Research Progress on Oral Semaglutide in the Treatment of Type 2 Diabetes

Pharmacokinetics of Oral Semaglutide

Oral semaglutide is mainly absorbed from the stomach. Studies have shown that food intake can affect gastric pH and prevent the maximum absorption of oral semaglutide. Therefore, patients should take oral semaglutide at least 30 minutes before meals to avoid food interference. The degree of absorption of semaglutide depends on the amount of SNAC bound to it. Studies have shown that when the SNAC is 300 mg, the blood concentration of semaglutide is the highest. After oral administration in patients with T2DM, the estimated absolute bioavailability of semaglutide is 0.4% to 1.0%, and the average steady-state concentrations of semaglutide after oral administration of 7 mg and 14 mg once daily are 7.6 mmol/L and 14.6mmol/L, respectively, reaching the maximum concentration within 1 hour after oral administration, and reaching steady state after continuous administration for 4 to 5 weeks. In healthy subjects, oral semaglutide is extensively bound to plasma albumin, has a half-life of 150 hours, and is present in the blood circulation for approximately 5 weeks after the last dose, with a clearance rate of 0.04 L/h. Oral semaglutide is metabolized through proteolytic cleavage of the peptide chain backbone and continuous β-oxidation of fatty acid side chains, and is excreted through urine and feces. About 3% is excreted in the urine as intact semaglutide.

The pharmacokinetic properties of oral semaglutide are not affected by patient-specific factors such as age, sex, race, ethnicity, and hepatic and renal function. Regardless of the severity of hepatic or renal impairment, it exhibits pharmacokinetic properties similar to those of the subcutaneous formulation. The drug exposure of oral semaglutide decreases with increasing body weight, but studies have found that oral semaglutide 7~14mg/d provides sufficient drug exposure for patients with a body weight of less than 188kg.

Since the absorption of oral semaglutide relies on SNAC delivery, it is important to evaluate drug-drug interactions. Multiple drug interaction studies have found that metformin, omeprazole, rosuvastatin, lisinopril, furosemide, warfarin, digoxin, ethinyl estradiol/levonorgestrel None of the other drugs significantly affected the drug concentration of oral semaglutide.

Safety of Oral Semaglutide

The most common adverse reactions of semaglutide are gastrointestinal reactions, including nausea, vomiting, abdominal pain, diarrhea, loss of appetite, and constipation. They are generally mild to moderate, and the occurrence of gastrointestinal reactions is related to the dosage. The study found that the incidence of hypoglycemia was low when semaglutide was used as monotherapy, and the combination of semaglutide and insulin did not significantly increase the incidence of hypoglycemia. This shows that semaglutide has good cardiovascular safety, but compared with subcutaneous injections, oral formulations have no advantage in reducing the occurrence of cardiovascular events in high-risk groups. Renal insufficiency does not affect the recommended dosing of semaglutide. There were no significant changes in the pharmacokinetics, safety, and tolerability of semaglutide after oral administration to patients with hepatic impairment. However, compared with patients with normal liver function, the exposure of SNAC in the preparation increased 3.64 times in patients with severe hepatic insufficiency.

Other adverse reactions of semaglutide are similar to those of GLP-1RA, with reports of slightly increasing the patient's heart rate, increasing amylase and lipase levels, and causing acute pancreatitis. The instructions warn that semaglutide should not be used in patients with a history of pancreatitis. A history or family history of medullary thyroid cancer is a contraindication to semaglutide.