How do GLP-1 (Glucagon-like peptide-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), increase the risk of adverse effects in individuals with a normal Body Mass Index (BMI)?

From the Guidelines

GLP-1 receptor agonists like liraglutide (Victoza) and semaglutide (Ozempic) are not recommended for individuals with normal BMI due to the risk of excessive weight loss and related complications, as well as potential gastrointestinal side effects and increased risk of hypoglycemia, as noted in the 2024 study published in the European Heart Journal 1. These medications work by slowing gastric emptying, increasing satiety, and reducing appetite, which can lead to significant weight reduction even in those who don't need to lose weight.

• In normal-weight individuals, this unnecessary weight loss may result in malnutrition, muscle wasting, and nutritional deficiencies.
• Additionally, these medications can cause gastrointestinal side effects like nausea, vomiting, and diarrhea, which may be more pronounced or less tolerable in those with normal BMI.
• The risk of hypoglycemia may also be elevated, especially if combined with other diabetes medications.
• Some patients might experience more severe adverse effects such as pancreatitis or gallbladder disease regardless of weight status, as reported in the 2024 study published in Anaesthesia 1. The use of GLP-1 receptor agonists in individuals with normal BMI should be carefully considered, and alternative treatments should be explored to minimize the risk of adverse effects, as suggested by the 2024 study published in Obesity Reviews 1.
• The potential benefits of GLP-1 receptor agonists, such as improved glycemic control and weight loss, must be weighed against the potential risks and complications.
• Careful monitoring and regular follow-up are essential to prevent excessive weight loss and associated complications in individuals with normal BMI who are treated with GLP-1 receptor agonists.

From the FDA Drug Label

The most common adverse reactions, reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea

GLP-1 Receptor Agonists Mechanism of Action: GLP-1 receptor agonists, such as semaglutide, work by mimicking the action of the GLP-1 hormone, which is involved in glucose metabolism and appetite regulation. They enhance glucose-dependent insulin secretion, decrease glucagon secretion, and slow gastric emptying, leading to improved glycemic control.

Increased Risk for Persons with Normal BMI: The FDA drug labels do not provide direct information on the increased risk of adverse effects in individuals with a normal Body Mass Index (BMI). However, the labels do report common adverse reactions, including gastrointestinal adverse reactions and hypoglycemia, which may be a concern for individuals with normal BMI taking GLP-1 receptor agonists. It is essential to consult a healthcare professional to discuss the potential risks and benefits of using these medications, especially for individuals with normal BMI 2, 2, 2.

From the Research

Mechanism of Action of GLP-1 Receptor Agonists

• GLP-1 receptor agonists, such as liraglutide and semaglutide, work by mimicking the action of the naturally occurring hormone glucagon-like peptide-1 (GLP-1) in the body 3, 4, 5, 6, 7.
• They bind to GLP-1 receptors in the brain and other parts of the body, leading to decreased appetite and increased feelings of fullness, resulting in weight loss.
• Additionally, GLP-1 receptor agonists have been shown to improve glycemic control, reduce blood pressure, and have beneficial effects on lipid profiles.

Increased Risk of Adverse Effects in Individuals with Normal BMI

• While GLP-1 receptor agonists have been shown to be effective for weight loss in individuals with overweight or obesity, their use in individuals with a normal BMI may increase the risk of adverse effects 4, 5, 6, 7.
• Common adverse effects of GLP-1 receptor agonists include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, as well as increased risk of pancreatitis, thyroid cancer, and gallbladder disease.
• The risk of these adverse effects may be higher in individuals with a normal BMI, as they may not have the same level of metabolic benefits as individuals with overweight or obesity.
• However, it is essential to note that the current evidence is primarily based on studies in individuals with overweight or obesity, and more research is needed to fully understand the risks and benefits of GLP-1 receptor agonists in individuals with a normal BMI.

Comparison of Different GLP-1 Receptor Agonists

• Semaglutide has been shown to be one of the most effective GLP-1 receptor agonists for weight loss, with a higher percentage of individuals achieving a 10% weight loss compared to other GLP-1 receptor agonists 3, 4, 6, 7.
• Liraglutide has also been shown to be effective for weight loss, although to a lesser extent than semaglutide.
• The safety profiles of different GLP-1 receptor agonists may vary, with semaglutide having a lower risk of gastrointestinal adverse events compared to other GLP-1 receptor agonists 7.