The Lancet OCTOBER 18, 2021

Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4)

Stefano Del Prato, Steven E. Kahn, Imre Pavo, et al.

Bottom Line

In patients with type 2 diabetes and high cardiovascular risk, once-weekly tirzepatide demonstrated superior glycemic control and weight reduction compared to titrated insulin glargine over 52 weeks, with no increased cardiovascular risk.

Key Findings

1. Tirzepatide achieved superior reductions in HbA1c at 52 weeks compared to insulin glargine, with mean reductions of 2.43% (10 mg) and 2.58% (15 mg) versus 1.44% with insulin glargine.

2. Tirzepatide induced significant dose-dependent weight loss (ranging from -7.1 kg to -11.7 kg) compared to a mean weight gain of 1.9 kg in the insulin glargine group.

3. The incidence of level 2 hypoglycemia (<54 mg/dL) or severe hypoglycemia was notably lower with tirzepatide (6–9%) compared to insulin glargine (19%).

4. Adjudicated MACE-4 events occurred in 109 participants, with no evidence of increased cardiovascular risk for tirzepatide compared to insulin glargine (hazard ratio 0.74; 95% CI 0.51–1.08).

5. Gastrointestinal adverse events (nausea, diarrhea, vomiting) were more frequent in tirzepatide-treated groups compared to the insulin glargine arm, primarily during the dose-escalation phase.

Study Design

Design

RCT

Open-Label

Sample

1,995

Patients

Duration

52 wk (primary), up to 104 wk

Median

Setting

Multicenter, international

Population Adults with type 2 diabetes inadequately controlled on 1-3 oral antihyperglycemic medications and increased cardiovascular risk

Intervention Tirzepatide (5 mg, 10 mg, or 15 mg) administered subcutaneously once weekly

Comparator Titrated insulin glargine administered once daily

Outcome Change in HbA1c from baseline to week 52

Study Limitations

• The study was conducted as an open-label trial, which may introduce bias in subjective reporting, particularly regarding adverse events.

• The primary outcome was focused on glycemic control (HbA1c reduction) rather than cardiovascular morbidity, though the study was designed to assess cardiovascular safety through MACE accrual.

• The duration of the cardiovascular safety assessment may be insufficient compared to dedicated, long-term cardiovascular outcomes trials.

Clinical Significance

Tirzepatide provides a highly effective therapeutic option for patients with inadequately controlled type 2 diabetes and established high cardiovascular risk, offering superior glycemic efficacy and weight management with a lower risk of hypoglycemia compared to basal insulin therapy.

Historical Context

SURPASS-4 was the fifth and final global Phase 3 registration trial for tirzepatide, a first-in-class dual GIP and GLP-1 receptor agonist, designed specifically to evaluate both glycemic efficacy and cardiovascular safety in a high-risk patient population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Tirzepatide is described as a 'twincretin' because it targets both GIP and GLP-1 receptors. How does the physiological role of GIP (glucose-dependent insulinotropic polypeptide) differ from GLP-1, and why is their combination expected to be more effective than GLP-1 alone for glycemic control?

Key Response

While both are incretins that stimulate insulin secretion in a glucose-dependent manner, GIP also plays a significant role in lipid metabolism and has potentially protective effects against the gastrointestinal side effects of GLP-1. In the brain, GIP receptors are found in areas regulating energy balance; synergism between GIP and GLP-1 is thought to enhance satiety and energy expenditure more than either hormone alone, leading to the superior HbA1c and weight reduction seen in SURPASS-4.

Resident

In SURPASS-4, patients in the insulin glargine arm followed a treat-to-target protocol aiming for a fasting blood glucose of <100 mg/dL. Despite this, the tirzepatide arms achieved lower mean HbA1c levels with significantly less hypoglycemia. How should this affect your clinical reasoning when choosing between a GLP-1/GIP agonist and basal insulin for a patient with an HbA1c >9.0%?

