Semaglutide vs Tirzepatide vs Retatrutide: The Complete Comparison

Introduction

The GLP-1 agonist space has evolved rapidly, from single-target drugs to dual and triple agonists. This guide compares the three most discussed compounds in this class.

Quick Comparison

Semaglutide (Ozempic/Wegovy)

Mechanism

Single GLP-1 receptor agonist with 94% homology to human GLP-1. Modified for weekly dosing through albumin binding and DPP-4 resistance.

Key Trial Data

STEP Trials (Weight Management):

• STEP 1: 14.9% weight loss at 68 weeks
• STEP 2 (diabetes): 9.6% weight loss
• STEP 3 (intensive lifestyle): 16% weight loss

SELECT Trial (Cardiovascular):

• 20% reduction in major cardiovascular events
• First GLP-1 to show CV benefit in non-diabetic obesity

Advantages

• Longest track record of the three
• Extensive safety data
• Oral formulation available (Rybelsus)
• Multiple approved indications

Tirzepatide (Mounjaro/Zepbound)

Mechanism

Dual GIP/GLP-1 receptor agonist. GIP (glucose-dependent insulinotropic polypeptide) adds complementary metabolic effects.

Key Trial Data

SURMOUNT Trials (Weight Management):

• SURMOUNT-1: Up to 22.5% weight loss at 72 weeks
• SURMOUNT-2: 15.7% weight loss in diabetics

SURPASS Trials (Diabetes):

• Superior A1C reduction vs semaglutide (SURPASS-2)
• Up to 2.4% A1C reduction

Advantages

• Greater weight loss than semaglutide in trials
• Superior glucose control
• Dual mechanism may provide more metabolic benefits

Retatrutide (In Development)

Mechanism

Triple agonist targeting GLP-1, GIP, and glucagon receptors. Glucagon adds increased energy expenditure and fat oxidation.

Key Trial Data

Phase 2 Results:

• Up to 24.2% weight loss at 48 weeks (highest dose)
• Dose-dependent response observed
• Significant liver fat reduction

Potential Advantages

• Highest weight loss observed in any drug trial
• Glucagon component may enhance fat burning
• Promising for NASH/liver disease

Current Status

• Phase 3 trials ongoing
• Expected FDA submission: TBD
• Brand name not yet determined

Side Effect Comparison

All three share similar GI side effects:

• Nausea (most common, usually transient)
• Vomiting
• Diarrhea
• Constipation

Differences:

• Tirzepatide may have slightly lower GI side effects in some studies
• Retatrutide Phase 2 showed manageable tolerability
• All improve with dose titration

Choosing Between Them

Currently Available (Approved)

Semaglutide if:

• Prefer established safety record
• Want oral option
• Primary concern is cardiovascular protection

Tirzepatide if:

• Maximizing weight loss is priority
• Have type 2 diabetes
• Can tolerate injection-only

Future Option

Retatrutide (pending approval):

• May offer highest efficacy
• Potential for liver disease applications
• Triple mechanism for metabolic syndrome

Cost and Access Considerations

• Brand medications are expensive ($1000+/month)
• Insurance coverage varies by indication
• Generic semaglutide not yet available
• Shortages have affected availability

Conclusion

Each generation of GLP-1 based therapies has shown improvements in efficacy. Semaglutide established the class, tirzepatide raised the bar with dual agonism, and retatrutide may push boundaries further with triple targeting. Choice depends on individual factors, availability, and clinical guidance.

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This comparison is for educational purposes. These are prescription medications requiring medical supervision.