What is the comparator in SURPASS-CVOT and why was dulaglutide chosen?

Dulaglutide (Trulicity, a GLP-1 receptor agonist) was selected as the active comparator because it already has established cardiovascular outcome data from the REWIND trial (2019), in which it reduced MACE by 12% relative to placebo. Using an active comparator rather than placebo is ethically appropriate in a population already expected to benefit from a GLP-1 agent, and it tests whether tirzepatide's additional GIP agonism provides incremental cardiovascular benefit beyond GLP-1 alone.

What population is enrolled in SURPASS-CVOT?

Adults with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors. This is a higher-risk diabetic population, distinct from the non-diabetic population enrolled in SELECT and SURMOUNT-MMO.

What does a non-inferiority result vs dulaglutide mean in practice?

If tirzepatide meets non-inferiority against dulaglutide, it would confirm a cardiovascular safety profile at least as good as an established GLP-1 agent in the same population — supporting its use in T2DM without CV concern. Superiority over dulaglutide would be a landmark finding suggesting that dual GIP/GLP-1 agonism provides additional cardiovascular benefit beyond GLP-1 agonism alone.

How does SURPASS-CVOT relate to the SURPASS weight-loss trials?

The SURPASS programme comprises six Phase 3 trials (SURPASS-1 through SURPASS-6) testing tirzepatide for glycaemic control and weight loss in type 2 diabetes. SURPASS-CVOT is the dedicated cardiovascular outcomes arm, using the same tirzepatide doses (5 mg, 10 mg, 15 mg) used in the glycaemic trials to provide a complete benefit–risk profile across metabolic and cardiovascular outcomes.

When is SURPASS-CVOT expected to report?

Eli Lilly has indicated primary results from SURPASS-CVOT are expected in the 2025–2026 timeframe, though the exact date depends on event accrual. As of mid-2026, full primary results have not been publicly disclosed in a peer-reviewed publication.

SURPASS-CVOT: Tirzepatide vs Dulaglutide Cardiovascular Outcomes in T2DM

Trial in one paragraph

SURPASS-CVOT (NCT04255433) is a Phase 3, randomised, double-blind, active-controlled cardiovascular outcomes trial comparing tirzepatide (5 mg, 10 mg, and 15 mg once weekly) with dulaglutide (1.5 mg once weekly) in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. The primary endpoint is a non-inferiority assessment of three-component MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) with a pre-specified superiority test if non-inferiority is demonstrated. By using dulaglutide — a GLP-1 receptor agonist with a proven 12% MACE reduction in its own REWIND trial — as the comparator, SURPASS-CVOT directly tests whether tirzepatide's additional GIP receptor agonism provides incremental cardiovascular benefit over GLP-1 agonism alone. As of mid-2026, the trial has completed enrolment and primary results are pending.

Design and population

SURPASS-CVOT was designed after the SURPASS glycaemic programme (SURPASS-1 through -5) demonstrated tirzepatide's superiority over established diabetes comparators for HbA1c reduction and weight loss, including a head-to-head superiority over semaglutide 1 mg (the diabetes dose) in SURPASS-2. The CVOT was a regulatory requirement for the T2DM cardiovascular safety dossier and is also positioned as a potential label-expansion study for a cardiovascular risk-reduction indication.

Randomisation in SURPASS-CVOT is 1:1:1:1, allocating participants to tirzepatide 5 mg, 10 mg, or 15 mg weekly, or dulaglutide 1.5 mg weekly, each with blinded matching injections to maintain double-blind design. All tirzepatide arms are dose-escalated from 2.5 mg using the standard four-week titration schedule. Background glucose-lowering therapy (metformin, SGLT2 inhibitors, DPP-4 inhibitors) is allowed but held stable; insulin use is subject to protocol-specified adjustment rules to prevent hypoglycaemia confounding.

