The Lancet November 13, 2021

Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

Stefano Del Prato, Steven E Kahn, Imre Pavo, Govinda J Weerakkody, Zhengyu Yang, John Doupis, et al.

Bottom Line

In adults with type 2 diabetes and high cardiovascular risk, once-weekly tirzepatide demonstrated superior reductions in HbA1c and body weight with lower incidences of hypoglycemia compared to titrated daily insulin glargine, without increasing cardiovascular risk.

Key Findings

1. At 52 weeks, mean HbA1c decreased from baseline by 2.24%, 2.43%, and 2.58% with tirzepatide (5 mg, 10 mg, and 15 mg respectively), compared to a 1.44% decrease with insulin glargine (estimated treatment difference for 15 mg vs glargine: -1.14%; p<0.0001).

2. Tirzepatide resulted in dose-dependent reductions in body weight at 52 weeks (up to a mean loss of 11.7 kg with the 15 mg dose), whereas participants taking insulin glargine experienced a mean weight gain of 1.9 kg.

3. The incidence of clinically significant or severe hypoglycemia (blood glucose <54 mg/dL) was markedly lower in the tirzepatide groups (6% to 9%) compared to the insulin glargine group (19%).

4. Tirzepatide did not increase the risk of major adverse cardiovascular events (MACE-4: cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina), with an adjudicated hazard ratio of 0.74 (95% CI 0.51-1.08) compared to insulin glargine.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

2,002

Patients

Duration

52 weeks

Median

Setting

Multicenter, global

Population Adults (≥18 years) with inadequately controlled type 2 diabetes (HbA1c 7.5-10.5%), a BMI ≥25 kg/m2, and established cardiovascular disease or high risk of cardiovascular events, treated with 1 to 3 oral glucose-lowering medications.

Intervention Subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) injected once weekly.

Comparator Subcutaneous insulin glargine (100 U/mL) injected once daily, titrated to target a fasting blood glucose of <100 mg/dL.

Outcome Change in glycated hemoglobin (HbA1c) from baseline to 52 weeks (assessed first for non-inferiority with a 0.3% boundary, followed by superiority).

Study Limitations

• The open-label design of the trial may have introduced bias, particularly regarding subjective reporting of adverse events and patient or investigator decisions regarding treatment discontinuation.

• The study was powered to demonstrate cardiovascular safety (non-inferiority by ruling out a hazard ratio > 1.3), not to definitively prove cardiovascular superiority or long-term outcomes benefit.

• Higher rates of gastrointestinal adverse events (nausea, diarrhea, vomiting) in the tirzepatide arms contributed to higher treatment discontinuation rates during the dose-escalation phase compared to the well-tolerated insulin glargine.

Clinical Significance

SURPASS-4 confirmed that the novel dual GIP/GLP-1 receptor agonist tirzepatide is highly efficacious for glycemic control and weight management in patients with advanced type 2 diabetes and high cardiovascular risk. By vastly outperforming basal insulin—a traditional gold standard for refractory hyperglycemia—while circumventing the weight gain and hypoglycemia typically associated with insulin therapy, tirzepatide offered a profound paradigm shift. Crucially, the trial fulfilled regulatory mandates for cardiovascular safety, clearing the pathway for its widespread clinical use prior to the completion of dedicated, multi-year cardiovascular outcome trials (CVOTs).

Historical Context

The treatment landscape for type 2 diabetes shifted significantly in the 2010s from a purely glucocentric approach to one prioritizing cardiovascular risk reduction, largely driven by the proven benefits of GLP-1 receptor agonists and SGLT2 inhibitors. Building upon the success of mono-incretin therapies, tirzepatide was engineered as the first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. The SURPASS clinical program was designed to systematically compare tirzepatide against various standards of care. SURPASS-4 was specifically tasked with evaluating the drug against a potent active comparator (insulin glargine) in a high-risk cardiovascular population to satisfy the FDA's 2008 post-rosiglitazone requirements for pre-approval cardiovascular safety profiling.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Tirzepatide is a dual GIP and GLP-1 receptor agonist. How does the addition of GIP agonism theoretically enhance the effects of GLP-1 alone on glycemic control and weight loss in type 2 diabetes?

