Incretin analogs

Inkterin analogues are drugs used to treat type 2 diabetes mellitus. They are synthetically prepared inkretins. Glucagon-like peptide 1 (GLP-1) or GLP-1 agonists are used in therapy.

Effect
náhled|400x400px|Pankreatický efekt inkretinů a role enzymu DPPIV (viz. historie analog)

Pancreatic effect
The effect of incretins on the pancreas is an increase in insulin secretion and a decrease in glukagonsecretion. There is also de novo insulin synthesis, GLUT 2 expression and protection of pancreatic beta cells, which slow the progression of DM (as the only antidiabetic agent).

Summary of the pancreatic effect
Due to the incretin effect postprandial glycaemia decreases.

Principle of incretin effect
We first administer glucose per os (p. o.). The intestinal wall responds by producing incretinswhich act on the pancreas via incretin receptors. This results in the pancreatic effect described above.

Administration of glucose p. o. causes higher insulin production than if administered intravenously.

Extrapancreatic effect
The effects can also be observed outside the pancreas, in the area of the GIT or the cardiovascular system.

Cardiovascular system
The effects on the cardiovascular system are still in the study phase, an antiatherogenic effectis expected.

GIT
The effect on the GIT is manifested in slowing down gastric emptying. This effect can be both negativ (see side effects below) and has its advantages. The benefit is the reduction of patient's weight.

Side effects
Side effects occur mainly in the GIT, such as dyspepsia such as abdominal pain, nauzea and others. They occur at the beginning of treatment and disappear within days to weeks.

History of incretin analogues
náhled|219x219px|Ze slin korovce jedovatého se izoloval exendin 4, inkretin, který znamenal přelom pro léčbu analogy In 1964–1967 several research groups independently described the incretin effect. Then, in 1971 a gastric inhibitory peptide (GIP), was described which has inhibitory effects on HCl secretion in the stomach. It is referred to by the alternative name as a glucose-dependent insulinotropic peptide due to its insulinotropic effects. 1985 saw the description of the cleavage product of glucagon GLP-1 (glucon-like peptide).

Before GIP and GLP-1 or their analogs could be used in practice, the problem of their early enzymatic degradation by the enzyme dipeptidyl peptidase IV (DPPIV)had to be solved. An ideal analogue of incretins was sought, which will not undergo early enzymatic degradation, and DPPIV inhibitors or  gliptins. or gliptins were also developed in parallel. The first to be approved for therapy was sitagliptin in 2006.

In 1992, exendin 4 was isolated from the saliva of the poison ivy, which binds to human GLP-1 receptors in a manner similar to GLP-1 but is resistant to DPPIV. The discovery of exendin 4 was a turning point for the later treatment of incretin analogues.

Present
Currently, three incretin analogues have been developed EXENATID (2005), LIRAGLUTID (2009) and LIXISENATID (2013). All should be administered subcutaneously (s.c.). When p.o. administration would break down them by GIT proteases.

Exenatid
Exenatid was the 1st therapeutically used incretin analogue. It came out under the name Byetta. t has been available in the Czech Republic since 2009. It is a synthetically prepared exendin 4, which is resistant to DPPIV. It is applied twice a day.

Exenatid LAR
Exenatid LAR (long acting release) has been available since 2012 under the name Bydureon. It can be found in the Czech Republic since 2014. It is retarded form of exenatide, which is applied once a week.

Liraglutid
Liraglutid is the 2nd therapeutically used incretin analogue that can be found under the name Victoza. It has been present in the Czech Republic since 2010. It is applied once a day.

Lixisenatid
Another species is Lixisenatide available under the name Lyxumia (in the Czech Republic since 2014). Structurally, it is derived from exendin 4, but unlike exendin 4, it lacks proline and six lysines are attached to the C-terminus of the peptide. It is applied once a day.

Indication
n the Czech Republic, incretin analogues (GLP-1 agonists) are indicated only for the treatment of type 2 diabetes mellitus. They are used as second or third choice preparations, most often in combination with metformin or sulfonylureas. The combination of an incretin analogue and basal insulin is clinically popular. Any other indications in the Czech Republic are so-called off-label (eg therapy of obesity using analog incretins).

Comparison of incretin analogues
Studies comparing the effects of exenatide, liraglutide and lixisenatide have been performed.

Exenatid vs. liraglutid
The study was performed in patients using metformin or glymepiride in combination with one of the two incretin analogues.

The results showed that a more significant decrease in postprandial glycaemia was observed with the use of exenatide, but a higher frequency of side effects.

Both exenatide and liraglutide caused comparable weight loss.

Liraglutide had a more significant decrease in glycated Hb and also a more significant decrease in fasting glucose. The use of liraglutide was accompanied by a lower frequency of adverse reactions compared to exenatide.

Exenatid vs. lixisenatid
During this study, metformin was used in combination with one of these two types of analogue.

Exenatide caused a greater decrease in glycated Hb, a greater weight loss and had more side effects than lixisenatide.

Future
The future of incretin analogs is associated with the development of new GLP-1 agonists, the development of fixed combinations with basal insulin, or the use of incretin analogs for indications other than DM2.

Development of new GLP-1 agonists
In 2010, the development of taspoglutide was stopped due to numerous allergic reactions and side effects. In 2014, albiglutide was released for the first time under the name Eperzan, which is not yet available in the Czech Republic. It is applied once a week.

Development of fixed combinations with basal insulin
In 2015, IDegLira was released under the name Xultophy, which is the first fixed combination on the market. It consists of a basal insulin called degludek and a GLP-1 liraglutide called IDegLira.

Use of incretin analogues for indications other than DM2
Incretin analogues can be used to treat obesity or type 1 diabetes mellitus. In the first case, the ability of incretin analogues to reduce weight by slowing gastric emptying is invoked. In 2015, liraglutide was made available for this purpose under the name Saxenda, which is not yet available in the Czech Republic. It is applied once a day..

In the second case, the protective function of pancreatic beta cells is applied, which mainly protects against disease progression. In DM1, a proportion of beta cells are still preserved (20-30%).

Related articles

 * Diabetes mellitus 2. typu (endokrinologie)


 * Perorální antidiabetika
 * Inkretiny

Source
1. Postgraduální medicína. Inkretinová analoga v terapii diabetes melitus. Dostupné z: https://zdravi.euro.cz/clanek/postgradualni-medicina/inkretinova-analoga-v-terapii-diabetes-melitus-481153

2. Časopis Remedia online. Liraglutid. Dostupné z: http://www.remedia.cz/Clanky/Aktuality/Liraglutid/6-E-B3.magarticle.aspx

3. Diabetes.co.uk. Byetta (exenatide). Dostupné z: https://www.diabetes.co.uk/diabetes-medication/diabetes-and-byetta.html