Semaglutide vs Tirzepatide: Comparing Clinical Trial Data

The semaglutide and tirzepatide trial programmes together constitute the deepest clinical evidence base in modern metabolic pharmacology. Both compounds are supported by multiple large Phase 3 trials, with overlapping endpoints (glycaemic control, body weight, cardiovascular outcomes) that permit meaningful comparison. This article walks through the major trials for each compound and explains what can and cannot be concluded from the current evidence.

The two-sentence framing: Tirzepatide produces larger effects on glycaemic and weight endpoints than semaglutide in direct head-to-head comparison. Semaglutide has the more mature cardiovascular-outcome evidence base, with tirzepatide’s definitive CV trial still in progress. The rest of the evidence fills in around that central comparison.

Trial programme overview

Each compound’s clinical programme is organised around a consistent naming convention:

Semaglutide:

• SUSTAIN programme: glycaemic control in type 2 diabetes (SUSTAIN-1 through -10)
• STEP programme: body weight in overweight/obesity (STEP 1–8)
• SELECT trial: cardiovascular outcomes in obesity without diabetes
• PIONEER programme: oral semaglutide (separate formulation, not covered here)

Tirzepatide:

• SURPASS programme: glycaemic control in type 2 diabetes (SURPASS-1 through -5)
• SURMOUNT programme: body weight in overweight/obesity (SURMOUNT-1 through -5)
• SURPASS-CVOT: cardiovascular outcomes (ongoing; no definitive readout as of 2025)

For semaglutide and tirzepatide research framing, researchers should be familiar with the pivotal trial in each track: SUSTAIN-6 for CV in T2DM, STEP 1 for obesity, SELECT for CV in obesity, SURPASS-2 for T2DM head-to-head, SURPASS-3 for insulin comparison, SURMOUNT-1 for obesity without diabetes, SURMOUNT-2 for obesity with T2DM. The rest of the trial programme fills in specific sub-populations and endpoints.

SURPASS-2: the definitive head-to-head in T2DM

Frías and colleagues’ SURPASS-2 trial, published in NEJM 2021, is the most important single trial for comparing the two compounds ¹. Design:

• Randomised, open-label (with blinded endpoint assessment)
• 1,879 adults with T2DM inadequately controlled on metformin
• Four arms: tirzepatide 5, 10, or 15 mg SC weekly vs. semaglutide 1 mg SC weekly
• Duration: 40 weeks
• Primary endpoint: change in HbA1c at week 40
• Key secondary endpoint: change in body weight

Results:

• HbA1c reduction: tirzepatide 5 mg (-2.01%), 10 mg (-2.24%), 15 mg (-2.30%); semaglutide 1 mg (-1.86%)
• Body weight reduction: tirzepatide 5 mg (-7.6 kg), 10 mg (-9.3 kg), 15 mg (-11.2 kg); semaglutide 1 mg (-5.7 kg)
• HbA1c < 7% target achievement: tirzepatide 82–86% across doses; semaglutide 79%
• Adverse events: similar profile across compounds, with GI events dominant in both

The clinical interpretation: at the doses tested, tirzepatide produces larger HbA1c reductions and substantially larger body-weight reductions than semaglutide. The magnitude of the weight-loss advantage grows with tirzepatide dose. Two caveats:

1. Dose comparison is asymmetric. SURPASS-2 used semaglutide 1 mg, which was the FDA-approved diabetes dose when the trial was designed. The higher 2.4 mg semaglutide dose (used in STEP 1 for obesity) was not available for comparison in SURPASS-2 because obesity-indication regulatory approval for that dose came later. At the matched-indication doses each compound is currently used, tirzepatide retains the advantage but the gap narrows.
2. Open-label design. Both patients and investigators knew which compound was being administered, which can introduce response bias. The primary endpoint (HbA1c) is lab-measured and less susceptible to bias than patient-reported outcomes, but the body-weight secondary endpoint is more sensitive to expectations.

Within these caveats, SURPASS-2 is the strongest direct comparison available and is the canonical reference for the “tirzepatide is more potent than semaglutide” framing.

STEP 1: the pivotal semaglutide obesity trial

Wilding and colleagues’ STEP 1 trial, published in NEJM 2021, was the pivotal obesity registration trial for semaglutide ². Design:

• Randomised, double-blind, placebo-controlled
• 1,961 adults without diabetes, BMI ≥ 30 or ≥ 27 with weight-related comorbidity
• Semaglutide 2.4 mg SC weekly vs. placebo
• Duration: 68 weeks (with active dose titration over first 16 weeks)
• Primary endpoint: percentage change in body weight at week 68

Results:

• Mean body-weight reduction: semaglutide arm -14.9%; placebo -2.4%
• Net treatment effect: approximately 12.4% greater reduction in the active arm
• Weight-loss threshold achievements: 86% of semaglutide arm achieved ≥5% loss; 69% achieved ≥10%; 50% achieved ≥15%
• Adverse events: GI effects dominant (nausea, vomiting, diarrhoea, constipation), typically mild-to-moderate and attenuating over time with the titration schedule

STEP 1 established semaglutide 2.4 mg as the reference obesity regimen and led to 2021 FDA approval under the brand name Wegovy. The trial produced a clinical body-weight effect larger than any prior non-surgical obesity intervention.

