Basal insulin analogues in the treatment of diabetes mellitus: What progress have we made?

Over the past few decades, continuous progress has been made in the development of insulin therapy. Basal insulins were developed around 60 years ago. However, existing basal insulins were found to have limitations. An ideal basal insulin should have the following properties viz. longer duration of action, a flat time-action profile, low day-to-day glycaemic variability, and the potential for flexible dosing. Basal insulins have advanced over the years, from lectin and neutral protamine Hagedorn to the currently available insulin degludec. Currently, the focus is on developing a basal insulin that can give coverage for the entire day, with lesser variability and flexible administration. Insulin degludec has been a significant leap in that direction. In addition, U300 insulin glargine and pegylated lispro represent further developments in basal insulin pharmacotherapeutics.

INTRODUCTION

Over the past few decades continuous progress has been made in the development of insulin therapy. Crystalline insulin was first isolated nearly 100 years ago in 1921. The need for basal insulin was felt around 60 years ago, and so longer-acting insulins like lectin and neutral protamine Hagedorn (NPH) were developed. Studies have also shown that missing two basal insulin injections per week can lead to a 0.20.3% increase in glycated hemoglobin (HbA1c). At the same time, existing basal insulins were found to have limitations. In order to counter these limitations, insulin analogues were developed. There are three kinds of insulin analogues: Rapid-acting insulin analogues, biphasic insulin analogues, and basal insulin analogs.[1]

NEED FOR BETTER INSULIN

The primary structure of insulin is based on a specific sequence of amino acids in the protein. The same structure is maintained throughout the vertebrate kingdom. Slight changes were made in this insulin structure to produce different analogs with desired pharmacokinetic properties.

The need of insulin analogues arises from the fact that the human insulin injections have a lag period of around 1/2 h between administration and onset of action. As a result, regular human insulin is not able to mimic the human physiology. Endogenous insulin, after secretion from the pancreas, enters the portal circulation, after which it reaches the systemic circulation. On the other hand, exogenous human insulin, after injection into sub-cutaneous tissue, enters the systemic circulation, and then about 10% of the originally administered insulin reaches the portal circulation. Thus, the portal and systemic gradient of insulin is inverted in the case of exogenous insulin. It is because of this reason that exogenous human insulin is not the best physiological way of using insulin therapy. Rapid-acting insulin analogs overcome this by being more in tune with the physiological rise and fall of glucose values after each meal.

The basal human insulin that is available is NPH, which lacks the desired 24 h effect. This limitation highlights the need for the development of basal insulin analogues including insulin detemir, insulin glargine and insulin degludec with duration of action of at least a day. In addition, a research study has established that insulin detemir has better glycaemic control with fewer hypoglycaemic epsiodes in children when compared to NPH insulin.[2]

THE IDEAL BASAL INSULIN

An ideal basal insulin should have the following properties viz. longer duration of action, a flat time-action profile, low day-to-day glycemic variability, and the potential for flexible dosing. Hypoglycemia in children and adults is still a concern, but with the advent of better devices, it is easier to detect and manage hypoglycemia. The present day insulins are also effective in minimizing the risk of developing hypoglycemia. The physicians thus aim to achieve tighter glucose control, as a result of which the HbA1c targets are improved. Insulindetemir, for instance, produce better HbA1c control with less hypoglycemia than NPH insulin.

Research studies have shown that in children/adolescents, an intramuscular instead of subcutaneous injection of insulin therapy leads to faster absorption and action, and also shorter duration of action. It has also been found that the rigidity of the insulin regimen interferes with the patient's lifestyle (diet/exercise), which is an integral part of any child or adolescent's life. Thus, there is a need for continuous change and readjustment in insulin therapy.

