Semaglutide vs Tirzepatide: Differences and Similarities

What is Semaglutide?

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes (T2D) and chronic weight management. It mimics the action of endogenous GLP-1, a hormone that regulates insulin secretion, glucagon suppression, and appetite. Semaglutide’s prolonged half-life (∼1 week) allows for once-weekly subcutaneous administration, making it a convenient option for long-term use.

How Does Semaglutide Work?

Semaglutide binds to GLP-1 receptors in the pancreas, brain, and gastrointestinal tract. Its mechanisms include:

1. Insulin Secretion: Glucose-dependent stimulation of insulin release.
2. Glucagon Suppression: Reduces hepatic glucose production.
3. Gastric Emptying: Slows digestion, promoting satiety.
4. Appetite Regulation: Acts on hypothalamic receptors to reduce hunger.

Semaglutide for Weight Loss

In the STEP clinical trials, semaglutide demonstrated significant weight loss efficacy. Participants receiving 2.4 mg weekly lost ~15% of body weight over 68 weeks, compared to 2.4% with placebo. Weight loss is attributed to reduced caloric intake via appetite suppression and delayed gastric emptying.

Semaglutide Mechanism of Action

As a selective GLP-1 analog, semaglutide enhances insulin sensitivity and promotes beta-cell proliferation. Its structure includes a fatty acid side chain, enabling albumin binding for extended activity.

Semaglutide Weight Loss Dosage Chart

Semaglutide Side Effects

Common: Nausea (44%), diarrhea (30%), vomiting (24%).
Rare: Acute pancreatitis, gallbladder disease, diabetic retinopathy.
Black Box Warning: Thyroid C-cell tumors in rodents; contraindicated in personal/family history of medullary thyroid carcinoma (MTC).

What is Tirzepatide?

Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. It targets both receptors, enhancing insulin secretion and appetite regulation beyond single GLP-1 agonists. Approved for T2D in 2022, it shows superior efficacy in weight loss compared to semaglutide.

Tirzepatide Mechanism of Action

Tirzepatide activates GLP-1 and GIP receptors:

1. GIP Receptor: Enhances insulin secretion and adipose tissue glucose uptake.
2. GLP-1 Receptor: Mirrors semaglutide’s effects (appetite, insulin, glucagon).
   Synergistic action improves glycemic control and weight loss.

Tirzepatide for Weight Loss

In SURMOUNT-1, participants lost up to 22.5% of body weight (15 mg dose) over 72 weeks. Dual agonism may amplify satiety signals and lipolysis, outperforming single GLP-1 agonists.

Tirzepatide Side Effects

Common: Nausea (33%), diarrhea (23%), constipation (12%).
Rare: Hypoglycemia (when combined with insulin/sulfonylureas), pancreatitis.
Warning: Similar thyroid tumor risk as semaglutide.

Semaglutide vs Tirzepatide: Differences

1. Mechanism:
   • Semaglutide: Single GLP-1 agonist.
   • Tirzepatide: Dual GIP/GLP-1 agonist.
2. Efficacy:
   • Weight Loss: Tirzepatide (15–22.5%) > Semaglutide (10–15%).
   • HbA1c Reduction: Tirzepatide (-2.3%) > Semaglutide (-1.8%).
3. Dosage:
   • Semaglutide: Max 2.4 mg/week.
   • Tirzepatide: Max 15 mg/week.
4. Molecular Structure:
   • Semaglutide: Modified GLP-1 with fatty acid side chain.
   • Tirzepatide: Synthetic 39-amino acid peptide with C18 diacid.

Semaglutide vs Tirzepatide: Similarities

1. Administration: Both are weekly subcutaneous injections.
2. Appetite Suppression: Central action on brain receptors.
3. Side Effects: GI disturbances dominate; thyroid tumor warnings.
4. Indications: T2D and obesity (off-label for tirzepatide pending approval).

Clinical Use and Precautions

Target Populations:

• Semaglutide: Patients with BMI ≥27 (comorbidities) or ≥30. Suitable for those needing moderate weight loss.
• Tirzepatide: Patients with BMI ≥30 or inadequate response to GLP-1 agonists.

Precautions:

• Avoid in pregnancy (Category C).
• Monitor for pancreatitis, gallbladder disease, and renal impairment.
• Contraindicated in personal/family history of MTC or Multiple Endocrine Neoplasia syndrome.

References

1. Davies, M., et al. (2021). Semaglutide 2.4 mg Once a Week in Adults with Overweight or Obesity. NEJM, 384(11), 989–1002.
2. Frías, J. P., et al. (2021). Tirzepatide versus Semaglutide Once Weekly in Type 2 Diabetes. NEJM, 385(6), 503–515.
3. FDA (2021). Wegovy (semaglutide) Prescribing Information. Retrieved from FDA.gov.
4. Lilly (2022). Mounjaro (tirzepatide) Prescribing Information. Retrieved from Mounjaro.com.
5. Jastreboff, A. M., et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. NEJM, 387(3), 205–216.