Key Response

GIP and GLP-1 are incretin hormones. While GLP-1 decreases appetite, slows gastric emptying, and stimulates glucose-dependent insulin release, GIP acts synergistically to further enhance insulin secretion. GIP may also have direct effects on adipose tissue to improve insulin sensitivity and lipid buffering, while potentially mitigating GLP-1 induced nausea, allowing for higher dosing and greater weight loss.

Resident

For a patient with T2D, an HbA1c of 9.2%, and a history of myocardial infarction, SURPASS-4 suggests tirzepatide over basal insulin. However, considering side effect profiles, what are the primary adverse events you must counsel this patient about, and how do you manage the titration schedule to minimize them?

Key Response

The primary adverse events of tirzepatide are gastrointestinal (nausea, vomiting, diarrhea). Residents must know to start at a low dose (2.5 mg once weekly) and escalate slowly (by 2.5 mg every 4 weeks) to mitigate GI distress, contrasting this with the risk of hypoglycemia and weight gain associated with insulin glargine.

Fellow

SURPASS-4 demonstrated no increased cardiovascular risk, with a hazard ratio for MACE-4 of 0.74. How does the cardiovascular safety and potential benefit profile of dual GIP/GLP-1 agonism compare mechanistically and clinically with established GLP-1 RAs and SGLT2 inhibitors in high-risk patients?

Key Response

Fellows should integrate this with SUSTAIN-6 and EMPA-REG. While GLP-1 RAs reduce atherothrombotic events and SGLT2is reduce heart failure/CKD progression, the SURPASS-4 CV data was a safety endpoint (non-inferiority). The mechanistic debate revolves around whether GIP provides additional CV benefit beyond GLP-1's known anti-atherosclerotic effects, pending SURPASS-CVOT results.

Attending

With SURPASS-4 showing superior HbA1c and weight reductions compared to titrated basal insulin, should we abandon the traditional paradigm of initiating basal insulin in patients with long-standing T2D and inadequate oral therapy? When would basal insulin still be the preferred next step?

Key Response

Attendings must weigh paradigm shifts against practicalities. While tirzepatide is superior for weight, HbA1c, and avoiding hypoglycemia, basal insulin remains necessary for patients with severe symptomatic hyperglycemia (catabolism or weight loss), suspected insulinopenia (late-stage beta-cell failure), or when cost and access preclude incretin use.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The SURPASS-4 trial utilized an open-label design for the treatment assignment. How might this lack of blinding introduce bias in both the titration of the comparator (insulin glargine) and the reporting of subjective adverse events, and what statistical or design steps can mitigate this?

Key Response

Open-label designs risk performance bias. Investigators might subconsciously under-titrate glargine to avoid hypoglycemia, artificially inflating tirzepatide's efficacy. Subjective AEs might also be over-reported. Mitigation involves using algorithmic, treat-to-target forced titration for glargine and blinded independent adjudication of hard endpoints.

Journal Editor

Given the relatively short duration (median 85 weeks) and event-driven nature, how does the high dropout rate or premature treatment discontinuation due to GI adverse events in the tirzepatide arms threaten the validity of the intention-to-treat analyses for CV safety?

Key Response

A rigorous reviewer would flag that high discontinuation rates (up to 11% in the highest tirzepatide arm vs 3% for glargine) can dilute the treatment effect in an ITT analysis, potentially biasing the results toward the null (non-inferiority). If patients stop the drug, adverse CV events might normalize between groups, making an unsafe drug appear safe.

Guideline Committee

Based on SURPASS-4, how should the ADA/EASD guidelines reposition dual GIP/GLP-1 receptor agonists in the treatment algorithm for patients with high ASCVD risk, and does the evidence warrant a distinct tier separating them from single GLP-1 RAs?

Key Response

Current ADA guidelines recommend GLP-1 RAs or SGLT2is for patients with high ASCVD risk independently of baseline HbA1c. The committee must decide if tirzepatide's superior glycemic/weight efficacy justifies prioritizing it over GLP-1 RAs, or if the lack of a completed superiority CVOT means it should remain grouped generally under highly effective incretins pending more data.

Clinical Landscape

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