Key Response

The study demonstrates that tirzepatide is more effective than even well-titrated basal insulin at lowering HbA1c, while simultaneously avoiding the traditional 'trade-off' of increased hypoglycemia and weight gain. For most T2D patients, even those with high baseline HbA1c, tirzepatide should now likely be considered prior to insulin initiation, unless there is evidence of symptomatic catabolism (insulinopenia).

Fellow

SURPASS-4 reported exploratory renal outcomes, including a lower rate of decline in eGFR and reduced progression to macroalbuminuria for tirzepatide versus insulin glargine. Considering the high CV risk of this cohort, how do these findings integrate with current SGLT2 inhibitor data for renal protection?

Key Response

While SGLT2 inhibitors remain the gold standard for renal protection (hemodynamic effect), the GLP-1/GIP class appears to offer complementary 'top-down' benefits by reducing inflammatory markers and oxidative stress. SURPASS-4 suggests tirzepatide provides significant renoprotection in a high-risk CV population, potentially making it a primary adjunct to SGLT2i therapy to arrest the progression of diabetic kidney disease through independent mechanisms.

Attending

The SURPASS-4 trial used a cardiovascular non-inferiority design for safety. Given that the hazard ratio for MACE-4 was 0.74 (95% CI 0.54-1.03) when compared to insulin glargine, does this evidence allow us to treat tirzepatide as a cardioprotective agent equivalent to semaglutide or liraglutide in patients with established CVD?

Key Response

Strictly speaking, no. While the point estimate (0.74) is highly suggestive of a CV benefit, the confidence interval crossed 1.0, and the trial was powered for non-inferiority against a margin of 1.8, not for superiority. Until the dedicated CVOT (SURPASS-CVOT) is completed, tirzepatide is proven 'CV safe' rather than 'CV protective,' unlike semaglutide (SUSTAIN-6) or liraglutide (LEADER) which have established MACE reduction evidence.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the implications of the open-label design of SURPASS-4. How might the lack of blinding influence the 'treat-to-target' titration of insulin glargine and the subsequent interpretation of the efficacy of tirzepatide?

Key Response

Open-label designs can introduce 'performance bias.' Clinicians and patients knew which treatment they were receiving; this may lead to less aggressive insulin titration in the comparator arm due to 'insulin fatigue' or fear of hypoglycemia, potentially exaggerating the efficacy gap. Furthermore, the reporting of subjective gastrointestinal adverse events is more prone to expectation bias in an unblinded study compared to a double-blinded trial.

Journal Editor

A major criticism of SURPASS-4 is the choice of insulin glargine as the active comparator. Does this comparison offer sufficient clinical utility given the current standard of care, or does it represent a 'straw man' argument designed to favor the newer, more expensive agent?

Key Response

While insulin glargine was a standard comparator for years, modern guidelines (ADA/EASD) prioritize GLP-1 RAs before insulin. An editor would flag that a comparison against a GLP-1 RA (like semaglutide, as seen in SURPASS-2) provides more actionable data for current practice. However, since many high-risk patients are still transitioned to insulin, the data remains relevant for showing that insulin is no longer the 'most potent' option for glycemic control.

Guideline Committee

The 2024 ADA Standards of Care recommend GLP-1 RAs with proven CVD benefit for patients with established ASCVD. Based on SURPASS-4, should Tirzepatide be elevated to the same 'Level A' recommendation for MACE reduction as Semaglutide, or should it remain secondary for CV-risk patients until SURPASS-CVOT results are published?

Key Response

Current guidelines require 'proven' benefit for the top-tier recommendation. SURPASS-4 established safety (non-inferiority) but failed to reach statistical significance for MACE reduction (superiority). Therefore, guidelines should maintain the distinction: GLP-1 RAs with proven benefit (Semaglutide/Liraglutide/Dulaglutide) are preferred for MACE reduction, while Tirzepatide is preferred for patients where the primary goals are superior glycemic control and weight loss.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin

Population

T2DM patients with established cardiovascular disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin was associated with a lower rate of cardiovascular death and hospitalization for heart failure compared to placebo.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide significantly reduced the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to placebo.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide demonstrated non-inferiority and superiority in reducing cardiovascular events compared to placebo.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis