The Lancet August 19, 2023

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

W Timothy Garvey, Juan P Frias, Ania M Jastreboff, Carel W le Roux, Naveed Sattar, Diego Aizenberg, Huzhang Mao, Shuyu Zhang, Nadia N Ahmad, Mathijs C Bunck, Imane Benabbad, Xiaotian M Zhang; SURMOUNT-2 investigators

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Bottom Line

In adults with obesity and type 2 diabetes, treatment with the dual GIP/GLP-1 receptor agonist tirzepatide (10 mg or 15 mg) resulted in substantial, clinically meaningful reductions in body weight of up to 14.7% at 72 weeks, vastly outperforming placebo.

Key Findings

1. At week 72, the least-squares mean change in bodyweight was -12.8% with tirzepatide 10 mg and -14.7% with tirzepatide 15 mg, compared to -3.2% with placebo (treatment differences of -9.6% and -11.6% percentage points, respectively; p<0.0001).

2. A bodyweight reduction of 5% or higher was achieved by significantly more participants receiving tirzepatide 10 mg (79%) and 15 mg (83%) compared with placebo (32%).

3. Nearly half of the participants on the 15 mg dose achieved ≥15% bodyweight reduction.

4. Tirzepatide was associated with significant improvements in HbA1c (a secondary endpoint, with robust reductions of nearly 2%), waist circumference, lipid parameters, and systolic blood pressure.

5. The most frequent adverse events were gastrointestinal (nausea, diarrhea, vomiting), which were primarily mild to moderate in severity and occurred mainly during dose escalation, leading to treatment discontinuation in <5% of tirzepatide-treated patients.

Study Design

Design

RCT

Double-Blind

Sample

938

Patients

Duration

72 wk

Median

Setting

Multicenter, 7 countries

Population Adults (aged ≥18 years) with a BMI of ≥27 kg/m2 and type 2 diabetes (HbA1c 7-10%) on stable lifestyle and/or specific oral antihyperglycemic therapies for ≥3 months.

Intervention Once-weekly subcutaneous tirzepatide (10 mg or 15 mg), escalated progressively over up to 20 weeks, alongside a lifestyle intervention.

Comparator Once-weekly subcutaneous matching placebo alongside a lifestyle intervention.

Outcome Co-primary endpoints: percent change in bodyweight from baseline and the proportion of participants achieving a bodyweight reduction of ≥5% at 72 weeks.

Study Limitations

• The trial excluded patients with very poorly controlled type 2 diabetes (HbA1c >10%) and those on complex insulin regimens, limiting the generalizability to more advanced diabetic populations.

• A 72-week follow-up period, while standard for weight loss registration trials, does not capture the very long-term safety profile or durability of weight maintenance.

• Despite clinical trial support, real-world tolerability of the gastrointestinal side effects might differ outside of a highly monitored setting.

• The study did not encompass primary cardiovascular outcomes, which are being assessed in separate, ongoing cardiovascular outcome trials (e.g., SURPASS-CVOT).

Clinical Significance

SURMOUNT-2 represents a landmark achievement in the overlapping fields of diabetology and obesity medicine. Historically, patients with type 2 diabetes exhibit more resistance to weight-loss therapies than non-diabetic individuals. Tirzepatide’s ability to induce a ~15% mean body weight reduction in this specific demographic is unprecedented for pharmacotherapy, offering outcomes that approach those of metabolic surgery. Concurrently, it offers robust glycemic control, shifting the treatment paradigm of type 2 diabetes from a glucocentric approach to a dual weight- and glucose-targeted strategy.

Historical Context

The GLP-1 receptor agonist semaglutide previously set a new standard for medical weight loss (STEP trials), but its efficacy in patients with type 2 diabetes (STEP 2, ~9.6% weight loss) was notably lower than in non-diabetics (STEP 1, ~14.9%). The SURMOUNT-1 trial demonstrated extraordinary weight loss (up to 20.9%) with tirzepatide—a dual GIP and GLP-1 receptor agonist—in adults with obesity but without diabetes. SURMOUNT-2 answered the critical next question: how effective is tirzepatide in the more treatment-resistant diabetic population? By achieving near 15% weight loss, tirzepatide established a new efficacy benchmark for treating adiposity in patients with concurrent type 2 diabetes.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the dual agonism of GIP and GLP-1 receptors by tirzepatide synergistically contribute to both glycemic control and weight loss compared to selective GLP-1 receptor agonists alone?

Key Response

Tirzepatide activates both GIP and GLP-1 receptors. GLP-1 slows gastric emptying, increases satiety, and promotes glucose-dependent insulin release. GIP agonism synergistically enhances this insulin secretion, improves insulin sensitivity in adipose tissue, and may reduce nausea, allowing for higher dosing and greater net weight loss than selective GLP-1 agonists.

Resident

A 55-year-old patient with type 2 diabetes and a BMI of 34 kg/m2 is currently on metformin and a sulfonylurea with an A1c of 8.2%. If initiating tirzepatide based on the SURMOUNT-2 trial, what specific medication adjustments should be made and why?

