How Do Antidiabetic Glucagon-like Peptide-1 Agonists Work?

The FDA has updated the labels of all the GLP-1 receptor agonist class of drugs with an additional warning in the “Warnings and Precautions” section about the risk of inhalation of gastric contents into the lungs (pulmonary aspiration) during deep sedation and general anesthesia.

The GLP-1 receptor agonist drug class that has been updated include semaglutide (Ozempic, Rybelsus, Wegovy); liraglutide (Saxenda, Victoza); and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 tirzepatide (Mounjaro, Zepbound).

The FDA has received rare postmarketing reports of pulmonary aspiration in patients taking GLP-1 receptor agonists who were undergoing elective surgeries or procedures that required deep sedation or general anesthesia, in spite of following pre-operative fasting as recommended.

Available data are insufficient to recommend whether modifying the pre-operative fasting recommendations, or discontinuing the GLP-1 receptor agonists temporarily can reduce the risk of pulmonary aspiration during deep sedation and anesthesia.

Healthcare providers should apprise patients of the risk for pulmonary aspiration and advise them to inform if they are taking GLP-1 receptor agonists, if they plan to undergo any elective surgery or other medical procedures that require deep sedation or general anesthesia.

FDA has evaluated reports of suicidal thoughts or actions in patients treated with GLP-1 agonists.

Preliminary evaluation has shown no evidence suggesting the use of GLP-1 agonists causes suicidal thoughts or actions.

FDA reviews of the clinical trials, including large outcome studies and observational studies, did not find an association between use of GLP1 agonists and the occurrence of suicidal thoughts or actions.

Owing to the small number of suicidal thoughts or actions observed in both treated patients and in comparative control groups, the FDA cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to investigate this issue.

Instruct patients not to stop taking GLP-1 agonists without first consulting a healthcare professional, as stopping these medicines may worsen their condition.

Patients should contact their healthcare professional if new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior develops.

Call or text 988 or go to https://988lifeline.org, which provides free support for people in distress 24 hours a day, 7 days a week.

Antidiabetic glucagon-like peptide-1 agonists (also known as GLP-1 agonists) are a class of drugs used with a proper diet and exercise to control high blood sugar in people with type 2 diabetes mellitus (T2DM) and obesity. T2DM is a long-term medical condition in which the body does not use insulin normally and, therefore, cannot control the amount of sugar in the blood. Controlling high blood sugar helps in preventing kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems and may also reduce the risk of a heart attack or stroke. Obesity is an abnormal or excessive fat accumulation that presents a health risk. A body mass index (BMI is calculated by considering a person’s weight and height to measure body size) of more than 25 is considered overweight and more than 30 is considered obese.

GLP-1 agonists are synthetic (man-made) hormones that resemble and act like GLP-1 which is one of the gut hormones involved in controlling the blood sugar.

GLP-1 agonists are not used to treat insulin-dependent or type 1 diabetes (a condition in which the body does not produce insulin and therefore cannot control the amount of sugar in the blood) and diabetic ketoacidosis (increased ketones in the blood or urine).

GLP-1 agonists are available as injectable powder for suspension and a solution (liquid) in a prefilled dosing pen to be injected subcutaneously (under the skin) in the stomach, thigh, or upper arm. 

GLP-1 agonists work in the following ways:

• They belong to a class of drugs called "incretin mimetics" because these drugs mimic the effects of incretins. 
• Incretins are hormones that are produced and released into the blood by the intestine in response to food. 
• GLP-1 is an incretin, one of the gut hormones, involved in controlling blood sugar, mainly acting on the insulin that the body produces after meals.
• GLP-1 is responsible for various functions such as:
  • Stimulation of insulin from the pancreas in response to food
  • Slowing down the absorption of glucose from the gut
  • Reduces gastric emptying
  • Inhibits the action of glucagon, a hormone that increases glucose production by the liver
  • Reduces appetite and promotes satiety or stomach fullness

Antidiabetic GLP-1 agonists are used in the following conditions:

• T2DM: as an adjunct to diet and exercise to improve glycemic control in adults
• Obesity/weight management: adjunctive therapy to a reduced calorie diet and increased physical activity for chronic weight management in adults with a BMI of ≥30 kg/m2 (obese) or a BMI of ≥27 kg/m2 (overweight) who have at least one weight-related condition (hypertension, T2DM, dyslipidemia).

Some of the common side effects include:

• Diarrhea
• Nausea
• Vomiting
• Stomach upset
• Bloating
• Heartburn
• Headache
• Constipation
• Decreased appetite
• Dry mouth
• Weakness
• Dyspepsia (a feeling of burning, pain, or discomfort in the digestive tract)
• Pain, itching, or redness at the injection site

Other rare side effects include:

• Hypoglycemia (low blood sugar level)
  • Sudden sweating
  • Fast heartbeat
  • Blurred vision
  • Tingling in hands/feet
• Dizziness (feeling faint, weak, or unsteady)
• Abdominal distention
• Gastroesophageal reflux disease
• Hyperkalemia (high blood potassium level)
• Dyslipidemia (blood lipid levels that are too high or low)
• Pancreatitis
• Signs of kidney problems 
• Change in the amount of urine
• Swelling in legs/feet
• Signs of urinary tract infection
• Burning/painful/frequent/urgent urination
• Pink/bloody urine
• Risk of pulmonary aspiration during deep sedation or general anesthesia during surgery

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of antidiabetic GLP-1 agonists include:

• Adlyxin
• Albiglutide
• Bydureon
• Bydureon BCise
• Byetta
• Dulaglutide
• Exenatide injectable solution
• Exenatide injectable suspension
• Exenatide subdermal implant
• Liraglutide
• Liraglutide/insulin degludec
• Lixisenatide
• Lixisenatide/insulin glargine
• Mounjaro
• Ozempic
• Rybelsus
• Saxenda
• Semaglutide
• Soliqua 100/33
• Tanzeum
• tirzepatide
• Trulicity
• Victoza
• Wegovy
• Xultophy
• Zepbound