Tirzepatide clinical trials: what SURMOUNT and SURPASS show

Last updated 2026-07-27

What clinical trials support tirzepatide's approval?

Tirzepatide's FDA approvals rest on two separate trial programs, run for two separate indications, and it helps to keep them straight because people often mix them up. The SURPASS program (SURPASS-1 through SURPASS-5, plus later regional and cardiovascular outcome extensions) tested tirzepatide against placebo, insulin, and other GLP-1 drugs in adults with type 2 diabetes. This program led to FDA approval of Mounjaro in May 2022 ^[1]. The SURMOUNT program (SURMOUNT-1 through SURMOUNT-4, and beyond) tested the same molecule, same dose range, in adults with obesity or overweight plus at least one weight-related condition, without diabetes as the entry criterion in most of the trials. This program led to FDA approval of Zepbound in November 2023 ^[2]. Same drug, same molecule (tirzepatide), different brand name depending on the approved use. Mounjaro is not approved for weight loss as a standalone indication, and Zepbound is not indicated for type 2 diabetes management, even though the drug inside the pen is identical. Insurance coverage, prior authorization rules, and even manufacturing lot allocation have at times differed between the two brands, which matters more than it should for something that's chemically the same molecule. Both programs were run by Eli Lilly and published primarily in the New England Journal of Medicine and The Lancet, with primary registration on ClinicalTrials.gov under the NCT identifiers cited throughout this article.

What did SURMOUNT-1 find about weight loss?

SURMOUNT-1 (NCT04184622) is the trial most people mean when they cite "tirzepatide weight loss data." It enrolled 2,539 adults with obesity or overweight plus a weight-related comorbidity, excluding diabetes, and randomized them to placebo or tirzepatide at 5mg, 10mg, or 15mg weekly for 72 weeks ^[3]. The published results, from the New England Journal of Medicine in 2022, reported mean weight reductions of 15.0% on the 5mg dose, 19.5% on 10mg, and 20.9% on 15mg, compared with 3.1% on placebo ^[3]. A commonly cited secondary figure, 22.5%, comes from a subgroup analysis using a different estimand (treatment-regimen effect excluding discontinuations) rather than the primary intention-to-treat result, so you'll see both numbers depending on which analysis a source pulls from. The trial also reported that 96.3% of participants on the 15mg dose lost at least 5% of body weight, and more than half lost at least 20% ^[3]. That's a meaningfully different response profile than older weight-loss drugs, and it's the main reason tirzepatide got compared to bariatric surgery outcomes in some commentary, though no head-to-head surgical comparison trial exists. For people mapping this to the maintenance dose they're actually injecting, the Tirz Rx dosage guide breaks down how the 5mg/10mg/15mg range in these trials corresponds to typical titration schedules.

How does tirzepatide compare to semaglutide in trials?

SURPASS-2 (NCT03987919) is the head-to-head trial diabetes researchers cite most. It randomized 1,879 adults with type 2 diabetes to tirzepatide (5mg, 10mg, or 15mg) or semaglutide 1mg weekly, both added to metformin, for 40 weeks ^[4]. All three tirzepatide doses reduced A1C more than semaglutide 1mg: reductions of 2.01, 2.24, and 2.30 percentage points for tirzepatide versus 1.86 points for semaglutide, from a baseline around 8.3% ^[4]. Weight loss also favored tirzepatide: 7.6kg, 9.3kg, and 11.2kg across the three tirzepatide doses versus 5.7kg with semaglutide ^[4]. There's no published head-to-head trial directly comparing Zepbound to Wegovy (semaglutide's weight-loss brand) in people without diabetes, but a real-world retrospective cohort study published in JAMA Internal Medicine in 2024, using electronic health record data on over 18,000 patients, found tirzepatide associated with significantly greater weight loss than semaglutide at 3, 6, and 12 months ^[5]. That's observational data, not a randomized trial, so it carries the usual caveats about confounding, but it's the closest large-scale comparison available as of this writing. | Trial | Population | Comparator | Primary outcome |

What does SURMOUNT-2 show for people with type 2 diabetes?

SURMOUNT-2 (NCT04657003) matters because SURMOUNT-1 excluded people with diabetes, and weight loss tends to be blunted in people who have type 2 diabetes compared to those without it, across every GLP-1 drug studied so far. SURMOUNT-2 enrolled 938 adults with obesity or overweight and type 2 diabetes, randomizing them to placebo, tirzepatide 10mg, or tirzepatide 15mg for 72 weeks. Published in The Lancet in 2023, it found mean weight reductions of 13.4% (10mg) and 14.7% (15mg) versus 3.2% with placebo ^[6]. That's a smaller percentage than SURMOUNT-1's non-diabetic population, roughly two-thirds the effect size, which lines up with what's been seen in semaglutide trials too (STEP 2 showed a similar pattern). A1C dropped by 2.1 to 2.2 percentage points in the tirzepatide groups from a baseline near 8.0%, versus 0.5 points with placebo ^[6]. For someone managing both diabetes and weight, this is the trial that actually reflects their situation, not SURMOUNT-1.