Implications for research framing: when researchers discuss “the semaglutide weight-loss effect” in a non-diabetes context, the STEP 1 framework (2.4 mg/week SC, 68 weeks, ~15% loss) is the implicit reference. Protocols using lower doses or shorter durations should expect smaller effects.

SURMOUNT-1: the pivotal tirzepatide obesity trial

Jastreboff and colleagues’ SURMOUNT-1 trial, published in NEJM 2022, was the pivotal obesity registration trial for tirzepatide ³. Design:

• Randomised, double-blind, placebo-controlled
• 2,539 adults without diabetes, BMI ≥ 30 or ≥ 27 with weight-related comorbidity
• Four arms: tirzepatide 5, 10, or 15 mg SC weekly vs. placebo
• Duration: 72 weeks (20-week titration to target dose)
• Primary endpoint: percentage change in body weight at week 72

Results:

• Mean body-weight reduction: tirzepatide 5 mg (-15.0%), 10 mg (-19.5%), 15 mg (-20.9%); placebo (-3.1%)
• Net treatment effect at highest dose: approximately 17.8% greater reduction
• Weight-loss threshold achievements at 15 mg: 96% achieved ≥5%; 91% achieved ≥10%; 79% achieved ≥15%; 57% achieved ≥20%
• Adverse events: similar class profile to semaglutide (GI events dominant)

The 15 mg dose’s ~21% weight loss is substantially greater than STEP 1’s ~15% with semaglutide 2.4 mg. The comparison is population-matched (similar BMI entry criteria, similar non-diabetes status) and time-matched approximately (STEP 1 was 68 weeks, SURMOUNT-1 was 72 weeks). Direct comparison is not quite head-to-head (different trials, different sponsors) but is as close as cross-trial comparison gets in this space.

SURMOUNT-1 led to 2023 FDA approval of tirzepatide for obesity under the brand name Zepbound.

SELECT: cardiovascular outcomes in obesity without diabetes

Lincoff and colleagues’ SELECT trial, published in NEJM 2023, extended the semaglutide cardiovascular-outcome evidence base to obese patients without diabetes ⁴. Design:

• Randomised, double-blind, placebo-controlled
• 17,604 adults with BMI ≥ 27 and established cardiovascular disease but without diabetes
• Semaglutide 2.4 mg SC weekly vs. placebo
• Duration: mean follow-up 39.8 months
• Primary endpoint: composite of CV death, non-fatal MI, non-fatal stroke (MACE-3)

Results:

• Primary MACE endpoint: 6.5% in semaglutide arm vs. 8.0% in placebo; HR 0.80 (95% CI 0.72–0.90)
• Relative risk reduction: approximately 20%
• Secondary endpoints: reductions in CV death (-15%), heart failure composite endpoint (-18%)
• Body weight: secondary effect, ~9.4% reduction in active arm (smaller than STEP 1 due to different population and trial design)

SELECT was important because it decoupled the cardiovascular benefit from the diabetes status of the patient. Prior GLP-1R agonist CV trials (including SUSTAIN-6) were in T2DM patients where the benefit could theoretically be mediated through glycaemic control. SELECT showed the benefit persists in patients whose primary indication is obesity-driven cardiovascular risk rather than glucose-driven risk.

For research framing, SELECT is the current reference for “GLP-1 cardiovascular benefit” in obese patients, and it does not have a direct tirzepatide equivalent yet.

SUSTAIN-6: the earlier CV evidence in T2DM

Marso and colleagues’ SUSTAIN-6 trial, published in NEJM 2016, was the first major cardiovascular-outcome trial for semaglutide and remains important as the T2DM CV reference ⁵. Design:

• Randomised, double-blind, placebo-controlled
• 3,297 T2DM patients at high cardiovascular risk
• Semaglutide 0.5 or 1.0 mg SC weekly vs. placebo
• Duration: 104 weeks
• Primary endpoint: composite MACE-3

Results: semaglutide produced 26% relative reduction in MACE-3. The trial was originally designed as a non-inferiority trial but the MACE reduction was statistically significant for superiority.

SUSTAIN-6 moved GLP-1R agonism from a “diabetes drug with weight-loss side effect” into a “cardiovascular-prevention therapy” category, which was a substantial expansion of the clinical research framing and led to guideline changes.

SURPASS-3 and the insulin comparison track

Ludvik and colleagues’ SURPASS-3 trial, published in The Lancet 2021, tested tirzepatide against insulin degludec rather than against another GLP-1 class compound ⁶. This matters because insulin is the standard escalation therapy when T2DM is inadequately controlled on oral drugs, and the clinical question is whether patients should advance to insulin or to a modern incretin agonist.

