Semaglutide vs Tirzepatide: Which GLP-1 Is Better for Weight Loss?

The Two Leading GLP-1 Medications for Weight Loss

Semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound) are the two most prescribed GLP-1 receptor agonists for weight management. Both have demonstrated remarkable efficacy in clinical trials, but they work through different mechanisms and produce different outcomes. Understanding these differences is essential for anyone evaluating their options.

This article compares the two head-to-head across clinical trial data, mechanisms, side effects, cost, and practical considerations. For a broader overview of how these compounds work, see our GLP-1 Agonists Guide.

Mechanism of Action: Single vs Dual Agonist

The fundamental difference between these two medications lies in their receptor targets:

Semaglutide is a selective GLP-1 receptor agonist. It mimics the incretin hormone GLP-1, which stimulates insulin secretion, suppresses glucagon release, slows gastric emptying, and acts on hypothalamic appetite centers to reduce food intake. It targets one receptor through one pathway.^[1]

Tirzepatide is a dual GLP-1/GIP receptor agonist. In addition to activating GLP-1 receptors, it also activates glucose-dependent insulinotropic polypeptide (GIP) receptors. GIP signaling enhances insulin sensitivity, improves lipid metabolism, and may contribute to fat oxidation through mechanisms distinct from GLP-1 alone. The dual-agonist approach produces additive metabolic effects that exceed what either pathway achieves independently.^[2]

This mechanistic difference explains why tirzepatide generally produces greater weight loss than semaglutide in clinical trials. Activating two complementary metabolic pathways is more effective than saturating one. For a detailed comparison including dosing protocols, see our Tirzepatide vs Semaglutide comparison page.

Clinical Trial Data: STEP vs SURMOUNT

Both compounds have been evaluated in large, well-designed phase 3 clinical trials. Here are the headline numbers:

Semaglutide — STEP Trials

• STEP 1: 2.4 mg weekly semaglutide produced 14.9% mean body weight loss vs 2.4% with placebo over 68 weeks (n=1,961)
• STEP 2: In participants with type 2 diabetes, semaglutide 2.4 mg produced 9.6% weight loss vs 3.4% with placebo
• STEP 3: Combined with intensive behavioral therapy, semaglutide produced 16.0% weight loss
• STEP 5: Over 104 weeks (2 years), semaglutide maintained 15.2% weight loss

Tirzepatide — SURMOUNT Trials

• SURMOUNT-1: Tirzepatide 15 mg produced 22.5% mean body weight loss vs 2.4% with placebo over 72 weeks (n=2,539)
• SURMOUNT-2: In participants with type 2 diabetes, tirzepatide 15 mg produced 14.7% weight loss
• SURMOUNT-3: Combined with intensive lifestyle intervention, tirzepatide produced 26.6% weight loss
• SURMOUNT-4: Continued treatment maintained 18.4% weight loss at 88 weeks; switching to placebo resulted in significant regain

Head-to-Head Comparison

Metric	Semaglutide 2.4 mg	Tirzepatide 15 mg
Mean weight loss	14.9%	22.5%
Participants losing >20%	~32%	~57%
Dosing frequency	Weekly	Weekly
Administration	Subcutaneous injection	Subcutaneous injection
Titration period	16-20 weeks	20 weeks
FDA approval (obesity)	2021 (Wegovy)	2023 (Zepbound)

The data consistently shows tirzepatide produces approximately 50% more weight loss than semaglutide at maximum doses. The SURPASS-2 trial, which directly compared tirzepatide to semaglutide 1 mg for type 2 diabetes, confirmed tirzepatide's superiority in both glycemic control and weight reduction.^[2]

Side Effect Comparison

Both medications share similar gastrointestinal side effects, which are dose-dependent and typically most severe during titration:

• Nausea: Semaglutide ~44%, Tirzepatide ~31% (tirzepatide may cause less nausea due to GIP receptor modulation)
• Diarrhea: Semaglutide ~30%, Tirzepatide ~23%
• Vomiting: Semaglutide ~24%, Tirzepatide ~12%
• Constipation: Semaglutide ~24%, Tirzepatide ~23%
• Injection site reactions: Both ~5-7%

Notably, tirzepatide appears to cause fewer gastrointestinal side effects than semaglutide despite producing more weight loss. This may be attributable to the GIP receptor component, which has been shown to reduce nausea in preclinical models.

Both medications carry boxed warnings for thyroid C-cell tumors (observed in rodents) and are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or MEN2 syndrome.

Cost and Accessibility

As of early 2026, both medications face significant cost and access challenges:

• Semaglutide (Wegovy): ~$1,350/month list price. Insurance coverage is inconsistent for obesity indication. An oral version (Wegovy pill) was approved in December 2025 at ~$149/month, potentially improving access.
• Tirzepatide (Zepbound): ~$1,060/month list price. Eli Lilly has offered direct-to-consumer pricing through LillyDirect as low as $550/month without insurance.

Supply constraints that plagued both medications in 2023-2024 have largely resolved by early 2026. Compounded versions of semaglutide became widely available during the shortage but face increasing FDA scrutiny — see our article on compounded vs brand-name semaglutide for details.

Which Is Better for Weight Loss?

Based on the evidence:

• For maximum weight loss: Tirzepatide produces superior results at maximum doses (22.5% vs 14.9% mean weight loss). If raw efficacy is the primary concern, tirzepatide has the stronger data.
• For tolerability: Tirzepatide causes fewer GI side effects, which may improve adherence. Nausea is the most common reason people discontinue GLP-1 therapy.
• For cost: Both are expensive. Tirzepatide's list price is slightly lower and Lilly has been more aggressive with direct pricing programs.
• For oral option: Only semaglutide has an FDA-approved oral formulation (Rybelsus for diabetes, Wegovy pill for obesity). Tirzepatide is injection-only as of 2026.
• For established track record: Semaglutide has been on the market longer (Ozempic since 2017, Wegovy since 2021) with more post-marketing safety data.

Neither medication is objectively "better" for every patient. The choice depends on individual factors including tolerability, insurance coverage, injection comfort, and the magnitude of weight loss desired. Both represent major advances over previous obesity medications. For how these compare to the next generation, see our retatrutide guide and the retatrutide vs tirzepatide comparison.

The Weight Regain Problem

One critical consideration applies equally to both medications: weight regain after discontinuation. The STEP 1 extension and SURMOUNT-4 trials both showed that stopping treatment leads to significant weight regain, with participants recovering approximately two-thirds of lost weight within one year of cessation.

This positions both semaglutide and tirzepatide as chronic medications rather than short-term interventions. The long-term implications — including cost, cardiovascular effects, and decade-scale safety — are still being evaluated. Combining GLP-1 therapy with sustainable lifestyle changes remains the most evidence-based approach to minimizing regain. Visit our weight loss goal page for a comprehensive view of all available approaches.