Survodutide vs. Tirzepatide: Next-Gen Comparison

Two dual-agonist peptides are reshaping how we think about obesity treatment — and they're not the same drug. Tirzepatide (sold as Mounjaro and Zepbound) already has FDA approval and millions of prescriptions behind it. Survodutide, still in Phase 3 trials, takes a fundamentally different approach to the same problem. Both combine GLP-1 receptor activation with a second hormonal target. But the second target is where things get interesting. Tirzepatide pairs GLP-1 with GIP (glucose-dependent insulinotropic polypeptide). Survodutide pairs GLP-1 with glucagon. That single difference changes everything — from how these drugs burn fat to which organs they affect most.

If you're tracking the next generation of weight loss therapeutics, this comparison matters. Here's what the clinical data actually shows.

Table of Contents

• How They Work: Two Different Dual-Agonist Strategies
• Weight Loss: Head-to-Head Numbers
• MASH and Liver Disease
• Cardiovascular Outcomes
• Side Effects and Tolerability
• Approval Status and Availability
• Comparison Table
• What the Phase 3 Trials Will Tell Us
• The Bottom Line
• References

How They Work: Two Different Dual-Agonist Strategies

Both survodutide and tirzepatide activate the GLP-1 receptor. That's their common ground. GLP-1 receptor agonism suppresses appetite, slows gastric emptying, and improves insulin sensitivity — the same mechanism behind semaglutide and other incretin therapies.

The split comes with their second target.

Tirzepatide: GLP-1 + GIP

Tirzepatide activates both GLP-1 and GIP receptors. GIP has a complex role in metabolism. It was traditionally considered an "obesity hormone" because it promotes fat storage after meals. But when combined with GLP-1 activation, GIP agonism appears to amplify weight loss rather than oppose it. The exact mechanism is still debated, but researchers believe GIP receptor activation in the brain may amplify satiety signaling beyond what GLP-1 alone achieves.

Tirzepatide also improves insulin secretion through both receptor pathways, making it effective for type 2 diabetes as well as obesity. In the SURPASS clinical trial program for type 2 diabetes, tirzepatide reduced HbA1c by up to 2.4 percentage points — a level of glycemic control that rivals or exceeds most available diabetes therapies.

The GIP component also appears to improve lipid profiles and may contribute to cardiovascular risk reduction, though the relative contribution of GIP versus GLP-1 to these benefits is still being untangled.

Survodutide: GLP-1 + Glucagon

Survodutide mimics oxyntomodulin, a natural gut hormone that activates both GLP-1 and glucagon receptors. This is a bolder pharmacological bet. Glucagon has historically been seen as the "opposite" of insulin — it raises blood sugar and mobilizes energy stores. That sounds counterproductive for a weight loss drug.

But glucagon receptor activation does something GIP cannot: it directly increases energy expenditure. Glucagon stimulates hepatic lipid oxidation, ramps up thermogenesis, and increases the liver's metabolic rate. In theory, survodutide doesn't just reduce calorie intake — it also forces the body to burn more of what it has stored.

The trade-off? Glucagon agonism can raise blood glucose. The GLP-1 component needs to counterbalance that effect, making the dose ratio between the two receptor activities a careful balancing act. Getting this ratio wrong could mean either negating the weight loss benefits (too little glucagon) or destabilizing blood sugar (too much glucagon relative to GLP-1).

This is why survodutide's development has required more pharmacological fine-tuning than tirzepatide's GLP-1/GIP combination, where both receptor activations push metabolism in broadly complementary directions.

Weight Loss: Head-to-Head Numbers

No direct head-to-head trial between survodutide and tirzepatide has been completed. But we can compare results from their respective clinical programs.

Survodutide Phase 2 Results (46 Weeks)

A Phase 2 dose-finding trial enrolled 387 adults with obesity (BMI ≥ 27 kg/m²) without type 2 diabetes. Participants received weekly subcutaneous injections at four dose levels or placebo for 46 weeks — a 20-week escalation phase followed by 26 weeks at maintenance dose.

Weight loss by dose (intent-to-treat analysis):

• 0.6 mg: -6.2%
• 2.4 mg: -12.5%
• 3.6 mg: -13.2%
• 4.8 mg: -14.9%
• Placebo: -2.8%

Among participants who actually reached and maintained the 4.8 mg dose, average weight loss hit -18.7%. In that same group, 98% lost at least 5% of their body weight, 82% lost at least 10%, and 67% lost at least 15%. Over a third — 38% — lost 20% or more.

