What is the number needed to treat (NNT) with semaglutide (glucagon-like peptide-1 (GLP-1) receptor agonist) and tirzepatide (dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist)?

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Number Needed to Treat with Semaglutide and Tirzepatide

Based on the most recent evidence, tirzepatide has a lower number needed to treat (NNT) compared to semaglutide for weight loss outcomes, with tirzepatide 15mg achieving 20.9% weight loss versus 15.1% for semaglutide at 72 weeks in patients with obesity.

Efficacy Comparison for Weight Loss

Semaglutide

  • In clinical trials of adults with obesity without diabetes, subcutaneous semaglutide 2.4mg weekly achieved a mean weight loss of 15.1% versus 2.4% for placebo over 68 weeks 1
  • Oral semaglutide (50mg/day) achieved similar results but is not yet FDA approved for obesity alone 1
  • In patients with type 1 diabetes (off-label use), semaglutide produced approximately 9.1% body weight reduction over 12 months 2

Tirzepatide

  • In a 72-week randomized controlled trial of 2,539 adults with obesity without diabetes, tirzepatide demonstrated dose-dependent weight loss 1:
    • 15mg dose: 20.9% weight loss
    • 10mg dose: 19.5% weight loss
    • 5mg dose: 15.0% weight loss
    • Placebo: 3.1% weight loss
  • In patients with type 1 diabetes (off-label use), tirzepatide produced approximately 21.4% body weight reduction over 12 months 2

Comparative Effectiveness

  • A meta-analysis of RCTs including 12,371 adults with overweight or obesity without diabetes reported that tirzepatide 15mg weekly was associated with greater weight loss compared to semaglutide 2.4mg weekly (mean difference 5.1%; 95% CI 0.6%-9.8%) 1
  • In a 2024 network meta-analysis comparing subcutaneous tirzepatide to semaglutide in type 2 diabetes, tirzepatide showed more pronounced weight reduction at all dose levels 3:
    • Tirzepatide 15mg: 9.57kg reduction vs placebo
    • Tirzepatide 10mg: 7.67kg reduction vs placebo
    • Tirzepatide 5mg: 5.27kg reduction vs placebo
    • Semaglutide 2.0mg: 4.97kg reduction vs placebo
    • Semaglutide 1.0mg: 4.04kg reduction vs placebo
    • Semaglutide 0.5mg: 2.52kg reduction vs placebo

Cardiovascular Benefits and NNT

  • In the SELECT study of 17,604 participants with cardiovascular disease and BMI ≥27 without diabetes, semaglutide 2.4mg reduced the composite incidence of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.80; 95% CI 0.72-0.90) 1
  • Based on this data, the absolute risk reduction was approximately 2.5% (11.2% event rate in placebo vs 8.7% in GLP-1 RA group), yielding an NNT of 40 patients to prevent one cardiovascular event 1

Glycemic Control

  • In type 2 diabetes, tirzepatide demonstrated superior glycemic control compared to semaglutide 4, 3:
    • Tirzepatide 15mg: -2.30 percentage points in HbA1c
    • Tirzepatide 10mg: -2.24 percentage points in HbA1c
    • Tirzepatide 5mg: -2.01 percentage points in HbA1c
    • Semaglutide 1mg: -1.86 percentage points in HbA1c

Safety Considerations

  • Both medications have similar safety profiles with primarily gastrointestinal adverse events 4, 3:
    • Nausea: 17-22% for tirzepatide vs 18% for semaglutide
    • Diarrhea: 13-16% for tirzepatide vs 12% for semaglutide
    • Vomiting: 6-10% for tirzepatide vs 8% for semaglutide
  • Hypoglycemia risk is low with both medications, though slightly higher with tirzepatide 15mg (1.7%) compared to semaglutide (0.4%) 4

Clinical Implications

  • For weight loss in obesity, tirzepatide has a lower NNT compared to semaglutide, with approximately 5-6 patients needing treatment with tirzepatide 15mg versus semaglutide 2.4mg to achieve one additional patient with ≥10% weight loss 1
  • For cardiovascular risk reduction, current evidence supports an NNT of approximately 40 with semaglutide, while cardiovascular outcomes data for tirzepatide is still pending 1
  • Both medications demonstrate favorable effects on glycemic control with low hypoglycemia risk, making them suitable options for patients with diabetes requiring weight management 1

Practical Considerations

  • Tirzepatide was FDA approved for obesity treatment in November 2023 1
  • Both medications are administered as once-weekly subcutaneous injections, though oral semaglutide is available for diabetes (not yet for obesity) 1
  • Cost and insurance coverage remain significant barriers to access for many patients 1
  • Gastrointestinal side effects are common but typically mild to moderate and often improve with continued use 1, 4

References

1
Guideline

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Dr.Oracle Medical Advisory Board & Editors, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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