Introduction
The first hormone with incretin activity was isolated from an extract of porcine duodenal mucus. The main biological effect of the peptide is glucose-dependent stimulation of insulin secretion, which is why its name is a glucose-dependent insulinotropic polypeptide (GIP). The site of its synthesis is the K-cells of the intestinal mucosa, mainly in the duodenum and jejunum. In patients with type 2 diabetes and obesity, there is a significant decrease in the incretin effect, and a decrease in insulin secretion in response to an oral load (Atta-ur-Rahman, 2019, p. 17). A decrease in the incretin effect entails a violation of the insulin response to carbohydrate intake and an increase in blood glucose levels. When studying the cause of the decrease in the incretin response in patients with type 2 diabetes, it was found that this is associated with a lower secretion of GLP-1 (Atta-ur-Rahman, 2019, p. 21). At the stage of prediabetes, there is also a decrease in GLP-1 secretion, but less pronounced than in patients with type 2 diabetes.
Discussion
Research results show that the secretion of GLP-1 and GIP is stimulated by intestinal absorption of fats and carbohydrates. GLP-1 secretion is also affected by protein absorption. Moreover, for the release of incretin hormones from K- and L-cells, simple contact of these nutrients with the intestinal mucosa is sufficient, which leads to a rapid rise in the level of insulin in the blood. It should be emphasized that it is necessary to develop alternative methods of treating type 2 diabetes (Atta-ur-Rahman, 2019). This is explained primarily by the mechanism of treatment with incretins, which cause the disease to recess, but not disappear. In other words, together with the complexity of the treatment itself and the administration of incretins, they do not give the most effective result (Atta-ur-Rahman, 2019). The complexity of the disease dictates the need to correct not just hyperglycemia, but the entire set of risk factors for the development of cardiovascular complications in patients (Atta-ur-Rahman, 2019). In addition, the exact mechanism of the beneficial effect of GLP-1 on the cardiovascular system is not completely clear. This effect can be mediated both by a direct effect on the heart and blood vessels, and indirectly, through a decrease in body weight (Atta-ur-Rahman, 2019). All of the above factors predetermine the need and relevance of developing alternative ways to treat and prevent type 2 diabetes.
Exenatide is the first representative of incretin mimetics, a new class of drugs with a different mechanism of action than all previously known mechanisms based on the incretin effect. Incretins are called hormones that stimulate the secretion of insulin in response to food intake – glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Exenatide is a synthetic protein analog that is 53% identical in structure to GLP-1. Interacting with the GLP-1 receptor in the pancreas and other organs and tissues, exenatide causes similar GLP-1 effects that regulate glucose levels:
- stimulates insulin secretion,
- suppresses the secretion of glucagon,
- slows down the rate of evacuation of food from the stomach,
- reduces appetite and promotes faster satiety.
The results of comparative studies with insulin showed that exenatide at a dose of 10 mcg/day is equivalent to insulin glargine and aspart in terms of the effectiveness of glycemic control (Azer, 2021, p. 67). Compared with insulin glargine, a significant decrease in HbA1c levels was observed in both groups of patients – by 1.1% (Azer, 2021, p. 56). In all studies, both compared with PSSP and with insulin, weight loss was noted with exenatide therapy (Azer, 2021). Weight loss in type 2 diabetes patients, most of whom are overweight or obese, is an advantage of this drug (Azer, 2021). It is known that in type 2 diabetes obesity is associated with an increased risk of death, while weight loss is accompanied by an improvement in HbA1c and cardiovascular risk factors – dyslipidemia.
At the same time, there are limitations in the treatment of exenatide. First, the incidence of nausea during exenatide therapy varies from 45% to 51%. Secondly, exenatide is distinguished by its high cost of treatment compared to previously known hypoglycemic drugs. On the other hand, the drug is easy to use, given in fixed doses, and does not require patient education in dose titration and carbohydrate counting (Azer, 2021). The defining indication for prescribing exenatide is weight loss, as well as the ability to better control the level of postprandial glycemia, unlike most previously used drugs. These characteristics make exenatide a popular therapy option for a specific category of patients with type 2 diabetes.
The next most commonly used mimetic with type 2 diabetes is liraglutide. In a large comparative study LEAD (Liraglutide Effect and Action in Diabetes), the effect of liraglutide was compared with metformin, glimepiride, rosiglitazone, and placebo. The use of liraglutide led to a greater decrease in the level of HbA1c, which contributed to a more significant weight loss (Azer, 2021). The researchers also studied the efficacy and safety of combinations of liraglutide with metformin, rosiglitazone, and glimepiride. The LEAD-6 study compared exenatide 10 µg twice daily with liraglutide 1.8 µg daily (Azer, 2021). In the liraglutide group, there was a more significant reduction in HbA1c, as well as a greater number of patients who reached the target blood sugar level (Rodriguez-Saldana, 2019). For the treatment of obesity, the drug liraglutide at a dose of 3 mg per day is successfully used. Liraglutide showed high efficacy in the treatment of non-alcoholic fatty liver disease in the Lira-NAFLD study. Frequent side effects of incretin mimetics: nausea; vomiting; diarrhea; abdominal discomfort. GLP-1 is strictly contraindicated in pregnancy; type 1 diabetes; ketoacidosis; the presence of pancreatitis, pancreatic cancer; the presence of medullary thyroid cancer in a personal or family history; the presence of multiple endocrine neoplasia syndrome; severe damage to the liver, kidneys.
- Main pluses: high efficiency; weight loss; minimal risk of hypoglycemia (Rodriguez-Saldana, 2019).
- Disadvantages: high price; injection route.
Together with all of the above, one of the latest inventions in this area is the lixisenatide mimetic. The European Commission has approved the use of Lyxumia (lixisenatide) in adult patients with type 2 diabetes. Lyxumia (lixisenatide) is a glucagon-like peptide-1 (GLP-1) receptor agonist for once-daily injection. The drug should be given to adult patients with type 2 diabetes mellitus for glycemic control simultaneously with oral drugs aimed at lowering blood sugar levels (Rodriguez-Saldana, 2019). The alternative is basal insulin if previously conventional therapy in combination with diet and exercise has not produced the desired effect (Rodriguez-Saldana, 2019). The efficacy and safety of Lyxumia (lixisenatide) have been evaluated in GetGoal clinical trials.
Conclusion
In conclusion, the use of the drug in patients with type 2 diabetes helped to achieve a decrease in the level of glycohemoglobin, as well as postprandial insulin in the blood of participants (Rodriguez-Saldana, 2019). The researchers also noted the positive effect of the drug on the weight of patients. However, the main disadvantage of this memetic is that it is still being researched, therefore there is no accurate information about the nature of its side effects (Rodriguez-Saldana, 2019). In addition, these drugs are recommended to be taken in combination with other elements, and not on their own, although this method is also possible.
Reference List
Atta-ur-Rahman. (2019) Frontiers in clinical drug research – diabetes and obesity. Sharjah: Bentham Science Publishers.
Azer, S. A. (2021) Clinical cases in internal medicine. Edinburgh: Elsevier Health Sciences.
Rodriguez-Saldana, J. (Ed.). (2019) The diabetes textbook. Clinical principles, patient management and public health issues. New York: Springer International Publishing.