The Lancet August 14, 2021

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial

Bernhard Ludvik, Francesco Giorgino, Esteban Jódar, Juan P Frias, Laura Fernández Landó, Katelyn Brown, Ross Bray, Ángel Rodríguez

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Bottom Line

In patients with type 2 diabetes inadequately controlled on metformin (with or without an SGLT2 inhibitor), once-weekly tirzepatide was superior to titrated daily insulin degludec in reducing HbA1c and body weight over 52 weeks, with a lower risk of hypoglycemia.

Key Findings

1. At 52 weeks, all three doses of tirzepatide provided superior reductions in HbA1c compared to insulin degludec: -1.93% (5 mg), -2.20% (10 mg), and -2.37% (15 mg) versus -1.34% for degludec (estimated treatment difference ranging from -0.59% to -1.04%; p<0.0001 for all).

2. Tirzepatide resulted in significant, dose-dependent body weight reductions ranging from -7.5 kg (5 mg) to -12.9 kg (15 mg), compared to a weight gain of +2.3 kg in the insulin degludec arm.

3. A significantly higher proportion of patients treated with tirzepatide (up to 93%) achieved the HbA1c target of <7.0% compared to those on insulin degludec (61%).

4. Normoglycemia (HbA1c <5.7%) was achieved by 26% to 48% of participants treated with tirzepatide, compared to only 5% of those treated with insulin degludec.

5. The risk of clinically significant hypoglycemia (<54 mg/dL) was significantly lower in the tirzepatide groups (1% to 2%) compared to the insulin degludec group (7%).

6. Gastrointestinal adverse events (predominantly nausea, diarrhea, and vomiting) were the most frequent side effects with tirzepatide, mostly mild to moderate and occurring primarily during the initial dose-escalation phase.

Study Design

Design

RCT

Open-Label

Sample

1,444

Patients

Duration

52 wk

Median

Setting

13 countries

Population Adults (≥18 years) with type 2 diabetes inadequately controlled (baseline HbA1c 7.0-10.5%, BMI ≥25) on stable doses of metformin with or without an SGLT2 inhibitor, who were insulin-naive.

Intervention Once-weekly subcutaneous injection of tirzepatide (5 mg, 10 mg, or 15 mg), initiated at 2.5 mg and escalated by 2.5 mg every 4 weeks until the assigned dose was reached.

Comparator Once-daily subcutaneous injection of titrated insulin degludec, adjusted once weekly following a treat-to-target algorithm to a fasting blood glucose target of <90 mg/dL.

Outcome Non-inferiority of tirzepatide 10 mg and/or 15 mg versus insulin degludec in the mean change from baseline in HbA1c at 52 weeks.

Study Limitations

• The open-label design, necessitated by the visual and administrative differences between a once-weekly fixed-dose pen (tirzepatide) and a once-daily titratable pen (insulin degludec), introduces potential bias, particularly regarding subjective safety reporting.

• The 52-week duration is sufficient for assessing primary glycemic endpoints but too short to evaluate long-term microvascular or macrovascular cardiovascular outcomes.

• The efficacy of the active comparator (insulin degludec) depended on participant and investigator adherence to a treat-to-target titration algorithm, which can occasionally result in suboptimal insulin optimization compared to real-world intensive management.

• The study population was predominantly White, which may limit the generalizability of the findings to more diverse demographic groups with type 2 diabetes.

Clinical Significance

SURPASS-3 demonstrated that the dual GIP/GLP-1 receptor agonist tirzepatide is a highly efficacious alternative to basal insulin for patients with advanced type 2 diabetes failing oral therapies. Its ability to simultaneously drive profound reductions in HbA1c (frequently achieving normoglycemia) and substantial weight loss—while avoiding the weight gain and higher hypoglycemia risk characteristic of basal insulin—represents a major clinical paradigm shift. These findings strongly support prioritizing incretin-based dual agonists over insulin to achieve comprehensive metabolic and weight targets.

Historical Context

For decades, basal insulin has been the standard of care for patients with type 2 diabetes unable to achieve glycemic targets with oral medications alone. However, insulin therapy is frequently complicated by undesired weight gain and hypoglycemia. The advent of GLP-1 receptor agonists introduced a class of agents capable of lowering both glucose and weight. Tirzepatide, a first-in-class dual GIP and GLP-1 receptor agonist, was developed to synergistically build upon this incretin effect. The SURPASS clinical trial program was launched to rigorously test tirzepatide across the T2D disease spectrum. SURPASS-3 specifically addressed a pivotal clinical juncture—the need for injectable therapy escalation—by pitting tirzepatide directly against insulin degludec, challenging the traditional stepwise progression to basal insulin.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the dual GIP and GLP-1 receptor agonism of tirzepatide mechanistically provide an advantage over basal insulin degludec in terms of both glycemic control and weight management?

Key Response

GLP-1 slows gastric emptying, increases glucose-dependent insulin secretion, and decreases glucagon. GIP synergizes by further enhancing glucose-dependent insulin release and may directly impact adipose tissue to improve insulin sensitivity. Unlike exogenous basal insulin (degludec), which drives weight gain and carries a hypoglycemia risk independently of oral glucose intake, tirzepatide's effects are glucose-dependent and centrally suppress appetite, leading to weight loss and a lower hypoglycemia risk.

Resident

When managing a patient with T2D poorly controlled on metformin and an SGLT2 inhibitor, what specific patient characteristics and potential adverse effects would lead you to choose tirzepatide over initiating basal insulin like degludec, based on SURPASS-3?

