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

Abstract

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, and 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 and 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. 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 < .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 < .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 < .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 < .001 for all). 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%).

Conclusions and 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.

Figure 1.. Screening, Randomization, and Flow of Patients in the SURPASS-5 Trial

^aIncludes 1 participant each with absence of type 2 diabetes diagnosis, body mass index <23, serum calcitonin level ≥35 ng/L, not able to meet study requirements or of completing protocol due to drug/alcohol misuse or psychiatric disorder as judged by the investigator, and history of active/untreated malignancy or in remission. ^bSee eTable 3 in Supplement 2 for the details of the adverse events that led to study drug discontinuation. ^cStudy discontinuations include both before and after the primary end point visit.

Figure 2.. Outcomes in a Study of the Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control

Arrowheads on the x-axis indicate the time points when maintenance doses of 5-mg, 10-mg, and 15-mg tirzepatide were achieved. Error bars represent 95% CI for the estimated mean. A and C, Treatment regimen estimand (corresponding analyses used the full analysis set) that evaluated treatment effects regardless of treatment adherence or use of rescue therapy. Missing values at week 40 were imputed 100 times using method of multiple imputation based on the placebo group. Analysis of covariance model was used with treatment, country, and baseline metformin use as fixed effects and baseline glycated hemoglobin A1c (HbA_1c) value as a covariate. C, Logistic regression was used with the same fixed effects and covariate as that for analysis of covariance model. See eFigure 2 in Supplement 2 for corresponding data for the efficacy estimand. B, D, E, and F, Efficacy estimand (corresponding analyses used the efficacy analysis set) that evaluated treatment effects using on-treatment data without use of rescue therapy. Mixed-model for repeated measures was used with treatment, visit, treatment × visit interaction, country, baseline metformin use, baseline HbA_1c category (≤8.0% or >8.0% [≤64 mmol/mol or >64 mmol/mol]) (except for HbA_1c related analyses) as fixed effects and baseline endpoint value as a covariate. The number of patients assessed at each time point for HbA_1c, fasting serum glucose, body weight, and insulin glargine dose over time are described in eTable 3 in Supplement 2. F, Insulin doses were log-transformed before analysis to account for their skewed distribution and estimated ratio to baseline were transformed back for interpretation expressed as percent change from baseline to week 40 and estimated percent difference vs placebo.