GLP 1 RA (Glucagon Like Peptide 1 – Receptor Agonists) – medications for the treatment of type 2 diabetes and obesity.

Abbreviations used in the text:

GLP 1 – Glucagon-like peptide 1

GIP – Glucose-dependent insulinotropic peptide

Incretins – INtestine seCRETion INsulin – i.e., intestinal hormones that control insulin secretion after food intake.

In order to understand the effects and use of this group of medications, it is necessary to understand what incretins are. These are substances, naturally secreted in the digestive tract, and they initiate a complex physiological, neurological, and hormonal response to the passage of food through the intestines. Incretins are intestinal hormones which control the secretion of gastric acid, gastric emptying, intestinal motility, nutrient absorption, and hormonal regulation of nutrient metabolism. There are two types of incretins, GLP1 and GIP.

 

GIP was discovered first, in 1970. It is a 42 amino acid peptide, secreted from enteroendocrine K cells concentrated in the duodenum and proximal jejunum. K cells are the first to react to food.

GLP-1 was discovered in 1983. It is an intestinal hormone with 30-31 amino acids. After a meal, enteroendocrine L cells in the ileum and colon secrete two forms of GLP-1: GLP-1(7-37) and GLP-1(7-36). GLP-1(7-36) is mostly (≈80%) in active form in circulation.

The natural stimulus for the secretion of these two incretin hormones is the passage of food through the intestines. GIP and GLP-1 enter the systemic circulation almost simultaneously, even though the L cells are located in more distant parts of the intestine. Immediately after the secretion of GIP, GLP-1 is also secreted, stimulated by vagus signals. Activation of the vagus occurs when food passes through the stomach. GLP-1 secretion lasts longer, as food passes into the ileum and colon. When they enter the circulation, they have a short but sufficient time to achieve their effect. Already in the portal circulation, 50% is broken down by the enzyme dipeptidyl-peptidase 4 (DPP4). The half-life of incretin hormones is about 5 minutes.

GLP-1 achieves its effects by binding to membrane receptors. Receptors for GLP-1 are located in β, α, and δ cells of the pancreas, lungs, kidneys, heart, stomach, vagal neurons, hypothalamus, and blood vessels. The main role of incretin hormones is to regulate the secretion of hormones from the endocrine pancreas. These medications stimulate insulin secretion from β cells in a rational way and do not cause hypoglycemia. Also, and perhaps more importantly, they inhibit the secretion of another pancreatic hormone, glucagon, from α cells. In some people with diabetes, the problem is precisely the inability to inhibit glucagon. Glucagon constantly releases glucose out of the liver into the blood. Glucagon inhibition – reduces hepatic glucose production – this effect is also achieved in T1DM. GLP-1 also stimulates the secretion of somatostatin from δ cells in the pancreas.

The second role of incretin hormones is in appetite regulation, by acting on satiety centers in the hypothalamus and on gastric motility. They prevent excessive food intake and weight gain in a natural way. GLP-1 increases satiety and decreases hunger. This role has enabled the creation of medications to treat obesity. In the liver, it stimulates the synthesis of glycogen, reduces lipogenesis, and stimulates the oxidation of fatty acids – reducing steatosis. Clinical trials are ongoing to examine the effect of semaglutide on liver steatosis.

The third role is in reducing systemic inflammation and atherosclerosis, by direct and indirect action. Direct effects of GLP-1 in blood vessels are: increased nitrite oxide secretion from the endothelium with vasodilation, decreased activation and proliferation of smooth muscle cells, decreased accumulation of lipids in the blood vessel wall and reduced inflammation. Indirect effects are the result of lowering glycemia, lipids, and weight. Precisely this third role has launched the medications, acting on the incretin concept, to the top of all recommendations for diabetes treatment.

Insulin receptors and GLP-1 Receptors are located in the brain. Insulin receptors are found in olfactory regions, cerebral cortex, hypothalamus, hippocampus and cerebellum: they regulate inflammation, oxidative stress, autophagy in neurodegenerative diseases, memory and neuronal survival. GLP-1 receptors are found in the occipital and frontal lobes, hypothalamus and thalamus. They improve mitochondrial function and reduce oxidative stress. They also reduce CNS inflammation and decrease neurodegeneration. Since GLP-1 has been found to have an antiapoptotic effect on nerve cells, possible future indications are Parkinson’s disease and Alzheimer’s disease.

The different biological effect of these two incretin hormones is presented in the table below:

GIP GLP-1
Peptide with 42 amino acids Peptide with 30/31 amino acids
It is released from the duodenum K cells It is released from the ileum and colon L cells
Stimulates insulin secretion Stimulates insulin secretion
Does not inhibit glucagon secretion Inhibits glucagon secretion
Does not affect gastric motility Slows down motility of the stomach
Does not reduce satiety and BW Reduces satiety and BW
Stimulates the expansion of ß cell mass Stimulates the expansion of ß cell mass
Normal secretion in persons with T2DM Decreased secretion in persons with T2DM
Stimulates lipoprotein lipase and synthesis of fatty acids in adipocytes – energy “saving” Numerous direct and indirect CV effects

In persons with diabetes, the secretion or function of “intestinal” hormones is weakened or completely absent. Development of a group of medications called “GLP1 RA”, which were compensating the function of these substances in the body, began after the importance of those substances was discovered. Before them, DPP-4 inhibitors were in use (Januvia – Merck, the most popular, Onglyza – Astra, Galvus – Novartis), but they did not show an effect on appetite and a good CV effect.

