What is the Surpass 5 trial in cardiovascular health?

Understanding the SURPASS-5 Trial

SURPASS-5 is a phase 3 randomized clinical trial that evaluated tirzepatide (a dual GIP/GLP-1 receptor agonist) versus placebo in adults with type 2 diabetes inadequately controlled on insulin glargine, demonstrating superior glycemic control and weight loss at 40 weeks. 1, 2

Trial Design and Context

The SURPASS-5 trial is part of a comprehensive phase 3 clinical program (SURPASS-1 through SURPASS-5) designed to establish tirzepatide's efficacy and safety across diverse patient populations with type 2 diabetes 1, 2. This specific trial examined tirzepatide as add-on therapy to basal insulin, addressing a critical clinical scenario where patients remain inadequately controlled despite insulin therapy 3.

Key Trial Parameters

• Primary endpoint assessment occurred at 40 weeks, consistent with SURPASS-1 and SURPASS-2 (while SURPASS-3 and SURPASS-4 extended to 52 weeks) 4
• Three tirzepatide doses were evaluated: 5 mg, 10 mg, and 15 mg administered once weekly 1, 2
• Comparator: Placebo added to background insulin glargine therapy 1
• Patient population: Adults with type 2 diabetes inadequately controlled on insulin glargine 2

Mechanism of Action

Tirzepatide represents a novel pharmacological approach as the first dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist 1, 2. The rationale stems from evidence showing that co-infusion of GLP-1 and GIP produces synergistic effects, resulting in significantly increased insulin response and glucagonostatic response compared to separate administration of each hormone 3.

• Molecular structure: Tirzepatide is a synthetic peptide containing 39 amino acids based on the native GIP sequence 3
• Dual receptor activation provides enhanced glucose-lowering effects beyond traditional GLP-1 receptor agonists alone 3

Primary Efficacy Outcomes

Glycemic Control

Across the SURPASS program, tirzepatide demonstrated potent glucose-lowering effects 1, 2. In SURPASS-5 specifically, participants receiving tirzepatide achieved superior HbA1c reductions compared to placebo at 40 weeks 4.

• Dose-response relationship: Higher tirzepatide doses (15 mg > 10 mg > 5 mg) produced progressively greater HbA1c reductions 5
• Clinical significance: The magnitude of glucose lowering positions tirzepatide as a preferred option for patients with compelling need for high glucose-lowering effects 1

Weight Loss

Weight reduction represents a major distinguishing feature of tirzepatide therapy, with clinically meaningful weight loss observed across all SURPASS trials 1, 2.

• Categorical weight loss analysis from SURPASS-1 through SURPASS-4 (including treatment-adherent participants, N=3,188) revealed that participants achieving ≥15% body weight reduction experienced the greatest improvements in cardiometabolic parameters 5
• Predictors of ≥15% weight reduction included higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, and lower baseline HbA1c, fasting serum glucose, and non-HDL cholesterol 5
• Progressive benefits: Greater categorical weight reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%) correlated with larger reductions in HbA1c, triglycerides, ALT, waist circumference, and blood pressure 5

Patient-Reported Outcomes

SURPASS-5 incorporated comprehensive patient-reported outcome (PRO) assessments to evaluate quality of life and treatment satisfaction 4.

PRO Instruments Used

• EQ-5D-5L: Measured overall quality of life 4
• Impact of Weight on Self-Perceptions: Assessed weight-related psychological effects 4
• Ability to Perform Physical Activities of Daily Living: Evaluated functional capacity 4
• Diabetes Treatment Satisfaction Questionnaire: Measured treatment satisfaction (used in SURPASS-2 through SURPASS-5) 4

Key PRO Findings

• At week 40, tirzepatide improved patients' quality of life measured by general health and weight-related PROs compared to placebo 4
• Dose-dependent improvements: Higher tirzepatide doses generally resulted in greater increases in PRO scores 4
• Significant health and weight-related quality of life improvements were observed versus comparators across all five SURPASS studies 4

Safety Profile

The adverse event profile in SURPASS-5 was consistent with the broader SURPASS program 1, 2.

• Most adverse events were gastrointestinal in nature, typical of GLP-1 receptor agonist class effects 1
• Relatively low withdrawal rate in active treatment arms despite gastrointestinal side effects 1
• Adverse effects comparable to established GLP-1 receptor agonists, suggesting acceptable tolerability 3
• Hypoglycemia risk remains low, an important consideration for patients requiring intensive glucose lowering 1

Clinical Implications and Future Directions

Positioning in Treatment Algorithm

Tirzepatide will likely be recommended as a preferred option in the American Diabetes Association treatment algorithm for patients with compelling need for high glucose-lowering effects, low hypoglycemia risk, and weight loss 1. However, definitive positioning awaits results from the cardiovascular outcomes trial (CVOT) or other outcome-based trials 1.

Important Caveats

• Cardiovascular outcomes data pending: While GLP-1 receptor agonists have demonstrated favorable cardiovascular outcomes, tirzepatide's dual mechanism requires dedicated cardiovascular outcomes assessment 1, 3
• Long-term safety and efficacy beyond 40-52 weeks requires ongoing evaluation 3
• Cost considerations will influence real-world uptake and access, similar to challenges faced by PCSK9 inhibitors despite proven efficacy 6

Patient Selection Considerations

Based on multivariate analysis from SURPASS-1 through SURPASS-4, clinicians can identify patients most likely to achieve substantial weight reduction (≥15%) with tirzepatide 5:

• Prioritize higher doses (10 mg or 15 mg) for maximum benefit 5
• Female patients demonstrate higher likelihood of achieving ≥15% weight reduction 5
• Younger patients respond more favorably 5
• Patients on metformin background therapy achieve better outcomes 5
• Better baseline glycemic control (lower HbA1c and fasting glucose) predicts greater weight loss 5
• Lower baseline non-HDL cholesterol associates with enhanced weight reduction 5