Inclusion criteria for this study were

• T2D
• glycated hemoglobin (HbA1c) ≥7.0% and ≤10.5% at screening
• body mass index (BMI) ≥25 kg/m² with stable weight
• insulin-naive (except short-term use or treatment of gestational diabetes), and
• stable dose of metformin (≥1500 mg/day) with or without SGLT-2 inhibitor.2

Exclusion criteria for this study were

• type 1 diabetes (T1D) 
• history of pancreatitis
  
• estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m², and 
• history of proliferative diabetic retinopathy or maculopathy (or nonproliferative diabetic retinopathy requiring acute treatment).2

This study randomized 1444 adults with T2D across Argentina, Austria, Greece, Hungary, Italy, Poland, Puerto Rico, Romania, South Korea, Spain, Taiwan, Ukraine, and the United States in 1:1:1:1 ratio to receive either tirzepatide 5, 10, or 15 mg, or titrated insulin degludec with metformin with or without an SGLT-2 inhibitor.2

The primary objective of the study was to demonstrate that tirzepatide 10 and/or 15 mg once weekly are noninferior to insulin degludec for change from baseline in HbA1c at 52 weeks.2

The SURPASS-3 study design included a 52-week study period. The starting dose of tirzepatide was 2.5 mg once weekly for 4 weeks, escalated in 2.5 mg increments every 4 weeks until the assigned dose of 5, 10, or 15 mg was achieved, which took up to 20 weeks. The starting dose of insulin degludec was 10 IU/day ideally at bedtime titrated with the goal of fasting serum glucose (FSG) less than 90 mg/dL following a treat-to-target algorithm with a 16-week initial insulin titration period (SURPASS-3 Study Design).2

Baseline demographics and clinical characteristics of randomized patients are presented in SURPASS-3 Baseline Demographics and Clinical Characteristics.2

Treatment discontinuation in SURPASS-3 is summarized in Summary of Treatment Discontinuation in SURPASS-3 . In patients treated with tirzepatide, the most common reason for treatment discontinuation was adverse events (AEs).2

Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data from the phase 3 clinical trials of tirzepatide. Efficacy estimand evaluates the treatment effect prior to discontinuation of the study drug without confounding effects of antihyperglycemic rescue therapy. Treatment-regimen estimand evaluates the treatment effect irrespective of adherence to the study drug or initiation of rescue antidiabetic drugs. Differences in reported data may reflect the application of these estimands. This response presents data reflecting the efficacy estimand. For treatment-regimen estimand results, please refer to the manuscript cited and/or the US prescribing information, where applicable.3

At 52 weeks, tirzepatide 5, 10, and 15 mg were superior compared with insulin degludec in

• mean change in HbA1c from baseline
• mean change in weight from baseline, and
• proportion of participants achieving HbA1c <7.0% (SURPASS-3: Primary and Secondary Endpoints at 52 Weeks).2

The most frequently reported AEs for patients treated with tirzepatide were gastrointestinal in nature. Most cases of nausea, vomiting, and diarrhea were mild to moderate in severity and usually occurred during the dose escalation period and decreased with continued use.2

Overview of AEs and treatment-emergent adverse events (TEAEs) with ≥5% frequency is provided in SURPASS-3: Overview of Adverse Events Through 52 Weeks  and Treatment-Emergent Adverse Events With ≥5% Frequency Through 52 Weeks in SURPASS-3.

Hypoglycemia frequency is provided in SURPASS-3: Hypoglycemia Frequency Through Week 52.2