Insulin analog/ja: Difference between revisions

===Glargine insulin===

{{main|Insulin glargine}}

Sanofi-[[Aventis]] developed glargine as a longer-lasting insulin analogue, and sells it under the brand name Lantus. It was created by modifying three amino acids. Two positively charged [[arginine]] molecules were added to the C-terminus of the B-chain, and they shift the isoelectric point from 5.4 to 6.7, making glargine more soluble at a slightly acidic [[pH]] and less soluble at a physiological pH. Replacing the acid-sensitive [[asparagine]] at position 21 in the A-chain 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. When the pH 4.0 solution is injected, most of the material precipitates and is not bioavailable. A small amount is immediately available for use, and the remainder is sequestered in subcutaneous tissue. 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. The onset of action of subcutaneous insulin glargine is somewhat slower than NPH human insulin. It is clear solution as there is no zinc in formula. The biosimilar insulin glargine-yfgn (Semglee) was approved for medical use in the United States in July 2021, and in the European Union in March 2018.

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==Comparison with other insulins==

{{main|NPH insulin}}

NPH (Neutral Protamine Hagedorn) insulin is an intermediate-acting insulin with delayed absorption after subcutaneous injection, used for basal insulin support in diabetes type 1 and type 2. NPH insulins are suspensions that require shaking for reconstitution prior to injection. Many people reported problems when being switched to intermediate acting insulins in the 1980s, using NPH formulations of [[porcine]]/[[bovine]] insulins. Basal insulin analogs were subsequently developed and introduced into clinical practice to achieve more predictable absorption profiles and clinical efficacy.

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===Animal insulin===

[[File:Insulin hexamer 4INS.png|thumb|[[Ribbon diagram]] of a [[pig|porcine]] insulin hexamer. Porcine insulin differs from human insulin by only one amino acid.]]

The amino acid sequence of animal insulins in different mammals may be similar to human insulin (insulin human INN), there is however considerable viability within vertebrate species. [[Pig|Porcine]] insulin has only a single amino acid variation from the human variety, and [[cattle|bovine]] insulin varies by three amino acids. Both are active on the human [[Receptor (biochemistry)|receptor]] with approximately the same strength. Bovine insulin and porcine insulin may be considered as the first clinically used insulin analogs (naturally occurring, produced by extraction from animal pancreas), at the time when biosynthetic human insulin (insulin human rDNA) was not available. There are extensive reviews on structure-relationship of naturally occurring insulins (phylogenic relationship in animals) and structural modifications. Prior to the introduction of biosynthetic human insulin, insulin derived from sharks was widely used in Japan.  Insulin from some species of fish may be also effective in humans.  Non-human insulins have caused [[Allergy|allergic]] reactions in some patients related to the extent of purification, formation of non-neutralising antibodies is rarely observed with recombinant human insulin (insulin human rDNA) but allergy may occur in some patients.  This may be enhanced by the preservatives used in insulin preparations, or occur as a reaction to the preservative.  Biosynthetic insulin (insulin human rDNA) has largely replaced animal insulin.

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==Modifications==

Before biosynthetic human [[Recombinant DNA|recombinant]] analogues were available, porcine insulin was chemically converted into human insulin. 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. Semisynthetic insulins were clinically used for some time based on chemical modification of animal insulins, for example [[Novo Nordisk]] enzymatically converted porcine insulin into semisynthetic 'human' insulin by removing the single amino acid that varies from the human variety, and chemically adding the human amino acid.

Normal unmodified insulin is soluble at physiological pH. 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.  These insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours.  However, some insulin analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin varieties, and results from long-term usage (e.g. more than 10 years) are currently not available but required for assessment of clinical benefit.

Unmodified human and porcine insulins tend to [[complex (chemistry)|complex]] with [[zinc]] in the blood, forming [[hexamer]]s. Insulin in the form of a hexamer will not bind to its receptors, so the hexamer has to slowly equilibrate back into its monomers to be biologically useful.  Hexameric insulin delivered subcutaneously is not readily available for the body when insulin is needed in larger doses, such as after a meal (although this is more a function of subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly to the cell receptors, and therefore, avoids this problem).  Zinc combinations of insulin are used for slow release of basal insulin. Basal insulin support is required throughout the day representing about 50% of daily insulin requirement, the insulin amount needed at mealtime makes up for the remaining 50%. Non hexameric insulins (monomeric insulins) were developed to be faster acting and to replace the injection of normal unmodified insulin before a meal. There are phylogenetic examples for such monomeric insulins in animals.

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==Carcinogenicity==

All insulin analogs must be tested for [[carcinogenicity]], as insulin engages in cross-talk with [[Insulin-like growth factor|IGF]] pathways, which can cause abnormal cell growth and tumorigenesis.  Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties. There has been concern with the mitogenic activity and the potential for carcinogenicity of glargine. Several epidemiological studies have been performed to address these issues. Recent study result of the 6.5 years Origin study with glargine have been published.

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==Research on safety, efficacy, and comparative effectiveness==

{{Further|Comparative effectiveness research}}

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 [[Glycated hemoglobin|(HbA1c)]] were comparable, treatment with [[Insulin glargine|glargine]] and [[Insulin detemir|detemir]] resulted in fewer cases of [[hypoglycemia]] when compared to [[NPH insulin]].  Treatment with detrimir also reduced the frequency of serious hypoglycemia.  This review did note limitations, such as low glucose and HbA1c targets, that could limit the applicability of these findings to daily clinical practice.

In 2007, Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector (IQWiG) [https://web.archive.org/web/20080208123345/http://www.iqwig.de/index.658.en.html report], concluded that there is currently "no evidence" available of the superiority of rapid-acting insulin analogs over synthetic human insulins in the treatment of adult patients with type 1 diabetes.  Many of the studies reviewed by IQWiG were either too small to be considered statistically reliable and, perhaps most significantly, none of the studies included in their widespread review were blinded, the gold-standard methodology for conducting clinical research.  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.  IQWiG is regarded with skepticism by some doctors in Germany, being seen merely as a mechanism to reduce costs.  But the lack of study blinding does increase the risk of bias in these studies. The reason this is important is because patients, if they know they are using a different type of insulin, might behave differently (such as testing blood glucose levels more frequently, for example), which leads to bias in the study results, rendering the results inapplicable to the diabetes population at large.  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.

In 2008, the [[Canadian Agency for Drugs and Technologies in Health]] (CADTH) found, in its comparison of the effects of insulin analogues and biosynthetic human insulin, that insulin analogues failed to show any clinically relevant differences, both in terms of glycemic control and adverse reaction profile.