The Lancet JUNE 26, 2023

Tirzepatide Once Weekly for the Treatment of Obesity in People With Type 2 Diabetes (SURMOUNT-2)

W. Timothy Garvey, Juan P. Frias, Ania M. Jastreboff, et al.

Bottom Line

The SURMOUNT-2 trial demonstrates that once-weekly subcutaneous tirzepatide at doses of 10 mg and 15 mg produces significant, clinically meaningful weight loss in adults with obesity and type 2 diabetes.

Key Findings

1. At 72 weeks, the least-squares mean change in body weight was -12.8% for the 10 mg dose and -14.7% for the 15 mg dose, compared to -3.2% in the placebo group (all p<0.0001).

2. A significantly higher proportion of participants achieved weight reduction thresholds of ≥5% body weight (79% with 10 mg and 83% with 15 mg, versus 32% with placebo).

3. Tirzepatide was associated with secondary improvements in cardiometabolic markers, including significant reductions in HbA1c, systolic blood pressure, and improvements in lipid profiles.

4. The safety profile was characterized primarily by mild-to-moderate gastrointestinal adverse events (nausea, diarrhea, vomiting), which occurred most frequently during the dose-escalation phase.

Study Design

Design

RCT

Double-Blind

Sample

938

Patients

Duration

72 wk

Median

Setting

Multicenter, Global

Population Adults aged ≥18 years with obesity (BMI ≥27 kg/m2) and type 2 diabetes (HbA1c 7-10%) on stable antihyperglycemic therapy.

Intervention Once-weekly subcutaneous tirzepatide (titrated to 10 mg or 15 mg) plus lifestyle intervention.

Comparator Matching once-weekly subcutaneous placebo plus lifestyle intervention.

Outcome Percent change in body weight from baseline to week 72 and percentage of participants achieving weight reduction of ≥5%.

Study Limitations

• The study population was predominantly White (76%) and Hispanic/Latino (60%), which may limit the generalizability to more diverse global populations.

• Gastrointestinal adverse events, though generally mild, led to higher rates of discontinuation compared to placebo, although overall discontinuation rates remained low (<5%).

• The trial did not directly compare the 10 mg and 15 mg doses, making it difficult to determine the incremental clinical benefit of the higher dose versus potential tolerability trade-offs.

Clinical Significance

SURMOUNT-2 provides robust evidence for a weight-centric therapeutic approach in patients with type 2 diabetes. By achieving weight loss magnitudes previously reserved for surgical interventions, tirzepatide offers a potent pharmacological tool to address the dual challenges of glycemic control and obesity-related cardiometabolic risk.

Historical Context

The SURMOUNT program builds on the success of earlier incretin-based therapies (like the STEP trials for semaglutide). Tirzepatide, a dual GIP/GLP-1 receptor agonist, was already approved for type 2 diabetes (as Mounjaro) when SURMOUNT-2 established its efficacy specifically for weight management in this high-risk population, where weight loss is typically more difficult to achieve than in patients without diabetes.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Tirzepatide is described as a 'twincretin' because it acts as a dual agonist. Which two incretin hormones does it mimic, and how does the addition of the second hormone theoretically enhance weight loss compared to a selective GLP-1 receptor agonist?

Key Response

Tirzepatide mimics both Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). While GLP-1 reduces appetite and slows gastric emptying, the addition of GIP agonism is thought to act synergistically by improving insulin sensitivity and potentially modulating lipid metabolism and energy expenditure in adipose tissue, leading to the superior weight loss seen in the SURMOUNT trials compared to semaglutide.

Resident

In the SURMOUNT-2 trial, patients with type 2 diabetes (T2D) achieved a mean weight loss of approximately 15%. How should a clinician adjust existing glucose-lowering medications, such as sulfonylureas or insulin, when initiating tirzepatide to minimize the risk of hypoglycemia?

Key Response

While tirzepatide itself has a glucose-dependent mechanism and a low intrinsic risk of hypoglycemia, its potent glucose-lowering effect necessitates a proactive reduction in the doses of secretagogues (sulfonylureas) or insulin. Residents should be aware that significant weight loss also improves underlying insulin sensitivity, which may require further downward titration of these medications over the course of the 72-week treatment period.

Fellow

The weight loss achieved in SURMOUNT-2 (T2D population) was notably less than that seen in SURMOUNT-1 (non-diabetic population). What are the metabolic and physiological hypotheses explaining why individuals with type 2 diabetes often experience a 'blunted' weight loss response to incretin-based therapies?

