Tirzepatide vs Semaglutide: The Head-to-Head Data Explained

It's the question everyone asks: Tirzepatide or semaglutide? Zepbound or Wegovy? Mounjaro or Ozempic? Which one is "better"?

We finally have an answer—or at least, we have direct comparison data. The SURMOUNT-5 trial put both medications head-to-head in the same patients for the first time. Combined with data from the SURPASS-2 diabetes trial and years of individual studies, we can now make evidence-based comparisons.

The short answer: tirzepatide produces more weight loss. But the full picture is more nuanced than headlines suggest.

The Headline Numbers: SURMOUNT-5

SURMOUNT-5 is the trial everyone was waiting for. It randomized 751 adults with obesity (no diabetes) to receive either tirzepatide or semaglutide for 72 weeks. Same patients, same conditions, direct comparison.

The difference is substantial: 6.5 percentage points more weight loss with tirzepatide (p<0.001). For someone starting at 250 pounds, that's roughly an additional 16 pounds lost—50 pounds total versus 34 pounds.

At the high-response end, tirzepatide really separates: nearly twice as many patients achieved 25% or greater weight loss. That's surgical-level outcomes without surgery.

Why Does Tirzepatide Work Better? The Mechanism

Understanding why requires understanding what these drugs actually are:

Here's what's counterintuitive: tirzepatide has weaker GLP-1 activity than semaglutide, yet produces more weight loss. The GIP component appears to be the key differentiator.

What GIP Adds

GIP (glucose-dependent insulinotropic polypeptide) has complex effects:

• Enhanced insulin secretion when blood sugar is high
• Glucagon release when blood sugar is low (protection against hypoglycemia)
• Direct effects on fat cells that may improve fat metabolism
• Additional satiety signaling through different brain pathways
• Possible better muscle preservation (research ongoing)

Tirzepatide also displays "biased agonism"—it preferentially activates certain signaling pathways (cAMP) over others (β-arrestin). This may reduce receptor desensitization, meaning the drug remains effective longer without the body adapting to it.

Diabetes Data: SURPASS-2

Before SURMOUNT-5, the SURPASS-2 trial compared tirzepatide to semaglutide 1mg (Ozempic dose, not Wegovy dose) in people with type 2 diabetes:

Tirzepatide doubled the weight loss and achieved better blood sugar control. The percentage reaching normal blood sugar (A1C <5.7%) was remarkable: 51% with tirzepatide 15mg versus 20% with semaglutide.

A caveat: SURPASS-2 used semaglutide 1mg, not 2.4mg. The comparison wasn't quite fair to semaglutide. SURMOUNT-5 used the proper weight-loss doses for both medications.

Breaking Down the Numbers Further

Responder Rates by Threshold

Weight Loss Achieved	Tirzepatide 15mg	Semaglutide 2.4mg
≥5% weight loss	91%	86%
≥10% weight loss	78%	67%
≥15% weight loss	64%	51%
≥20% weight loss	57%	32%
≥25% weight loss	32%	16%

At every threshold, tirzepatide outperforms. But notice that the gap widens at higher thresholds—tirzepatide is especially better at producing dramatic results. At the ≥20% mark (surgical-level outcomes), tirzepatide achieves nearly twice the success rate.

Non-Responder Rates

The flip side: how many people don't respond? Based on achieving less than 5% weight loss:

• Tirzepatide non-responders: ~9%
• Semaglutide non-responders: ~14%

Tirzepatide has a higher success floor—fewer people fail to respond meaningfully.

Side Effect Comparison

Despite the efficacy differences, side effect profiles are remarkably similar:

Both medications cause nausea, diarrhea, vomiting, and constipation in similar proportions. Both have similar discontinuation rates. The tolerability profile is essentially equivalent—getting more weight loss doesn't mean getting more side effects.

Some patients report that tirzepatide "feels" gentler despite producing more weight loss. This may relate to the partial (versus full) GLP-1 receptor activation, though it's difficult to study systematically.

Muscle Loss: Does Tirzepatide Preserve More?

One of the most intriguing emerging differences: body composition. Early data suggests tirzepatide may preserve more lean mass during weight loss:

• SURMOUNT-1 (tirzepatide): ~25.7% of weight lost was lean mass
• STEP 1 (semaglutide): ~39-45% of weight lost was lean mass

This is a meaningful difference. If you lose 50 pounds, that's either ~13 pounds of muscle (tirzepatide) or ~20-22 pounds of muscle (semaglutide). Better muscle preservation means:

• Higher resting metabolism
• Better functional strength
• Potentially better long-term maintenance
• Less "skinny fat" appearance

Long-Term Data: Three Years of Tirzepatide

SURMOUNT-1 extension data now extends to 176 weeks (3.4 years)—the longest published data for tirzepatide:

The sustained 24% weight loss at three years is remarkable. And the diabetes prevention is dramatic: only 0.4-2% of tirzepatide users developed diabetes versus 13.3% of placebo users.

