Latest Management of Obesity Using Semaglutide and Tirzepatide
Tirzepatide at 15mg weekly offers superior weight loss (20.9%) compared to semaglutide 2.4mg weekly (14.9%), making it the most effective pharmacological option for obesity management when combined with lifestyle interventions. 1
Mechanism of Action and FDA Approval Status
- 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; FDA approved for obesity treatment in 2021 1
- Tirzepatide is a dual-hormone agonist that acts on both GLP-1 receptors and glucose-dependent insulinotropic polypeptide (GIP) receptors; FDA approved for obesity treatment in November 2023 1
Efficacy Comparison
Semaglutide
- Subcutaneous semaglutide 2.4mg weekly demonstrated mean weight loss of 14.9% at 68 weeks in STEP 1 trial (vs 2.4% with placebo) 1
- STEP 3 trial showed 16.0% weight loss at 68 weeks (vs 5.7% with placebo) when combined with intensive lifestyle intervention 1
- Oral semaglutide (50mg daily) achieved 15.1% weight loss but is not yet FDA approved for obesity alone 1
Tirzepatide
- In a 72-week RCT, tirzepatide demonstrated dose-dependent weight loss: 15.0% (5mg), 19.5% (10mg), and 20.9% (15mg) compared to 3.1% with placebo 1
- A recent meta-analysis showed tirzepatide 15mg weekly was associated with greater weight loss compared to semaglutide 2.4mg weekly (mean difference 5.1%) 1
- In patients with type 2 diabetes and obesity, tirzepatide 10mg and 15mg showed statistically significant greater reductions in weight, BMI, and HbA1c versus semaglutide 2.4mg 2
Cardiovascular Benefits
- GLP-1 receptor agonists have been shown to decrease risk of cardiovascular disease events in adults with overweight or obesity without diabetes 1
- The SELECT study demonstrated that semaglutide 2.4mg reduced the composite incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80) in patients with cardiovascular disease and BMI ≥27 1
- Semaglutide has been shown to reduce heart failure-related symptoms and improve physical limitations in patients with heart failure and preserved ejection fraction 1
Weight Maintenance and Long-Term Use
- After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks) 1
- In the STEP 4 trial, participants who switched from semaglutide to placebo after 20 weeks regained 6.9% of lost weight during 48 weeks of placebo administration 1
- These results suggest that long-term use of these medications is necessary for sustained weight management 1
- Patients should be counseled that antiobesity medications must be used in conjunction with lifestyle changes and may need to be used lifelong 1
Safety Profile and Adverse Effects
- Both medications are generally well-tolerated with similar safety profiles 2
- Gastrointestinal disorders are the most common adverse events for both medications 3
- Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 1
- In the STEP 6 trial, 86% of participants on semaglutide 2.4mg reported adverse events, with 59% reporting gastrointestinal disorders that were mostly mild to moderate 3
Practical Considerations for Clinical Use
- Both medications are administered subcutaneously once weekly 1
- Dose escalation is recommended to minimize gastrointestinal side effects 4
- For patients with type 2 diabetes, these medications offer dual benefits of weight loss and improved glycemic control 1, 2
- Liraglutide (3mg daily) is an alternative GLP-1 receptor agonist that may be preferred for some patients due to cost and availability, though it achieves less weight loss (8.0% at 56 weeks) 1
Special Populations
- In East Asian populations, semaglutide 2.4mg achieved 13.2% weight loss at 68 weeks (vs 2.1% with placebo) and significantly reduced abdominal visceral fat area by 40.0% 3
- Weight loss appears to be lower in individuals with type 2 diabetes compared to those without diabetes 1
Algorithmic Approach to Selection
For patients with BMI ≥30 or BMI ≥27 with weight-related complications who have failed lifestyle interventions alone:
For patients with type 2 diabetes and obesity:
- Tirzepatide offers superior glycemic control and weight loss compared to semaglutide 2
For patients with cardiovascular disease and obesity:
- Both medications may offer cardiovascular benefits, with semaglutide having specific evidence from the SELECT trial 1
For patients with cost/access concerns:
- Consider liraglutide as an alternative, though with less efficacy 1