An incretin analog

Inkterin analogues are medicinal substances used for the therapy of type 2 diabetes mellitus . They are synthetically prepared incretins . Substances similar to glucagon-like peptide 1 (GLP-1) or GLP-1 agonists are used in therapy.

Effect[edit | edit source]

Pancreatic effect of incretins and the role of DPPIV enzyme (see history of analogues)

Pancreatic effect[edit | edit source]

The effect of incretins on the pancreas is to increase the secretion of insulin and, conversely, to decrease the secretion of glucagon . Furthermore, de novo insulin synthesis, GLUT 2 expression and pancreatic beta cell protection occur , which slow down the progression of DM (as the only antidiabetic drug).

Pancreatic effect summary[edit | edit source]

Thanks to the incretin effect , there is a decrease in postprandial glycemia.

The principle of the incretin effect[edit | edit source]

First we give glucose per os (po). The intestinal wall responds by producing incretins , which act on the pancreas via incretin receptors. This results in the pancreatic effect , which is described above.

The administration of glucose after causes a higher production of insulin than if it were given intravenously.

Extrapancreatic effect[edit | edit source]

Effects can also be observed outside the pancreas, namely in the GIT or cardiovascular system.

Cardiovascular system[edit | edit source]

The effects on the cardiovascular system are still in the phase of studies, an antiatherogenic effect is assumed .

GIT[edit | edit source]

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

Adverse effects[edit | edit source]

Adverse effects are mainly manifested in the GIT, namely dyspepsia type such as abdominal pain, nausea and others. They occur at the beginning of treatment and disappear over a period of days to weeks.

History of incretin analogs[edit | edit source]

Exendin 4 , an incretin, was isolated from poison ivy saliva , which marked a breakthrough for analog therapy

In 1964–1967 , several research groups independently described the incretin effect. Then, in 1971 , gastric inhibitory peptide ( GIP ) was described, which has inhibitory effects on the secretion of HCl in the stomach. It is referred to by an alternative name as glucose-dependent insulinotropic peptide precisely because of its insulinotropic effects. The year 1985 brought the description of the cleavage product of glucagon GLP-1 (glucone-like peptide).

Before GIP and GLP-1 or their analogues could be used in practice, the problem of their early enzymatic degradation by dipeptidyl peptidase IV (DPPIV) had to be solved. An ideal analog of incretins that would not be subject to early enzymatic degradation was sought, and DPPIV inhibitors, or gliptins , were also developed in parallel . Sitagliptin was the first to be approved for therapy in 2006 .

In 1992 , exendin 4 was isolated from poison ivy saliva , 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 breakthrough for later incretin analog therapy.

Present[edit | edit source]

Currently, three incretin analogs have been developed, namely EXENATID (2005), LIRAGLUTID (2009) and LIXISENATID (2013). All must be administered subcutaneously ( sc ). GIT proteases would break them down after administration.

Exenatide[edit | edit source]

Exenatide was the 1st therapeutically used incretin analog. It was released under the name Byetta . It 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 .

Exenatide LAR[edit | edit source]

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

Liraglutide[edit | edit source]

Liraglutide 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 .

Lixisenatide[edit | edit source]

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

Indication[edit | edit source]

In 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-line preparations, most often in combination with metformin or sulfonylurea derivatives. Clinically, a combination of an incretin analogue and basal insulin is popular. Any other indications are so-called off-label in the Czech Republic (e.g. obesity therapy using incretin analogues).

Comparison of incretin analogs[edit | edit source]

Studies have been conducted that compare the effects of exenatide, liraglutide, and lixisenatide.

Exenatide vs. liraglutide[edit | edit source]

The study was conducted on patients using metformin or glimepiride in combination with one of these two incretin analogues.

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

Both exenatide and liraglutide caused comparable weight loss .

Liraglutide had a more significant decrease in glycated Hb as well as a more significant decrease in fasting blood glucose. The use of liraglutide was accompanied by a lower frequency of side effects compared to exenatide.

Exenatide vs. lixisenatide[edit | edit source]

During this study, metformin was used in combination with one of these two types of analogues.

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

Future[edit | edit source]

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

Development of new GLP-1 agonists[edit | edit source]

In 2010 , the development of the drug taspoglutide was suspended 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[edit | edit source]

In 2015, IDegLira was made available under the name Xultophy , which is the first ever fixed combination on the market. It consists of a basal insulin called degludec and a GLP-1 liraglutide called IDegLira .

Use of incretin analogues for indications other than DM2[edit | edit source]

Incretin analogs can be used to treat obesity or type 1 diabetes mellitus . In the first case, the ability of incretin analogs to reduce weight by slowing gastric emptying is used. 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 the beta cells of the pancreas is used, when protection against the progression of the disease is mainly achieved. In DM1, a proportion of beta cells is still preserved (20–30%).