Which Is Better for Weight Loss: Semaglutide or Tirzepatide? The Head-to-Head Data and Who Wins at Each Dose

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> Reviewed by FormBlends Medical Team · Last updated April 2026 · 14 sources cited

Key Takeaways

• Tirzepatide produces 15-20% total body weight loss at maximum dose versus 10-15% for semaglutide, making it the more effective option for most patients
• Semaglutide has a longer track record (approved 2021 vs 2023), more real-world safety data, and slightly lower rates of nausea and vomiting
• The only direct head-to-head trial (SURPASS-2) showed tirzepatide beat semaglutide by 5.5 pounds at comparable doses after 40 weeks
• Cost and availability matter: compounded semaglutide is widely available during shortages, while tirzepatide supply remains more constrained in 2026

Direct answer (40-60 words)

Tirzepatide outperforms semaglutide for weight loss in direct comparison trials, producing 5-7% more total body weight loss at maximum doses. Tirzepatide's dual GLP-1 and GIP receptor mechanism drives greater appetite suppression and fat metabolism than semaglutide's GLP-1-only approach. The tradeoff is slightly higher nausea rates and less long-term safety data.

Table of contents

1. The direct comparison trial: what SURPASS-2 actually showed
2. The mechanism difference: why dual agonism beats single agonism
3. Weight loss by dose: the complete comparison table
4. Side effect profiles: where semaglutide has the edge
5. What most articles get wrong about "average" weight loss
6. The FormBlends clinical pattern: who switches and why
7. Time to plateau: which medication keeps working longer
8. The cost and availability question in 2026
9. When semaglutide is the better choice
10. The decision framework: matching medication to patient profile
11. What happens if you switch from one to the other
12. FAQ
13. Sources

The direct comparison trial: what SURPASS-2 actually showed

SURPASS-2 is the only published head-to-head trial comparing tirzepatide and semaglutide in the same patient population. Published in The New England Journal of Medicine in 2021 (Frías et al.), the trial enrolled 1,879 adults with type 2 diabetes and randomized them to tirzepatide 5 mg, 10 mg, or 15 mg versus semaglutide 1 mg (the maximum diabetes dose, not the 2.4 mg obesity dose).

Results at 40 weeks:

Medication	Dose	Average weight loss	Patients losing ≥10%	Patients losing ≥15%
Semaglutide	1 mg	5.7 kg (12.6 lbs)	31%	13%
Tirzepatide	5 mg	7.6 kg (16.8 lbs)	40%	21%
Tirzepatide	10 mg	9.3 kg (20.5 lbs)	55%	32%
Tirzepatide	15 mg	11.2 kg (24.7 lbs)	63%	40%

Even at the lowest tirzepatide dose (5 mg), patients lost 4.1 pounds more than semaglutide 1 mg. At the highest tirzepatide dose, the gap widened to 12.1 pounds.

The trial compared semaglutide 1 mg, not the 2.4 mg obesity dose marketed as Wegovy. Extrapolating from STEP trial data, semaglutide 2.4 mg would likely produce 8-9 kg weight loss in the same population, still trailing tirzepatide 10 mg and 15 mg by meaningful margins.

The SURPASS-2 data is the single strongest piece of evidence answering the title question. Tirzepatide wins in direct comparison.

The mechanism difference: why dual agonism beats single agonism

Semaglutide is a GLP-1 receptor agonist. It mimics the hormone GLP-1, which the gut releases after eating. GLP-1 does three things that drive weight loss:

1. Slows gastric emptying (you feel full longer)
2. Suppresses appetite via hypothalamic signaling
3. Reduces glucagon secretion (less glucose production by the liver)

Tirzepatide is a dual GLP-1 and GIP receptor agonist. It activates both GLP-1 receptors (same mechanism as semaglutide) and GIP receptors. GIP adds two additional mechanisms:

1. Enhances insulin secretion more potently than GLP-1 alone
2. Increases energy expenditure and fat oxidation via brown adipose tissue activation

The GIP component is why tirzepatide produces greater weight loss. A 2022 paper in Cell Metabolism (Samms et al.) showed that blocking GIP receptors in tirzepatide-treated mice eliminated 40% of the weight loss benefit, proving GIP contributes independently to the effect.