What happens after tirzepatide is stopped? (SURMOUNT-4)

SURMOUNT-4 (NCT05024032) answers a question almost everyone asks eventually: what happens if you stop. The trial had two phases. All participants got 36 weeks of open-label tirzepatide titrated to a maximum tolerated dose (10mg or 15mg). Then responders were randomized to either continue tirzepatide or switch to placebo for another 52 weeks. Published in JAMA in 2024, the results showed that participants who continued tirzepatide lost an additional 5.5% of body weight during the second phase, while those switched to placebo regained 14% of body weight on average, ending up with only about 9.9% total loss from baseline compared to 25.3% in the continuation group ^[8]. That's the trial-grounded answer to "is tirzepatide a lifetime drug." For most people in this study, stopping meant substantial regain within about a year. It doesn't mean everyone regains at the same rate, individual metabolic response varies a lot, but the average trend was clear and consistent with what's been shown for semaglutide discontinuation in the STEP 1 extension study. Anyone planning a stop-and-restart approach should read the Tirz Rx cycle length breakdown before assuming maintenance is optional.

What are the real side effects seen in the trials?

Gastrointestinal side effects dominate the adverse event tables across every SURPASS and SURMOUNT trial, and they're dose-dependent, meaning higher doses produce more of them. In SURMOUNT-1, nausea occurred in 24-33% of tirzepatide-treated participants depending on dose (versus 10% on placebo), diarrhea in 17-23% (versus 10%), constipation in 15-17% (versus 6%), and vomiting in 10-13% (versus 2%) ^[3]. These effects clustered mostly during dose escalation and tended to decrease over time, which is the entire rationale behind slow titration schedules rather than jumping straight to a maintenance dose. Gallbladder-related events (cholelithiasis, cholecystitis) occurred more often on tirzepatide than placebo across the pooled SURMOUNT data, consistent with what's seen across the whole GLP-1 class; rapid weight loss itself is an independent risk factor for gallstone formation, so this isn't unique to the drug's mechanism. Injection site reactions were reported but generally mild. Serious hypoglycemia was rare in SURMOUNT-1 (participants without diabetes) but showed up more often in SURPASS trials where tirzepatide was combined with sulfonylureas or insulin, which is expected given how those drugs work. Anyone on background insulin or a sulfonylurea needs their diabetes provider adjusting those doses proactively, not reactively, when starting tirzepatide. For a plain look at how these side effects map onto injection technique and site choice, see Tirz Rx injection sites and Tirz Rx how to inject.

Does tirzepatide carry a thyroid cancer warning?

Yes. Zepbound and Mounjaro both carry a boxed warning, the FDA's most serious label warning category, about thyroid C-cell tumors. The warning is based on findings in rodent studies, where tirzepatide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) ^[9]. The FDA prescribing information states: "Tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in rats... It is unknown whether Zepbound causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans" ^[9]. Because of this, tirzepatide is contraindicated in anyone with a personal or family history of MTC, and in anyone with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) ^[9]. This isn't a minor footnote, it's an absolute contraindication, meaning the drug should not be prescribed at all in those cases, more than used cautiously. No human case of tirzepatide-caused MTC has been confirmed in the trial data to date, but the mechanism seen in rodents is taken seriously enough to drive the label language and screening question every prescriber should ask before the first dose.

Is there a signal for pancreatitis in the tirzepatide trials?

Acute pancreatitis was reported in the tirzepatide trial programs at low but nonzero rates, and it appears in the label as a warning, not a boxed warning. Across the SURPASS and SURMOUNT pooled safety data referenced in the FDA label, pancreatitis was reported in a small number of participants on tirzepatide versus comparators, consistent with the signal seen across the GLP-1 receptor agonist class going back to earlier drugs like exenatide and liraglutide ^[9]. The absolute numbers are small, this is not a common event, but it's serious enough that the label instructs discontinuing tirzepatide if pancreatitis is suspected, and not restarting it if pancreatitis is confirmed ^[9]. Anyone with a personal history of pancreatitis should have an explicit conversation with their prescriber before starting, since most trials either excluded or closely monitored people with that history.

How do the SURPASS diabetes trials compare to insulin and other drugs?

