Is Trulicity (dulaglutide) different from Zepbound (tirzepatide)?

Yes, Trulicity and Zepbound are fundamentally different medications with distinct mechanisms of action and superior efficacy profiles favoring Zepbound.

Key Pharmacological Differences

Trulicity (dulaglutide) is a selective GLP-1 receptor agonist, while Zepbound (tirzepatide) is a dual GIP/GLP-1 receptor agonist 1. This represents a fundamental difference in their mechanism of action:

• Dulaglutide acts solely on GLP-1 receptors, stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner 1
• Tirzepatide activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptors, though its affinity for the GLP-1 receptor is approximately five times less than endogenous GLP-1 1

Comparative Efficacy: Tirzepatide Demonstrates Superior Outcomes

Tirzepatide produces significantly greater reductions in HbA1c and body weight compared with dulaglutide 1. This superiority has been demonstrated across multiple clinical trials:

Glycemic Control

• In head-to-head comparisons, tirzepatide achieved HbA1c reductions of -2.4% (5 mg), -2.6% (10 mg), and -2.8% (15 mg) versus -1.3% with dulaglutide 0.75 mg 2
• The estimated mean treatment differences versus dulaglutide were -1.1% to -1.5% across tirzepatide doses (all p<0.0001) 2

Weight Loss

• Tirzepatide demonstrated dose-dependent weight reductions of -5.8 kg (5 mg), -8.5 kg (10 mg), and -10.7 kg (15 mg) compared with only -0.5 kg for dulaglutide 2
• This represents weight reductions of 7.8% to 13.9% with tirzepatide versus 0.7% with dulaglutide 2

Mechanistic Advantages of Dual Agonism

The dual GIP/GLP-1 receptor activation provides complementary metabolic benefits beyond single GLP-1 agonism 3:

• Beta-cell function: Tirzepatide significantly improved HOMA2-B and reduced proinsulin/insulin ratios more than dulaglutide 4
• Insulin sensitivity: Tirzepatide 10 and 15 mg significantly decreased fasting insulin and HOMA2-IR compared with both placebo and dulaglutide 4
• Direct metabolic effects: Only 13-21% of insulin resistance improvements with tirzepatide were attributable to weight loss alone, suggesting the dual receptor agonism confers distinct mechanisms independent of weight reduction 4

GIP Receptor Effects

• GIP receptor activation augments glucagon secretion during euglycemia/hypoglycemia but inhibits it during hyperglycemia 1
• GIP receptors are expressed on pancreatic alpha cells, while only 10-15% of alpha cells express GLP-1 receptors 1

Pharmacokinetic Differences

Both medications are long-acting formulations administered once weekly, but achieve prolonged action through different molecular modifications 1:

• Dulaglutide: Prolonged elimination from conjugation with the fragment crystallizable region of immunoglobulin G 1
• Tirzepatide: Modified to prevent dipeptidyl peptidase-4 cleavage with dual receptor binding properties 1

Clinical Positioning

For patients requiring maximal glycemic control and weight loss, tirzepatide represents the superior choice based on direct comparative evidence 1, 2. However, both medications share:

• Minimal hypoglycemia risk when used as monotherapy 1
• Similar gastrointestinal side effect profiles (nausea, constipation), though tirzepatide may have higher diarrhea incidence 3, 2
• Cardiovascular benefits in patients with type 2 diabetes, though tirzepatide's CV outcomes are still being definitively assessed in SURPASS-CVOT 1, 5

Important Caveats

• Dulaglutide has established cardiovascular outcome data showing MACE reduction 1
• Tirzepatide's cardiovascular safety and superiority versus dulaglutide are being evaluated in ongoing trials 5
• Both medications are contraindicated in patients at risk for thyroid C-cell tumors 1

The choice between these agents should prioritize tirzepatide when maximal metabolic benefit is needed, while dulaglutide remains appropriate when established cardiovascular outcome data is prioritized or cost considerations are paramount 1, 2.