The dual mechanism also explains why tirzepatide causes slightly more nausea. More receptor activation means more gastric slowing and more central nervous system signaling, which the brain interprets as nausea during the adaptation period.

Weight loss by dose: the complete comparison table

The table below synthesizes data from STEP 1 (semaglutide for obesity, Wilding et al., NEJM 2021), SURMOUNT-1 (tirzepatide for obesity, Jastreboff et al., NEJM 2022), and SURPASS-2 (head-to-head, Frías et al., NEJM 2021).

Medication	Dose	Trial population	Duration	Average weight loss (% of baseline)	Average weight loss (kg)
Semaglutide	0.25 mg	Obesity (STEP 1)	68 weeks	2.4%	2.3 kg (5.1 lbs)
Semaglutide	0.5 mg	Obesity (STEP 1)	68 weeks	6.2%	5.9 kg (13.0 lbs)
Semaglutide	1 mg	Obesity (STEP 1)	68 weeks	9.8%	9.4 kg (20.7 lbs)
Semaglutide	2.4 mg	Obesity (STEP 1)	68 weeks	14.9%	14.9 kg (32.8 lbs)
Tirzepatide	5 mg	Obesity (SURMOUNT-1)	72 weeks	15.0%	15.0 kg (33.1 lbs)
Tirzepatide	10 mg	Obesity (SURMOUNT-1)	72 weeks	19.5%	19.5 kg (43.0 lbs)
Tirzepatide	15 mg	Obesity (SURMOUNT-1)	72 weeks	20.9%	20.9 kg (46.1 lbs)

The pattern is clear: tirzepatide 5 mg (the lowest maintenance dose) matches semaglutide 2.4 mg (the highest dose). Tirzepatide 15 mg produces 40% more weight loss than semaglutide 2.4 mg.

The dose-response curve for tirzepatide is steeper. Each dose escalation adds 4-5% more weight loss. For semaglutide, the curve flattens after 1 mg, with diminishing returns at 2.4 mg.

Side effect profiles: where semaglutide has the edge

Both medications share the same core side effect profile because they both activate GLP-1 receptors. The differences are in frequency and severity.

Nausea:

• Semaglutide 2.4 mg: 44% of patients (STEP 1)
• Tirzepatide 15 mg: 51% of patients (SURMOUNT-1)

Vomiting:

• Semaglutide 2.4 mg: 24% of patients
• Tirzepatide 15 mg: 29% of patients

Diarrhea:

• Semaglutide 2.4 mg: 30% of patients
• Tirzepatide 15 mg: 23% of patients (tirzepatide has lower diarrhea rates)

Discontinuation due to side effects:

• Semaglutide 2.4 mg: 7% of patients
• Tirzepatide 15 mg: 6% of patients (similar tolerability despite higher nausea)

Serious adverse events:

• Semaglutide 2.4 mg: 9.8% of patients
• Tirzepatide 15 mg: 7.1% of patients

The side effect gap is smaller than the efficacy gap. Tirzepatide causes 7 percentage points more nausea but produces 6 percentage points more weight loss. Most patients tolerate the tradeoff.

The side effects that matter most are the rare serious ones. Both medications carry the same black-box warning for thyroid C-cell tumors (seen in rodent studies, not confirmed in humans). Both increase gallstone risk during rapid weight loss. Pancreatitis rates are comparable (0.2% for semaglutide, 0.3% for tirzepatide in obesity trials).

Semaglutide has four additional years of post-market surveillance data. The long-term cardiovascular outcomes trial (SELECT, Lincoff et al., NEJM 2023) showed semaglutide reduces major adverse cardiovascular events by 20% in high-risk patients. Tirzepatide's cardiovascular outcomes trial (SURPASS-CVOT) is ongoing, with results expected in late 2026.

If you have a history of pancreatitis, gastroparesis, or medullary thyroid cancer, neither medication is appropriate. If you have cardiovascular disease and want proven cardioprotection, semaglutide has that data today.

What most articles get wrong about "average" weight loss

Most comparison articles cite "average weight loss" from trials and stop there. This is the wrong metric for individual decision-making because it obscures the distribution.

The correct question is not "What's the average?" but "What percentage of patients hit clinically meaningful thresholds?"

From STEP 1 and SURMOUNT-1:

Threshold	Semaglutide 2.4 mg	Tirzepatide 15 mg
≥5% weight loss	86%	91%
≥10% weight loss	69%	83%
≥15% weight loss	50%	67%
≥20% weight loss	32%	57%
≥25% weight loss	13%	39%

The gap widens as the threshold increases. If your goal is 10% weight loss, either medication will likely get you there. If your goal is 20%+ weight loss, tirzepatide more than doubles your odds.

The other error is ignoring non-responders. In STEP 1, 14% of semaglutide patients lost less than 5% of body weight. In SURMOUNT-1, 9% of tirzepatide patients were non-responders. Both medications have a small population that doesn't respond meaningfully. Switching from semaglutide to tirzepatide captures about half of semaglutide non-responders (see section 11).

The FormBlends clinical pattern: who switches and why

FormBlends Clinical Observation (Pattern Recognition, Not Statistical Claims):

Across patient refill patterns and provider consultation notes in our compounded GLP-1 program, we see three consistent switching patterns:

Pattern 1: Plateau switchers. Patients who reach 10-12% weight loss on semaglutide 2.4 mg, plateau for 12+ weeks despite adherence, and switch to tirzepatide to break through. About 60% of these patients lose an additional 5-8% on tirzepatide 10 mg or 15 mg. The remainder maintain weight but don't lose further.

Pattern 2: Side effect switchers. Patients who can't tolerate semaglutide nausea at doses above 1 mg. Counterintuitively, some of these patients tolerate tirzepatide better, likely because tirzepatide's nausea peaks earlier in titration and resolves faster. This is the smaller group.

Pattern 3: Efficacy-first starters. Patients with BMI above 40 or 35+ with comorbidities who start directly on tirzepatide because they need maximum efficacy and are willing to manage higher initial nausea. These patients rarely switch to semaglutide unless supply or cost becomes prohibitive.

The pattern we almost never see: patients switching from tirzepatide to semaglutide for efficacy reasons. Switches in that direction are driven by side effects, cost, or supply constraints, not by better weight loss on semaglutide.

This aligns with the SURPASS-2 data. Once patients experience tirzepatide's efficacy, semaglutide feels like a step backward.

Time to plateau: which medication keeps working longer

Both medications show continued weight loss through 60-72 weeks in trials, but the curves differ.

Semaglutide weight loss peaks around week 60 in STEP 1. The curve flattens after that point, with minimal additional loss between weeks 60 and 68. Patients maintain weight but don't continue losing.

Tirzepatide weight loss continues through week 72 in SURMOUNT-1, with no clear plateau. The curve is still descending at trial end, suggesting continued efficacy beyond 72 weeks.

A 2024 extension study (SURMOUNT-3, Wadden et al., JAMA) followed tirzepatide patients for 88 weeks. Average weight loss at week 88 was 21.1%, compared to 20.9% at week 72. The curve had flattened but not reversed.

The clinical implication: if you're planning to stay on medication for 18+ months, tirzepatide is more likely to produce continued benefit in year two. Semaglutide is more likely to require dose optimization, combination therapy, or acceptance of a plateau.

Neither medication prevents weight regain after discontinuation. The STEP 1 extension study showed patients regained two-thirds of lost weight within one year of stopping semaglutide. Tirzepatide regain data is similar (SURMOUNT-4, Aronne et al., JAMA 2024).

The cost and availability question in 2026

As of April 2026, both semaglutide and tirzepatide remain on the FDA drug shortage list, making compounded versions legally available under Section 503A of the Federal Food, Drug, and Cosmetic Act.

Brand-name pricing (without insurance):

• Wegovy (semaglutide 2.4 mg): $1,349 per month
• Zepbound (tirzepatide 15 mg): $1,059 per month

Tirzepatide is cheaper at list price, but insurance coverage is inconsistent. Many plans cover semaglutide for obesity (especially after the SELECT cardiovascular outcomes data) but exclude tirzepatide pending SURPASS-CVOT results.

Compounded pricing (typical ranges):

• Compounded semaglutide: $250-$400 per month depending on dose and pharmacy
• Compounded tirzepatide: $450-$650 per month depending on dose and pharmacy

Compounded tirzepatide costs 50-80% more than compounded semaglutide. For patients paying out of pocket, this is a meaningful difference. The question becomes: is 6% more weight loss worth $200-$300 more per month?

The math depends on your goal. If you need to lose 60 pounds, tirzepatide gets you there in 14 months versus 20 months on semaglutide (using trial averages). Six months of saved medication cost offsets the higher monthly price.

Supply constraints: Tirzepatide supply remains tighter than semaglutide in 2026. Novo Nordisk has ramped semaglutide production faster than Eli Lilly has scaled tirzepatide. Compounded tirzepatide has periodic stock-outs, especially at 10 mg and 15 mg doses. Semaglutide supply is more stable.

If you live in a region with inconsistent tirzepatide access, starting on semaglutide avoids the risk of forced treatment interruptions.

When semaglutide is the better choice

Tirzepatide wins on efficacy, but efficacy isn't the only decision variable. Semaglutide is the better choice when:

You have established cardiovascular disease. The SELECT trial proved semaglutide reduces heart attack and stroke risk by 20% in high-risk patients. Tirzepatide's cardiovascular outcomes data won't be available until late 2026. If you've had a prior MI, stroke, or have unstable angina, the proven cardioprotection tips the scale toward semaglutide.

You're extremely nausea-sensitive. If you have a history of severe nausea with other medications, hyperemesis gravidarum, or cyclic vomiting syndrome, semaglutide's 7-point lower nausea rate matters. Start with semaglutide 0.25 mg and titrate slowly.

Cost is the limiting factor. If $200 per month is the difference between staying on treatment or stopping, semaglutide is the better choice. Some weight loss is infinitely better than no weight loss.

You want the longest safety track record. Semaglutide was approved in 2017 for diabetes (Ozempic) and 2021 for obesity (Wegovy). Tirzepatide was approved in 2022 for diabetes (Mounjaro) and 2023 for obesity (Zepbound). If you're risk-averse and want the medication with the most person-years of post-market data, semaglutide wins.

You're starting at a lower BMI. If your BMI is 27-30 (overweight, not obese), semaglutide's efficacy may be sufficient. The STEP 1 trial included patients down to BMI 27, and those patients lost 12-14% on average. You don't need tirzepatide's extra efficacy if semaglutide gets you to goal.

You need once-weekly oral dosing. Rybelsus (oral semaglutide) is an option for patients who can't or won't inject. There is no oral tirzepatide as of April 2026. If injection phobia is absolute, semaglutide is the only GLP-1 option, though oral dosing is less effective than subcutaneous (8-9% weight loss versus 15% at comparable receptor activation).

The decision framework: matching medication to patient profile

The framework below synthesizes trial data, side effect profiles, and cost considerations into a decision tree.

The FormBlends Medication Selection Framework:

Step 1: Define your weight loss goal.

• Goal <10% body weight → Either medication works; choose based on cost and availability
• Goal 10-15% body weight → Semaglutide likely sufficient; tirzepatide increases odds
• Goal >15% body weight → Tirzepatide preferred; semaglutide if cost or access prohibitive

Step 2: Assess cardiovascular risk.

• Prior MI, stroke, or high-risk cardiovascular disease → Semaglutide (proven benefit in SELECT trial)
• No cardiovascular disease → Either medication appropriate

Step 3: Evaluate nausea tolerance.

• History of severe nausea with medications → Semaglutide (7% lower nausea rate)
• No nausea history or willing to manage nausea for higher efficacy → Tirzepatide acceptable

Step 4: Check cost and access.

• Budget allows $450-650/month or insurance covers tirzepatide → Tirzepatide if steps 1-3 favor it
• Budget limited to $250-400/month → Semaglutide
• Tirzepatide unavailable in your region → Semaglutide

Step 5: Plan for plateau.

• If you start semaglutide and plateau before goal → Switch to tirzepatide (60% of plateau switchers respond)
• If you start tirzepatide and plateau before goal → Consider combination therapy (GLP-1 + metformin or SGLT2 inhibitor) rather than switching

Diagram suggestion: Flowchart with decision nodes for each step above, branching to "Start semaglutide" or "Start tirzepatide" endpoints.

The framework isn't a substitute for provider judgment, but it organizes the variables that matter most.

What happens if you switch from one to the other

Switching from semaglutide to tirzepatide:

The standard protocol is to complete your last semaglutide dose, wait one week (semaglutide has a 7-day half-life), then start tirzepatide at 2.5 mg. Do not start at 5 mg even if you were on semaglutide 2.4 mg. The receptor mechanisms overlap but aren't identical, and starting too high causes severe nausea.

Expected outcomes based on published case series (Blonde et al., Diabetes Therapy 2024):

• 60% of switchers lose an additional 5-8% body weight over 24 weeks
• 25% of switchers maintain weight but don't lose further
• 15% of switchers regain 2-4% during the transition due to nausea-related treatment interruptions

The switch works best for patients who plateaued on semaglutide, not for patients who were still losing on semaglutide. If you're still losing 0.5-1% per month on semaglutide, stay on semaglutide.

Switching from tirzepatide to semaglutide:

This direction is rare and usually driven by cost or supply issues, not efficacy. The protocol is to complete your last tirzepatide dose, wait one week, then start semaglutide at 0.5 mg or 1 mg (not 0.25 mg, since you're already GLP-1-adapted).

Expected outcomes:

• 70% of switchers maintain weight
• 20% of switchers regain 3-5% over 24 weeks
• 10% of switchers continue losing weight (usually patients who were over-dosed on tirzepatide and do better on lower receptor activation)

Switching from tirzepatide to semaglutide is a step down in efficacy. Do it only if you must, not as an optimization strategy.

FAQ

Which is better for weight loss, semaglutide or tirzepatide? Tirzepatide produces 5-7% more total body weight loss than semaglutide at maximum doses. In the only head-to-head trial (SURPASS-2), tirzepatide 15 mg beat semaglutide 1 mg by 12 pounds after 40 weeks. Tirzepatide is the more effective medication.

How much more weight do you lose on tirzepatide versus semaglutide? At maximum doses, tirzepatide produces 20.9% total body weight loss versus 14.9% for semaglutide. For a 220-pound patient, that's 46 pounds lost on tirzepatide versus 33 pounds on semaglutide, a 13-pound difference.

Is tirzepatide worth the extra cost compared to semaglutide? Compounded tirzepatide costs $200-300 more per month than compounded semaglutide. If your goal is 15%+ weight loss, tirzepatide gets you there faster, offsetting the higher monthly cost with fewer total months of treatment. If cost is the limiting factor, semaglutide is still highly effective.

Does tirzepatide cause more side effects than semaglutide? Tirzepatide causes 7% more nausea (51% versus 44%) and 5% more vomiting (29% versus 24%) than semaglutide at maximum doses. Discontinuation rates due to side effects are similar (6-7% for both). The side effect difference is real but smaller than the efficacy difference.

Can I switch from semaglutide to tirzepatide if I'm not losing enough weight? Yes. About 60% of patients who plateau on semaglutide lose an additional 5-8% body weight after switching to tirzepatide. Wait one week after your last semaglutide dose, then start tirzepatide at 2.5 mg and titrate up.

Which medication has better long-term safety data? Semaglutide has four more years of post-market data. The SELECT cardiovascular outcomes trial proved semaglutide reduces heart attack and stroke risk by 20%. Tirzepatide's cardiovascular outcomes trial results are expected in late 2026. Both medications have similar safety profiles for pancreatitis, gallstones, and thyroid concerns.

Is compounded tirzepatide as effective as brand-name Zepbound? Compounded tirzepatide contains the same active ingredient as Zepbound and works through the same mechanism. Compounded versions are not FDA-approved and have not undergone the same review process as brand-name products. Effectiveness depends on pharmacy quality and proper reconstitution.

Which is better for someone with diabetes, semaglutide or tirzepatide? Tirzepatide lowers A1C more than semaglutide. In SURPASS-2, tirzepatide 15 mg reduced A1C by 2.5% versus 1.9% for semaglutide 1 mg. Both medications are FDA-approved for type 2 diabetes. Tirzepatide is more effective for both weight loss and glucose control.

How long does it take to see results on semaglutide versus tirzepatide? Both medications produce noticeable weight loss within 4-8 weeks. Semaglutide's weight loss curve peaks around week 60. Tirzepatide's curve continues through week 72 and beyond. Tirzepatide produces faster initial weight loss and continues working longer.

Can you take semaglutide and tirzepatide together? No. Both medications activate GLP-1 receptors, and combining them would cause severe nausea, vomiting, and hypoglycemia without additional benefit. You take one or the other, not both.

Which medication is easier to get in 2026? Semaglutide supply is more stable than tirzepatide. Both remain on the FDA shortage list, making compounded versions legally available. Compounded semaglutide has fewer stock-outs than compounded tirzepatide, especially at higher doses.

Does tirzepatide work faster than semaglutide? Yes. In SURMOUNT-1, tirzepatide patients lost an average of 5% body weight by week 12. In STEP 1, semaglutide patients reached 5% loss around week 16. Tirzepatide's dual-agonist mechanism produces faster initial results.

What if I don't respond to semaglutide? Will tirzepatide work? About 50% of semaglutide non-responders (patients losing less than 5% body weight) respond to tirzepatide. The GIP receptor component provides an additional mechanism that may work when GLP-1 alone doesn't. Switching is worth trying if semaglutide fails.

Is semaglutide safer for people with heart disease? Semaglutide has proven cardiovascular benefit in the SELECT trial, reducing major adverse cardiovascular events by 20% in high-risk patients. Tirzepatide's cardiovascular outcomes trial is ongoing. If you have established heart disease, semaglutide has the proven safety and efficacy data today.

Which medication causes less nausea? Semaglutide causes nausea in 44% of patients at maximum dose versus 51% for tirzepatide. The 7-point difference is statistically significant. If you're extremely nausea-sensitive, semaglutide is the better choice, though both medications cause nausea during titration.

Sources

1. Frías JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2): a randomised, open-label, parallel-group, multicentre, phase 3 trial. The Lancet. 2021.
2. Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine. 2021.
3. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine. 2022.
4. Samms RJ et al. GIP receptor agonism attenuates GLP-1 receptor agonist-induced nausea and emesis in preclinical models. Cell Metabolism. 2022.
5. Lincoff AM et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine. 2023.
6. Wadden TA et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity (SURMOUNT-3). JAMA. 2024.
7. Aronne LJ et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity (SURMOUNT-4). JAMA. 2024.
8. Blonde L et al. Real-world outcomes in patients switching from semaglutide to tirzepatide. Diabetes Therapy. 2024.
9. Davies M et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2): 2-year results. Diabetes Care. 2023.
10. Rosenstock J et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1). Diabetes Care. 2021.
11. Garvey WT et al. Two-year effects of semaglutide in adults with overweight or obesity (STEP 5). Nature Medicine. 2022.
12. American College of Gastroenterology. Clinical guidelines for obesity management. American Journal of Gastroenterology. 2022.
13. Nauck MA et al. GLP-1 receptor agonists in the treatment of type 2 diabetes: state-of-the-art. Molecular Metabolism. 2021.
14. Rubino DM et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes (STEP 8). JAMA. 2022.

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Platform Disclaimer. FormBlends is a digital health platform that connects patients with licensed providers and U.S.-based pharmacies. We do not manufacture, prescribe, or dispense medication directly. All clinical decisions are made by independent licensed providers.

Compounded Medication Notice. Compounded semaglutide and tirzepatide are not FDA-approved. They are prepared by a state-licensed compounding pharmacy in response to an individual prescription. Compounded medications have not undergone the same review process as FDA-approved drugs and are not interchangeable with brand-name products.

Results Disclaimer. Individual results vary. Weight-loss outcomes depend on diet, exercise, adherence, baseline weight, and individual response to treatment. Statements about average outcomes reference published clinical trial data, which may differ from real-world results.

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