Key Response

Patients with T2D often exhibit greater metabolic resistance, including altered adipokine profiles, chronic low-grade inflammation, and potentially impaired GIP/GLP-1 receptor sensitivity. Additionally, as glucose levels normalize, the 'glucosuric' effect (loss of calories through urine) diminishes, and the anabolic effects of improved glycemic control may partially counteract the weight-loss-inducing effects of the medication.

Attending

With the results of SURMOUNT-2 demonstrating weight loss efficacy approaching bariatric surgery levels, should the treatment paradigm for type 2 diabetes shift from a 'glucose-centric' approach to a 'weight-centric' approach? What are the implications for long-term cardiovascular outcomes while awaiting the SURPASS-CVOT results?

Key Response

SURMOUNT-2 suggests that for the subset of T2D patients where obesity is the primary driver, tirzepatide can induce profound metabolic surgery-like results. While we await specific CVOT data for tirzepatide (SURPASS-CVOT), the magnitude of weight loss and improvement in all cardiometabolic markers (BP, lipids, HbA1c) suggests that a weight-centric approach may provide comprehensive risk reduction, though GLP-1 RAs with proven CV benefit currently remain the first-line recommendation for those with established ASCVD.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

SURMOUNT-2 utilized two different estimands (the 'efficacy estimand' and the 'treatment-regimen estimand') to analyze the primary endpoints. Critically evaluate how the handling of 'intercurrent events'—such as treatment discontinuation or the use of rescue medication—affects the interpretability of the results for clinical practice versus drug regulatory approval.

Key Response

The efficacy estimand (treatment-policy) reflects the average effect of the drug regardless of adherence, which is vital for public health and real-world expectations. The treatment-regimen (on-treatment) estimand focuses on the biological effect of the drug if taken as intended. In SURMOUNT-2, the treatment-regimen estimand showed slightly higher weight loss (15.7% vs 14.7% for the 15mg dose), highlighting that while the drug is potent, real-world results are slightly attenuated by tolerability-driven discontinuation.

Journal Editor

Despite the impressive efficacy, the SURMOUNT-2 trial reports a relatively high rate of gastrointestinal adverse events (up to 25% nausea in the 15mg group) and a study discontinuation rate of about 10% due to adverse events. To what extent does this 'tolerability ceiling' threaten the external validity of the study when applied to a broader, less-monitored T2D population?

Key Response

As an editor, the concern is that clinical trial participants are often more motivated and receive more intensive monitoring and counseling than the general population. If 1 in 10 patients must stop the drug due to side effects under trial conditions, the real-world 'effectiveness' may be significantly lower than the 'efficacy' reported, particularly if dose-titration protocols are not strictly followed in primary care.

Guideline Committee

Current ADA (American Diabetes Association) guidelines emphasize weight management as a primary goal of T2D care. Does the 15% weight loss observed in SURMOUNT-2 justify moving tirzepatide to a 'preferred' status over other GLP-1 RAs like semaglutide, and how does the lack of long-term CVOT data at the time of the trial impact the strength of this recommendation?

Key Response

According to the ADA Standards of Care, tirzepatide currently carries a 'Very High' efficacy rating for both glucose and weight loss. SURMOUNT-2 provides Level A evidence for its weight-loss potency in T2D. However, until head-to-head trials (like SURMOUNT-5) and CVOT trials are completed, guidelines may maintain a preference for GLP-1 RAs with established MACE reduction (like semaglutide or liraglutide) specifically for patients with high cardiovascular risk, while prioritizing tirzepatide for those where obesity management is the predominant clinical need.

Clinical Landscape

Noteworthy Related Trials

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5/1.0mg weekly

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Semaglutide reduced the risk of cardiovascular events compared to placebo while demonstrating significant weight loss benefits.

2021

STEP 2 Trial

n = 1,210 · Lancet

Tested

Semaglutide 2.4mg weekly

Population

Adults with T2DM and overweight or obesity

Comparator

Semaglutide 1.0mg weekly or Placebo

Endpoint

Percent change in body weight from baseline at week 68

Key result: Once-weekly semaglutide 2.4mg was superior to 1.0mg and placebo for weight loss in patients with type 2 diabetes.

2022

SURMOUNT-1 Trial

n = 2,539 · NEJM

Tested

Tirzepatide 5/10/15mg weekly

Population

Adults with obesity without diabetes

Comparator

Placebo

Endpoint

Percent change in body weight from baseline at week 72

Key result: Tirzepatide demonstrated substantial and sustained weight reduction in participants with obesity, establishing its efficacy outside the diabetes population.

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