An insulin analog (
also called an insulin analogue) is any of several types of
medical insulin that are altered forms of the hormone
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, different from any occurring in nature, but still available to the human body for performing the same action as human insulin in terms of
controlling blood glucose levels in diabetes. Through
genetic engineering
Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...
of the underlying
DNA, the
amino acid sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...
of insulin can be changed to alter its
ADME
ADME is an abbreviation in pharmacokinetics and pharmacology for " absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug le ...
(absorption, distribution, metabolism, and excretion) characteristics. Officially, the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) refers to these agents as insulin receptor ligands (because, like insulin itself, they are
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
of the
insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose ho ...
), although they are usually just referred to as insulin analogs or even (loosely but commonly) just insulin (without further specification).
These modifications have been used to create two types of insulin analogs: those that are more readily absorbed from the injection site and therefore act faster than natural insulin injected
subcutaneously
The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and macro ...
, intended to supply the bolus level of insulin needed at mealtime (prandial insulin); and those that are released slowly over a period of between 8 and 24 hours, intended to supply the basal level of insulin during the day and particularly at nighttime (basal insulin). The first insulin analog (insulin Lispro rDNA) was approved for human therapy in 1996 and was manufactured by
Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
.
Fast acting
Lispro
Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
developed and marketed the first rapid-acting insulin analogue (insulin lispro rDNA) Humalog. It was engineered through
recombinant DNA
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...
technology so that the penultimate
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
and
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
residues on the C-terminal end of the B-chain were reversed. This modification did not alter the insulin receptor binding, but blocked the formation of insulin
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
s and hexamers. This allowed larger amounts of active monomeric insulin to be available for
postprandial
Prandial relates to a meal. Postprandial (from post prandium) means after eating a meal, while preprandial is before a meal.
Usages of postprandial
The term ''postprandial'' is used in many contexts.
Gastronomic or social
Refers to activities p ...
(after meal) injections.
Aspart
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
created "aspart" and marketed it as NovoLog/NovoRapid (UK-CAN) as a rapid-acting insulin analogue. It was created through
recombinant DNA
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...
technology so that the amino acid, B28, which is normally
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
, is substituted with an
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
residue. The sequence was inserted into the
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
genome, and the yeast expressed the insulin analogue, which was then harvested from a
bioreactor
A bioreactor refers to any manufactured device or system that supports a biologically active environment. In one case, a bioreactor is a vessel in which a chemical reaction, chemical process is carried out which involves organisms or biochemistry, ...
. This analogue also prevents the formation of hexamers, to create a faster acting insulin. It is approved for use in CSII pumps and Flexpen, Novopen delivery devices for subcutaneous injection.
Glulisine
Glulisine is rapid acting insulin analog from
Sanofi-Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
, approved for use with a regular syringe, in an
insulin pump
An insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin therapy.
The device configuration may vary depending on design. A traditional pump ...
. Standard syringe delivery is also an option. It is sold under the name Apidra. The FDA-approved label states that it differs from regular human insulin by its ''rapid onset and shorter duration of action''.
Long acting
Detemir insulin
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
created insulin detemir and markets it under the trade name Levemir as a long-lasting insulin analogue for maintaining the basal level of insulin.
The basal level of insulin may be maintained for up to 20 hours, but the time is affected by the size of the injected dose.
This insulin has a high affinity for serum albumin, increasing its duration of action.
Degludec insulin
This is an ultralong-acting insulin analogue developed by
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
, which markets it under the brand name Tresiba. It is administered once daily and has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir).
Glargine insulin
Sanofi-
Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Sy ...
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
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
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
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
at position 21 in the A-chain by
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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.
Comparison with other insulins
NPH
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
The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus s ...
/
bovine
Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including cattle, bison, African buffalo, water buffalos, and the four-horned and spiral-horned antelopes. The evolutionary relationship betwee ...
insulins. Basal insulin analogs were subsequently developed and introduced into clinical practice to achieve more predictable absorption profiles and clinical efficacy.
Animal insulin
![Insulin hexamer 4INS](https://upload.wikimedia.org/wikipedia/commons/d/d1/Insulin_hexamer_4INS.png)
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.