Semaglutide's longest data is STEP 5 at 104 weeks, showing 15.2% sustained weight loss. The SELECT trial has 4+ years of follow-up but focused on cardiovascular outcomes rather than maximum weight loss.

Beyond Weight: Cardiovascular and Metabolic Effects

Cardiovascular Protection

Semaglutide has the evidence advantage here. The SELECT trial (17,604 patients) demonstrated a 20% reduction in major cardiovascular events (heart attack, stroke, cardiovascular death) with semaglutide. This led to FDA approval for cardiovascular risk reduction.

Tirzepatide doesn't yet have cardiovascular outcome trial results. The SURPASS-CVOT trial is ongoing but won't report until 2027. Based on the metabolic improvements tirzepatide produces, most experts expect similar or better cardiovascular benefits—but we don't have proof yet.

Sleep Apnea

Tirzepatide is the first medication ever FDA-approved for obstructive sleep apnea. The SURMOUNT-OSA trial showed tirzepatide reduced the apnea-hypopnea index (AHI) by 25.3 events per hour versus 5.3 with placebo. Many patients moved from severe to mild OSA or complete resolution.

Semaglutide hasn't been specifically studied for sleep apnea outcomes, though weight loss from any method improves OSA.

Liver Disease (NAFLD/NASH)

Both show remarkable effects on fatty liver disease:

• Tirzepatide: 73.3% achieved NASH resolution at 15mg (SYNERGY-NASH trial)
• Semaglutide: 62.9% achieved NASH resolution at 2.4mg (ESSENCE trial)

Tirzepatide appears to have an edge for liver disease, though both are dramatically effective.

Practical Considerations

Cost Comparison (January 2026)

Option	Tirzepatide	Semaglutide
List Price (monthly)	$1,086 (Zepbound)	$1,349 (Wegovy)
Manufacturer Direct Program	$399-449/month (LillyDirect vials)	$499/month (NovoCare)
With Insurance (best case)	$25-50/month	$25/month
Compounded (where available)	$200-400/month	Restricted (shortage resolved)

Tirzepatide is slightly cheaper at list price and through manufacturer programs. Both are expensive without insurance or assistance programs.

Administration

Both are weekly subcutaneous injections with similar pen devices. Tirzepatide has a slightly shorter half-life (5 days vs 7 days), though both provide adequate coverage for weekly dosing.

Dose Titration

Semaglutide: 0.25mg → 0.5mg → 1.0mg → 1.7mg → 2.4mg (monthly increases)

Tirzepatide: 2.5mg → 5mg → 7.5mg → 10mg → 12.5mg → 15mg (monthly increases)

Tirzepatide has more dose options, allowing finer titration if side effects are limiting.

Switching Between Medications

What if you've been on one and want to try the other?

Semaglutide → Tirzepatide

This is the more common direction (seeking better results). Key points:

• No washout period required
• Start tirzepatide approximately 1 week after last semaglutide dose
• Always start at 2.5mg regardless of previous semaglutide dose
• No direct dose equivalency—mechanisms are different
• Expect some GI symptoms during transition; titrate up slowly

Tirzepatide → Semaglutide

Less common (usually due to cost or insurance). Same principles:

• Start semaglutide ~1 week after last tirzepatide
• Begin at 0.25-0.5mg and titrate up
• May experience some weight regain if switching to less effective medication

Who Might Choose Which?

Consider Tirzepatide If:

• Maximum weight loss is the primary goal
• You have type 2 diabetes (excellent A1C control)
• You have sleep apnea (only FDA-approved medication)
• You have fatty liver disease (NASH)
• You tried semaglutide and plateaued
• Muscle preservation is especially important to you
• You can access it (insurance, cost)

Consider Semaglutide If:

• You have established cardiovascular disease (proven 20% MACE reduction)
• It's what your insurance covers
• You prefer proven long-term safety data (more years of widespread use)
• You want the oral option (oral Wegovy now available)
• Cost is prohibitive for tirzepatide
• 15% weight loss would meet your goals

Either Is Excellent If:

• You have obesity and related health conditions
• You've struggled with traditional dieting
• You're committed to lifestyle changes alongside medication
• You understand this is likely long-term treatment

The Bottom Line

Head-to-head, tirzepatide produces approximately 6.5 percentage points more weight loss than semaglutide—20% versus 13.7% in SURMOUNT-5. It achieves higher responder rates at every threshold and may preserve more muscle mass.

But semaglutide is no slouch. A 14-15% weight loss is still revolutionary compared to any previous medication. It has proven cardiovascular benefits, more years of safety data, and now an oral option.

The "better" choice depends on your specific situation: your health conditions, your goals, your insurance coverage, and what's available to you. Both medications represent genuine breakthroughs. Both can change lives.