XULTOPHY

Insulin degludec is an ultra-long-acting form of insulin used for the treatment of hyperglycemia caused by Type and Type 2 Diabetes. 1, 2, 3, 4, 5 Insulin is typically prescribed for the management of diabetes mellitus to mimic the activity of endogenously produced human insulin, a peptide hormone produced by beta cells of the pancreas that promotes glucose metabolism. 1, 2, 3, 4, 5 Insulin is released from the pancreas following a meal to promote the uptake of glucose from the blood into internal organs and tissues such as the liver, fat cells, and skeletal muscle. 1, 2, 3, 4, 5 Absorption of glucose into cells allows for its transformation into glycogen or fat for storage. 1, 2, 3, 4, 5 Insulin also inhibits hepatic glucose production, enhances protein synthesis, and inhibits lipolysis and proteolysis among many other functions. 1, 2, 3, 4, 5 Insulin is an essential treatment in the management of Type 1 Diabetes (T1D) which is caused by an autoimmune reaction that destroys the beta cells of the pancreas, resulting in the body not being able to produce or synthesize the insulin needed to manage circulating blood sugar levels. 1, 2, 3, 4, 5 As a result, people with T1D rely primarily on exogenous forms of insulin, such as insulin degludec, to lower glucose levels in the blood. 1, 2, 3, 4, 5 Insulin is also used in the treatment of Type 2 Diabetes (T2D), another form of diabetes mellitus that is a slowly progressing metabolic disorder caused by a combination of genetic and lifestyle factors that promote chronically elevated blood sugar levels. 1, 2, 3, 4, 5 Without treatment or improvement in non-pharmacological measures such as diet and exercise to lower blood glucose, high blood sugar eventually causes cellular resistance to endogenous insulin, and in the long term, damage to pancreatic islet cells. 1, 2, 3, 4, 5 Insulin is typically prescribed later in the course of T2D, after several oral medications such as Metformin, Gliclazide, or Sitagliptin have been tried, when sufficient damage has been caused to pancreatic cells that the body is no longer able to produce insulin on its own. 1, 2, 3, 4, 5 Marketed as the brand name product Tresiba, insulin degludec has a duration of action up to 42 hours allowing for once-daily dosing, typically at bedtime. 1, 2, 3, 4, 5 Due to its duration of action, Tresiba is considered "basal insulin" as it provides low concentrations of background insulin that can keep blood sugar stable between meals or overnight. 1, 2, 3, 4, 5 Basal insulin is often combined with short-acting "bolus insulin" such as Insulin lispro, Insulin glulisine, or Insulin aspart to provide higher doses of insulin required following meals.

Use of basal and bolus insulin together is intended to mimic the pancreas'production of endogenous insulin, with the goal of avoiding any periods of hypoglycemia. 1, 2, 3, 4, 5 Compared to endogenous insulin, insulin degludec has an added hexadecanedioic acid on lysine at the B29 position, allowing for the formation of multi-hexamers. 1, 2, 3, 4, 5 When injected Subcutaneous, these multi-hexamers form a drug depot store from which monomers are slowly and continuously absorbed into circulation. 1, 2, 3, 4, 5 As a result, Insulin Degludec has a protracted time action profile due to the delayed absorption from subcutaneous tissue depots into the systemic circulation. 1, 2, 3, 4, 5 Compared to available long-acting analogs such as Insulin glargine and Insulin detemir, which have a duration of action of 20-24 hours, insulin degludec provides a consistent level of basal insulin over 42 hours with a low peak: trough ratio. 1, 2, 3, 4, 5 Limitations of shorter-acting analogs include more frequent dosing and less stable pharmacokinetics, which may negatively impact patient adherence and glucose control, particularly nocturnal control. 1, 2, 3, 4, 5 Without an adequate supply of insulin to promote absorption of glucose from the bloodstream, blood sugar levels can climb to dangerously high levels and can result in symptoms such as fatigue, headache, blurred vision, and increased thirst. 1, 2, 3, 4, 5 If left untreated, the body starts to break down fat, instead of glucose, for energy which results in a build-up of ketone acids in the blood and a syndrome called ketoacidosis, which is a life-threatening medical emergency.

In the long term, elevated blood sugar levels increase the risk of heart attack, stroke, and diabetic neuropathy. 1, 2, 3, 4, 5 Insulin Degludec was approved by the FDA in September as the product Tresiba, for use in providing glycemic control to adults with diabetes mellitus.

Insulin degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

Insulin is a natural hormone produced by beta cells of the pancreas.

In nondiabetic individuals, the pancreas produces a continuous supply of low basal insulin levels and spikes of insulin following meals. 1, 2, 3, 4, 5 Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to an absorptive state. 1, 2, 3, 4, 5 Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. 1, 2, 3, 4, 5 Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). 1, 2, 3, 4, 5 Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. 1, 2, 3, 4, 5 It mimics the basal insulin levels in diabetic individuals.

The onset of action of insulin detemir is 1-2 hours and its duration of action is up to 24 hours.

Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. 1, 2, 3, 4, 5.

In patients with type 1 diabetes, after 8 days of once-daily subcutaneous dosing with 0.4 U/kg, maximum insulin degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (t max ).

After the first dose, the median onset of appearance was around one hour.

The glucose-lowering effect lasted at least 42 hours after the last of 8 once-daily injections.

Insulin degludec concentration reaches steady-state levels after 3-4 days.

Using a one-compartment pharmacokinetics model, the apparent volume of distribution was estimated to be 10.6 L for the pediatric population and 13.9 L for the adult population.

All insulin degludec metabolites are inactive.

The liver and kidney play the major role in metabolizing insulin.

However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system.

30-80% of circulating insulin is removed by the kidney.

The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue.

On average, the half-life at a steady state is approximately 25 hours independent of dose.

The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individuals) after a single subcutaneous dose of 0.4 units/kg.

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An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia.

Mild episodes of hypoglycemia can usually be treated with oral glucose.

Lowering the insulin dosage and adjusting meal patterns or exercise may be needed.

More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose.

After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid the reoccurrence of hypoglycemia.

Hypokalemia must be corrected appropriately.

Insulin degludec was investigated in studies covering fertility, embryo-fetal development, and pre and post-natal development in rats and during the period of embryo-fetal development in rabbits.

Human insulin (NPH insulin) was included as a comparator.

In these studies, insulin degludec caused pre and post-implantation losses and visceral/skeletal abnormalities when given Subcutaneous at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which was probably secondary to maternal hypoglycemia.