GLP-1 Comparison Guide: Tirzepatide vs Semaglutide vs Retatrutide

GLP-1 drugs — medications that mimic a natural "fullness hormone" your gut releases after eating — are the most effective pharmacologic weight-loss tools available today. But they are not interchangeable. Semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro, Zepbound), and retatrutide activate different receptor combinations, produce different magnitudes of weight loss, and carry different trade-offs for body composition, liver fat, and side effects.

This guide synthesizes clinical trial data to help you understand what actually differentiates these drugs. We cover weight loss results, body composition (fat versus lean mass), liver fat reduction, side effect profiles, and a framework for thinking about which might suit different goals.

Medical Disclaimer: These are prescription medications requiring medical supervision. This guide synthesizes published research for educational purposes. Work with a clinician for any treatment decisions.

At a Glance: Quick Comparison

A note on comparisons: Direct cross-drug comparisons are difficult because trials differ in duration, population (obesity vs T2D), and methodology. Where possible, we cite head-to-head studies. Where not, we note the limitations.

Retatrutide data is from 48-week Phase 2 trials in T2D populations. Semaglutide and tirzepatide obesity data is from 68-72 week trials. Not directly comparable.

How These Drugs Work

All three drugs belong to the incretin class — hormones released after eating that coordinate appetite, insulin, and metabolism. They activate different combinations of receptors (protein docking sites on cells that trigger specific responses). Understanding these differences explains why outcomes vary.

The Three Receptors

Receptor Binding (Normalized to Native Hormone)

Semaglutide has the highest GLP-1 potency but no GIP or glucagon activity. Think of it as a powerful volume knob on your appetite — it turns down hunger effectively, but that's all it does directly. Weight loss comes from eating less; fat cells aren't receiving any direct signal.

Tirzepatide adds full GIP receptor activation. GIP (glucose-dependent insulinotropic polypeptide) receptors are expressed in fat cells, enabling direct signaling — like adding a thermostat to your fat tissue. This triggers a thermogenic effect called "futile calcium cycling" that burns energy without producing useful work. The result: your fat cells waste energy instead of hoarding it.

Retatrutide adds glucagon receptor activation on top of GIP and GLP-1. Glucagon is insulin's opposite — where insulin says "store fuel," glucagon says "release and burn it." This signal goes directly to the liver, commanding it to mobilize stored fat. It's an active burning signal, not just a passive effect from eating less.

Weight Loss Results: What Trials Actually Show

Semaglutide — STEP-1 (Obesity, 68 weeks)

Study: STEP-1 | Population: Non-diabetic obesity | Duration: 68 weeks | Dose: 2.4mg weekly

Tirzepatide — SURMOUNT-1 (Obesity, 72 weeks)

Study: SURMOUNT-1 | Population: Non-diabetic obesity | Duration: 72 weeks | Doses: 5mg, 10mg, 15mg weekly

Retatrutide — Phase 2 (T2D, 48 weeks)

Study: NEJM Phase 2 | Population: Type 2 diabetes | Duration: 48 weeks | Doses: 1mg–12mg weekly

Critical caveat: Retatrutide's 48-week T2D data cannot be directly compared to semaglutide/tirzepatide's 68-72 week obesity data. Different populations, different durations. Phase 3 obesity trials are ongoing.

Head-to-Head: SURMOUNT-5 (Tirzepatide vs Semaglutide)

Study: SURMOUNT-5 | Population: Non-diabetic obesity | Duration: 72 weeks | Design: Direct randomized comparison

This is the only true head-to-head comparison. At comparable maximum doses, tirzepatide produces approximately 47% more weight loss than semaglutide.

Body Composition: Fat vs Lean Mass Loss

Why This Matters

Weight loss is not just about the scale. Losing muscle mass reduces metabolic rate, strength, and long-term success. The ratio of fat to lean mass lost varies significantly between drugs — and critically, between populations.

Obesity Trials (Non-Diabetic)

In non-diabetic obesity, tirzepatide shows meaningfully better lean mass preservation than semaglutide. This is likely due to GIP receptor activation in adipose tissue.

