Switching from Dulaglutide to Tirzepatide: Subgroup Analysis of SURPASS-SWITCH

A subgroup analysis of the SURPASS-SWITCH trial, published in BMJ Open Diabetes Research & Care, provides granular evidence supporting the clinical rationale for escalating from single-incretin to dual-incretin peptide therapy in type 2 diabetes.¹

Background

The incretin-based therapy landscape has evolved rapidly. GLP-1 receptor agonists like dulaglutide became standard of care for T2D management, but the arrival of tirzepatide — a dual GIP/GLP-1 receptor agonist — raised a practical question: how should clinicians transition patients already on a GLP-1 agonist to this more potent peptide therapy?

SURPASS-SWITCH was designed to answer this directly.¹

Trial Design

This phase IV, randomized, open-label, active-controlled, parallel-group, multicenter trial enrolled adults with:

• HbA1c ≥7.0% to ≤9.5%
• Stable dulaglutide dose for ≥6 months
• Stable oral antihyperglycemic medications (0–3 agents) for ≥3 months
• BMI ≥25 kg/m²
• Stable body weight

Participants were randomized to either continue dulaglutide or switch to tirzepatide, with follow-up at week 40.¹

Subgroup Results

The prespecified subgroup analysis examined outcomes stratified by:

• Baseline HbA1c level
• Baseline BMI
• Race/ethnicity
• Duration of diabetes
• Age and sex

Key findings across all subgroups:

• HbA1c reduction was consistently greater with tirzepatide, with the largest absolute reductions in patients who started with higher baseline HbA1c
• Weight reduction was consistently greater with tirzepatide, with the most pronounced effects in non-Hispanic/non-Latino participants
• Safety profile was similar across all subgroups, with nausea and diarrhea remaining the most common adverse events¹

The Peptide Therapeutics Angle

Tirzepatide's dual-agonist mechanism illustrates a broader trend in peptide drug design: polypharmacology through a single molecule. By engineering a peptide that engages both the GIP and GLP-1 receptors, tirzepatide achieves:

• Enhanced insulin secretion (GIP pathway)
• Superior appetite suppression (GLP-1 pathway)
• Synergistic weight loss effects not fully explained by either pathway alone

This approach — one peptide, multiple targets — is increasingly the template for next-generation incretin therapies, including retatrutide (triple agonist) and other pipeline candidates.¹

Clinical Takeaways

For clinicians managing T2D patients on GLP-1 agonists:

1. Switching is safe and effective — the transition from dulaglutide to tirzepatide is well-tolerated with predictable glycemic and weight benefits
2. Benefits are consistent — subgroup heterogeneity was minimal, suggesting broad applicability
3. Expect GI side effects — nausea and diarrhea are common during transition but generally manageable
4. The dual-agonist advantage is real — GIP co-activation adds measurable benefit over GLP-1 alone

---

Footnotes

1. Violante-Ortiz R, Rose L, Sharma P, Gomez Valderas E, Chivukula KK. "Safety and efficacy of switching from dulaglutide to tirzepatide across clinically relevant baseline characteristics in participants with T2D: subgroup analysis of SURPASS-SWITCH." BMJ Open Diabetes Res Care. 2026 Mar 30. PMID: 41912265. ↩ ↩² ↩³ ↩⁴ ↩⁵