What is the role of GLP-1 (Glucagon-like peptide-1) agonists, such as liraglutide (Saxenda) (liraglutide) or semaglutide (Wegovy) (semaglutide), in the treatment of obesity?

From the Guidelines

GLP-1 agonists, such as semaglutide (Wegovy) and liraglutide (Saxenda), are effective treatments for obesity, with semaglutide generally producing greater weight loss results, and should be used in conjunction with lifestyle modifications to achieve optimal outcomes. These medications mimic the natural hormone GLP-1, which regulates appetite and food intake by acting on the brain's hunger centers. Typical dosing for Saxenda is 3.0 mg injected subcutaneously once daily, while Wegovy is administered weekly, starting at 0.25 mg and gradually increasing to 2.4 mg 1. Both medications require a slow dose escalation to minimize gastrointestinal side effects, such as nausea, vomiting, diarrhea, and constipation, which often improve over time 1.

Key Points

• Patients can expect weight loss of 5-15% of their initial body weight, with semaglutide generally producing greater results, as seen in the STEP trials, where mean weight loss at 68 weeks was 14.9% and 16.0% for semaglutide, compared to 2.4% and 5.7% for placebo, respectively 1.
• GLP-1 agonists are typically prescribed for individuals with a BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities like hypertension or type 2 diabetes 1.
• These medications work by increasing feelings of fullness, delaying gastric emptying, and reducing hunger signals, leading to decreased caloric intake, and also improve insulin sensitivity and may have beneficial effects on cardiovascular health, as shown in the SELECT study, where semaglutide reduced the incidence of cardiovascular death, MI, or stroke in patients with pre-existing CVD who were overweight or obese, but without diabetes 1.
• Long-term use of GLP-1 agonists is necessary, as weight regain commonly occurs when treatment is discontinued, with mean weight regain of 11.6% of lost weight after cessation of semaglutide treatment 1.

Recommendations

• Semaglutide (Wegovy) is recommended as a first-line treatment for obesity, due to its greater efficacy in weight loss and cardiovascular benefits, as shown in the STEP trials and the SELECT study 1.
• Liraglutide (Saxenda) may be considered as an alternative option, especially for patients who prefer a daily dosing regimen or have concerns about the cost or availability of semaglutide 1.
• GLP-1 agonists should be used in conjunction with lifestyle modifications, including a reduced-calorie diet and regular physical activity, to achieve optimal outcomes 1.

From the FDA Drug Label

Semaglutide lowers fasting and postprandial blood glucose and reduces body weight. Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). The mechanism of blood glucose lowering also involves a delay in gastric emptying.

GLP-1 agonists, such as semaglutide (Wegovy) and liraglutide (Saxenda), play a role in the treatment of obesity by:

• Reducing body weight
• Lowering blood glucose levels
• Delaying gastric emptying
• Stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner 2 3

Key points:

• Semaglutide and liraglutide are GLP-1 receptor agonists that help reduce body weight and improve glycemic control
• These medications have been shown to be effective in reducing fasting and postprandial glucose levels and body weight in clinical trials 2 3

From the Research

Role of GLP-1 Agonists in Obesity Treatment

• GLP-1 receptor agonists (GLP-1 RAs) have emerged as effective therapies for achieving substantial weight loss and improving cardiometabolic risk in individuals with obesity 4.
• Two subcutaneous GLP-1 RAs, liraglutide and semaglutide, have been evaluated in several clinical trials for weight loss, with semaglutide showing a greater impact on weight loss, resulting in a mean weight loss of 9-16 kg 4.
• GLP-1 RAs have been proven to be safe and effective in clinical trials, and are considered promising anti-obesity drugs, with liraglutide accounting for approximately 56% of the global obesity drug market 5.

Efficacy and Safety of GLP-1 Agonists

• Semaglutide 2.4mg has been shown to have an absolute advantage in weight loss and decreased HbA1c, but also has a higher incidence of total adverse events and can cause hypoglycemia 6.
• Liraglutide 3.0mg was less effective than semaglutide 2.4mg, but had a higher incidence of serious adverse events 6.
• A phase 2 trial found that semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared to placebo at all doses, with the most common adverse events being dose-related gastrointestinal symptoms, primarily nausea 7.

Future Developments in GLP-1 Agonists

• Oral GLP-1 RAs are under development and have shown similar weight loss efficacy to semaglutide 2.4mg 8.
• Combinations of GLP-1 with other entero-pancreatic hormones, such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin, are being investigated to enhance weight loss and cardiometabolic benefits 8.
• Tirzepatide, a dual GLP-1/GIP receptor agonist, has been approved for glycaemic control in type 2 diabetes and obesity management, and has shown significant weight loss effects in phase 3 trials 8.