T2D Trials

Head-to-Head: Clamp Study (T2D, 28 weeks)

Study: Tirzepatide Clamp Study | Population: T2D | Duration: 28 weeks | Design: Direct comparison, same methodology

Key finding: In this head-to-head T2D comparison, ratios are virtually identical. Tirzepatide achieves 64% more absolute fat loss, but not a better proportion.

Why Population Matters: The Incretin Defect

The dramatic difference between populations comes down to GIP receptor function:

• In non-diabetics: GIP signaling works fully. Tirzepatide's GIP component provides a real body composition advantage (75:25 vs 60:40) by directly engaging fat cells.
• In T2D: GIP signaling is impaired at the receptor level (the "incretin defect"). Tirzepatide "fixes" the broken pathway rather than supercharging it. The ratio advantage largely disappears, though absolute fat loss remains higher.

Retatrutide gap: No non-diabetic body composition data exists. The 63:37 ratio is from T2D only — we cannot know how it performs in metabolically healthy individuals.

Liver and Visceral Fat

Why Liver Fat Matters

Hepatic fat drives metabolic dysfunction, insulin resistance, and progression to NASH and fibrosis. For many people — particularly those with South Asian phenotype or family history of metabolic disease — reducing liver fat is a primary health target beyond the scale number.

Liver Fat Reduction by Study

Caveat: These are different populations (NAFLD vs T2D vs MASLD with baseline liver fat >10%). Direct comparison is not valid, but the magnitude of difference is notable.

The Glucagon Difference

Semaglutide and tirzepatide reduce liver fat indirectly — you eat less, lose weight, and liver fat decreases as a consequence.

Retatrutide activates the glucagon receptor, which directly tells the liver to mobilize and burn its stored fat. This is an active signal, not a passive effect. In the Phase 2 MASLD substudy:

• 93% of patients on 12mg achieved resolution of hepatic steatosis (liver fat below 5%)
• 100% of patients on 8-12mg achieved at least 30% liver fat reduction by week 24

Tirzepatide vs Semaglutide: Direct Comparison

For the clearest head-to-head view, here is how tirzepatide and semaglutide compare across key dimensions.

Weight Loss

Tirzepatide produces approximately 47% more weight loss than semaglutide at comparable obesity doses (20.2% vs 13.7% in SURMOUNT-5).

Body Composition

In non-diabetic populations, tirzepatide preserves more lean mass (75:25 vs 60:40). In T2D, the difference narrows to nearly identical ratios, though tirzepatide still achieves more absolute fat loss.

Side Effects

• GI profile is similar in nature, but tirzepatide may be slightly better tolerated due to GIP's antiemetic effect
• Semaglutide has higher gallbladder risk (2.6x baseline vs no significant increase for tirzepatide)
• Neither affects heart rate

Approval and Access

Both are FDA-approved. Semaglutide has an oral option (Rybelsus). Brand pricing and insurance coverage vary by region.

Which to Choose?

Ozempic vs Mounjaro: Which Is Better for Weight Loss?

This is one of the most searched comparisons. Ozempic (semaglutide) and Mounjaro (tirzepatide) are both weekly injections, but they work differently and produce different results.

The Key Differences

Bottom Line

Mounjaro produces more weight loss with better muscle preservation in most populations. Ozempic has a longer track record and cardiovascular outcome data (SELECT trial). If your doctor offers both, Mounjaro typically delivers stronger results — but availability and insurance coverage vary.

Zepbound vs Wegovy: The Obesity-Approved Options

Zepbound and Wegovy are the obesity-specific versions of these drugs at higher doses.

The Key Differences

Which Should You Choose?

Choose Wegovy if:

• Cardiovascular risk reduction is a primary goal (SELECT trial data)
• You prefer a drug with longer real-world experience
• Zepbound isn't available or covered by your insurance

Choose Zepbound if:

• Maximizing weight loss is the priority
• Body composition matters (preserving muscle)
• You have a history of gallbladder issues
• GI tolerance has been a problem with GLP-1s

Retatrutide vs Tirzepatide: The Triple Agonist

Important: No head-to-head trial exists. Retatrutide Phase 2 data (48 weeks, T2D) cannot be directly compared to tirzepatide's SURMOUNT trials (72 weeks, non-diabetic obesity). The comparisons below are illustrative, not definitive.