Numerous medications have been registered from the group GLP-1RA.
Byetta (daily application) and Bydureon (weekly application) were the first. Due to greater digestive side effects, they are no longer popular.

Victoza – liraglutide is still popular. 2 forms have been registered – for the treatment of T2D and for the treatment of obesity. Victoza is taken once a day. It is well tolerated. It is administered via a pen that has 3 doses: 0.6, 1.2 and 1.8mg. It always starts with the lowest dose, which increases over 7 days, up to a maximum of 1.8mg per day. For example, a man was given Victoza for the treatment of diabetes type 2. The medication is introduced by receiving 0.6mg every day sc for 7 days. Then it goes to 1.2mg sc – also for 7 days or longer. The therapeutic dose for diabetes is 1.8mg sc every day. With this dose, glycemia and weight are reduced. Victoza is approved for the treatment of type 2 diabetes in children aged 10 years. It can also be given to obese children with T1 diabetes, as it reduces hyperglycemia (by inhibiting glucagon secretion), insulin dose, body weight, and frequent hypoglycemia.

Saxenda – liraglutide for obesity treatment. The pen for Saxenda looks the same as for Victoza, but there are additional doses of 2.4mg and 3.0mg. Saxenda is registered for the treatment of obesity, even in people who do not have diabetes. The principle of introducing the therapy is the same, only it is continued for another 7 days with 2.4mg sc every day and on – the therapeutic dose for obesity is 3mg sc every day.

Xultophy – the combination of Victoza and insulin degludec is also registered. It is the best medication for the treatment of type 2 diabetes, but the most expensive as well. Victoza in it reduces appetite, weight and protects the heart, while insulin additionally keeps sugar under control. It is applied every day sc.

Innovations in GLP-1 receptor agonist therapy continued to proceed in two directions. Medications for sc application once a week were synthesized and tested, as well as the medications for oral administration.

GLP-1RA weekly sc are:
Ozempic – semaglutide. For its use there are 3 pens with different doses. It starts with a pen of 0.25mg which contains 4 doses of medication. Each dose is administered once a week sc. Then the pen for 4 doses of 0.5mg is taken. Likewise, each dose is administered once a week sc for a month. And, after the gradual introduction of the medication, it is continued with a therapeutic dose of semaglutide of 1mg once a week. Due to its enviable effect on BW loss, Ozempic has also been used by obese people who do not have diabetes. High demand has caused a shortage of this medication. Novo Nordisk suggested that Ozempic should be used only for the treatment of T2D and that higher-dose of semaglutide (Wegovy) be used for the treatment of obesity.

Wegovy – semaglutide with an indication for obesity. It also starts with gradual introduction of the medication – but after a month of a dose of 1mg, it is continued weekly with 1.7mg sc for one month and in the end the therapeutic dose is 2.4mg per week. Wegovy is approved for the obesity treatment in children from the age of 12.

Rybelsus – oral semaglutide. In order to achieve the maximum absorption of the medication, the use of the medication is clearly defined. It is taken with 120ml of water on an empty stomach, immediately after waking up. The earliest breakfast is 30 minutes after taking the medication. It works for 24 hours and reduces glycemia only after eating. It does not cause hypoglycemia on an empty stomach. It has an effect on reducing appetite, but it is less significant than sc semaglutide. Also, a gradual increase in the dose is necessary: 3mg orally in the morning is taken for a month. Then the dose is increased to 7mg orally in the morning for one month. And after – the therapeutic dose is 14mg orally every morning on an empty stomach.

Indications for the use of GLP-1RA:
T2 diabetes in children older than 12 years and adults with HbA1c 7%.
Obesity: BMI (body mass index)  30, or BMI ≥28 kg/m2 and proven cardiovascular disease.

Contraindications for the use of GLP-1RA: medullary carcinoma of the thyroid gland, syndrome of multiple endocrine neoplasia, chronic pancreatitis with cysts in the pancreas.

Side effects of GLP-1RA: nausea, vomiting, diarrhea or constipation are the most common side effects. They are reduced by using smaller meals, not overeating and by taking more fluids. Avoiding fatty, fried and strongly spiced foods is also helpful. Changing the time of day when the medication is given can also be useful (e.g. in the evening instead of in the morning). All these ailments are temporary. If side effects persist, a person can use a smaller dose of the medication, instead the therapeutic one. There have been recorded cases of pancreatitis, which were successfully treated with standard therapy.

Combined effects of GIP and GLP-1RA: the twin-incretin concept. GIP-Rc agonist Tirzepatid – (2022) has a GLP-1R/GIPR dual agonist effect. On this medication (Monjaro), the loss in BW is greater than on GLP-1RA.

In conclusion:

• The discovery of incretin hormones introduced a multidisciplinary approach and linked food intake with the functioning of the digestive tract, endocrine pancreas, liver, nervous system, heart and blood vessels, and kidneys.
• The incretin concept opened up therapeutic possibilities in T2 diabetes and obesity.
• It displaced the glucocentric approach of T2DM treatment to a cardio-nephro protective treatment approach.
• In the future – it is possible to use the neuroprotective properties of incretin hormones for the treatment of neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease).