Ozempic vs. Zepbound: GLP-1 Brand Comparison

In May 2025, the New England Journal of Medicine published the results of SURMOUNT-5, the first head-to-head clinical trial comparing tirzepatide (the active ingredient in Zepbound) against semaglutide (the active ingredient in Ozempic and Wegovy). After 72 weeks, participants on tirzepatide lost an average of 20.2% of their body weight. Those on semaglutide lost 13.7%. That 6.5 percentage point gap -- roughly 50 pounds versus 33 pounds -- settled a debate that millions of patients and their doctors had been having for years. But weight loss numbers alone don't tell the full story. The right choice between these two drugs depends on what you're treating, what side effects you can tolerate, what your insurance covers, and what your doctor thinks about the full picture of your health.

Table of Contents

• The Basics: What Each Drug Is
• How They Work: One Hormone vs. Two
• Weight Loss: The Numbers
• The SURMOUNT-5 Head-to-Head Trial
• Cardiovascular Benefits
• Kidney Protection
• Side Effects and Tolerability
• FDA-Approved Uses
• Dosing and Administration
• Cost and Insurance
• Recent Developments
• Which One Is Right for You?
• The Bottom Line
• References

The Basics: What Each Drug Is

Ozempic is Novo Nordisk's brand name for semaglutide. It was originally FDA-approved in 2017 for type 2 diabetes management. It's also available as Wegovy (at a higher dose) for weight management, and Rybelsus (in pill form) for diabetes. A 25mg oral version of Wegovy was approved in December 2025 -- the first oral GLP-1 for weight loss.

Zepbound is Eli Lilly's brand name for tirzepatide, approved by the FDA in November 2023 specifically for weight management. The same molecule is sold as Mounjaro for type 2 diabetes treatment. Zepbound was also approved for moderate-to-severe obstructive sleep apnea in adults with obesity.

Both are injectable medications administered once weekly via a pen device. Both require a prescription and gradual dose escalation over several months.

How They Work: One Hormone vs. Two

This is the fundamental difference between these two drugs, and it likely explains the gap in weight loss outcomes.

Semaglutide (Ozempic/Wegovy) is a GLP-1 receptor agonist. It mimics a single hormone: glucagon-like peptide-1. GLP-1 is naturally released by your gut after eating, and it does several things simultaneously. It tells your pancreas to release insulin (lowering blood sugar), slows stomach emptying (making you feel full longer), and signals your brain to reduce appetite.

Tirzepatide (Zepbound/Mounjaro) is a dual GIP/GLP-1 receptor agonist. It mimics two hormones: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). GIP is another gut hormone that influences insulin secretion, but it also appears to directly affect fat cell metabolism and energy expenditure. The dual-agonist mechanism means tirzepatide hits two hormonal pathways instead of one.

Think of it this way: semaglutide plays one instrument very well. Tirzepatide plays two instruments at once. The combined effect appears to produce a stronger metabolic response.

Weight Loss: The Numbers

Before SURMOUNT-5, doctors had to compare results from separate trials with different patient populations. Those indirect comparisons consistently favored tirzepatide, but they weren't definitive. Here's how the key trials stacked up:

Standalone Trial Results

Trial	Drug	Dose	Duration	Average Weight Loss
STEP 1	Semaglutide (Wegovy)	2.4 mg	68 weeks	~15% of body weight
SURMOUNT-1	Tirzepatide (Zepbound)	5 mg	72 weeks	~15% of body weight
SURMOUNT-1	Tirzepatide (Zepbound)	10 mg	72 weeks	~19.5% of body weight
SURMOUNT-1	Tirzepatide (Zepbound)	15 mg	72 weeks	~21% of body weight

Real-World Data

Clinical trials use carefully selected patients. Real-world data reflects what happens in ordinary medical practice, where patients have more comorbidities, less follow-up, and varying levels of adherence.

