How does semaglutide facilitate weight loss?

From the Guidelines

Semaglutide facilitates weight loss by mimicking the effects of GLP-1, suppressing appetite, delaying gastric emptying, and increasing glucose-dependent insulin release.

Mechanism of Action

• Semaglutide acts on the hypothalamus to suppress appetite and delay gastric emptying, leading to reduced food intake and weight loss 1.
• It also increases glucose-dependent insulin release and decreases glucagon secretion, which helps to improve glucose metabolism and reduce weight 1.

Clinical Trials

• The STEP trials demonstrated that semaglutide resulted in significant weight loss, with a mean weight loss of 14.9% and 16.0% at 68 weeks, compared to 2.4% and 5.7% with placebo, respectively 1.
• A clinical trial that randomized 667 adults with obesity without diabetes to either semaglutide or placebo for 68 weeks found that mean weight loss with 50 mg/d oral semaglutide was 15.1% vs 2.4% for placebo 1.

Dosage and Administration

• Semaglutide is dosed once weekly and is available in 2.4 mg and 1.0 mg formulations 1.
• The medication should be titrated every 4 weeks as tolerated by the patient, with a goal of achieving the maximum tolerated dose 1.

Safety and Efficacy

• Semaglutide has been shown to be effective in reducing weight and improving weight-related comorbidities, with a low risk of undesirable adverse effects and low risk of treatment discontinuation due to adverse events 1.
• Common side effects of semaglutide include gastrointestinal side effects such as nausea, vomiting, and diarrhea, as well as injection site reactions and elevated heart rate 1.
• Semaglutide has also been shown to have cardioprotective effects, with a reduced risk of cardiovascular events in adults with overweight or obesity without diabetes 1.

From the FDA Drug Label

Semaglutide lowers fasting and postprandial blood glucose and reduces body weight. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.

Semaglutide facilitates weight loss by:

• Reducing body weight as part of its pharmacodynamic effects
• Delaying gastric emptying, which reduces the rate at which glucose appears in the circulation postprandially, potentially leading to reduced caloric intake and weight loss 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
• Semaglutide has been shown to have a significant effect on weight regulation, with a longer half-life and producing greater weight loss compared to other GLP-1 receptor agonists 4

Efficacy of Semaglutide

• Semaglutide 2.4 mg was associated with mean weight losses of 14.9%-17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68 5
• 69%-79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg, and 51%-64% achieved ≥15% weight loss 5
• Semaglutide has demonstrated the largest weight loss of any obesity medication to date, with reductions of approximately 15% of initial weight at 68 weeks 6

Comparison with Other GLP-1 Receptor Agonists

• A meta-analysis found that semaglutide produced a greater effect on mean weight loss compared to liraglutide, but did not produce a significant difference compared to efinopegdutide 7
• Semaglutide, liraglutide, and efinopegdutide were well-tolerated and were associated with primarily minimal to moderate severity adverse effects, most of which were gastrointestinal 7

Safety Profile

• The safety profile of semaglutide 2.4 mg was consistent across trials, primarily gastrointestinal adverse events 5
• The usual adverse effects observed in patients treated with semaglutide include gastrointestinal adverse events, like nausea, vomiting, diarrhea, constipation, and abdominal cramps 3