Notably, weight loss curves hadn't plateaued at 46 weeks, suggesting longer treatment could push these numbers higher.

Tirzepatide SURMOUNT-1 Results (72 Weeks)

The landmark SURMOUNT-1 trial enrolled 2,539 adults with obesity or overweight (BMI ≥ 30, or ≥ 27 with a comorbidity) without diabetes. Participants received weekly subcutaneous tirzepatide at three doses or placebo for 72 weeks.

Weight loss by dose:

• 5 mg: -15.0%
• 10 mg: -19.5%
• 15 mg: -20.9%
• Placebo: -3.1%

At the highest dose, 90% of participants lost at least 10%, 78% lost at least 15%, and 63% lost at least 20%. Mean waist circumference dropped by 19.9 cm compared to 3.4 cm with placebo.

Interpreting the Comparison

Raw numbers suggest tirzepatide delivers greater weight loss: -20.9% at 15 mg over 72 weeks versus survodutide's -14.9% at 4.8 mg over 46 weeks (intent-to-treat). But these trials can't be directly compared. SURMOUNT-1 ran 26 weeks longer than the survodutide Phase 2 study, and trial populations, dose escalation schedules, and endpoints differed.

The survodutide per-protocol analysis (participants who stayed on full dose) showed -18.7% at 46 weeks — a trajectory that could close the gap over a longer trial. The Phase 3 SYNCHRONIZE trials, which run for 76 weeks, will provide a fairer comparison.

Metric	Survodutide (4.8 mg, 46 wk)	Tirzepatide (15 mg, 72 wk)
Mean weight loss (ITT)	-14.9%	-20.9%
Mean weight loss (per-protocol)	-18.7%	-22.5%
≥ 5% weight loss	82.8% (ITT)	96%
≥ 10% weight loss	68.8% (ITT)	90%
≥ 15% weight loss	54.7% (ITT)	78%
≥ 20% weight loss	32.8% (ITT)	63%
Trial duration	46 weeks	72 weeks
Trial phase	Phase 2	Phase 3

MASH and Liver Disease

This is where survodutide may have a real edge. Metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) is a liver disease driven by fat accumulation, inflammation, and progressive fibrosis. It affects roughly 5% of U.S. adults and has no broadly approved pharmacotherapy.

Glucagon receptor activation directly increases hepatic lipid oxidation — the liver burns its own stored fat. That gives survodutide a theoretical advantage over GIP-based approaches for liver disease.

Survodutide MASH Trial

A 48-week Phase 2 trial enrolled 293 adults with biopsy-confirmed MASH and liver fibrosis (stages F1 to F3). Participants received weekly survodutide at 2.4 mg, 4.8 mg, or 6.0 mg, or placebo.

Results for the primary endpoint — MASH resolution with no worsening of fibrosis:

• 2.4 mg: 47%
• 4.8 mg: 62%
• 6.0 mg: 43%
• Placebo: 14%

The 4.8 mg dose stood out, with 62% of participants achieving MASH resolution — a response rate that matches or exceeds anything reported for a pharmacotherapy in MASH trials. The dip at 6.0 mg likely reflects higher dropout rates due to gastrointestinal side effects at that dose.

Tirzepatide MASH Data

Eli Lilly reported that tirzepatide met its primary endpoint in a Phase 2 MASH trial, with one analyst calling the results "best any MASH drug has ever shown in Phase 2 or Phase 3." The survodutide results were described as "roughly in line" with tirzepatide's MASH data, though detailed comparisons are limited because full tirzepatide MASH data aren't yet published in peer-reviewed form.

Both drugs show strong MASH signals. But survodutide's glucagon mechanism provides a biologically distinct rationale for liver fat reduction that doesn't depend solely on weight loss.

Why MASH Matters for This Comparison

MASH affects an estimated 16 million Americans and is projected to become the leading cause of liver transplant. There is no widely approved drug for MASH as of early 2026 (resmetirom received limited approval for a specific subset in 2024). A dual-agonist that treats both obesity and liver disease simultaneously would address two massive unmet needs with a single injection. The MASH data may ultimately determine which drug captures the larger market — particularly if survodutide's liver benefits prove superior to tirzepatide's in head-to-head analysis.