Key Response

Tirzepatide is preferred in patients with comorbid obesity (given the significant weight loss observed) and those at high risk for hypoglycemia. However, residents must consider GI side effects (nausea, vomiting, diarrhea) which are common with tirzepatide. Degludec might be chosen if the patient cannot tolerate GI side effects, has severe symptomatic hyperglycemia requiring immediate reversal of catabolism, or has contraindications to incretins like a personal or family history of medullary thyroid cancer.

Fellow

The SURPASS-3 trial included a stratum of patients already on an SGLT2 inhibitor. How does the physiological pairing of a dual GIP/GLP-1 agonist with an SGLT2 inhibitor address the 'ominous octet' of T2D pathophysiology more comprehensively than pairing an SGLT2 inhibitor with basal insulin?

Key Response

Combining an SGLT2i (which induces glycosuria and reduces glucotoxicity) with tirzepatide targets multiple defects simultaneously: pancreatic alpha/beta cell dysfunction (via GLP-1/GIP), the incretin defect, appetite dysregulation, and insulin resistance (indirectly via weight loss). Basal insulin only acts as a hormone replacement to suppress hepatic glucose output and increase peripheral uptake, often exacerbating weight gain without addressing the underlying incretin defect or hyperglucagonemia.

Attending

SURPASS-3 positions a highly efficacious incretin-based therapy ahead of basal insulin for first injectable therapy. How does this finding challenge our historical 'treat-to-target' insulin-centric approach, and what are the practical barriers to fully adopting this paradigm shift in primary care?

Key Response

Historically, basal insulin was the default next step for severe A1c elevations after oral agent failure. SURPASS-3 proves tirzepatide achieves greater A1c reductions (up to 2.37%) plus massive weight loss, without the hypoglycemia of insulin. The paradigm shifts from glucocentric 'rescue' to holistic cardiometabolic disease modification. However, systemic barriers include high drug cost, complex insurance prior authorizations, and supply chain shortages, making insulin a much more accessible fallback.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

SURPASS-3 utilized an open-label design due to the differing delivery devices and titration schedules of tirzepatide and degludec. How might the open-label nature introduce bias into the titration of insulin degludec or the reporting of subjective endpoints, and how could the statistical analysis plan account for this?

Key Response

In an open-label trial, investigators might conservatively titrate insulin degludec out of fear of hypoglycemia, potentially undermining the active comparator's efficacy. Additionally, subjective reporting of GI adverse events could be influenced by patient expectations. A rigorous statistical plan must evaluate whether degludec dosing achieved the pre-specified fasting glucose targets (e.g., <90 mg/dL) to prove the comparator was optimized, establishing that tirzepatide's superiority wasn't merely due to under-dosed insulin.

Journal Editor

As a peer reviewer, a major concern in trials comparing novel agents to insulin is whether the insulin group was adequately titrated. How rigorously did the SURPASS-3 investigators push the degludec dose, and does the final mean insulin dose reflect an optimized active control or clinical inertia?

Key Response

A tough reviewer would heavily scrutinize the treat-to-target algorithm for degludec. If the fasting blood glucose targets were not rigorously met or if the final mean dose of degludec was lower than expected for a highly insulin-resistant obese T2D cohort, the superiority of tirzepatide in A1c reduction might be artificially inflated. Evaluating the proportion of degludec patients reaching the FBG target is essential to validate the superiority claim.

Guideline Committee

Current ADA/EASD guidelines recommend GLP-1 receptor agonists over basal insulin as the first injectable therapy for T2D. Based on SURPASS-3, should guidelines create a distinct, preferential recommendation for dual GIP/GLP-1 agonists over standard GLP-1 RAs and insulin, and what evidence gaps remain?

Key Response

SURPASS-3 provides strong evidence that tirzepatide is superior to basal insulin in dual-endpoint achievement (glycemia and weight). Along with SURPASS-2, guidelines must weigh whether to create a distinct tier for 'highly effective weight-management and glycemic agents.' However, the committee must consider that long-term cardiovascular outcomes trial (CVOT) data are still pending for tirzepatide. Until CV benefit is definitively proven, it cannot entirely supersede GLP-1 RAs with established cardiovascular benefits in high-risk patients, though it firmly supports avoiding basal insulin as a first-line injectable.

Clinical Landscape

Noteworthy Related Trials

2017

SUSTAIN 4 Trial

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Tested

Semaglutide 0.5mg or 1.0mg once weekly

Population

T2DM inadequately controlled on metformin with or without sulfonylurea

Comparator

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Endpoint

Change in HbA1c from baseline to week 30

Key result: Semaglutide significantly reduced HbA1c and bodyweight compared to insulin glargine, with a higher rate of gastrointestinal adverse events.

2017

DEVOTE Trial

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Tested

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Population

T2DM with high cardiovascular risk

Comparator

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Endpoint

First occurrence of a major adverse cardiovascular event (3-point MACE)

Key result: Insulin degludec was non-inferior to insulin glargine for cardiovascular events and resulted in a lower rate of severe hypoglycemia.

2021

SURPASS-2 Trial

n = 1,879 · NEJM

Tested

Tirzepatide 5mg, 10mg, or 15mg once weekly

Population

T2DM inadequately controlled on metformin

Comparator

Semaglutide 1mg once weekly

Endpoint

Change in HbA1c from baseline to week 40

Key result: Tirzepatide at all doses was non-inferior and superior to semaglutide with respect to the mean change in the HbA1c level.

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