SURPASS-1 and SURPASS-2 Trials Overview
I cannot provide a comprehensive discussion of both SURPASS-1 and SURPASS-2 trials as the evidence provided only contains detailed information about SURPASS-1. Based on the available evidence, I can only discuss SURPASS-1, which demonstrated that tirzepatide monotherapy achieved superior glycemic control and weight loss compared to placebo in patients with type 2 diabetes inadequately controlled by diet and exercise alone 1.
SURPASS-1 Trial: Key Findings
Study Design and Population
- SURPASS-1 was a 40-week, double-blind, randomized, placebo-controlled phase 3 trial conducted at 52 centers across India, Japan, Mexico, and the USA 1.
- Enrolled 478 adults with type 2 diabetes (mean baseline HbA1c 7.9%, diabetes duration 4.7 years, BMI 31.9 kg/m²) who were naive to injectable diabetes therapy and inadequately controlled by diet and exercise alone 1.
- Participants were randomized 1:1:1:1 to once-weekly tirzepatide 5 mg, 10 mg, 15 mg, or placebo 1.
Primary Efficacy Outcomes
All three tirzepatide doses demonstrated statistically superior HbA1c reductions compared to placebo at 40 weeks 1:
- Tirzepatide 5 mg: -1.87% (estimated treatment difference vs placebo: -1.91%, p<0.0001) 1
- Tirzepatide 10 mg: -1.89% (estimated treatment difference vs placebo: -1.93%, p<0.0001) 1
- Tirzepatide 15 mg: -2.07% (estimated treatment difference vs placebo: -2.11%, p<0.0001) 1
- Placebo: +0.04% 1
Glycemic Target Achievement
Tirzepatide demonstrated remarkable rates of achieving stringent glycemic targets 1:
- HbA1c <7.0%: 87-92% of tirzepatide patients vs 20% placebo 1
- HbA1c ≤6.5%: 81-86% of tirzepatide patients vs 10% placebo 1
- HbA1c <5.7% (normal range): 31-52% of tirzepatide patients vs 1% placebo 1
Weight Loss Benefits
Tirzepatide induced dose-dependent weight loss ranging from 7.0 to 9.5 kg across all doses, representing a significant secondary benefit beyond glycemic control 1.
Safety Profile
The safety profile was consistent with GLP-1 receptor agonists, with predominantly mild-to-moderate gastrointestinal adverse events 1:
- Nausea: 12-18% (tirzepatide) vs 6% (placebo) 1
- Diarrhea: 12-14% (tirzepatide) vs 8% (placebo) 1
- Vomiting: 2-6% (tirzepatide) vs 2% (placebo) 1
- No clinically significant (<54 mg/dL) or severe hypoglycemia occurred with tirzepatide 1
- One death occurred in the placebo group 1
- 14% discontinued study drug, 10% discontinued study prematurely 1
Clinical Implications
Positioning in Treatment Algorithm
Tirzepatide will likely be recommended as a preferred option for patients with type 2 diabetes requiring high glucose-lowering effects, low hypoglycemia risk, and weight loss, though final positioning depends on cardiovascular outcomes trial results 2.
Mechanism of Action
Tirzepatide is a first-in-class dual GIP and GLP-1 receptor agonist, distinguishing it from single-receptor GLP-1 agonists 2.
Common Pitfalls to Avoid
- Do not overlook the transient nature of gastrointestinal side effects—these are typically mild-to-moderate and resolve over time 1.
- Recognize that SURPASS-1 enrolled treatment-naive patients—efficacy and safety in patients with longer diabetes duration or on background medications requires evaluation of other SURPASS trials 2.
- Cardiovascular outcomes data are pending—definitive placement in treatment algorithms awaits completion of cardiovascular outcomes trials 2.
SURPASS-2 Trial
No detailed evidence for SURPASS-2 was provided in the available literature. The general SURPASS program overview indicates that SURPASS-2 through SURPASS-5 evaluated tirzepatide with various background medications versus different comparators (semaglutide, insulin degludec, insulin glargine) in different patient populations 2, but specific results cannot be discussed without the primary trial data.