Cardiovascular Outcomes

Tirzepatide: SURPASS-CVOT

The SURPASS-CVOT trial, published in the New England Journal of Medicine in December 2025, tested tirzepatide against dulaglutide (a GLP-1 agonist) in patients with type 2 diabetes and atherosclerotic cardiovascular disease.

Tirzepatide was noninferior to dulaglutide for the primary composite endpoint (cardiovascular death, myocardial infarction, or stroke). An expanded endpoint including coronary revascularization showed a significant 12% reduction (hazard ratio 0.88, 95% CI 0.88–0.96).

Survodutide: Trials Pending

The SYNCHRONIZE Cardiovascular Outcomes Trial will assess survodutide's cardiovascular safety in patients at elevated cardiovascular risk. The trial is enrolling approximately 4,935 participants with BMI of 27 or greater and established cardiovascular disease or chronic kidney disease. Results are not yet available.

This remains a significant data gap. Cardiovascular safety is a regulatory requirement for metabolic drugs, and survodutide's glucagon component raises legitimate questions. Glucagon can increase heart rate and blood pressure acutely. It also stimulates hepatic glucose output, which affects cardiovascular risk factors indirectly. The GLP-1 component should counterbalance some of these effects — semaglutide and other GLP-1 agonists have demonstrated cardiovascular benefit — but only a large outcomes trial can confirm whether the net effect of the GLP-1/glucagon combination is cardiovascularly neutral or beneficial.

Side Effects and Tolerability

Both drugs produce gastrointestinal side effects as their most common adverse events. This is expected for any drug that activates GLP-1 receptors.

Survodutide Safety (Phase 2)

• Treatment-related adverse events: 90.9% (survodutide) vs. 75.3% (placebo)
• Most common: nausea, vomiting, diarrhea
• Serious adverse events: 4.2% (survodutide) vs. 6.5% (placebo)
• Discontinuation rate: 24.6% (survodutide) vs. 3.9% (placebo)
• Most discontinuations occurred during dose escalation
• No deaths reported in the Phase 2 trial

Tirzepatide Safety (SURMOUNT-1)

• Serious adverse events: 5.1–6.9% across dose groups vs. 6.8% (placebo)
• Discontinuation due to adverse events: 4.3–7.1% across dose groups vs. 2.6% (placebo)
• In SURPASS-CVOT, adverse events leading to discontinuation were 13.2% (tirzepatide) vs. 10.1% (dulaglutide), largely driven by GI side effects

The discontinuation rate for survodutide (24.6%) in Phase 2 is notably higher than tirzepatide's in Phase 3 trials. Phase 3 dose optimization may reduce this number. The glucagon component can add nausea and appetite suppression on top of GLP-1 effects, potentially making the early dose escalation period rougher.

Safety Metric	Survodutide (Phase 2)	Tirzepatide (Phase 3)
Most common AEs	Nausea, vomiting, diarrhea	Nausea, diarrhea, constipation
Serious AE rate	4.2%	5.1–6.9%
Discontinuation rate	24.6%	4.3–7.1%
Trial phase	Phase 2	Phase 3

Approval Status and Availability

Tirzepatide is FDA-approved and available by prescription:

• Mounjaro — approved for type 2 diabetes (May 2022)
• Zepbound — approved for chronic weight management (November 2023)

Survodutide remains investigational. It has not received any marketing approval. However, it has received several regulatory designations that signal confidence in its development:

• FDA Breakthrough Therapy designation
• FDA Fast Track designation
• EMA PRIME (Priority Medicines) designation
• China NMPA Breakthrough Therapy designation

These designations don't guarantee approval, but they streamline the review process and reflect regulatory acknowledgment that survodutide addresses an unmet medical need.