SURPASS-4 (NCT03730662) is one of the more clinically relevant diabetes trials because it compared tirzepatide against insulin glargine, a standard-of-care comparator, in 2,002 adults with type 2 diabetes at high cardiovascular risk, over a median of 52 weeks (with some follow-up extending further) ^[7]. All three tirzepatide doses (5mg, 10mg, 15mg) reduced A1C more than insulin glargine: reductions ranging roughly from 2.2 to 2.6 percentage points versus 1.4 points with glargine, from a baseline near 8.5% ^[7]. Tirzepatide groups lost weight (roughly 7 to 12kg depending on dose) while the insulin glargine group gained about 1.9kg, which is the expected direction for insulin (it's an anabolic hormone) but is exactly the tradeoff many patients want to avoid. SURPASS-4 also reported cardiovascular outcome data as a secondary analysis, and did not show an increased risk of major adverse cardiovascular events (MACE) with tirzepatide compared to insulin glargine, though it wasn't statistically powered as a dedicated cardiovascular outcomes trial in the way some other diabetes drugs have been formally tested (the dedicated tirzepatide cardiovascular outcomes trial, SURPASS-CVOT, has since reported results comparing tirzepatide to dulaglutide, though full analysis is beyond the SURPASS 1-5 numbering most people ask about).

Compounded tirzepatide versus the trial drug: is it the same thing?

This is the question with the murkiest answer, and it deserves an honest one. Every trial cited in this article, SURPASS and SURMOUNT alike, tested Eli Lilly's manufactured tirzepatide, delivered in FDA-approved, quality-controlled prefilled pens or vials as Mounjaro or Zepbound. Compounded tirzepatide, made by 503A or 503B pharmacies, is not the product studied in any of these trials. It may use tirzepatide sourced from a different manufacturer, but the FDA has not evaluated compounded tirzepatide for safety, effectiveness, or manufacturing quality the way it evaluates approved drugs ^[10]. The FDA removed tirzepatide from its drug shortage list in late 2023, and reinstated enforcement discretion limits on compounding tirzepatide as a result, since compounding is legally permitted mainly during confirmed shortages or for legitimate patient-specific customization (like a different dose form) ^[10]. Whether a given compounded product matches the purity, sterility, and dosing accuracy of the branded pens is a pharmacy-by-pharmacy question, not something the SURPASS or SURMOUNT trials can answer, because they never tested compounded versions. Anyone using a compounded product should ask their pharmacy directly about third-party testing (USP or similar), sourcing, and whether the pharmacy is a 503A or 503B facility, since the regulatory oversight differs meaningfully between those two categories. If you're mapping trial doses onto a compounded product, the Tirz Rx dosage calculator and how to reconstitute Tirz Rx guides walk through how vial concentrations translate to the milligram doses actually used in these trials. Tirz Rx's own content is provider-reviewed and focuses on connecting readers with a licensed prescriber and a fulfilling pharmacy partner rather than compounding or selling the drug itself.

How long do the trial benefits actually last, and are there longer trials coming?

Most of the headline trials (SURMOUNT-1, SURPASS-2, SURPASS-4) ran 40 to 72 weeks, which tells you a lot about the first year but less about year three or year five. SURMOUNT-1 did include a longer 88-week extension in some analyses, and SURMOUNT-4's 88-week total design (36 weeks open-label plus 52 weeks randomized) is the closest thing to true withdrawal data currently published ^[8]. Beyond that window, the field is genuinely thin. Long-term cardiovascular outcome data specific to weight-management dosing (not diabetes dosing) is still emerging, and the dedicated SURMOUNT-MMO trial (looking at long-term morbidity and mortality outcomes in people with obesity) is designed to run for several years, with results expected later in the decade. So the honest answer: we have strong one- to two-year data. We don't yet have five- or ten-year outcome data on cardiovascular events, cancer risk, or bone density changes with tirzepatide specifically, and anyone telling you otherwise is overstating what's published so far.

Frequently asked questions

What is the SURMOUNT-1 trial and what did it find?

SURMOUNT-1 (NCT04184622) tested tirzepatide against placebo in 2,539 adults with obesity or overweight, without diabetes, over 72 weeks. The 15mg dose produced average weight loss of 20.9% versus 3.1% on placebo, with over 96% of participants losing at least 5% of body weight. It's the primary trial behind Zepbound's FDA approval for weight management.

What is the SURPASS trial program?

SURPASS is the trial program (SURPASS-1 through SURPASS-5, plus extensions) that tested tirzepatide in adults with type 2 diabetes, comparing it to placebo, insulin glargine, and semaglutide. It led to Mounjaro's FDA approval in May 2022. SURPASS-2 showed tirzepatide reduced A1C by up to 2.30 percentage points versus 1.86 with semaglutide 1mg.

Is tirzepatide more effective than semaglutide?

In the SURPASS-2 head-to-head trial, tirzepatide reduced A1C and body weight more than semaglutide 1mg in people with type 2 diabetes. A 2024 JAMA Internal Medicine observational study of over 18,000 patients also found greater weight loss with tirzepatide than semaglutide, but no randomized trial has directly compared Zepbound to Wegovy in people without diabetes.

