Insulin analog
Through genetic engineering of the underlying DNA, the amino acid sequence of insulin can be changed to alter its ADME (absorption, distribution, metabolism, and excretion) characteristics.
It was engineered through recombinant DNA technology so that the penultimate lysine and proline residues on the C-terminal end of the B-chain were reversed.
The FDA-approved label states that it differs from regular human insulin by its rapid onset and shorter duration of action.
As a result, this insulin binds to serum albumin with high affinity, increasing its duration of action.
[4] This is an ultralong-acting insulin analogue developed by Novo Nordisk, which markets it under the brand name Tresiba.
Replacing the acid-sensitive asparagine at position 21 in the A-chain (A21) by glycine is needed to avoid deamination and dimerization of the arginine residue.
These three structural changes and formulation with zinc result in a prolonged action when compared with biosynthetic human insulin.
As the glargine is used, small amounts of the precipitated material will move into solution in the bloodstream, and the basal level of insulin will be maintained up to 24 hours.
[9][better source needed] The biosimilar insulin glargine-yfgn (Semglee) was approved for medical use in the United States in July 2021,[10] and in the European Union in March 2018.
There are extensive reviews on structure-relationship of naturally occurring insulins (phylogenic relationship in animals) and structural modifications.
Chemical modifications of the amino acid side chains at the N-terminus and/or the C-terminus were made in order to alter the ADME characteristics of the analogue.
Analogues have been created that have a shifted isoelectric point so that they exist in a solubility equilibrium in which most precipitates out but slowly dissolves in the bloodstream and is eventually excreted by the kidneys.
Unmodified human and porcine insulins tend to complex with zinc in the blood, forming hexamers.
Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties.
[22][23] A meta-analysis completed in 2007 and updated in 2020 of numerous randomized controlled trials by the international Cochrane Collaboration found that the effects on blood glucose and glycated haemoglobin A1c (HbA1c) were comparable, treatment with glargine and detemir resulted in fewer cases of hypoglycemia when compared to NPH insulin.
However, IQWiG's terms of reference explicitly disregard any issues which cannot be tested in double-blind studies, for example a comparison of radically different treatment regimes.
Numerous studies have concluded that any increase in testing of blood glucose levels is likely to yield improvements in glycemic control, which raises questions as to whether any improvements observed in the clinical trials for insulin analogues were the result of more frequent testing or due to the drug undergoing trials.
