Tirzepatide Research: SURPASS & SURMOUNT Phase 3 Trial Data
A trial-by-trial look at tirzepatide — the dual GIP/GLP-1 agonist known commercially as Mounjaro and Zepbound — covering the SURPASS diabetes programme, the SURMOUNT obesity programme, cardiovascular data and the documented side-effect profile.
Mechanism of action
Tirzepatide is a synthetic 39-amino-acid peptide developed by Eli Lilly that activates two incretin receptors: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Single-agonist GLP-1 compounds engage only the second of these.
A C20 fatty di-acid moiety attached to the backbone drives albumin binding, slowing renal clearance and extending the half-life to roughly five days — the basis for once-weekly dosing.
Dual agonism appears to be more than additive: GIP receptor activity contributes to insulin sensitivity and adipose-tissue handling of nutrients, while GLP-1 activity drives satiety, delayed gastric emptying and glucose-dependent insulin secretion. The SURPASS and SURMOUNT programmes were designed to test whether this translates into larger measurable effects than GLP-1 agonism alone.
Clinically it is marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management, in both cases as a weekly subcutaneous injection.
The studies
The tirzepatide evidence base rests on two large phase 3 programmes — SURPASS for glycaemic control and SURMOUNT for weight management — plus dedicated sleep-apnoea and cardiovascular work. Each card states the objective, the design, the headline result and the source publication.
SURPASS programme
SURPASS-2 — tirzepatide versus semaglutide in type 2 diabetes
To compare the efficacy and safety of once-weekly tirzepatide (5, 10 and 15 mg) against once-weekly semaglutide 1 mg in adults with type 2 diabetes inadequately controlled on metformin.
1,879 adults with type 2 diabetes · 40 weeks · randomised, open-label, active-comparator controlled
- 2.30%
- HbA1c reduction (15 mg)
- 11.2 kg
- Mean weight loss (15 mg)
- 46%
- Reached HbA1c < 5.7%
vs 1.86% semaglutide
vs 5.7 kg semaglutide
on 15 mg vs 19% semaglutide
- SURPASS-2 was the first head-to-head trial showing a dual GIP/GLP-1 agonist outperforming a GLP-1-only comparator on both glucose and weight endpoints.
- The effect was dose-dependent across the 5, 10 and 15 mg arms.
- Gastrointestinal adverse events were the most common issue in both arms and were broadly comparable in frequency.
SURPASS-3 — tirzepatide versus long-acting insulin
To compare weekly tirzepatide with titrated daily insulin glargine in adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor.
Adults with poorly controlled type 2 diabetes · 52 weeks · randomised, open-label, active-comparator controlled
- up to 93%
- Reached HbA1c < 7.0%
- −7.5 to −12.9 kg
- Mean weight change
- Lower
- Hypoglycaemia risk
vs insulin glargine
insulin arm gained weight
vs titrated insulin
Benefits shown in the data
- Tirzepatide produced significantly greater HbA1c reductions than insulin glargine.
- Patients lost 7.5-12.9 kg instead of the weight gain typically seen with insulin therapy.
- Blood-sugar stability came with a lower rate of hypoglycaemia than titrated long-acting insulin.
- This trial is the clearest comparison of a dual incretin against the traditional insulin standard of care.
- The combination of better glycaemic control, weight loss and less hypoglycaemia is what drove the shift in treatment guidelines.
SURMOUNT programme
SURMOUNT-1 — obesity and weight management
To evaluate once-weekly tirzepatide for chronic weight management in adults with obesity, or overweight with at least one weight-related complication, and without diabetes.
2,539 adults · 72 weeks · randomised, double-blind, placebo-controlled
- 20.9%
- Mean weight loss (15 mg)
- 15.0%
- Mean weight loss (5 mg)
- 57%
- Participants losing ≥ 20% body weight
vs 3.1% placebo
vs 3.1% placebo
on 15 mg
- SURMOUNT-1 produced the largest average weight reduction recorded for a once-weekly injectable in a non-surgical trial at the time of publication.
- Waist circumference, blood pressure, insulin and lipid measures all improved alongside weight.
- Weight loss had not fully plateaued by week 72, suggesting the ceiling was not reached within the trial period.
SURMOUNT-1 three-year extension — diabetes prevention
To determine whether continued tirzepatide sustains weight loss and prevents participants with baseline prediabetes from progressing to type 2 diabetes.
SURMOUNT-1 participants with prediabetes at baseline · 176 weeks total · randomised, double-blind, placebo-controlled
- 94%
- Reduction in progression to type 2 diabetes
- 22.5%
- Weight loss at 72 weeks (15 mg)
- Maintained
- Weight loss over 3 years
vs placebo
≈24 kg
with continued treatment
Benefits shown in the data
- Continued weekly treatment maintained the large weight reduction achieved in the first 72 weeks.
- The risk of progressing from prediabetes to type 2 diabetes fell by 94% compared with placebo.
- This is the longest controlled human dataset for tirzepatide in a non-diabetic obese population.
- The prevention signal is the strongest published for any incretin to date, but depends on staying on treatment.
SURMOUNT-4 — what happens after withdrawal
To document body-weight changes when tirzepatide is discontinued, testing whether obesity management requires ongoing treatment or a single course.