Design:

• Randomised, open-label (with blinded endpoint assessment)
• 1,444 T2DM patients inadequately controlled on metformin ± SGLT2 inhibitors
• Four arms: tirzepatide 5, 10, or 15 mg SC weekly vs. insulin degludec titrated to fasting glucose target
• Duration: 52 weeks
• Primary endpoint: HbA1c change

Results: tirzepatide produced larger HbA1c reductions than insulin at all three doses, and (critically) patients on tirzepatide lost weight (~7–12 kg depending on dose) while patients on insulin gained weight (~2 kg). The clinical interpretation is that tirzepatide can substitute for insulin initiation in many T2DM patients, avoiding the weight gain and hypoglycaemia risk that accompany insulin therapy.

The SURPASS-3 MRI substudy, published by Gastaldelli and colleagues in Lancet Diabetes & Endocrinology 2022, added a liver fat endpoint using MRI-measured hepatic fat fraction ⁷. Tirzepatide at 10 and 15 mg doses produced 30–45% relative reduction in liver fat content from baseline over 52 weeks; insulin degludec produced minimal change. This positioned tirzepatide as a potential NAFLD-targeting compound, not just a diabetes or obesity drug.

SURMOUNT-2: tirzepatide in obesity with T2DM

Garvey and colleagues’ SURMOUNT-2 trial, published in The Lancet 2023, extended the SURMOUNT programme into the obesity-with-diabetes population ⁸. Design:

• Randomised, double-blind, placebo-controlled
• 938 patients with obesity (BMI ≥ 27) plus T2DM
• Tirzepatide 10 or 15 mg SC weekly vs. placebo
• Duration: 72 weeks
• Primary endpoint: percentage body weight change

Results: tirzepatide 10 mg produced -12.8% weight loss; tirzepatide 15 mg produced -14.7%; placebo produced -3.2%. The effect in obese patients with T2DM was smaller than in obese patients without diabetes (SURMOUNT-1 showed -19.5% and -20.9% at the same doses), consistent with the general observation that weight loss is harder to achieve in T2DM patients than in non-diabetes obesity populations.

SURMOUNT-2 completed the programme coverage for tirzepatide across the major metabolic indications: T2DM (SURPASS), T2DM inadequately controlled (SURPASS-3), obesity without diabetes (SURMOUNT-1), obesity with diabetes (SURMOUNT-2).

What the trial data can and can’t conclude

Can conclude:

• Tirzepatide produces larger HbA1c and body-weight reductions than semaglutide in direct T2DM comparison (SURPASS-2)
• Both compounds produce clinically meaningful weight loss in obesity without diabetes (STEP 1, SURMOUNT-1)
• The absolute weight-loss effect size is larger with tirzepatide (~21% at 15 mg) than with semaglutide (~15% at 2.4 mg) at the approved obesity doses
• Semaglutide reduces major adverse cardiovascular events in T2DM with CV risk (SUSTAIN-6) and in obesity without diabetes but with CV disease (SELECT)
• Tirzepatide can substitute for insulin initiation in T2DM (SURPASS-3), with weight-loss advantage
• Tirzepatide substantially reduces liver fat content in T2DM (SURPASS-3 MRI substudy)

Cannot yet conclude:

• Whether tirzepatide produces equivalent or superior cardiovascular benefit to semaglutide (SURPASS-CVOT is ongoing; no definitive readout available)
• Whether the weight-loss difference between the two compounds reflects mechanism or dose; the 2.4 mg semaglutide dose (STEP 1 regimen) has not been compared head-to-head against tirzepatide in a published trial
• Whether liver-fat reduction from tirzepatide translates to clinically meaningful NAFLD outcomes (hepatic events, fibrosis progression); the trials to date are biomarker-level, not clinical-event-level

Practical research framing

For researchers using semaglutide or tirzepatide in protocols, the trial data supports several design considerations:

• Endpoint selection: HbA1c and body weight are well-characterised; cardiovascular events require long-duration trials and are not feasible in most research contexts
• Dose-response expectations: tirzepatide has published dose-response curves from SURPASS-1 through -5 and SURMOUNT-1 through -5; semaglutide has similar data from SUSTAIN and STEP programmes
• Titration schedule: both compounds require gradual dose escalation to manage GI side effects; skipping titration produces worse tolerability without improved early efficacy. Standard semaglutide titration is 0.25 mg weekly × 4 weeks, then 0.5 mg weekly × 4 weeks, then up-titration toward the target (up to 2.4 mg for obesity); tirzepatide titrates in 2.5 mg weekly steps every 4 weeks toward 5, 10, or 15 mg target doses
• Population specifics: weight-loss effects are largest in non-diabetes obesity populations; smaller in T2DM and in patients with lower baseline BMI; smaller again in very elderly populations
• Comparator choice: research protocols should match the comparator to the research question. Head-to-head against an older GLP-1 analog tests class-advancement; against placebo tests absolute effect; against a different drug class (insulin, SGLT2 inhibitor) tests positioning

Where to order

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For the full class narrative including retatrutide and the mechanism story, see the GLP-1 research overview. For a use-case-level comparison including AOD-9604 and 5-Amino-1MQ, see best peptides for fat loss.