“Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial”, 2022-02-08 (; backlinks):
Question: [previously: SURPASS-4] What is the effect of once-weekly subcutaneous tirzepatide compared with placebo when added to titrated insulin glargine on glycemic control in patients with type 2 diabetes?
Results: In this randomized clinical trial that included 475 adults, mean change in hemoglobin A1c at 40 weeks was −2.40% with 10-mg tirzepatide, −2.34% with 15-mg tirzepatide and −0.86% with placebo; the differences between each tirzepatide group vs the placebo group were statistically-significant.
Meaning: Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically-significant improvements in glycemic control after 40 weeks.
Importance: The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described.
Objective: To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.
Design, Setting, & Participants: Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.
Interventions: Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved.
Main Outcomes & Measures: The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels.
Results: Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group…The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%–21% vs 10%) and nausea (13%–18% vs 3%).
At week 40, mean HbA1c change from baseline was −2.40% with 10-mg tirzepatide and −2.34% with 15-mg tirzepatide vs −0.86% with placebo (10 mg: difference vs placebo, −1.53% [97.5% CI, −1.80% to −1.27%]; 15 mg: difference vs placebo, −1.47% [97.5% CI, −1.75% to −1.20%]; p < 0.001 for both). Mean HbA1c change from baseline was −2.11% with 5-mg tirzepatide (difference vs placebo, −1.24% [95% CI, −1.48% to −1.01%]; p < 0.001).
Mean body weight change from baseline was −5.4 kg with 5-mg tirzepatide, −7.5 kg with 10-mg tirzepatide, −8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, −7.1 kg [95% CI, −8.7 to −5.4]; 10 mg: difference, −9.1 kg [95% CI, −10.7 to −7.5]; 15 mg: difference, −10.5 kg [95% CI, −12.1 to −8.8]; p < 0.001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%–90% vs 34%; p < 0.001 for all).
Conclusions & Relevance: Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically-significant improvements in glycemic control after 40 weeks.
Trial Registration: ClinicalTrials.gov Identifier: NCT04039503.