Semaglutide – Mechanism, precautions and side effects

What is this drug, semaglutide? The suffix -glutide indicates that this drug is acting on diabetes, and semaglutide is classified as a GLP-1 receptor agonist. GLP is nothing but a glucagon-like peptide, so this GLP-1 can control blood glucose levels by increasing the insulin secretion from the pancreas, and it also increases the glucagon action, which opposes the elevation of blood glucose levels.

In this way, GLP-1 can control blood glucose levels, but it has a few limitations. Glucagon-like peptides have a short duration of action, and they can be converted into metabolites by one of the enzymes DPP-4, dipeptidyl peptidase-4. This enzyme can control the action of GLP-1, so GLP-1 shows a very short duration of action. This is the endogenous mediator that can control glucose levels, but it has a short duration of action.

Semaglutide as GLP-1 agonist

Semaglutide is a GLP-1 receptor agonist that acts just like GLP-1, so it also increases insulin secretion as well as glucagon action, but at the same time, this drug is not metabolized by the DPP-4 enzyme. That's why this drug is somewhat long-acting and can control excessive glucose levels in diabetic patients.

So semaglutide has two advantages. First, it is not metabolized by the DPP-4 enzyme, which increases the bioavailability of this drug. Second, semaglutide can bind to albumin. When this drug binds to albumin, it cannot be easily metabolized, even though it cannot be easily cleared by renal clearance. So this drug can stay within the blood circulation for longer periods. That's why this drug is one of the long-acting GLP-1 agonists.

Clinical uses

Semaglutide can be used in the management of type 2 diabetes mellitus along with diet and exercise. For this purpose, this drug is available as a tablet as well as a subcutaneous injection.

Semaglutide not only reduces glucose levels, but it also reduces appetite, thereby reducing body weight. That's why this drug can be used in the management of obesity. In those patients with a body mass index greater than 30 kg per square meter, this semaglutide can be given as a subcutaneous injection, but one important thing is that the subcutaneous injection intended for obesity is not equivalent to the subcutaneous injection indicated for diabetes mellitus. Since the dosage and strengths are somewhat variable, even the route of administration is similar, but they are indicated for different purposes.

So this drug is useful in the management of type 2 diabetes mellitus as well as for the management of obesity, and particularly among the GLP-1 agonists, semaglutide is available as an oral formulation to control diabetes mellitus. Similarly, this drug shows a beneficial effect in the management of obesity as it reduces appetite, resulting in decreased body weight in the patients, but this drug is not indicated for children; it is only available for the treatment of obesity in adults.

Apart from these, this drug has a few limitations, but semaglutide should not be given to patients with pancreatitis. Since this drug produces pancreatitis, it is not indicated in patients with any history of pancreatitis. Similarly, this drug is not useful in the treatment of type-I diabetes, which is associated with insulin deficiency, and even semaglutide is not the first-line therapy for the management of diabetes mellitus; it can be combined with other drugs to produce efficient control of blood glucose, and this drug is available in oral tablet form, which improves patient compliance.

How semaglutide acts?

Semaglutide can produce its action by acting on three organs. Its main action is attributed to its action on the pancreas, where from the beta cells it can increase insulin secretion, resulting in decreased glucose levels. Similarly, this drug can act on the brain, where it can reduce appetite, so because of the loss of appetite, semaglutide can reduce body weight. That's why it can be used in the management of obesity. Similarly, this drug can also produce some delayed gastric emptying, resulting in a decreased absorption of glucose. Because of all these actions, semaglutide can be used in the treatment of type 2 diabetes mellitus as well as in the treatment of obesity.

On the beta cells, GLP-1 receptors are expressed, which are G-protein-coupled receptors. Semaglutide can act on this GLP-1 receptor, which results in its activation, leading to stimulation of the adenylyl cyclase system. By activating this enzyme, ATP can now be converted into cyclic AMP. This cyclic AMP plays an important role within the beta cells. It can stimulate one group of enzymes, protein kinase A. This protein kinase A can control the activity of various ion channels.

It can impact the activity of ATP-sensitive potassium channels, through which potassium can go outside, and voltage-gated calcium channels and voltage-gated sodium channels. Now, protein kinase A can inhibit these ATP-sensitive potassium channels so that potassium cannot go outside, and at the same time, it can stimulate the calcium channels so calcium can enter the beta cells, resulting in the depolarization.

