The Lancet AUGUST 06, 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, et al.

Bottom Line

In patients with type 2 diabetes inadequately controlled on metformin, once-weekly tirzepatide at all tested doses (5, 10, and 15 mg) demonstrated superior glycemic control and weight reduction compared to titrated basal insulin degludec at 52 weeks, with a lower risk of hypoglycemia.

Key Findings

1. At week 52, mean HbA1c reductions were significantly greater with tirzepatide compared to insulin degludec: -1.93% (5 mg), -2.20% (10 mg), and -2.37% (15 mg) versus -1.34% for insulin degludec (all p<0.0001).

2. Body weight decreased significantly with tirzepatide (-7.5 kg, -10.7 kg, and -12.9 kg, respectively) whereas it increased with insulin degludec (+2.3 kg; estimated treatment differences of -9.8 kg to -15.2 kg, p<0.0001).

3. A significantly higher proportion of participants achieved an HbA1c <7.0% with tirzepatide (82–93%) compared to insulin degludec (61%; p<0.0001).

4. Hypoglycemic events (<54 mg/dL or severe) were reported in 1% to 2% of patients in tirzepatide groups compared to 7% in the insulin degludec group.

5. The most frequent adverse events in the tirzepatide arms were gastrointestinal (nausea 12–24%, diarrhea 15–17%, vomiting 6–10%), which were generally mild to moderate and decreased over time.

Study Design

Design

RCT

Open-Label

Sample

1,444

Patients

Duration

52 wk

Median

Setting

Multicenter, multinational

Population Adults with type 2 diabetes (HbA1c 7.0–10.5%) inadequately controlled by metformin with or without an SGLT2 inhibitor.

Intervention Once-weekly subcutaneous tirzepatide (5, 10, or 15 mg).

Comparator Once-daily subcutaneous titrated insulin degludec (starting dose 10 units, titrated to fasting blood glucose <90 mg/dL).

Outcome Mean change from baseline in HbA1c at 52 weeks.

Study Limitations

• The trial was open-label, which may introduce observer bias, particularly regarding the reporting of subjective adverse events.

• Study duration of 52 weeks is insufficient to evaluate long-term microvascular or macrovascular cardiovascular outcomes.

• The population consisted of insulin-naive participants, limiting the generalizability to patients already requiring more complex insulin regimens.

• Higher rates of discontinuation due to adverse events in the tirzepatide groups compared to the insulin degludec group could influence efficacy estimands.

Clinical Significance

The SURPASS-3 results provide a strong evidence base for considering tirzepatide as a preferred therapeutic option over basal insulin when intensification beyond metformin and/or SGLT2 inhibitors is required for type 2 diabetes, offering a superior combination of glycemic efficacy, weight loss, and safety profile regarding hypoglycemia.

Historical Context

Before the approval of tirzepatide, clinicians often defaulted to basal insulin as the next step for patients failing oral antidiabetic therapy. SURPASS-3 was pivotal in demonstrating that a dual-agonist (GIP and GLP-1) could outperform titrated basal insulin in both efficacy and safety (hypoglycemia risk), signaling a paradigm shift in the diabetes treatment hierarchy toward GLP-1/GIP receptor agonists.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Discuss the physiologic mechanism of dual GIP and GLP-1 receptor agonism in tirzepatide and how this differs from the mechanism of action of insulin degludec in lowering blood glucose.

Key Response

Tirzepatide is a 'twincretin' that mimics both Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1). It enhances glucose-dependent insulin secretion, suppresses glucagon, and delays gastric emptying, whereas insulin degludec is a long-acting basal insulin analogue that provides a steady exogenous supply of insulin to facilitate peripheral glucose uptake and suppress hepatic glucose production without affecting appetite or weight.

Resident

In a patient with Type 2 Diabetes currently on metformin and an SGLT2 inhibitor with an HbA1c of 8.6%, what are the primary clinical trade-offs demonstrated in SURPASS-3 when choosing between adding tirzepatide versus insulin degludec?

