Side effects include muscle atrophy, digestive tract side effects, and the possibility of tumors (in mouse experiments, but unknown in humans, benign or malignant). People with a family history of tumors, people at high risk of tumors, and people who are already taking hypoglycemic drugs (such as biguanides) are not suitable for use.
As for semaglutide, the side effects are not too big, otherwise you would not take it as a weight loss drug.
As a glucagon-like peptide-1 (GLP-1) analog, the main function of this thing is to bind to the GLP-1 receptor, and then play the role that the GLP-1 hormone should play to regulate the metabolic activity of cells.
GLP-1 is a hormone secreted by endocrine cells (L cells) in the small intestine and solitary nucleus neurons in the brainstem when eating. Its main function is to slow down gastric emptying and inhibit acid secretion. This is its first bad side effect (of course, it is also one of the reasons for weight loss), that is, it reduces appetite, may cause indigestion and nausea and bloating, and in severe cases may cause pancreatitis or intestinal obstruction.
Then comes our favorite signaling pathway link.
GLP-1 receptor is a type of G protein-coupled receptor (GPCR), and the G protein that cooperates with it is an activated G protein Gs.
This receptor can affect cells through three pathways: activating adenylate cyclase to produce the second messenger cAMP; activating PI3K to produce the second messenger phosphatidylinositol-3-phosphate (PI3P); the intracellular tail of the activated GPCR is phosphorylated by G protein-coupled receptor kinases (GRKs), recruiting β-arrestin, terminating the occurrence of traditional GPCR signals and activating pERK1/2 (extracellular signal-regulated kinase 1/2).
Let’s talk about them one by one. First, the cAMP pathway. After cAMP is produced, it can activate PKA and Epac2, promote potassium efflux, prompt the opening of L-type VDCC, and calcium ion influx, thereby promoting the expression and secretion of insulin. At the same time, it activates cAMP-GEF to promote the proliferation and differentiation of pancreatic β cells, and also activates CREB to promote Bcl-2 and Bcl-xL’s resistance to cell apoptosis.
Then, the activation of PI3K and the production of PI3P activated PKB (protein kinase B, also known as Akt) and PDK (phosphoinositide-3-phosphate-dependent protein kinase). The activation of PKB inhibited apoptosis and programmed necrosis caused by caspase, inflammation caused by NF-κB, and the expression of glucose-6-phosphatase (the enzyme hydrolyzes 6-phosphate glucose, causing glucose to be unable to enter glycolysis) promoted by FOXO1, which protected pancreatic β cells to a certain extent and promoted the use of glucose by cells. The activation of PDK promoted the activation of PKC (protein kinase C), which in turn promoted the activation of MARK and PDX-1, and also promoted the proliferation and differentiation of pancreatic β cells.
Finally, the recruited β-arrestin activated pERK1/2 (extracellular signal-regulated kinase 1/2), resulting in the activation of Bcl-2 and Bcl-xL, thereby promoting cell resistance to apoptosis.
These pathways promote insulin secretion and protect pancreatic β cells, so at least there is no big problem with pancreatic β cells.
Then there is the popular muscle aspect. Due to the energy deficit caused by semaglutide’s appetite suppression, it is possible to cause excessive muscle gluconeogenesis and induce muscle atrophy. I don’t have any good solutions in this regard. I suggest taking protein powder or other amino acid supplements.
As for tumors, I personally think that in addition to thyroid cancer, we should also be careful of neuroendocrine tumors (such as insulinomas), because in mouse experiments, GLP-1R agonists not only induced medullary thyroid carcinoma (MTC), but also occasionally neuroendocrine tumors (such as insulinomas). But if I remember correctly, this is mentioned in the instructions for semaglutide. Of course, if you don’t read it carefully, it’s another matter.
Some people may worry about hypoglycemia, but the problem is that in the mechanism of action of this thing, promoting insulin secretion is dependent on glucose, so unless it is used in combination with other hypoglycemic drugs (such as exogenous insulin, sulfonylurea hypoglycemic drugs), in the presence of insulinoma/hyperinsulinemia, severe dietary control or long-term fasting, there is a risk of hypoglycemia (then again, who would do this?).
Mainly speaking, the side effects of semaglutide are basically only manifested in the digestive tract and digestive glands, so it can be said to be a relatively safe weight loss drug.