The population includes adults with type 2 diabetes (HbA1c 7.0–10.5%; 53–91 mmol/mol), aged ≥40 with established cardiovascular disease (MI, stroke, PAD) or aged ≥50 with two or more cardiovascular risk factors. The estimated enrolment is approximately 12,500–14,000 participants — a larger sample than SELECT, reflecting the active-controlled design's need for sufficient events to achieve both non-inferiority and superiority with adequate power.

Primary endpoint and statistical plan

The primary endpoint is the time to first confirmed MACE event in the pooled tirzepatide arms (5 mg + 10 mg + 15 mg combined) versus dulaglutide, analysed using a Cox proportional hazards model with non-inferiority margin defined as an upper 95% confidence interval bound of <1.30 for the hazard ratio. If non-inferiority is established, a pre-specified hierarchical superiority test is conducted against the same dulaglutide comparator. Individual tirzepatide dose arms are secondary analyses.

The use of dulaglutide rather than placebo is methodologically important but also creates interpretative complexity. Dulaglutide itself reduces MACE by approximately 12% versus placebo in the REWIND trial diabetic population (HR 0.88, 95% CI 0.79–0.99). If tirzepatide demonstrates non-inferiority to dulaglutide, the absolute cardiovascular risk versus true placebo is not directly estimable from SURPASS-CVOT alone — it requires indirect estimation using REWIND as the placebo-controlled anchor.

Secondary endpoints

Secondary pre-specified endpoints include:

Cardiovascular death alone
Non-fatal MI alone
Non-fatal stroke alone
Hospitalisation for heart failure
All-cause mortality
HbA1c change from baseline
Body weight change from baseline
Renal outcomes (eGFR decline, macroalbuminuria)
Composite cardiorenal endpoint (CV death, HF hospitalisation, renal progression)

The renal secondary endpoint is a notable addition: tirzepatide's effects on blood pressure, weight, and glycaemia predict a nephroprotective effect, and demonstrating this in SURPASS-CVOT would add a cardiorenal dimension to the label analogous to SGLT2 inhibitor data.

Safety signals

The safety experience across the SURPASS programme (SURPASS-1 through SURPASS-5; combined n >6,000) establishes tirzepatide's class-consistent GI adverse event profile in a diabetic population. Nausea and diarrhoea are the most common complaints and are most prominent during the initial four-week dose increments. Hypoglycaemia is a specific concern in the diabetic CVOT population, particularly in participants on background insulin, and the protocol's insulin-adjustment rules are designed to limit confounded events. In SURPASS-4 (tirzepatide vs. insulin glargine), any hypoglycaemia was substantially lower with all tirzepatide doses versus insulin glargine.

Cholelithiasis rates of approximately 0.5–1% are consistent with GLP-1-class experience and weight-loss-related biliary changes. Pancreatitis was rare across SURPASS trials. Diabetic retinopathy worsening — a known GLP-1-class concern in patients with pre-existing advanced retinopathy who undergo rapid glycaemic improvement — was observed at low rates in SURPASS trials and is a monitored endpoint in SURPASS-CVOT. No unexpected cardiac, renal, or hepatic safety signals have emerged from the SURPASS programme.

Outcomes table

Parameter	Tirzepatide (SURPASS programme)	Dulaglutide comparator (REWIND ref)
Primary MACE (SURPASS-CVOT)	Pending	Active comparator (in-trial)
MACE vs placebo (dulaglutide REWIND)	—	HR 0.88 (0.79–0.99), p=0.026
HbA1c reduction at max dose (SURPASS-1)	−2.11% (15 mg) vs. −0.04% placebo	—
Weight loss vs semaglutide 1 mg (SURPASS-2)	−12.4 kg (15 mg) vs −6.2 kg sema 1 mg	—
SBP reduction (SURPASS-2, 15 mg)	−7.6 mmHg vs −4.0 mmHg sema 1 mg	—
LDL-C change (SURPASS-2, 15 mg)	−12.8% vs −7.3% sema 1 mg	—
Estimated enrolment	~12,500–14,000 participants

Methodological strengths and caveats

SURPASS-CVOT's use of an active comparator is both a strength and a complication. Using dulaglutide rather than placebo is ethically appropriate and clinically relevant — in 2026, standard of care in high-risk T2DM includes a GLP-1 agent or SGLT2 inhibitor — but it makes the comparison harder to interpret for regulatory and formulary purposes. If the trial shows non-inferiority but not superiority, the question becomes whether tirzepatide is meaningfully different from dulaglutide and whether the NICE cost-effectiveness calculation supports its preferential use.

