What is the efficacy and safety of tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) for weight loss?

Tirzepatide for Weight Loss: Efficacy and Safety

Tirzepatide is highly effective for weight loss, producing a mean weight reduction of 15% at 72 weeks in non-diabetic obese patients, with even greater reductions (20.9%) at higher doses of 15 mg, making it one of the most potent pharmacological options for weight management. 1

Efficacy for Weight Loss

• Tirzepatide, as a dual GIP/GLP-1 receptor co-agonist, produces significant weight loss with a mean weight reduction of 8.47 kg compared to usual care, with 3-67% of participants achieving at least 10% weight reduction from baseline 2

• When compared with placebo in patients without diabetes mellitus, tirzepatide results in:

  • 16.32% mean reduction in body weight percentage 3
  • 13.95 kg mean reduction in absolute body weight 3
  • 5.89 kg/m² reduction in BMI 3
  • 12.31 cm reduction in waist circumference 3

• Tirzepatide demonstrates dose-dependent weight loss effects, with higher doses (15 mg) achieving up to 20.9% weight reduction in non-diabetic obese patients 1

• Tirzepatide shows superior weight loss efficacy compared to selective GLP-1 receptor agonists like semaglutide, with a mean difference of -5.65 kg 4, 5

Mechanism of Action

• Tirzepatide works by activating both GIP and GLP-1 receptors, which are key mediators of insulin secretion and are expressed in brain regions that regulate food intake 4

• The dual receptor activation mechanism appears to provide enhanced weight loss compared to selective GLP-1 receptor agonists 4

• GLP-1 and GIP receptors in the hypothalamus and brainstem nuclei mediate appetite, satiety, energy intake and expenditure 1

Safety Profile

• The most common adverse events are gastrointestinal in nature, similar to other GLP-1 receptor agonists but potentially more pronounced 3, 6, 5:

  • Nausea (relative risk 3.11 compared to placebo) 3
  • Vomiting (relative risk 5.94 compared to placebo) 3
  • Diarrhea (relative risk 2.92 compared to placebo) 3
  • Constipation (relative risk 2.85 compared to placebo) 3

• Serious adverse events are not statistically significantly increased compared to placebo (relative risk 0.93) 3

• However, serious gastrointestinal events (relative risk 3.07) and discontinuation due to adverse events (relative risk 2.29) are significantly higher with tirzepatide compared to placebo 3

• Hypoglycemia risk with tirzepatide is slightly higher compared to placebo and GLP-1 receptor agonists, but significantly lower than insulin 5

Clinical Recommendations

• The American Medical Association recommends tirzepatide for chronic weight management in adults with:

  • Obesity (BMI ≥30 kg/m²) or
  • Overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity 2

• Tirzepatide must be used in conjunction with lifestyle modifications for optimal results 2

• To minimize gastrointestinal side effects, consider these management strategies 1:

  • Start at a low dose and titrate upward slowly
  • Reduce meal size
  • Limit alcohol and carbonated drinks
  • Avoid high-fat diet

Cardiovascular Effects

• GLP-1 receptor agonists have demonstrated cardioprotective effects through multiple mechanisms:

  • Improved myocardial substrate utilization
  • Anti-inflammatory and anti-atherosclerotic effects
  • Reduced myocardial ischemia injury
  • Lower systemic and pulmonary vascular resistance
  • Improved lipid profiles 1

• While specific cardiovascular outcome trials for tirzepatide are still ongoing, meta-analyses of existing trials show no increased cardiovascular risk 4, 5

Practical Considerations

• Tirzepatide produces greater weight loss in non-diabetic individuals (15-20.9%) compared to those with diabetes (4-6.2%) 1

• The weight loss efficacy of tirzepatide is comparable to what has previously only been reported with bariatric surgery 1

• Gastrointestinal side effects tend to be more common at higher doses but may improve over time with continued use 6, 5

• Careful monitoring for cardiac arrhythmias/tachycardia is recommended, with consideration of beta blockers if symptomatic 1