferred in patients at risk of hypoglycemia.
  • Treatment initiation

    • Initiate with 8 - 10 units once a day or 0.1 - 0.2 units/kg once a day.
    • If the glycated hemoglobin is more than 8% before the initiation of basal insulin, treatment may be initiated at a higher dose (0.2 - 0.3 units/kg once a day).

Insulin Degludec Dosage adjustment:

  • The dose may be adjusted by 10% - 15% or 2 - 4 units at weekly or twice weekly intervals until the target blood glucose levels are achieved.
  • Patients who develop hypoglycemia:

    • Reduce the dose by 4 units or 10 - 20% of the usual dose.
  • When prandial or pre meals insulin is added to the regimen:

    • The dose should be reduced by 4 units or 10% of the dose if the glycated hemoglobin is less than 8%.
  • Patients receiving enteral feeding:

    • Advise 30 - 50% of the total daily dose as basal insulin and 50 - 70% of the TDD prior to feeding.
  • Diabetic patients undergoing surgery:

    • Administer 60 - 80% of the usual dose of long-acting insulin in the morning or night before surgery.
  • Conversion from other long-acting insulins:

    • Insulin Degludec should be initiated at the same dose of the previously administered long-acting insulin.
  • If the dose is missed:

    • Administer the same dose as soon as possible. Ensure at least a gap of eight hours between 2 doses [Ref].

Insulin Degludec Dose in Children:

  • Insulin dosing may vary with weight, age, duration of diabetes, caloric intake, physical activity, other concomitant medications, and the type of diabetes.
  • It is aimed to achieve a euglycemic state. Insulin Degludec provides basal coverage.
  • Most type 1 patients will still require short or rapid-acting insulin for prandial cover.
  • Type 2 diabetes patients may require basal insulin along with oral anti-diabetic medications or basal and prandial insulin.
  • Insulin Degludec is available in vials and FlexTouch pens as U-100 and U-200. FlexTouch pens U-200 can not deliver units that are odd in number.

Insulin Degludec dose in the treatment of Type 1 diabetes mellitus:

  • General insulin dosing:

    • The usual maintenance total daily insulin dose ranges between 0.5 - 1 unit/kg/day in divided doses.
    • Treatment is initiated at a lower dose and adjusted according to the blood glucose levels.
    • Patients in partial remission or the honeymoon phase of diabetes may require less than 0.5 units/kg/day.
    • Prepubertal children not in remission may require 0.7 - 1 units/kg/day
    • During puberty and the adolescents period, the dose may substantially increase and the patients may require more than 1.2 units/kg/day.
    • The total daily dose is administered as 50 - 75% basal insulin and 25 - 50% prandial insulin.
    • Basal insulin may be any of the long-acting insulins like NPH, detemir, glargine, and Degludec. Prandial insulin may be regular insulin or the rapid-acting insulins (lispro, glulisine, and Aspart).
    • Basal insulin is usually given as once daily (except NPH that may be given twice) while the prandial insulin is administered as twice or thrice daily prior to meals.

Insulin Degludec-specific dosing:

It should not be advised to children requiring 5 units or less.

Insulin-naive patients:

  • The usual initial total daily dose is 0.2 - 0.4 units/kg/day out of which 1/3rd to 1/2 is administered as insulin Degludec and the rest is administered as short or rapid-actin insulin prior to each meal (prandial insulin).

Insulin-experienced patients:

  • Patients already on long-acting insulin should be advised 80% of the insulin Degludec dose when switching from another long-acting insulin.

Dosage adjustment:

The dose should be adjusted every 3 - 4 days based on the patient's glucose levels and insulin requirement.


Insulin Degludec dose in children with Type 2 diabetes mellitus:

General insulin dosing:

Long-acting insulin may be added to metformin or other antidiabetic medicines as a once-daily subQ injection if the plasma glucose is more than 25 mg/dl or the glycated hemoglobin is 9% or more. Prandial insulin may be added if the target glucose is not reached despite the optimal dose.

Insulin Degludec-specific dosing:

  • Insulin-naive patients:

    • 8 - 10 units once a day initially
  • Insulin-experienced patients:

    • Patients should be advised insulin Degludec at 80% of the total daily dose of long or intermediate-acting insulin from which the patient is being converted
  • Dosage adjustment:

    • The dose should be adjusted every 3 to 4 days based on the patient’s plasma glucose and the metabolic requirements.