A real-world study found that over 6 months, patients on tirzepatide lost significantly more weight than those on semaglutide: mean loss of 6.6 kg versus 3.1 kg (p < 0.001), or 5.3% versus 2.7% of body weight.

An interesting caveat: in patients with diabetes, the weight loss difference between the two drugs was not statistically significant. The tirzepatide advantage appears most pronounced in people without diabetes who are using these drugs primarily for weight management.

Meta-Analysis Findings

A 2025 systematic review and meta-analysis comparing the two drugs across multiple studies found that tirzepatide produced significantly greater weight loss (mean difference = 4.23 kg; 95% CI: 3.22-5.25; p < 0.01). The advantage was dose-dependent: tirzepatide doses above 10 mg showed a 6.50 kg advantage over semaglutide, compared to 3.89 kg at 10 mg or below.

The SURMOUNT-5 Head-to-Head Trial

This is the trial that matters most. Published in the New England Journal of Medicine in May 2025, SURMOUNT-5 was the first direct comparison of tirzepatide and semaglutide for weight loss.

Trial design: 751 adults with obesity (BMI 30+) or overweight with comorbidities, randomized 1:1. All participants were without type 2 diabetes. The trial was conducted across 32 sites in the United States and Puerto Rico. Participants received the maximum tolerated dose of either tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks.

Primary result: Tirzepatide produced a mean weight loss of 20.2% versus 13.7% for semaglutide (p < 0.001). In absolute terms, that's approximately 50 pounds lost with tirzepatide versus 33 pounds with semaglutide.

Who achieved major weight loss milestones:

Weight Loss Threshold	Tirzepatide	Semaglutide
At least 10%	86%	72%
At least 15%	70%	50%
At least 20%	54%	30%
At least 25%	32%	16%

Nearly one-third of tirzepatide patients lost at least 25% of their body weight. Only 16% of semaglutide patients achieved the same.

Cardiometabolic improvements: Both drugs improved blood pressure, glycemia, and lipid levels, with greater weight loss producing greater improvements. The difference in systolic blood pressure between the two groups may be clinically meaningful, as reductions of 2-5 mm Hg have been shown to reduce cardiovascular event risk.

Important limitation: SURMOUNT-5 was an open-label trial, meaning participants knew which drug they were receiving. Blinding is the gold standard for minimizing bias, and its absence is a real limitation. However, objective endpoints like body weight are less susceptible to placebo effects than subjective outcomes.

Cardiovascular Benefits

This is where the comparison gets more nuanced. Semaglutide has a proven cardiovascular track record. Tirzepatide's is still being established.

Semaglutide (Ozempic): The SELECT Trial

The SELECT trial was a landmark study of 17,604 patients with overweight/obesity and established cardiovascular disease but without diabetes. Semaglutide reduced the risk of major adverse cardiovascular events (MACE -- cardiovascular death, nonfatal heart attack, or nonfatal stroke) by 20% compared to placebo (6.5% vs. 8.0%; HR 0.80; 95% CI 0.72-0.90; p < 0.001).

A 2025 analysis published in The Lancet found something surprising: waist circumference reduction accounted for no more than 33% of the cardiovascular benefit. This means semaglutide's heart protection goes beyond just weight loss. It appears to have direct anti-inflammatory and vascular effects.

Ozempic also carries an FDA-approved indication for reducing the risk of major cardiovascular events in adults with type 2 diabetes and known heart disease.

Tirzepatide (Zepbound): The SURPASS-CVOT Trial

The SURPASS-CVOT trial, published in the NEJM in December 2025, was the largest and longest study of tirzepatide to date: over 13,000 participants across 30 countries, followed for a median of 4 years.

The trial compared tirzepatide to dulaglutide (Trulicity), another GLP-1 drug already proven to reduce cardiovascular events. Results showed tirzepatide was noninferior to dulaglutide for MACE (12.2% vs. 13.1%; HR 0.92; 95.3% CI 0.83-1.01), meeting noninferiority but narrowly missing statistical superiority (p = 0.09).