What happens if you stop taking tirzepatide?

In SURMOUNT-4, participants switched from tirzepatide to placebo after 36 weeks regained an average of 14% of body weight over the next year, ending with about 9.9% total loss versus 25.3% in those who continued treatment. Regain is common after stopping, though individual results vary.

Does tirzepatide cause thyroid cancer?

No human case of tirzepatide-caused thyroid cancer is confirmed. But Zepbound and Mounjaro carry an FDA boxed warning because the drug caused dose-dependent thyroid C-cell tumors, including medullary thyroid carcinoma, in rodent studies. It's contraindicated in anyone with a personal or family history of MTC or MEN 2 syndrome.

What are the most common side effects reported in tirzepatide trials?

Gastrointestinal effects dominate: nausea (24-33%), diarrhea (17-23%), constipation (15-17%), and vomiting (10-13%) in SURMOUNT-1, all higher than placebo and roughly dose-dependent. These effects were most common during dose escalation and tended to ease over time as the body adjusted.

Is compounded tirzepatide the same as what was tested in the trials?

No. Every SURPASS and SURMOUNT trial tested Eli Lilly's manufactured tirzepatide (Mounjaro or Zepbound). Compounded tirzepatide from 503A or 503B pharmacies was never studied in these trials and the FDA has not evaluated its safety or effectiveness the same way it evaluates approved drugs.

What is SURMOUNT-2 and why does it matter for people with diabetes?

SURMOUNT-2 (NCT04657003) tested tirzepatide specifically in adults with obesity and type 2 diabetes, since SURMOUNT-1 excluded diabetics. Weight loss was smaller (13.4-14.7% versus 3.2% on placebo) than in SURMOUNT-1's non-diabetic population, matching a pattern seen across GLP-1 drugs where diabetes tends to blunt weight-loss response.

Does tirzepatide increase pancreatitis risk?

A small pancreatitis signal appears across the SURPASS and SURMOUNT trial safety data, consistent with the broader GLP-1 drug class. It's uncommon but serious enough that the FDA label instructs stopping tirzepatide if pancreatitis is suspected and not restarting if it's confirmed.

How long do tirzepatide trials actually track people for?

Most headline trials ran 40 to 72 weeks. SURMOUNT-4 extended to 88 weeks total with a withdrawal phase. Longer-term data (3 to 5+ years) on cardiovascular outcomes and other long-term effects is still emerging; the SURMOUNT-MMO trial is designed to answer that but results aren't fully published yet.

Did the SURPASS trials show cardiovascular benefit?

SURPASS-4 compared tirzepatide to insulin glargine in adults with type 2 diabetes at high cardiovascular risk and did not show increased major cardiovascular event risk, but it wasn't designed as a dedicated cardiovascular outcomes trial. A dedicated cardiovascular outcomes trial (SURPASS-CVOT) has since reported comparative data against dulaglutide.

What's the difference between Mounjaro and Zepbound in the trials?

They're the same drug, tirzepatide, tested in two separate trial programs for two separate FDA-approved uses. Mounjaro (approved May 2022) comes from the SURPASS diabetes trials. Zepbound (approved November 2023) comes from the SURMOUNT weight-management trials. Neither is officially approved for the other's indication.

Sources

1. FDA, Zepbound approval announcement: Zepbound (tirzepatide) FDA approval for chronic weight management in November 2023
2. NEJM, SURMOUNT-1 trial results: SURMOUNT-1 weight loss results by dose (5mg, 10mg, 15mg) versus placebo at 72 weeks
3. NEJM, SURPASS-2 trial results: SURPASS-2 head-to-head A1C and weight results, tirzepatide versus semaglutide 1mg
4. JAMA Internal Medicine, tirzepatide vs semaglutide real-world cohort: Real-world retrospective cohort study finding greater weight loss with tirzepatide than semaglutide
5. The Lancet, SURMOUNT-2 trial results: SURMOUNT-2 weight and A1C results in adults with obesity and type 2 diabetes
6. The Lancet, SURPASS-4 trial results: SURPASS-4 tirzepatide versus insulin glargine A1C and weight results
7. JAMA, SURMOUNT-4 trial results: SURMOUNT-4 withdrawal phase showing weight regain after switching to placebo
8. FDA, Zepbound prescribing information: Boxed warning on thyroid C-cell tumors and contraindication in MEN 2 and personal/family MTC history
9. ClinicalTrials.gov, SURMOUNT-1 registration: SURMOUNT-1 trial registration, design, and NCT identifier
10. ClinicalTrials.gov, SURPASS-2 registration: SURPASS-2 trial registration, design, and NCT identifier