Key Response

Initiating a potent incretin mimetic like tirzepatide significantly increases the risk of hypoglycemia when combined with insulin secretagogues like sulfonylureas. The clinician must reduce the dose of or discontinue the sulfonylurea while up-titrating tirzepatide to safely achieve the dual benefits of weight loss and glycemic control.

Fellow

The SURMOUNT-2 trial demonstrated significant weight reduction, but how does the magnitude of weight loss with tirzepatide in this cohort of patients with type 2 diabetes compare to the SURMOUNT-1 cohort without diabetes, and what pathophysiological mechanisms explain this difference?

Key Response

Patients with type 2 diabetes typically experience attenuated weight loss with incretin therapies compared to those without diabetes (up to 14.7% in SURMOUNT-2 vs. over 20% in SURMOUNT-1). Fellows should understand that factors like concomitant insulinogenic medications, increased renal glucose reabsorption, baseline hyperinsulinemia, and altered energy homeostasis in T2D blunt the weight-loss efficacy of these agents.

Attending

With the unprecedented weight loss seen in SURMOUNT-2, how do we pragmatically transition from a glucocentric model to an adiposity-centric model in clinical practice, and what are the implications for long-term deprescribing of other cardiometabolic medications?

Key Response

SURMOUNT-2 marks a paradigm shift where weight losses exceeding 10-15% can induce profound metabolic shifts. Attendings must pivot practice to prioritize early, aggressive adiposity reduction, which often necessitates preemptive deprescribing of antihypertensives and lipid-lowering agents due to rapid, medication-independent improvements in insulin resistance and cardiovascular risk profiles.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

SURMOUNT-2 utilized an estimand framework to account for treatment discontinuation and rescue medications. How does the choice between the treatment-policy estimand and the efficacy estimand impact the interpretation of tirzepatide's true biological effect versus its real-world effectiveness?

Key Response

The treatment-policy estimand reflects real-world effectiveness regardless of adherence or rescue therapies, while the efficacy estimand reflects the biological potential if taken as directed without rescue therapy. Researchers must critically evaluate how missing data and intercurrent events are handled, as these choices dictate whether the trial answers a pragmatic or explanatory research question.

Journal Editor

Given that gastrointestinal adverse events often lead to unblinding in incretin trials, how robust is the placebo control in SURMOUNT-2, and what methodological safeguards are required to ensure that patient-reported outcomes like satiety or quality of life are not biased by functional unblinding?

Key Response

Because a high percentage of patients on tirzepatide experience GI side effects like nausea, a significant portion of the treatment arm is effectively unblinded. A critical editor would flag this as a threat to internal validity, especially for subjective secondary endpoints, demanding sensitivity analyses or objective biomarker surrogates to confirm the observed effects are not exaggerated by placebo effects.

Guideline Committee

Based on SURMOUNT-2, should current ADA and AACE guidelines elevate dual GIP/GLP-1 agonists above SGLT2 inhibitors and GLP-1 RAs as absolute first-line therapy for patients with type 2 diabetes and obesity, and what additional data are required to make this a Class I recommendation?

Key Response

Current ADA guidelines recommend GLP-1 RAs or SGLT2is for patients with high ASCVD risk or a compelling need for weight loss. While SURMOUNT-2 provides Level A evidence for superior weight efficacy, elevating tirzepatide to absolute first-line ahead of established agents requires definitive cardiovascular outcomes data (like the pending SURPASS-CVOT trial) and cost-effectiveness analyses to justify superseding therapies with proven cardioprotective and renoprotective profiles.

Clinical Landscape

Noteworthy Related Trials

2021

STEP 2

n = 1,210 · Lancet

Tested

Semaglutide 2.4 mg weekly

Population

Adults with overweight or obesity and type 2 diabetes

Comparator

Placebo and Semaglutide 1.0 mg

Endpoint

Percentage change in body weight and proportion achieving >=5% weight loss

Key result: Semaglutide 2.4 mg achieved a mean weight reduction of 9.6% compared to 3.4% with placebo in patients with T2DM.

2021

SURPASS-2

n = 1,879 · NEJM

Tested

Tirzepatide 5 mg, 10 mg, or 15 mg weekly

Population

Adults with type 2 diabetes inadequately controlled on metformin

Comparator

Semaglutide 1.0 mg weekly

Endpoint

Change in HbA1c from baseline to 40 weeks

Key result: Tirzepatide was superior to semaglutide in reducing both HbA1c and body weight across all doses.

2022

SURMOUNT-1

n = 2,539 · NEJM

Tested

Tirzepatide 5 mg, 10 mg, or 15 mg weekly

Population

Adults with obesity or overweight without diabetes

Comparator

Placebo

Endpoint

Percentage change in body weight and proportion with >=5% weight reduction

Key result: Tirzepatide resulted in substantial and sustained reductions in body weight (up to 20.9% on 15 mg) compared to placebo.

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