What is the role of semaglutide and tirzepatide in the management of obesity?

Role of Semaglutide and Tirzepatide in Obesity Management

Tirzepatide demonstrates superior weight loss outcomes compared to semaglutide and should be considered the preferred pharmacological option for obesity management when available, with tirzepatide 15mg producing approximately 20.9% weight reduction versus 14.9% with semaglutide 2.4mg. 1, 2

Mechanism of Action

• Semaglutide is a GLP-1 receptor agonist that acts on the hypothalamus to suppress appetite, delay gastric emptying, increase glucose-dependent insulin release, decrease glucagon secretion, and increase pancreatic β-cell growth 1
• Tirzepatide is a dual-hormone agonist that acts on both GLP-1 receptors and glucose-dependent insulinotropic polypeptide (GIP) receptors, offering enhanced weight loss effects compared to GLP-1 receptor agonists alone 1

Efficacy Comparison

• Tirzepatide 15mg weekly demonstrates superior weight loss (20.9%) compared to semaglutide 2.4mg weekly (14.9%) in clinical trials 1, 2
• In the SURMOUNT-5 trial, tirzepatide showed a least-squares mean percent change in weight at 72 weeks of -20.2% compared to -13.7% with semaglutide (P<0.001) 2
• For patients with both obesity and type 2 diabetes, tirzepatide 10mg and 15mg are associated with statistically significant greater reductions in weight, BMI, and HbA1c versus semaglutide 2.4mg 3
• Participants receiving tirzepatide are more likely than those receiving semaglutide to achieve weight reductions of at least 10%, 15%, 20%, and 25% 2

Cardiovascular Benefits

• Semaglutide 2.4mg has demonstrated significant cardiovascular benefits in people with obesity, reducing the composite incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80) in patients with cardiovascular disease and BMI ≥27 1, 4
• The SELECT study represents the first cardiovascular outcome trial showing that subcutaneous semaglutide 2.4mg can reduce major adverse cardiovascular events in obese, non-diabetic patients with pre-existing cardiovascular disease 4
• Both semaglutide and tirzepatide have shown improvements in heart failure with preserved ejection fraction with obesity-related phenotype, enhancing prognosis, functional capacity, and quality of life 4

FDA Approval Status

• Semaglutide 2.4mg weekly was FDA-approved for obesity treatment in 2021 1
• Tirzepatide received FDA approval for obesity treatment in November 2023 1
• Both medications are approved as adjuncts to a reduced-calorie eating pattern and increased physical activity in individuals with BMI ≥30 kg/m² or ≥27 kg/m² with one or more obesity-associated comorbid conditions 5

Administration and Dosing

• Both semaglutide and tirzepatide are administered as subcutaneous injections once weekly 1
• Gradual dose titration is recommended for both medications to mitigate gastrointestinal side effects 1
• For obesity management, semaglutide is titrated up to 2.4mg weekly, while tirzepatide is typically titrated to 10mg or 15mg weekly 1
• Oral semaglutide (14mg) is FDA-approved only for type 2 diabetes treatment and shows less efficacy for weight loss (approximately 5.7% weight reduction) compared to injectable formulations 1, 6

Safety Profile and Adverse Effects

• Both medications share similar adverse effect profiles, with gastrointestinal effects predominating, including nausea, vomiting, diarrhea, constipation, and abdominal pain 1
• Most adverse events are mild to moderate in severity and occur primarily during dose escalation 2
• Both medications have minimal risk for hypoglycemia when used as monotherapy 1
• Both semaglutide and tirzepatide are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1
• Pancreatitis has been reported in clinical trials, but causality has not been established 5

Weight Maintenance Considerations

• After cessation of treatment, significant weight regain occurs, highlighting the need for long-term use 1
• Patients should be counseled that these medications must be used in conjunction with lifestyle changes and may need to be used lifelong 1

Special Populations

• Weight loss appears to be lower in individuals with type 2 diabetes compared to those without diabetes 1
• For patients with type 2 diabetes, both medications offer dual benefits of weight loss and improved glycemic control 1

Clinical Decision Algorithm

1. For patients with BMI ≥30 kg/m² or ≥27 kg/m² with obesity-associated comorbidities:

   • First choice: Tirzepatide 15mg weekly (if available and affordable) 1, 2
   • Alternative: Semaglutide 2.4mg weekly 1

2. For patients with both obesity and type 2 diabetes:

   • Tirzepatide 10mg or 15mg weekly is preferred due to superior effects on both weight and glycemic control 3

3. For patients with obesity and established cardiovascular disease:

   • Either medication is appropriate, with semaglutide having more robust cardiovascular outcomes data 1, 4

4. For patients unable to use injectable medications:

   • Oral semaglutide 14mg may be considered, though weight loss efficacy is significantly lower (approximately 5.7%) 6

Practical Considerations

• Both medications should be used as adjuncts to reduced-calorie diet and increased physical activity 5
• Healthcare professionals should review concomitant medications and minimize those that promote weight gain 5
• For those not reaching treatment goals, consider intensifying treatment with additional approaches (e.g., metabolic surgery, additional pharmacologic agents, and structured lifestyle management programs) 5
• Cost and insurance coverage may significantly impact treatment decisions 1