Comparison Table

Feature	Survodutide	Tirzepatide
Developer	Boehringer Ingelheim / Zealand Pharma	Eli Lilly
Mechanism	GLP-1 + glucagon receptor dual agonist	GLP-1 + GIP receptor dual agonist
Administration	Weekly subcutaneous injection	Weekly subcutaneous injection
FDA status	Investigational (Phase 3)	Approved (Mounjaro, Zepbound)
Peak weight loss (ITT)	-14.9% at 46 weeks	-20.9% at 72 weeks
MASH efficacy	62% resolution at 4.8 mg	Phase 2 positive (limited data)
CV outcomes data	Pending (SYNCHRONIZE-CVOT)	Noninferior to dulaglutide
Unique advantage	Increased energy expenditure, liver fat reduction	Established safety record, broad dataset
Key risk	Higher GI discontinuation, glucose effects	GI intolerance at higher doses

What the Phase 3 Trials Will Tell Us

Several large survodutide trials are underway with primary completion expected in 2026:

SYNCHRONIZE-1: Adults with obesity without type 2 diabetes. 76-week trial measuring percent weight change and response rates at 5%, 10%, 15%, and 20% thresholds, plus cardiometabolic markers. Recruitment is complete.

SYNCHRONIZE-2: Adults with obesity and type 2 diabetes. Similar 76-week design. This trial will reveal whether glucagon agonism complicates glucose management in diabetic populations — a real concern given glucagon's blood sugar–raising effects.

SYNCHRONIZE-CVOT: Cardiovascular outcomes trial enrolling approximately 4,935 participants with elevated CV risk. Event-driven design comparing survodutide to placebo.

LIVERAGE: Long-term efficacy and safety in adults with noncirrhotic MASH at fibrosis stages F2 and F3.

These trials will answer the questions the Phase 2 data couldn't: Does survodutide's weight loss catch up with tirzepatide over 76 weeks? Is the MASH benefit durable? Is the glucagon component safe for the heart?

The Bottom Line

Tirzepatide is the proven option. With Phase 3 data from the SURMOUNT and SURPASS programs, FDA approval, and millions of real-world prescriptions, its efficacy and safety profile are well established. It delivers 15–22% weight loss depending on dose, with strong signals for MASH and cardiovascular benefit.

Survodutide is the ambitious challenger. Its glucagon component offers something tirzepatide cannot — direct stimulation of energy expenditure and hepatic fat oxidation. Phase 2 data show weight loss of up to 18.7% at just 46 weeks and MASH resolution rates of 62%, both impressive for a drug still in development. But higher discontinuation rates, the absence of Phase 3 weight loss data, and no cardiovascular outcomes results leave significant questions open.

These are not interchangeable drugs. They represent two distinct pharmacological hypotheses about how to treat obesity and its metabolic complications. Tirzepatide says combining GLP-1 with GIP creates the most effective appetite suppression. Survodutide says pairing GLP-1 with glucagon addresses both sides of the energy equation — intake and expenditure.

The SYNCHRONIZE results expected in 2026 will determine whether survodutide's mechanistic promise translates into clinical reality. Until then, tirzepatide remains the standard by which all dual-agonist therapies are measured.

References

1. Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." New England Journal of Medicine. 2022. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

2. Blüher M, et al. "Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial." The Lancet Diabetes & Endocrinology. 2024. https://www.sciencedirect.com/science/article/abs/pii/S221385872300356X

3. "Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial." JACC: Heart Failure. 2024. https://www.jacc.org/doi/10.1016/j.jchf.2024.09.004

4. "SURPASS-CVOT Published: Large Trial Confirms CVD Efficacy of Tirzepatide." TCTMD. 2025. https://www.tctmd.com/news/surpass-cvot-published-large-trial-confirms-cvd-efficacy-tirzepatide

5. "Evaluating the efficacy and safety of survodutide for obesity: a systematic review and meta-analysis of randomized controlled trials." PMC. 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12184113/

6. "Patients With Overweight or Obesity Show Significant Weight Loss in Phase 2 Survodutide Trial." AJMC. 2023. https://www.ajmc.com/view/patients-with-overweight-or-obesity-show-significant-weight-loss-in-phase-2-survodutide-trial

7. "SURPASS-CVOT: Is Tirzepatide Superior to Dulaglutide in Patients With T2D and ASCVD?" American College of Cardiology. 2026. https://www.acc.org/latest-in-cardiology/journal-scans/2026/01/07/14/20/surpass-cvot

8. "Obesity drug from Boehringer, Zealand succeeds in MASH trial." BioPharma Dive. 2024. https://www.biopharmadive.com/news/boehringer-zealand-mash-nash-obesity-drug-results/708475/