However, tirzepatide showed significant advantages in secondary outcomes:

• All-cause mortality: 16% lower than dulaglutide (HR 0.84; 95% CI 0.75-0.94)
• Triglycerides: 24.2% reduction vs. 10.2% with dulaglutide
• Systolic blood pressure: 6.2 mm Hg reduction vs. 4.1 mm Hg

A pre-specified indirect comparison estimated that tirzepatide reduced MACE by 28% and all-cause mortality by 39% compared to what a placebo would have shown.

The bottom line on cardiovascular protection: semaglutide has the direct placebo-controlled proof. Tirzepatide has strong evidence but no completed placebo-controlled cardiovascular outcomes trial (its comparator was an active drug, not placebo).

Kidney Protection

Semaglutide has clear kidney-protective evidence. In the SELECT trial's pre-specified kidney analysis, semaglutide reduced the main composite kidney endpoint by 22% compared to placebo (HR 0.78; 95% CI 0.63-0.96; p = 0.02). At 104 weeks, semaglutide preserved kidney function, with a 0.75 mL/min/1.73 m^2 advantage in estimated glomerular filtration rate (eGFR).

The dedicated FLOW trial went further. In 3,533 patients with type 2 diabetes and chronic kidney disease, semaglutide reduced the risk of major kidney outcomes by 24% (HR 0.76; 95% CI 0.66-0.88; p = 0.0003) and cardiovascular death by 29% (HR 0.71; 95% CI 0.56-0.89). The trial was stopped early because the benefits were so clear.

In January 2025, the FDA expanded Ozempic's label to include patients with type 2 diabetes and chronic kidney disease, making it the only GLP-1 approved for this combination.

Tirzepatide's SURPASS-CVOT trial showed slower decline in eGFR compared to dulaglutide, but dedicated kidney outcomes data comparable to the FLOW trial does not yet exist.

Side Effects and Tolerability

Both drugs share the same core side effect profile, driven by their GLP-1 activity. The most common adverse events are gastrointestinal: nausea, vomiting, diarrhea, constipation, and decreased appetite. These side effects are typically mild to moderate and tend to fade as your body adjusts during the dose escalation period.

Side Effect Comparison

Side Effect	Ozempic (Semaglutide)	Zepbound (Tirzepatide)
Nausea	Common (especially early)	Common (especially early)
Diarrhea	Common	Common
Vomiting	Common	Common
Constipation	Common	Common
Injection site reactions	Uncommon	Uncommon
Pancreatitis	Rare	Rare
Gallbladder disease	Rare	Rare
Thyroid cancer risk	Black box warning (animal studies)	Black box warning (animal studies)

In SURMOUNT-5, serious adverse events occurred in 4.8% of tirzepatide patients versus 3.5% of semaglutide patients. Six patients discontinued due to adverse events in each group. In SURPASS-CVOT, 13.3% of tirzepatide patients discontinued due to adverse events, compared to 10.2% of dulaglutide patients.

Both drugs carry the FDA's most serious warning (black box) about the risk of thyroid C-cell tumors, based on findings in animal studies. Neither drug should be used by people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.

FDA-Approved Uses

Indication	Ozempic (Semaglutide)	Zepbound (Tirzepatide)
Type 2 diabetes	Yes (Ozempic)	Yes (as Mounjaro)
Chronic weight management	Yes (as Wegovy)	Yes
Cardiovascular risk reduction (T2D + heart disease)	Yes	Not yet
Chronic kidney disease (T2D + CKD)	Yes (expanded Jan 2025)	Not yet
Obstructive sleep apnea (with obesity)	No	Yes
Oral formulation available	Yes (Rybelsus for diabetes; oral Wegovy approved Dec 2025)	No

Ozempic itself is technically approved for diabetes, not weight loss. But many doctors prescribe it off-label for weight management. Wegovy is the semaglutide brand approved specifically for weight loss at a higher dose (2.4 mg vs. Ozempic's maximum 2 mg).

