Semaglutide 8 mg

What is semaglutide?

Semaglutide is a synthetic peptide that belongs to the class of GLP-1 receptor agonists (glucagon-like peptide-1) and belongs to the most studied molecules in modern metabolic pharmacology. It is a structural analog of the endogenous human GLP-1 hormone, modified with three key changes: the amino acid at position 8 is changed from alanine to α-aminoisobutyric acid to protect against degradation by the enzyme DPP-4, a C18 fatty acid diacid is attached via a spacer to allow strong binding to serum albumin, and the amino acid at position 34 is changed from lysine to arginine. The result of the modifications is a very long plasma half-life of approximately 165 hours, corresponding to approximately one week, which enables weekly administration.

Semaglutide was developed by Novo Nordisk and was first approved by the FDA in December 2017 under the trade name Ozempic for the treatment of type 2 diabetes. In June 2021, the same molecule was approved at a higher dose under the trade name Wegovy for the treatment of overweight and obesity in adults. An oral preparation, Rybelsus, was approved in 2019 for type 2 diabetes — the only commercially available oral GLP-1 agonist that successfully overcomes gastrointestinal degradation through the use of the absorption enhancer SNAC. The pivotal clinical trials are part of the SUSTAIN program (type 2 diabetes), the STEP program (obesity) and the SELECT trial (cardiovascular outcomes in obese subjects).

Presentation 8 mg corresponds to a pharmaceutical concentration often used in multi-dose vials and pens intended for subcutaneous administration. The actual weekly dose during treatment is lower — between 0.25 mg and 2.4 mg per week depending on the indication and up-titration phase — and the total amount in one bottle is thus enough for several weeks of use.

How does semaglutide work?

Semaglutide binds selectively to the GLP-1 receptor, a G protein-coupled receptor expressed on pancreatic beta cells, alpha cells, gastric parietal cells, cardiac muscle cells and several centers in the brain, especially in the hypothalamus and brainstem. The binding activates the Gs protein, which increases intracellular cAMP and thereby triggers protein kinase A and Epac-mediated signaling.

Glucose-dependent insulin secretion is stimulated on the beta cells — that is, insulin is released only when blood sugar levels are elevated, which reduces the risk of hypoglycemia compared to sulfonylureas or exogenous insulin. Glucagon secretion from the alpha cells is suppressed, which further contributes to glucose homeostasis through reduced hepatic glucose production. On the stomach, gastric emptying is slowed down, which delays the absorption of carbohydrates and reduces postprandial glucose peaks.

Central nervous influence is central to weight reduction. The GLP-1 receptors in the nucleus arcuatus of the hypothalamus, in the nucleus tractus solitarii and in the area postrema mediate satiety signals and suppress appetite. The brain's reward system, including the ventral tegmentum and nucleus accumbens, is affected in ways that reduce cravings for particularly high-energy foods and alcohol—a finding that has fueled exploratory studies in alcohol addiction. Direct cardiovascular effects, documented in the SELECT trial, include reduced inflammation in the vessel wall, lowered blood pressure and improved endothelial parameters.

What can semaglutide potentially affect?

In pharmacological studies from the SUSTAIN, STEP and SELECT programs as well as in extensive post-marketing reporting, several physiological systems where semaglutide leaves a clear imprint reappear:

• Glucose homeostasis — lowered levels of HbA1c, fasting glucose and postprandial glucose via glucose-dependent insulin secretion and suppressed glucagon production.

• Body weight and body composition — reduction in fat mass and total body weight, documented to be approximately 15 percent at the highest approved dose of 2.4 mg per week in STEP-1.

• Appetite regulation and satiety — central influence in the hypothalamus and brainstem reduces appetite, delays gastric emptying and prolongs the feeling of satiety.

• Cardiovascular function — reduced risk of major cardiovascular events was documented in the SELECT trial in obese non-diabetic subjects, one of the most important findings in the class.

• Lipid metabolism — decreased levels of triglycerides, LDL and total cholesterol and increased HDL in clinical studies.

• Liver and renal function — reduced hepatic steatosis in non-alcoholic fatty liver disease and improved albuminuria in diabetic nephropathy have been documented.

Potential side effects of semaglutide

The side effect profile of semaglutide has been extensively documented in the SUSTAIN, STEP and SELECT programs as well as in post-marketing reporting since 2017. The profile is dominated by gastrointestinal side effects, especially during the up-titration phase. More rare but serious side effects occur and require attention during clinical follow-up.

• Gastrointestinal — nausea, vomiting, diarrhea, constipation, and abdominal pain are the most common side effects. The symptoms are typically most pronounced during the first weeks and with each dose increase, and decrease in intensity over time.

• Pancreatitis — acute pancreatitis has been reported. The risk increase is small but the occurrence is a key observation, especially in individuals with previous pancreatitis or gallstone disease.

• Gallbladder and biliary tract — cholelithiasis and cholecystitis are documented, likely linked to the rapid weight loss rather than a direct molecular effect.

• Thyroid C-cells — in animal studies, medullary thyroid cancer has been observed in rats, warranting caution for C-cell tumors in humans, although human relevance is questionable.

• Hypoglycaemia — the risk is low with monotherapy but increases significantly in combination with insulin or sulfonylureas, which is why dose adjustment of additional treatment is necessary.

• Dehydration and kidney function — severe and prolonged gastrointestinal side effects can cause dehydration and, in rare cases, acute kidney injury.

• Local reactions — redness, itching and skin reactions at the injection site, usually mild and transient.

The overall side effect picture of semaglutide — gastrointestinal effects, rare but serious reactions in the pancreas and biliary tract and a theoretical C-cell tumor risk — means that clinical use requires close monitoring of symptoms, weight development and relevant laboratory parameters (HbA1c, lipid status, liver and kidney function).