[Skip to Content]

Quiz

Clinical Pharmacy and Pharmacology

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 DiabetesThe SURPASS-5 Randomized Clinical Trial

Educational Objective
To learn about the efficacy and safety of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, when added to insulin glargine in patients with type 2 diabetes who have inadequate glycemic control.

1 Credit CME

JAMA

Published Online: February 8, 2022

Original Investigation

Article Information and Disclosures

Dominik Dahl, MD¹;

Yukiko Onishi, MD, PhD²;

Paul Norwood, MD³;

Ruth Huh, PhD⁴;

Ross Bray, PhD⁴;

Hiren Patel, MPharm⁴;

Ángel Rodríguez, MD, PhD⁵

Author Affiliations

¹Gemeinschaftspraxis für Innere Medizin und Diabetologie, Hamburg, Germany
²The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
³Valley Endocrine and Research, Fresno, California
⁴Eli Lilly and Company, Indianapolis, Indiana
⁵Lilly Spain, Alcobendas, Madrid, Spain

Read article on JAMA Network

Read Article Take Quiz

Key Points

Question 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?

Findings In this randomized clinical trial that included 475 adults, mean change in hemoglobin A_1c 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.

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 A_1c (HbA_1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA_1c levels.

Results Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA_1c, 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 HbA_1c 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 HbA_1c 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 HbA_1c 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

Take Quiz

Sign in to take quiz and track your certificates

Buy This Activity

Article Information

Corresponding Author: Ángel Rodríguez, MD, PhD, Lilly Spain, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain (rodriguez_angel@lilly.com).

Accepted for Publication: January 6, 2022.

Author Contributions: Dr Dahl had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Concept and design: Bray, Patel, Rodríguez.

Acquisition, analysis, or interpretation of data: Dahl, Onishi, Norwood, Huh, Bray, Patel, Rodríguez.

Drafting of the manuscript: Huh, Patel, Rodríguez.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Huh, Bray.

Administrative, technical, or material support: Rodríguez.

Supervision: Dahl, Onishi, Norwood, Patel, Rodríguez.

Other - Clinical and scientific contributions: Patel.

Conflict of Interest Disclosures: Dr Dahl reported receiving personal fees from Eli Lilly during the conduct of the study and personal fees from Afimmune, Novo Nordisk, and Novartis outside the submitted work. Dr Onishi reported receiving personal fees from Sumitomo Dainippon Pharma and Novo Nordisk outside the submitted work. Dr Norwood reported receiving grants from Eli Lilly during the conduct of the study and owning stock shares in Eli Lilly outside the submitted work. Dr Huh reported being an employee and shareholder of Eli Lilly and Company. Dr Bray reported being an employee and shareholder of Eli Lilly and Company. Dr Patel reported being an employee of and shareholder in Eli Lilly and Company during the conduct of the study. Dr Rodríguez reported being an employee and shareholder in Eli Lilly and Company. No other disclosures were reported.

Funding/Support: This study was sponsored by Eli Lilly and Company.

Role of the Funder/Sponsor: Eli Lilly and Company was involved in the study design and conduct; data collection, management, analyses, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The sponsor did not have the right to veto publication or to control the decision regarding to which journal the manuscript was submitted. Final decisions resided with the authors, which included employees of the sponsor.

Meeting Presentations: Part of the data presented in this article was presented at the 81st Scientific Sessions of the American Diabetes Association; June 25-29, 2021; and the 57th European Association for Study of Diabetes; September 28-October 01, 2021.

Additional Contributions: We thank the patients participating in the trial as well as the collaborating research coordinators and investigators who supported this work. We thank Weiguo Zhu, PhD, and Liping Liu, MS, for their contributions to the data preparation and analysis, for which they were compensated as part of their salary as employees of Eli Lilly and Company. Dr Shirin Ghodke, PhD, provided writing and editorial assistance, for which she was compensated as part of her salary as employee of Eli Lilly India Services Private Limited.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.