Dosing and Administration

Ozempic/Wegovy (Semaglutide)

Both are once-weekly subcutaneous injections. Ozempic uses a multi-dose pen (multiple injections from one pen). Wegovy uses a single-dose pen.

Ozempic dose escalation: 0.25 mg (weeks 1-4) -> 0.5 mg (weeks 5-8) -> 1 mg maintenance (with option to increase to 2 mg)

Wegovy dose escalation: 0.25 mg -> 0.5 mg -> 1 mg -> 1.7 mg -> 2.4 mg maintenance (each step lasting 4 weeks)

Zepbound/Mounjaro (Tirzepatide)

Once-weekly subcutaneous injection. Zepbound comes as a prefilled, single-use pen with a hidden needle, and also as single-use vials.

Zepbound dose escalation: 2.5 mg (weeks 1-4) -> 5 mg -> 7.5 mg -> 10 mg -> 12.5 mg -> 15 mg maximum

Both drugs are injected in the upper arm, thigh, or abdomen. Injection sites should be rotated.

Cost and Insurance

Both drugs cost approximately $1,000 per month at list price without insurance. The real-world cost depends heavily on your insurance plan, copay cards, and pharmacy benefits.

Key cost considerations:

• Ozempic often has better insurance coverage for diabetes diagnoses, since it's been on the market longer
• Zepbound may face more insurance exclusions when prescribed for weight management
• Manufacturer savings cards can reduce costs significantly for commercially insured patients
• Medicare Part D historically has not covered weight loss medications, though this is evolving
• Compounded semaglutide was available at lower cost during shortages, but the FDA resolved the tirzepatide shortage in late 2024, ending compounding allowances for that drug

Recent Developments

The GLP-1 space is evolving rapidly. Several developments in 2025 have shifted the field:

• Oral Wegovy approved (December 2025): The FDA approved a 25mg oral semaglutide tablet for weight management, making it the first oral GLP-1 for weight loss. This eliminates the need for weekly injections for semaglutide users.
• SURPASS-CVOT published (December 2025): Tirzepatide's cardiovascular outcomes data confirmed its cardiac safety and showed reduced all-cause mortality versus dulaglutide.
• SURMOUNT-5 published (May 2025): The head-to-head trial definitively showed tirzepatide's weight loss superiority.
• Next-generation drugs in development: Retatrutide (a triple agonist targeting GLP-1, GIP, and glucagon receptors) and orforglipron (an oral non-peptide GLP-1 agonist) are both in late-stage clinical trials.

For the latest on emerging GLP-1 therapeutics, see our profiles on semaglutide and tirzepatide.

Muscle Mass and Body Composition

One concern that applies to both drugs: weight loss from GLP-1 agonists isn't purely fat loss. Studies consistently show that 25-40% of the weight lost comes from lean mass (muscle), not just adipose tissue. This is a higher lean mass loss ratio than typically seen with diet and exercise alone.

For older adults or those with sarcopenia (age-related muscle loss), this is a real clinical consideration. Both semaglutide and tirzepatide produce similar proportions of lean-to-fat mass loss. Resistance training during treatment appears to help preserve muscle, and protein intake of at least 1.0-1.2 g/kg of body weight per day is generally recommended.

In SURMOUNT-5, body composition data showed that tirzepatide produced greater reductions in waist circumference than semaglutide, suggesting potentially more favorable fat distribution changes. But detailed lean mass preservation comparisons between the two drugs are still being analyzed.

Weight Regain After Stopping

Both drugs share a well-documented limitation: weight regain after discontinuation. Studies have shown that patients regain approximately two-thirds of lost weight within one year of stopping either semaglutide or tirzepatide. This frames these medications not as short-term treatments but as long-term or potentially lifelong therapies for many patients.