Open-label tirzepatide for 36 weeks, then randomised double-blind withdrawal to placebo or continued tirzepatide for 52 weeks
- +14.8%
- Weight regained on placebo
- −5.5%
- Additional loss on continued dosing
within 52 weeks
over the same period
Benefits shown in the data
- Participants who stayed on weekly tirzepatide continued to lose weight rather than plateauing.
- The regain on withdrawal indicates the effect depends on persistent receptor activation rather than a durable reset.
- This is the key trial cited when clinicians describe obesity management as chronic rather than episodic.
SURMOUNT-5 — tirzepatide versus semaglutide for weight loss
To compare maximum-dose tirzepatide (15 mg) directly against maximum-dose semaglutide (2.4 mg) for weight loss in adults with obesity and without diabetes.
72 weeks · randomised, open-label, active-comparator controlled
- Significantly greater
- Total weight loss
- 72 weeks
- Duration
tirzepatide vs semaglutide
Benefits shown in the data
- Tirzepatide produced significantly more total weight loss than semaglutide over 72 weeks in a non-diabetic obese population.
- SURMOUNT-5 is the obesity-specific counterpart to SURPASS-2 and points to the GIP component as the source of the additional effect.
SURMOUNT-OSA — obstructive sleep apnoea
To determine whether tirzepatide reduces the severity of moderate-to-severe obstructive sleep apnoea in adults with obesity, both with and without concurrent CPAP therapy.
469 adults across two parallel trials · 52 weeks · randomised, double-blind, placebo-controlled
- up to 29.3 events/hr
- Reduction in apnoea-hypopnoea index
- 17.7% – 19.6%
- Mean weight reduction
- ~50%
- Participants reaching remission or mild OSA
vs 5.5 placebo
- SURMOUNT-OSA was the first trial to show a pharmacological agent meaningfully reducing sleep-apnoea severity rather than only managing symptoms mechanically.
- Benefit was seen both in participants using CPAP and those who were not.
- Improvements in hypoxic burden and patient-reported sleep disturbance tracked with the reduction in body weight.
SURPASS programme
SURPASS-CVOT — cardiovascular outcomes
To assess cardiovascular outcomes with tirzepatide compared with dulaglutide in adults with type 2 diabetes and established atherosclerotic cardiovascular disease.
13,299 adults · median follow-up ~4.5 years · randomised, double-blind, active-comparator controlled
- Non-inferior
- Primary MACE endpoint
- Lower
- All-cause mortality
- Greater reduction
- HbA1c and weight
vs dulaglutide
numerically vs comparator
vs dulaglutide
- SURPASS-CVOT compared tirzepatide against an active GLP-1 agonist rather than placebo — a more demanding design than most outcome trials.
- Cardiovascular safety was established alongside superior metabolic control.
- Read the primary publication directly for the full endpoint definitions before citing individual numbers.
Cardiovascular
Real-world cardiovascular outcomes (target-trial emulation)
To emulate a long-term cardiovascular outcomes trial using healthcare claims data, comparing tirzepatide against a cardiovascular-neutral comparator (sitagliptin).
Cohort study of 52,971 patients using real-world claims data · 1-year follow-up
- −32%
- Major adverse cardiovascular events
- Reduced
- Myocardial infarction
- ~3 months
- Event-curve separation
vs sitagliptin at 1 year
after initiation
Benefits shown in the data
- Adding tirzepatide was associated with a 32% reduction in major adverse cardiovascular events at one year.
- Heart attacks and all-cause mortality both fell, with the curves separating within about three months.
- This is observational claims data, not a randomised trial — it is consistent with the randomised evidence but cannot establish causation on its own.
Storage & handling
Tirzepatide research material is supplied as a lyophilised powder. Store sealed vials refrigerated or frozen, protected from light and moisture.
Reconstitute with bacteriostatic water added slowly down the inner wall of the vial; swirl gently until fully dissolved — do not shake.
Keep reconstituted solution at 2-8 °C and use within the stability window defined by your lab's standard operating procedures. Avoid repeated freeze-thaw cycles.
Side-effect profile and warnings
Across the trials tirzepatide showed a predictable, dose-dependent side-effect profile. These are the points the published literature and the approved product labels emphasise.
Gastrointestinal effects
The most common adverse events are nausea (17-22%), diarrhoea (13-16%) and vomiting (6-10%). They peak during the initial dose-escalation phase and typically subside as the dose stabilises.
Boxed warning — thyroid C-cell tumours
Like all incretin mimetics, tirzepatide carries a boxed warning for medullary thyroid carcinoma (MTC) based on rodent studies. It is contraindicated for anyone with a personal or family history of MTC or MEN 2 syndrome.
Weight regain after stopping
SURMOUNT-4 showed 14.8% of lost weight returning within a year of discontinuation, so the effect depends on continued dosing rather than a one-off course.
Research use only
Mounjaro and Zepbound are the approved medicines. Research vials are not the approved product. Peptides Lab SA (PTY) Ltd supplies compounds strictly for in-vitro research use.
All information on this page is provided for laboratory and educational reference only. Peptides Lab SA (PTY) Ltd supplies compounds strictly for in-vitro research use. Nothing here is medical advice, a dosing recommendation, or a claim of human safety or efficacy.