Key Response

The trial demonstrated that tirzepatide (5mg, 10mg, or 15mg) was superior to titrated insulin degludec in HbA1c reduction and weight loss (tirzepatide lost 7-11kg vs. insulin gained 2.3kg). The primary trade-off is the higher incidence of gastrointestinal side effects (nausea, diarrhea) with tirzepatide versus the increased risk of hypoglycemia and weight gain associated with insulin degludec.

Fellow

The SURPASS-3 trial included a sub-study utilizing MRI to measure liver fat content (LFC). How do the effects of tirzepatide on ectopic fat deposition inform the management of patients with T2DM and concomitant metabolic-associated steatotic liver disease (MASLD)?

Key Response

Tirzepatide showed a significantly greater reduction in LFC (absolute reduction of ~8% with 15mg vs. ~3% with insulin). This suggests that the dual agonism of GIP/GLP-1 may exert unique metabolic effects on the liver, potentially through improved insulin sensitivity and reduced lipogenesis, making it a preferred choice for patients with T2DM and liver fat concerns compared to insulin.

Attending

Considering the high percentage of patients in the tirzepatide 15mg arm who achieved an HbA1c of <5.7% (near-normoglycemia) in SURPASS-3, how should this evidence change our conversation with patients regarding 'diabetes remission' versus 'intensive control' when transitioning to injectable therapies?

Key Response

SURPASS-3 showed that up to 51% of patients on tirzepatide 15mg reached an HbA1c <5.7%. This shifts the goal from merely avoiding complications to potentially achieving normoglycemia. Clinicians should discuss the potential for 'metabolic restoration' and significant weight loss with tirzepatide, which was previously rare with insulin-based injectable strategies.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically analyze the use of the 'treatment-regimen' versus 'efficacy' estimands in SURPASS-3. How does the handling of intercurrent events, such as the discontinuation of study drug due to GI intolerance, impact the generalizability of the superiority findings?

Key Response

The efficacy estimand (de facto) measures the effect regardless of adherence, while the treatment-regimen estimand focuses on the effect while on treatment. Because tirzepatide has higher discontinuation rates due to GI adverse events (up to 11% in the 15mg group), the efficacy estimand may underestimate the drug's biological potency while the treatment-regimen estimand provides a more realistic view of what a patient who tolerates the medication can expect.

Journal Editor

As a reviewer, how would you address the potential for 'performance bias' introduced by the open-label design of SURPASS-3, specifically regarding the titration of insulin degludec to a fasting blood glucose target of <90 mg/dL?

Key Response

The open-label design is a significant limitation; investigators knew which patients were on the 'novel' drug. A tough reviewer would flag whether the insulin degludec was titrated as aggressively as it would be in a blinded trial (though the trial used a standardized algorithm), as any failure to reach the target FBG in the comparator arm could artificially inflate the treatment effect size of tirzepatide.

Guideline Committee

Based on SURPASS-3 data, should the ADA Standards of Care be updated to prioritize dual GIP/GLP-1 RAs over basal insulin in all patients failing oral triple therapy, and how does this compare to the 2023/2024 recommendations regarding GLP-1 RAs as the preferred first injectable?

Key Response

Current ADA guidelines recommend GLP-1 RAs as the first injectable before insulin. SURPASS-3 provides Level 1 evidence that tirzepatide is superior to insulin degludec in both glucose and weight metrics. The committee must weigh the superior efficacy against cost and long-term safety data, but the evidence strongly supports tirzepatide as a preferred option over insulin for the majority of T2DM patients requiring injectable escalation.

Clinical Landscape

Noteworthy Related Trials

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide (once-weekly)

Population

T2DM patients at high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Semaglutide significantly reduced the risk of cardiovascular events compared to placebo.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide (once-daily)

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Liraglutide treatment led to a significant reduction in cardiovascular death and non-fatal events.

2017

DEVOTE Trial

n = 7,637 · NEJM

Tested

Insulin degludec

Population

T2DM patients at high cardiovascular risk

Comparator

Insulin glargine

Endpoint

Time to first occurrence of 3-point MACE

Key result: Insulin degludec demonstrated non-inferiority to insulin glargine regarding cardiovascular safety.

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