Author: Shi Chunhuan
Source: Endocrinology Channel in the Medical Community
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of hypoglycemic drugs. The GLP-1RA currently marketed in mainland China includes semaglutide, dulaglutide, losenatide, exenatide, liraglutide, lisinatide, benaglutide, how are these drugs used in clinical practice? Let's learn together.
1. Types and properties of the drug
Weekly formulations include semaglutide, dulaglutide, losenatide, and exenatide microspheres, and daily formulations include liraglutide and lisinatide.
There are also exenatide with 2 injections per day and benaglutide with 3 injections per day.
注：BMI-身体质量指数；T2DM-2型糖尿病
2. Approved indications
1. Domestic
| All 8 GLP-1RAs were approved for glycemic control in adult patients with T2DM who did not respond to metformin and sulfonylurea oral hypoglycemic drugs alone/in combination. Liraglutide and semaglutide injection are also approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adult patients with T2DM with cardiovascular disease. The marketing authorization applications for liraglutide and benaglutide for the indication of obesity or overweight received a Drug Registration Certificate approved by the National Medical Products Administration (NMPA) in March and July 2023, respectively [1,2]. In January 2024, semaglutide oral preparation received the Drug Registration Certificate approved and issued by the National Medical Products Administration (NMPA) [3] for the treatment of type 2 diabetes. |
2. Abroad
| In addition to T2DM, it is also used in other fields. Liraglutide, semaglutide, dulaglutide injection: approved in the United States for reducing the risk of adverse cardiovascular events in adult patients with type 2 diabetes mellitus with cardiovascular disease. Liraglutide injection (3.0 mg) and semaglutide injection (2.4 mg) are approved in the United States for adult quality management, mainly for patients with a BMI of ≥ 30 kg/m2 or patients with a BMI of ≥ 27 kg/m2 with complications. Liraglutide Injection (3.0mg) is the first GLP-1RA in the world to be approved by the US FDA and the European EMA for weight loss. |
3. Pharmacological effects
Some GLP-1RAs have other pharmacological effects in addition to hypoglycemic effects:
1. Rectangular action
GLP-1RA drugs can reduce the body weight of patients to varying degrees, but at this stage, only some drugs have been approved for the indication of weight loss therapy. According to the 2024 edition of the Medical Standards for Diabetes published by the American Diabetes Association [5], liraglutide and semaglutide are used at larger doses than for glucose reduction when used for weight loss.
2. Cardiovascular protection
Current evidence suggests that liraglutide, semaglutide, and dulaglutide all have cardiovascular protective effects.
3. Renal protection
At present, the evidence shows that dulaglutide, semaglutide and liraglutide have shown good visceral protective effects, and can be used as hypoglycemic drugs for patients with T2DM with renal impairment.
4. T2DM is not the treatment of alcoholic fatty liver disease
Current evidence suggests that liraglutide and semaglutide have been shown to be effective in the treatment of fatty liver disease, slowing the progression of fibrosis and reducing cardiovascular risk.
5. Treatment of polycystic ovary syndrome (PCOS).
In the study of GLP-1RAs in the treatment of PCOS, the current focus is mainly on short-acting exenatide and long-acting liraglutide. Compared with metformin alone, the combination of exenatide or liraglutide resulted in significant improvements in the number of spontaneous pregnancies, the frequency and regularity of menstrual cycles, and the pregnancy rate of in vitro fertilization in PCOS patients.
4. Dosage and storage conditions
Note: Oral semaglutide is not approved in the United States
5. Patients with whom GLP-1RA is contraindicated or used with caution[6]
1. The following patients are prohibited:
| (1) Those who are allergic to the active ingredients or any other excipients of such products; (2) patients with diabetic ketoacidosis; (3) Patients with a history or family history of medullary thyroid cancer; (4) Patients with multiple endocrine neoplasia type 2; (5) Patients with confirmed or suspected pancreatitis; (6) Females of gestational age, pregnant and lactating females who plan to become pregnant; (7) Those with wasting diseases (such as tuberculosis, tumors, etc.). |
2. For the following patients:
| (1) Patients with inflammatory bowel disease and diabetic gastroparesis; (2) Patients with a history or high risk of pancreatitis; (3) Patients with heart failure with New York College of Cardiology (NYHA) cardiac function grade IV; (4) Patients with T2DM under 18 years of age. Continental has not approved any GLP-1RA for the treatment of T2DM patients in children under 18 years of age, and the U.S. Food and Drug Administration approved liraglutide in 2019 for the treatment of T2DM patients in children and adolescents 10 years of age and older. |
6. Medication for patients with liver and kidney insufficiency
7. Medication for children and adolescents and pregnant or lactating women[4,7]
8. Adverse reactions and treatment measures
Gastrointestinal reactions, such as nausea, vomiting, and diarrhoea, are the most important adverse reactions, and are mostly mild, moderate, and transient, and can be tolerated by most patients. It is recommended to start with a small dose and gradually increase the dose, and those who are intolerant should discontinue the drug and change to another treatment regimen in a timely manner.
Other common adverse reactions include dizziness, headache, increased heart rate, nasopharyngitis, etc., which also need to be noted clinically.
Severe allergic reactions (such as immediate allergic reactions, angioedema) have been reported with the use of GLP-1RA, and if anaphylaxis occurs, the product should be discontinued, standard treatment should be given immediately, and the patient should be monitored until signs and symptoms subside. Do not use in patients with previous allergies to this drug. Semaglutide, liraglutide, and dulaglutide have high homology with human natural GLP-1 and occur rarely.
There have been occasional clinical case reports of acute pancreatitis associated with GLP-1RA therapy, but large randomized controlled trials and meta-analyses have shown that GLP-1RA treatment does not increase the risk of acute pancreatitis compared with placebo [8]. For safety reasons, patients with a history or high risk of pancreatitis should be cautious when using GLP-1RA, and patients who are being treated with GLP-1RA should be discontinued immediately if they develop acute pancreatitis, and other patients should be treated in a timely manner according to the treatment principles of acute pancreatitis.
Bibliography:
[1] On July 27, 2023, the drug approval certificate of the National Medical Products Administration (NMPA) was delivered to https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20230727153244168.html
[2] On March 31, 2023, the National Medical Products Administration (NMPA) released the information on the delivery of drug approval documents https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20230331132332108.html