BASAL INSULIN ANALOGUES

All the basal insulin analogues have a similar onset of action (between 1 and 2 h) but the duration of action varies (glargine: 20-30 h, detemir: 24 h and degludec: 42 h).[34] The differences in kinetics of basal insulin analogues are mainly due to structural variations. Both detemir and degludec have a 50 amino acid chain while glargine has a 53 amino acid chain. In glargine, there is the addition of two, and substitution of one amino acid. In detemir, there is a lack of B30 amino acid and an addition of acylated fatty acid side chain at B29 position. In degludec, there is a lack of B30; addition of glutamic acid spacer and diacylated fatty acid side chain at B29. The mechanism of prolongation of action of glargine involves precipitation at acidic pH, while the mechanism of prolongation of action of detemir and degludec involves binding to albumin and multi-hexamer formation respectively.[5] Both glargine and degludec have been classified as pregnancy category C molecules while detemir is classified as pregnancy category B.[678]

DEFINING HYPOGLYCEMIA

Glargine is a pro-drug that requires conversion from its monomeric soluble form to a microcrystalline precipitate in the subcutaneous tissue to obtain its long-acting pharmacokinetics. This process may be disturbed by its rapid access to the circulation after intramuscular injection, leading to hypoglycemia. A study has shown that accidental intramuscular injection of glargine can happen in 30% of children with type 1 diabetes mellitus (T1DM).[9]

The definition of hypoglycemia is debatable. According to the 2009 and 2014 ISPAD guidelines, <3.6 mmol/L (65 mg/dL) has been used most often for clinical definition, and (70 mg/dL) is the recommended lower target for blood glucose, whereas the ADA Working Group suggests 70 mg/dL as hypoglycemia. The WHO guidelines for neonatal hypoglycemia suggest that the newborn/infant/child with ‘signs of illness’ would be diagnosed with hypoglycemia if blood glucose is <2.5 mmol/L or 45 mg/dL; for healthy term/pre-term newborn – “feeding well,” the hypoglycemia cut-off value is <1.1 mmol/L or 19.8 mg/dL, and for an infant/child with severe malnutrition the value is <3.0 mmol/L or 54 mg/dL.[10111213]

INSULIN DEGLUDEC

Insulin degludec is neutral, soluble ultra-long-acting insulin that forms large multi-hexamer assemblies at physiological pH following subcutaneous injection. Its molecular structure is similar to the human insulin amino acid sequence, apart from deletion of threonine at position B30 and the addition of a 16-carbon fatty acid chain attached to lysine at position B29 via a glutamic acid spacer. When injected subcutaneously, insulin degludec produces multi-hexamers. These subsequently release monomers that are absorbed at a slow and steady rate into the circulation.[14] Pharmacokinetic/pharmacodynamic studies show that insulin degludec has a very long duration of action of 42 h, with a half-life exceeding 25 h, and variability of 25% with respect to glargine.

INSULIN DEGLUDEC IN CHILDREN

A study was recently conducted which investigated once-daily insulin degludec versus insulin detemir, both in combination with bolus insulin aspart in a 26 week trial, followed by another 26 week extension, in children and adolescents with T1DM. This trial (n = 350) was the first to look into the long-term safety of insulin degludec in children and adolescents (age: 1–18 years). The results showed that at 26 weeks, insulin degludec in combination with insulin aspart was noninferior to insulin detemir in combination with insulin aspart. Insulin degludec met the primary endpoint of noninferiority in HbA1c at 26 weeks. The mean basal insulin doses at the end of treatment were reduced by 31% in the insulin degludec group. In the 26-week extension, a lower insulin dose and a significantly greater reduction in fasting plasma glucose versus insulin detemir were achieved. Both regimens had similar rates of overall and nocturnal hypoglycemia, the rate of severe hypoglycemia was numerically higher with insulin degludec plus insulin aspart. Of note, patients on insulin degludec had significantly lower rates (59% less) of hyperglycemia with ketosis. No safety issues were found with insulin degludec or insulin detemir. Insulin degludec, however, is currently not approved in patients below the age of 18 years.

RECENT DEVELOPMENTS

New formulations of basal insulin that are under development are U300 glargine, which has completed phase III and pegylated insulin lispro, which is in phase III, insulin degludec/insulin aspart (IDegAsp), which is a soluble co-formulation of insulin degludec and insulin aspart, and IDegLira, which is a fixed-ratio combination of insulin degludec and liraglutide for T2DM.