What Retatrutide Adds

The glucagon receptor activation provides:

• Direct hepatic fat mobilization (the 86% liver fat reduction in MASLD patients)
• Higher basal metabolic rate
• But: dose-dependent heart rate increase

Weight Loss (Different Trials, Different Populations)

Retatrutide shows higher loss at a shorter duration in a metabolically different population. Whether this holds in Phase 3 obesity trials with longer follow-up remains to be seen.

Liver Fat (Different Populations)

The MASLD substudy selected patients with baseline liver fat >10%, which may inflate the relative reduction. Still, the glucagon receptor's direct hepatic signal appears to provide a mechanistic advantage.

The Trade-Off: Heart Rate

Plus elevated benign arrhythmia incidence (4-14% vs 2-3% placebo). The effect partially reverses by week 48, suggesting adaptation.

Current Status

Retatrutide is investigational (Phase 3 trials ongoing). Not available for routine clinical use as of early 2026.

Side Effects Comparison

By Receptor Source

Dose Sensitivity

Titration Difficulty

Semaglutide has the highest GLP-1 potency, which means the highest sensitivity to GI side effects. Tirzepatide's GIP component appears to have an antiemetic effect that buffers this. Retatrutide adds a second titration axis (heart rate) that semaglutide and tirzepatide do not have.

Which GLP-1 Should You Choose?

Rather than asking "which drug is best," the better question is: "What metabolic state am I trying to create?"

The Four Questions

1. How aggressive does weight loss need to be?

2. Is body composition a priority?

• Yes (athletes, older adults): Tirzepatide — better fat:lean ratio in non-diabetics
• Less concerned: Either works

3. Is liver/visceral fat the primary risk?

• Yes (MASLD, South Asian phenotype, family history): Consider retatrutide if available
• No: Tirzepatide or semaglutide

4. What's your cardiac history?

• Any arrhythmia concerns: Avoid retatrutide
• Clear cardiac history: All options open

Cost Comparison

GLP-1 drug costs vary significantly by brand, insurance, and compounding options.

List Prices (Without Insurance)

Insurance Coverage

Coverage varies widely:

• Diabetes indication (Ozempic, Mounjaro): Often covered with T2D diagnosis
• Obesity indication (Wegovy, Zepbound): Coverage improving but still inconsistent
• Prior authorization: Usually required; may need documented BMI ≥30 (or ≥27 with comorbidities)

Compounded Options

Compounded semaglutide and tirzepatide are available at lower cost (~$200-400/month) during the FDA shortage period. Key considerations:

• Legality: Only legal during active FDA shortage declarations
• Quality: Varies by pharmacy; look for 503B facilities with third-party testing
• Concentration: Usually sold as mg/mL; verify dosing matches brand equivalents

See our Semaglutide Guide for detailed cost and compounding information.

Evidence Gaps: What We Don't Know

Being explicit about what we don't know is part of honest synthesis. These gaps matter for anyone extrapolating from current evidence.

Frequently Asked Questions

Is tirzepatide better than semaglutide?

For weight loss and body composition in non-diabetic populations, tirzepatide produces more total loss with better lean preservation. For cardiovascular risk reduction, semaglutide has stronger outcome data (SELECT trial). "Better" depends on your goals.

Is Mounjaro the same as Zepbound?

Yes — both contain tirzepatide. Different brand names reflect different primary indications (diabetes vs obesity). Same molecule, same manufacturer (Eli Lilly), different FDA approvals.

Is Ozempic the same as Wegovy?

Yes — both contain semaglutide. Ozempic is approved for type 2 diabetes (max 2mg). Wegovy is approved for obesity at higher doses (max 2.4mg). Same molecule, same manufacturer (Novo Nordisk).