A superiority result would be methodologically landmark: it would be the first cardiovascular outcomes trial to demonstrate that adding GIP agonism to GLP-1 agonism provides incremental MACE reduction in T2DM — a mechanistic finding with broad implications for dual and triple agonist drug development. Conversely, non-inferiority without superiority would still support tirzepatide's use in T2DM cardiovascular prevention but would not differentiate it from dulaglutide on cardiovascular grounds alone.

UK implications

Tirzepatide holds NICE approval for T2DM (TA924, multiple sub-indications) and obesity (TA1026). SURPASS-CVOT data will feed directly into future NICE technology appraisal reviews for T2DM. A non-inferiority result vs. dulaglutide would support existing prescribing confidence; a superiority result could accelerate NICE guidance recommending tirzepatide as a preferred agent over GLP-1-only alternatives in high-cardiovascular-risk T2DM.

NHS England's position is notable: integrated care boards currently balance the acquisition costs of tirzepatide, semaglutide, and dulaglutide within diabetes budgets. SURPASS-CVOT data will influence this balance. If tirzepatide demonstrates cardiovascular superiority over dulaglutide, the cost-per-event-prevented calculation may justify its premium pricing in the secondary prevention diabetic population, similar to the SGLT2 inhibitor experience with EMPA-REG OUTCOME (empagliflozin) and DECLARE-TIMI 58 (dapagliflozin). Formulary decisions are expected within 12–18 months of primary publication.

Frequently asked questions

What is the comparator in SURPASS-CVOT and why was dulaglutide chosen?: Dulaglutide (Trulicity, a GLP-1 receptor agonist) was selected as the active comparator because it already has established cardiovascular outcome data from the REWIND trial (2019), in which it reduced MACE by 12% relative to placebo. Using an active comparator rather than placebo is ethically appropriate in a population already expected to benefit from a GLP-1 agent, and it tests whether tirzepatide's additional GIP agonism provides incremental cardiovascular benefit beyond GLP-1 alone.
What population is enrolled in SURPASS-CVOT?: Adults with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors. This is a higher-risk diabetic population, distinct from the non-diabetic population enrolled in SELECT and SURMOUNT-MMO.
What does a non-inferiority result vs dulaglutide mean in practice?: If tirzepatide meets non-inferiority against dulaglutide, it would confirm a cardiovascular safety profile at least as good as an established GLP-1 agent in the same population — supporting its use in T2DM without CV concern. Superiority over dulaglutide would be a landmark finding suggesting that dual GIP/GLP-1 agonism provides additional cardiovascular benefit beyond GLP-1 agonism alone.
How does SURPASS-CVOT relate to the SURPASS weight-loss trials?: The SURPASS programme comprises six Phase 3 trials (SURPASS-1 through SURPASS-6) testing tirzepatide for glycaemic control and weight loss in type 2 diabetes. SURPASS-CVOT is the dedicated cardiovascular outcomes arm, using the same tirzepatide doses (5 mg, 10 mg, 15 mg) used in the glycaemic trials to provide a complete benefit–risk profile across metabolic and cardiovascular outcomes.
When is SURPASS-CVOT expected to report?: Eli Lilly has indicated primary results from SURPASS-CVOT are expected in the 2025–2026 timeframe, though the exact date depends on event accrual. As of mid-2026, full primary results have not been publicly disclosed in a peer-reviewed publication.