Pregnancy Category C

  • Data are limited regarding the use of insulin Degludec in pregnant patients.
  • Insulin is preferred over other agents to treat hyperglycemia in pregnancy.
  • Hyperglycemia in pregnancy is associated with significant fetal adverse effects including congenital malformations.
  • For the best pregnancy outcomes, blood glucose should be kept as close to the target goals as possible without causing significant hypoglycemia.
  • Insulin requirements usually fall during the first trimester and increase in the second and third trimesters peaking at 28 - 32 weeks of gestation.
  • Insulin requirements fall rapidly following delivery.

Use during breastfeeding:

  • Breastfeeding should be continued while the mother is on insulin.
  • Experience with insulin Degludec during breastfeeding is limited.
  • The manufacturer recommends using it with caution during breastfeeding.

Insulin Degludec dose in Kidney disease:

  • Adjustment in the dose has not been provided by the manufacturer in patients with renal disease.
  • Blood glucose should be frequently monitored and the dose adjusted accordingly.

Use in Liver disease:

  • Adjustment in the dose has not been provided by the manufacturer in patients with liver disease.
  • Blood glucose should be frequently monitored and the dose adjusted accordingly.

Insulin Degludec Side effects (Common):

  • Central nervous system:

    • Headache
  • Endocrine & metabolic:

    • Severe hypoglycemia
  • Immunologic:

    • Antibody development
  • Respiratory:

    • Nasopharyngitis
    • Upper respiratory tract infection

Less Common Side Effects of Insulin Tresiba Include:

  • Cardiovascular:

    • Peripheral edema
  • Gastrointestinal:

    • Diarrhea
    • Gastroenteritis
  • Local:

    • Injection site reaction including
      • Discoloration
      • Erythema
      • Hematoma
      • Hemorrhage
      • Mass
      • Nodules
      • Pain
      • Pruritus
  • Respiratory:

    • Sinusitis

Rare side effects on Insulin Tresiba:

  • Endocrine & metabolic:

    • Hypokalemia
    • Weight gain

Insulin Degludec Contraindications:

  • Allergic reactions to insulin Degludec or any component of the formulation
  • Hypoglycemic episodes.

Insulin Degludec Warnings & Precautions

  • Glycemic control:

    • Changes in the insulin formulations and strengths may result in a change in blood glucose levels.
    • The most common side effect of insulins and insulin Degludec is hypoglycemia.
    • Patients who skip their meals, perform strenuous exercise, have renal or hepatic dysfunction are especially at risk of developing hypoglycemia.
    • Recovery from hypoglycemia may be delayed in patients on long-acting preparations of insulins like glargine, detemir, and insulin Degludec.
    • The symptoms of hypoglycemia may be masked in patients who experience recurrent hypoglycemia, those on Beta-Blockers, patients with long-standing diabetes, and patients with diabetic neuropathy.
    • Severe hypoglycemia may result in seizures, coma, brain damage, and even death.
  • Hypersensitivity:

    • Treatment must be discontinued if the patient develops allergic reactions.
    • Allergic reactions including anaphylaxis may be severe and life-threatening.
  • Hypokalemia:

    • Hypokalemia may occur in patients on insulin as a result of the intracellular shift of potassium. Hypokalemia may result in serious cardiac arrhythmias.
    • Potassium supplementation may be required.
  • Diabetic ketoacidosis:

    • Patients with diabetic ketoacidosis should be advised rapid or short-acting insulin.
    • It should be avoided in such patients.
  • Hepatic impairment:

    • Patients with hepatic impairment should be advised insulin Degludec with caution and may require dose adjustment.
  • Renal impairment:

    • Patients with renal impairment may require dose adjustment. It should be used with caution in patients with renal impairment.

Insulin degludec: Drug Interaction

Risk Factor C (Monitor therapy)

Alpha-Lipoic Acid

May enhance the hypoglycemic effect of Antidiabetic Agents.

Androgens

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol.

Antidiabetic Agents

May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.

Beta-Blockers

May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol.