Porcine
The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus s ...
insulin has only a single amino acid variation from the human variety, and
bovine
Bovines (subfamily Bovinae) comprise a diverse group of 10 genera of medium to large-sized ungulates, including cattle, bison, African buffalo, water buffalos, and the four-horned and spiral-horned antelopes. The evolutionary relationship betwee ...
insulin varies by three amino acids. Both are active on the human
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
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
allergic
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
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.
Modifications
Before biosynthetic human
recombinant analogues were available, porcine insulin was chemically converted into human insulin. Chemical modifications of the amino acid side chains at the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
and/or the
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
were made in order to alter the
ADME
ADME is an abbreviation in pharmacokinetics and pharmacology for " absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug le ...
characteristics of the analogue. Semisynthetic insulins were clinically used for some time based on chemical modification of animal insulins, for example
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
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
The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...
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
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
with
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
in the blood, forming
hexamer
In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
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.
Carcinogenicity
All insulin analogs must be tested for
carcinogenicity
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...
, as insulin engages in cross-talk with
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.
Research on safety, efficacy, and comparative effectiveness
A
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
completed in 2007 and updated in 2020 of numerous
randomized controlled trials
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
by the international
Cochrane Collaboration
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profess ...
found that the effects on blood glucose and glycated haemoglobin A1c
(HbA1c) were comparable, treatment with
glargine
Insulin glargine, sold under the brand name Lantus among others, is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is typically the recommended long acting insulin in the United Kingd ...
and
detemir resulted in fewer cases of
hypoglycemia
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
when compared to
NPH insulin
Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an intermediate-acting insulin given to help control blood sugar levels in people with diabetes. It is used by injection under the skin once to twice a day. Onset of ...
.
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
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
The Canadian Agency for Drugs and Technologies in Health, or CADTH, is a Canadian national organisation that provides research and analysis to healthcare decision-makers.
The organisation was established in 1989 by the country's federal governme ...
(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.
Timeline
* 1922 Banting and Best use bovine insulin extract on human
* 1923
Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
(Lilly) produces commercial quantities of bovine insulin
* 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark forerunner of
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
* 1926
Nordisk receives Danish charter to produce insulin as a non-profit
* 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to Novo
* 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
* 1946 Nordisk formulates Isophane porcine insulin a.k.a. Neutral Protamine Hagedorn or
NPH insulin
Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an intermediate-acting insulin given to help control blood sugar levels in people with diabetes. It is used by injection under the skin once to twice a day. Onset of ...
* 1946 Nordisk crystallizes a protamine and insulin mixture
* 1950 Nordisk markets NPH insulin
* 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer-lasting insulin
* 1978
Genentech
Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...
develop biosynthesis of recombinant human insulin in ''Escherichia coli'' bacteria using recombinant DNA technology
* 1981 Novo Nordisk chemically and enzymatically converts porcine insulin to 'human' insulin (Actrapid HM)
* 1982
Genentech
Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...
synthetic 'human' insulin approved, in partnership with Eli Lilly and Company, who shepherded the product through the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approval process
* 1983 Lilly produces biosynthetic recombinant "rDNA insulin human INN" (Humulin)
* 1985
Axel Ullrich
Axel Ullrich (born 19 October 1943) is a German cancer researcher and has been the director of the molecular biology department at the Max Planck Institute of Biochemistry in Martinsried, Germany since 1988. This department's research has primar ...
sequences the human insulin receptor
* 1988 Novo Nordisk produces synthetic, recombinant insulin ("insulin human INN")
* 1996 Lilly Humalog "insulin lispro INN" approved by the U.S. Food and Drug Administration
* 2003
Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Sy ...
Lantus "glargine" insulin analogue approved in USA
Glucose Control – Lantus receives FDA approval for flexible administration
/ref>
* 2004 Sanofi Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
Apidra insulin "glulisine" analogue approved in the USA.
* 2006 Novo Nordisk's Levemir "insulin detemir INN" analogue approved in the USA-
* 2013 Novo Nordisk's Tresiba "insulin degludec INN" analogue approved in Europe (EMA with additional monitoring]
References
External links
Analog Insulin
*
{{DEFAULTSORT:Insulin Analog
Insulin therapies
Eli Lilly and Company brands
Diabetes
Human proteins
Recombinant proteins
Peptide hormones