How is semaglutide (GLP-1 receptor agonist) used for weight loss?

From the Guidelines

Semaglutide is used for weight loss as a once-weekly subcutaneous injection, with a dosing regimen that has been shown to result in significant weight loss in clinical trials.

Key Points

• The FDA approved semaglutide for the treatment of obesity in 2021, with a recommended dose of 2.4 mg once weekly 1.
• Clinical trials, such as the STEP trials, have demonstrated that semaglutide results in significant weight loss, with a mean weight loss of 14.9% to 16.0% at 68 weeks, compared to 2.4% to 5.7% with placebo 1.
• The weight loss achieved with semaglutide is dose-dependent, with higher doses resulting in greater weight loss 1.
• Semaglutide has been shown to improve weight-related comorbidities and reduce the risk of cardiovascular events, with a hazard ratio of 0.80 for cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the SELECT trial 1.
• The AGA clinical practice guideline recommends using semaglutide 2.4 mg with lifestyle interventions for adults with obesity or overweight with weight-related complications, with a conditional recommendation due to variability in values and preferences 1.

Mechanism of Action

• Semaglutide is a GLP-1 receptor agonist that mimics the effects of GLP-1, suppressing appetite, delaying gastric emptying, and increasing glucose-dependent insulin release 1.
• GLP-1 receptors are expressed in multiple organs, including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, which may contribute to the pleiotropic benefits of semaglutide for weight loss, glucose control, and cardioprotection 1.

Clinical Use

• Semaglutide is typically initiated at a lower dose and titrated up to the recommended dose of 2.4 mg once weekly, with a protocolized dose escalation 1.
• Lifestyle interventions, such as a hypocaloric diet and regular physical activity, are often used in conjunction with semaglutide to enhance weight loss and improve overall health outcomes 1.

From the FDA Drug Label

Semaglutide lowers fasting and postprandial blood glucose and reduces body weight.

Semaglutide is used for weight loss by reducing body weight as part of its mechanism of action, in addition to lowering blood glucose levels. The exact mechanism of weight loss is not explicitly stated, but it can be inferred that it is related to its effects on:

• Glucose-dependent insulin secretion: stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner
• Delay in gastric emptying: reducing the rate at which glucose appears in the circulation postprandially 2

From the Research

Mechanism of Action

• Semaglutide promotes weight loss via appetite and hunger suppression, decreases energy intake, controls eating, and depresses the relative fondness for fatty, energy-dense foods 3
• The drug has a recognized effect on weight loss, and its pharmacokinetics show a drop in glycosylated hemoglobin A1c (HbA1c) and total body weight 3

Efficacy in Weight Loss

• Semaglutide has demonstrated safe and effective weight loss for overweight and obesity, including participants with concomitant type 2 diabetes mellitus (T2DM) 4
• The drug is associated with a greater percentage weight change from baseline and a higher likelihood of participants losing ≥5% of baseline fasting body weight at 12 weeks versus all available comparators 4
• Semaglutide has shown efficacy in reducing body weight in T2DM patients, with a mean weight loss reduction of 4.81 kg 5

Comparison with Other GLP-1 Receptor Agonists

• Semaglutide had a greater mean weight loss compared to liraglutide and dulaglutide 5
• Tirzepatide, a dual-agonist, produced greater weight loss compared to semaglutide 5
• Semaglutide demonstrated increased numerical weight loss compared to its comparators (dulaglutide, liraglutide, and exenatide) 5

Adverse Effects

• Common adverse effects observed in patients treated with semaglutide include gastrointestinal adverse events, like nausea, vomiting, diarrhea, constipation, and abdominal cramps 3
• Minor and moderate gastrointestinal events were common in patients treated with semaglutide 5

Clinical Use

• Semaglutide is indicated for weight management in patients with a BMI of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater 6
• The drug is approved for chronic weight management in adults with obesity or who are overweight, and it offers a new treatment in conjunction with a weight management program consisting of reduced calorie diet and increased physical activity 6