The STEP 1 extension trial showed that participants who stopped semaglutide regained about 11.6 percentage points of the 17.3% weight loss they had achieved. Tirzepatide discontinuation data from the SURMOUNT trials shows similar patterns.

This has significant implications for cost, insurance coverage, and treatment planning. A drug that costs $1,000/month becomes a very different financial proposition when it's a lifelong commitment versus a 12-month course.

Which One Is Right for You?

This isn't a question with a universal answer. Here's a framework for thinking about it:

Zepbound (tirzepatide) may be better if:

• Your primary goal is maximum weight loss
• You don't have type 2 diabetes (the weight loss advantage is most pronounced here)
• You have obstructive sleep apnea related to obesity
• You can tolerate and afford it

Ozempic/Wegovy (semaglutide) may be better if:

• You have type 2 diabetes with cardiovascular disease (proven MACE reduction)
• You have type 2 diabetes with chronic kidney disease (only GLP-1 approved for this)
• You prefer or need an oral option (oral Wegovy or Rybelsus)
• Your insurance covers semaglutide but not tirzepatide
• You want the drug with the longest real-world safety track record

Either drug could work well if:

• You need help with both blood sugar control and weight management
• You're looking for cardiometabolic improvements beyond just weight loss
• You're willing to commit to weekly injections and gradual dose escalation
• You understand these are long-term medications -- weight regain after discontinuation is well-documented for both

Neither drug replaces the need for dietary changes and physical activity. Both work best as part of a broader health management strategy.

The Bottom Line

Zepbound (tirzepatide) wins on weight loss. The SURMOUNT-5 trial showed a clear 6.5 percentage point advantage over semaglutide, and nearly a third of patients lost 25% or more of their body weight. Its dual GIP/GLP-1 mechanism appears to produce a stronger metabolic response than GLP-1 alone.

Ozempic/Wegovy (semaglutide) wins on breadth of evidence. It has proven cardiovascular risk reduction from SELECT, proven kidney protection from FLOW, more FDA-approved indications, an oral formulation, and a longer real-world safety track record. The SURPASS-CVOT trial narrowed the gap on cardiovascular data, but semaglutide still has the most complete evidence package.

Both drugs are effective, well-tolerated, and represent a genuine revolution in obesity and metabolic disease treatment. The difference between 13.7% and 20.2% weight loss matters at the population level, but either result would be meaningful for most individual patients.

Talk to your doctor about which one fits your specific health profile, insurance situation, and treatment goals. The best GLP-1 drug is the one you can access, afford, and take consistently.

References

1. Aronne, L.J., et al. "Tirzepatide as Compared with Semaglutide for the Treatment of Obesity." New England Journal of Medicine, 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2416394

2. Nicholls, S.J., et al. "Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes." New England Journal of Medicine, 2025. https://www.nejm.org/doi/abs/10.1056/NEJMoa2505928

3. Lincoff, A.M., et al. "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes." New England Journal of Medicine, 2023. https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

4. Perkovic, V., et al. "Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes." New England Journal of Medicine, 2024. https://www.nejm.org/doi/abs/10.1056/NEJMoa2403347

5. Colhoun, H.M., et al. "Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial." Nature Medicine, 2024. https://www.nature.com/articles/s41591-024-03015-5

6. Rodriguez, P.J., et al. "Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity." JAMA Internal Medicine, 2024. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2821080

7. Karagiannis, T., et al. "Comparative Efficacy of Tirzepatide vs. Semaglutide in Reducing Body Weight in Humans: A Systematic Review and Meta-Analysis." Obesity Reviews, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12151102/

8. Sattar, N., et al. "Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial." The Lancet, 2025. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01375-3/fulltext

9. "Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT)." American College of Cardiology, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2023/11/09/15/04/select

10. Goldenberg, R.M., et al. "Real-world effectiveness of tirzepatide versus semaglutide for weight loss." Diabetes, Obesity and Metabolism, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12046463/