How much weight can you lose on GLP-1 drugs?

Semaglutide: 13-15% average. Tirzepatide: 20-22% average. Retatrutide: 22-24% average. Individual results vary based on dose, adherence, and baseline.

Which GLP-1 has the fewest side effects?

All cause GI effects during titration. Tirzepatide may be slightly better tolerated due to GIP's antiemetic effect. Semaglutide has higher gallbladder risk. Retatrutide adds heart rate effects.

What's the difference between Ozempic and Mounjaro?

Ozempic (semaglutide) activates only the GLP-1 receptor. Mounjaro (tirzepatide) activates both GLP-1 and GIP receptors. This dual action gives Mounjaro stronger weight loss (~47% more) and better muscle preservation.

Can I switch from Ozempic to Mounjaro?

Yes, many people switch. Common approach: complete Ozempic at your current dose, then start Mounjaro at a low dose (2.5mg) and titrate up. Your doctor should supervise the transition — don't overlap them.

Why is tirzepatide better for body composition?

Tirzepatide activates GIP receptors in fat cells, which semaglutide cannot do. This direct signaling helps your body preferentially burn fat while sparing muscle. The result: 75% of weight lost is fat (vs 60% for semaglutide).

Which GLP-1 is best for someone with diabetes vs just weight loss?

For type 2 diabetes, tirzepatide shows superior HbA1c reduction and insulin sensitization. For weight loss without diabetes, tirzepatide still leads on total loss and body composition, but semaglutide has stronger cardiovascular outcome data (SELECT trial). If you have diabetes AND want the best metabolic package, tirzepatide hits both marks. If CV risk reduction is primary, semaglutide has the outcome data.

How do I switch between GLP-1 medications?

The standard approach: finish your current medication at the scheduled dose, then start the new one at the lowest titration dose on your next injection day. Don't overlap—stop one before starting the other. When switching from semaglutide to tirzepatide, start tirzepatide at 2.5mg regardless of your previous semaglutide dose, then titrate up based on tolerance. Your provider should supervise any transition.

Are compounded GLP-1s safe and effective?

Compounded semaglutide and tirzepatide can be safe and effective if sourced from reputable 503B outsourcing facilities that provide third-party testing certificates. The FDA allows compounding during active shortages. Key risks: quality varies significantly between pharmacies, no FDA oversight of the final product, and concentration/dosing may differ from brand equivalents. The cheapest option isn't always the safest—verify your source provides certificates of analysis and uses proper storage.

What's the cheapest way to get GLP-1 medication?

Insurance coverage is cheapest if you qualify—typically requires T2D diagnosis for Ozempic/Mounjaro or BMI ≥30 (or ≥27 with comorbidities) for Wegovy/Zepbound. Without coverage: compounded versions run $200–400/month (during shortages) versus $900–1,400/month list price. Some manufacturer savings cards reduce copays significantly. Telehealth programs offer compounded options but quality varies. The key trade-off: brand-name drugs have consistent quality but high cost; compounded options save money but require vetting your pharmacy.

References

Body Composition Studies

• STEP-1 DXA Substudy
• SURMOUNT-1 DXA Substudy
• Tirzepatide Clamp Study
• Retatrutide DXA Substudy

Clinical Trials

• SURMOUNT-1 (NEJM)
• SURMOUNT-5 (NEJM)
• Retatrutide Phase 2 (NEJM)
• SURPASS-3 MRI Substudy (Lancet)00027-0/fulltext)

Mechanistic

• GIP Futile Calcium Cycling (Cell Metabolism)00449-2)
• Tirzepatide Imbalanced Agonism (JCI Insight)

Safety

• GLP-1 and Gallbladder Risk (JAMA IM)

Related Guides

• GLP-1 Results Guide — clinical trial data on weight loss, body composition, and what to expect
• Semaglutide Guide — detailed semaglutide dosing, results, and safety
• Tirzepatide Guide — detailed tirzepatide trials and protocols
• Retatrutide Guide — investigational triple-agonist with liver-fat focus
• NAD+ Guide — cellular energy support for metabolic health