SURMOUNT-MMO: tirzepatide cardiovascular outcomes trial

Trial in one paragraph

SURMOUNT-MMO (A Study of Tirzepatide on the Reduction of Morbidity and Mortality in Adults With Obesity; NCT05556512) is a Phase 3, randomised, double-blind, placebo-controlled, event-driven cardiovascular outcomes trial sponsored by Eli Lilly. It is evaluating whether tirzepatide — the dual GIP and GLP-1 receptor agonist licensed as Mounjaro — reduces major adverse cardiovascular events (MACE) in adults with obesity and established cardiovascular disease who do not have diabetes. The trial mirrors the population and primary endpoint structure of the SELECT trial for semaglutide 2.4 mg, enabling an indirect comparison of the two most advanced weight-management agents. As of mid-2026, SURMOUNT-MMO is ongoing, with primary results expected in 2026–2027 once the pre-specified number of MACE events has been accrued.

Design and population

SURMOUNT-MMO is designed as a superiority trial with a three-component MACE primary endpoint. Randomisation is 1:1 (tirzepatide vs. matched placebo) with stratification by region, BMI category, and heart failure status. The tirzepatide arm uses the same dose-escalation schedule as the obesity indication: starting at 2.5 mg once weekly and escalating at four-week intervals to the maintenance dose of 15 mg weekly (the highest approved obesity dose). Participants may be dose-reduced to 10 mg or 5 mg for tolerability, consistent with clinical practice.

Key inclusion criteria: age ≥45 years; BMI ≥27 kg/m²; established cardiovascular disease (prior MI, prior stroke, or symptomatic peripheral arterial disease); absence of type 2 diabetes at screening (HbA1c <6.5%, or <48 mmol/mol). The exclusion of diabetes at baseline directly parallels the SELECT design, which is essential for future head-to-head contextualisation of the two molecules. The minimum enrolment target and planned follow-up have not been fully disclosed in the public protocol summary, but the event-driven design means follow-up will extend until enough cardiovascular events accumulate to power the primary analysis — likely several years of exposure.

The trial is being conducted at several hundred sites across multiple continents, including European and UK centres. The UK sites contribute a non-diabetic, cardiovascular-risk population that reflects NHS secondary prevention practice, adding real-world generalisability to the eventual results.

Primary endpoint and statistical plan

The primary endpoint — time to first occurrence of MACE (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) — is adjudicated by an independent clinical events committee blinded to treatment allocation. The statistical design uses a log-rank test with pre-specified superiority and non-inferiority boundaries, powered to detect a reduction of approximately 17–20% in MACE risk. This magnitude was chosen based on the SELECT trial's 20% relative risk reduction with semaglutide and the expectation that tirzepatide's greater weight-loss efficacy might produce a comparable or modestly superior cardiovascular benefit.

As of May 2026, no interim primary outcome results have been publicly reported. Eli Lilly has disclosed that the trial remains on track for readout, and no safety concerns have led to an early halt. Data monitoring committee reviews are conducted periodically under pre-specified O'Brien–Fleming stopping boundaries for both efficacy and harm. Interim signals from metabolic sub-studies — including improvements in systolic blood pressure (~6 mmHg), LDL-C, triglycerides, and CRP consistent with those seen in SURMOUNT-1 — provide mechanistic plausibility for a positive primary outcome, but sub-study data do not substitute for the powered MACE endpoint.

Secondary endpoints

Pre-specified secondary endpoints include:

• All-cause mortality
• CV death alone
• Non-fatal MI alone
• Non-fatal stroke alone
• Hospitalisation for heart failure or urgent heart-failure visit
• Changes in body weight, waist circumference, and BMI
• Glycaemic outcomes and incident type 2 diabetes prevention
• Patient-reported outcomes including physical function and health-related quality of life

The heart-failure hospitalisation endpoint is particularly watched given that SURMOUNT-HF (a separate tirzepatide trial in heart failure with preserved ejection fraction) reported significant improvements in the Kansas City Cardiomyopathy Questionnaire and six-minute walk distance — data that primes the hypothesis that tirzepatide may reduce HF exacerbations in the SURMOUNT-MMO population as a secondary finding.

Safety signals to date

The safety profile expected in SURMOUNT-MMO is anchored to the established tirzepatide experience across SURMOUNT-1 through SURMOUNT-4 and the SURPASS programme. Dominant adverse events are gastrointestinal — nausea, diarrhoea, vomiting, and constipation — and are most prevalent during dose escalation. These events drove discontinuation rates of 4–6% in earlier trials at 15 mg, lower than those seen with semaglutide 2.4 mg in SELECT (16.6% discontinuation for adverse events), which may reflect tirzepatide's slower titration or pharmacological differences.