It can also stimulate the sodium channels, resulting in the entry of sodium. Through all of these actions, beta cells are depolarized, resulting in the release of insulin from the beta cells. In this way, semaglutide can increase insulin secretion from the beta cells, thereby reducing blood glucose levels. This drug can also increase glucagon secretion, which reduces glucose levels, and it can also act on the brain, thereby reducing appetite and leading to a significant reduction in body weight.

Important precautions

One of the important precautions of semaglutide is that it can act on the pancreas, so it can produce some pancreatitis as one of its important side effects. So in those patients with any history of pancreatitis, this drug should be carefully given, and during the treatment, if any symptoms such as severe abdominal pain, nausea and vomiting, or unexpected weight loss occur, all of these should be carefully monitored. All of these may indicate the development of pancreatitis, so in such patients, this semaglutide should be carefully given.

Another important precaution is the risk of diabetic retinopathy. Normally, excessive glucose levels may result in diabetic retinopathy, so in such patients, semaglutide can further increase the risk even though it is going to reduce the glucose levels, but the risk of diabetic retinopathy is increased by semaglutide. So for diabetic patients with already-developed diabetic retinopathy, this drug should not be used. Since this drug is going to reduce the glucose levels, it can produce hypoglycemia, and some weakness can be observed in the patients.

This effect may be further increased by other drugs like insulin secretagogues. For instance, sulfonylureas can act on beta cells, and they also increase the secretion of insulin from the beta cells, so this insulin again produces hypoglycemia. When semaglutide is combined with insulin secretagogues like sulfonylureas, this combination may produce significant hypoglycemia. Similarly, insulin preparations can also increase the hypoglycemia produced by semaglutide. So when these drugs are combined with this semaglutide, care should be taken to reduce the risk of severe hypoglycemia in the patients.

Another important precaution is that this drug can produce some acute kidney failure, so in patients with any chronic renal failure, this drug should be avoided. Because of this acute kidney failure, semaglutide may produce a few of the symptoms, such as severe diarrhea, nausea and vomiting, and dehydration. If any of these symptoms are observed during the treatment of semaglutide, then the kidney functionality should be assessed in order to check for any development of acute kidney failure.

Finally, this drug can produce some hypersensitivity, resulting in angioedema and swelling of the lips, tongue, face, and neck. It can also produce some anaphylaxis, resulting in skin rashes and urticaria. In such conditions, this drug should be avoided.

This drug may increase the risk of thyroid C cell carcinoma, so thyroid cancer may be increased with semaglutide. On long-term therapy, it can develop a mass within the neck, resulting in dysphagia—difficulty swallowing. That's why semaglutide is not indicated as a first-line therapy, along with other anti-diabetic agents that can be given in order to reduce the risk of thyroid cancer.

Side effects

Semaglutide mainly produces gastro-intestinal side effects resulting in abdominal pain and diarrhea; it can produce some loss of appetite, which results in a reduction in body weight; and it can produce some dyspepsia, indigestion, and flatulence.

How is it given?

This drug is available as a tablet that can be used for the management of type 2 diabetes mellitus, but this tablet should be given at least 30 minutes before the first food intake. That's why it can be given in the early morning, and a 30-minute gap should be maintained between the administration of this tablet and any intake of food or even beverages. This tablet should be taken with plain water; it should not be combined with other liquids since the food can reduce the absorption of semaglutide.

This drug is given at an initial dose of 3 mg given once daily, and after 30 days of treatment, the dose can be slightly increased to 7 mg, again given once daily. Based on the efficacy of the treatment, further dose increments can be made; again, after 30 days, the dose may be increased up to 14 mg given once daily. So the maximum dose is 14 mg given as a single dose per day in order to control the blood glucose levels.

Similarly, it is available as a subcutaneous injection, again indicated for the management of type 2 diabetes mellitus. The initial dose is a 0.25 mg subcutaneous injection given once a week. Finally, this drug is also available as a subcutaneous injection for the management of obesity. For this purpose, the initial dose is again 0.25 mg given once a week.

Conclusion

Semaglutide is one of the long-acting GLP-1 receptor agonists; this drug is orally available to control type 2 diabetes mellitus; it is also available as a subcutaneous injection; and another formulation is available as a subcutaneous injection for the management of obesity. So this drug can be used for the management of both type 2 diabetes mellitus and obesity. Pancreatitis is one of the important side effects that can be observed with this drug, and this drug can also increase the risk of the development of thyroid cancer. That's why this drug is not used as a first-line therapy; it can be combined with other anti-diabetic agents to produce better control over blood glucose levels.