Direct Acting Antiviral Agents (HCV)

May enhance the hypoglycemic effect of Antidiabetic Agents.

Edetate CALCIUM Disodium

May enhance the hypoglycemic effect of Insulins.

Guanethidine

May enhance the hypoglycemic effect of Antidiabetic Agents.

Herbs (Hypoglycemic Properties)

May enhance the hypoglycemic effect of HypoglycemiaAssociated Agents.

Hyperglycemia-Associated Agents

May diminish the therapeutic effect of Antidiabetic Agents.

Hypoglycemia-Associated Agents

May enhance the hypoglycemic effect of other HypoglycemiaAssociated Agents.

Hypoglycemia-Associated Agents

Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.

Maitake

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Monoamine Oxidase Inhibitors

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Pegvisomant

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Prothionamide

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Quinolones

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use.

Ritodrine

May diminish the therapeutic effect of Antidiabetic Agents.

Salicylates

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Selective Serotonin Reuptake Inhibitors

May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.

Thiazide and Thiazide-Like Diuretics

May diminish the therapeutic effect of Antidiabetic Agents.

Risk Factor D (Consider therapy modification)

Dipeptidyl Peptidase-IV Inhibitors

May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia.

Glucagon-Like Peptide-1 Agonists

May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide.

Liraglutide

May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda).

Metreleptin

May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely.

Pioglitazone

May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure.

Pramlintide

May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control.

Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors

May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia.

Risk Factor X (Avoid combination)

Macimorelin

Insulins may diminish the diagnostic effect of Macimorelin.

Rosiglitazone

Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination.

Monitoring Parameters:

  • Monitor the patient’s blood sugars, glycated hemoglobin, and weight at regular intervals.
  • Prior to initiating therapy, renal and liver functions should be monitored.
  • The target premeals blood sugars should be kept between 70 – 130 mg/dl, Post-prandial blood sugars should be kept to less than 180 mg/dl, while the glycated hemoglobin to less than 7% (for most patients, although, it should be individualized).

How to administer Insulin degludec?

  • It is administered subQ into the thigh, upper arm, or abdomen using the U-100 insulin syringes.

Intramuscular, Intravenous, or administration via an insulin infusion pump should be avoided.

  • The rate of absorption varies depending on the site of injection.
  • The site of injection should be rotated to reduce the risk of lipodystrophy. It is administered as a once-daily injection at any time of the day.

Administration using FlexTouch pens:

  • Switching from a vial to flexpen does not need any dose conversion.
  • The number of units to be delivered is shown in the dose window for both U-100 and U-200.
  • However, U-200 can not be used to inject an odd number of units.
  • It should not be mixed with other insulin formulations or solutions.

Mechanism of action of Insulin Degludec:

  • Insulin regulates the metabolism of carbohydrates, fats, and proteins.
  • It stimulates glycogen synthesis and fatty acids in the liver.
  • In the skeletal muscles, it results in protein synthesis and increased glycogen synthesis.
  • In adipose tissues, it stimulates triglyceride synthesis, process lipoproteins to provide free fatty acids.
  • It also stimulates the cellular uptake of proteins and promotes potassium uptake by the cells by activating the sodium-potassium ATPases.
  • Insulin Degludec is a long-acting insulin analog that has slightly different amino acid sequences in its structure.
  • It lacks the amino acid threonine in position B-30 of the B-chain and has a side chain composed of glutamic acid and a C16 fatty acid.
  • The various insulin formulations are categorized based on their onset of action, peak, and duration of effect as rapid, short, intermediate, and long-acting insulin.
  • The onset and duration of action also depend on the site of administration, local blood supply, temperature, lipodystrophy, and exercise.

Insulin Degludec is a long-acting insulin analog.

The onset of action of insulin degludec is about one hour. 99% of it is bound to proteins and it has a half-life elimination of about 25 hours that is independent of the dose with a peak onset of action in about 9 hours. 

Insulin degludec Brand Names (International):

  • Tregludec
  • Tresiba

Insulin Degludec Brand Names in Pakistan:

No brands of Insulin Degludec available in Pakistan. It is, however, available in combination with insulin Aspart by the brand name of Insulin Ryzodeg

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