Cholelithiasis is a class and weight-loss-related risk. Pancreatitis has been observed at very low rates (below 0.3%) across tirzepatide trials. No excess thyroid C-cell tumour signal has emerged in human surveillance, though the preclinical rodent signal means ongoing monitoring continues. No cardiac arrhythmia concern has emerged.

Outcomes table

Methodological strengths and caveats

SURMOUNT-MMO benefits from the lessons of SELECT: its non-diabetic enrolment criterion, 1:1 randomisation, and adjudicated MACE endpoint are all methodologically robust. The parallel design to SELECT provides the best available platform for an indirect comparison of two distinct weight-management molecules in the same clinical population, even though a true head-to-head RCT between tirzepatide and semaglutide for cardiovascular outcomes does not exist and is unlikely to be conducted.

Key caveats: the data are not yet available, and all interim sub-study metrics (blood pressure, lipids, CRP) are surrogates that have historically produced false signals in cardiovascular prediction. Tirzepatide produces approximately 5–7 percentage points more weight loss than semaglutide 2.4 mg in head-to-head obesity trials, but whether this translates proportionally to MACE reduction is mechanistically uncertain — the relationship between weight loss and cardiovascular events is not linear, and other mechanisms (direct cardiac remodelling, blood pressure, glycaemia) carry independent weight. The SELECT trial's 20% MACE reduction serves as the benchmark: SURMOUNT-MMO powered at a similar relative risk reduction may not detect additional superiority.

UK implications

Tirzepatide (Mounjaro) is approved by the MHRA for obesity management in the UK, having received its obesity indication under NICE TA1026 with specialist prescribing conditions. The cardiovascular indication is a separate regulatory matter and will require a dedicated MHRA submission once SURMOUNT-MMO primary data are available. If tirzepatide achieves a MACE reduction comparable to — or larger than — semaglutide's 20%, it could join semaglutide 2.4 mg as the second obesity medicine with an approved cardiovascular risk-reduction label in the UK, changing prescribing economics and commissioning pathways in secondary prevention.

The NICE technology appraisal process for a new cardiovascular indication would assess the incremental cost-effectiveness ratio against existing standard of care, including semaglutide 2.4 mg for the same SELECT-eligible population. NHS formulary decisions will depend on the magnitude of benefit, the pricing of tirzepatide vs. semaglutide, and whether integrated care boards are prepared to fund a second agent in the same mechanistic class for secondary prevention. Clinicians and commissioners should monitor Eli Lilly's readout announcements in late 2026 and early 2027.

Related: Tirzepatide profile · Mounjaro (tirzepatide) · SELECT trial (semaglutide) · SURPASS-CVOT (tirzepatide in T2DM) · GLP-1 landscape 2026

Frequently asked questions

What is the primary endpoint of SURMOUNT-MMO?

Major adverse cardiovascular events (MACE): the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This mirrors the primary endpoint used in the SELECT trial for semaglutide.

Who is enrolled in SURMOUNT-MMO?

Adults with obesity (BMI ≥27) and established cardiovascular disease but without type 2 diabetes at enrolment. This population mirrors the SELECT trial design, allowing the eventual results to be compared against semaglutide 2.4 mg's cardiovascular outcomes.

When is the primary readout expected for SURMOUNT-MMO?

Eli Lilly has indicated a primary cardiovascular outcomes readout in 2026–2027. The trial is event-driven, so the exact timing depends on accrual of the pre-specified number of MACE events.

How does tirzepatide differ mechanistically from semaglutide in the cardiovascular context?

Tirzepatide is a dual GIP/GLP-1 receptor agonist, whereas semaglutide is a selective GLP-1 receptor agonist. Tirzepatide produces greater weight loss in obesity trials (SURMOUNT-1: up to 22.5% vs. semaglutide's ~15% in STEP-1) and may have additional cardioprotective pathways via GIP receptor agonism, including effects on lipid metabolism and adipose tissue inflammation. Whether this translates to superior MACE reduction is the central question SURMOUNT-MMO will answer.

Is tirzepatide currently approved for cardiovascular risk reduction in the UK?

As of mid-2026, tirzepatide (Mounjaro) holds MHRA approval for obesity management (TA1026) and type 2 diabetes. A cardiovascular risk-reduction indication awaits the primary outcome data from SURMOUNT-MMO.