Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5

Rodolfo J Galindo; Louis J Aronne; Deborah B Horn; Alexander D Miras; Julia P Dunn; Dachuang Cao; Clare J Lee; Chrisanthi A Karanikas; Robert J Heine; Beverly L Falcon; Georgios K Dimitriadis

doi:10.1007/s40618-026-02895-3

Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5

Rodolfo J Galindo
, Louis J Aronne
, Deborah B Horn
, Alexander D Miras
, Julia P Dunn
, Dachuang Cao
, Clare J Lee
, Chrisanthi A Karanikas
, Robert J Heine
, Beverly L Falcon
, Georgios K Dimitriadis

Eli Lilly and Company

Research output: Contribution to journal › Article › peer-review

2 Downloads (Pure)

Abstract

Background
Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D.

Purpose
Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5.

Methods
Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4%, were included in this analysis. Change from baseline in HbA1c, proportion of participants achieving normoglycemia (i.e., HbA1c < 5.7% and FSG < 100 mg/dL), percent change from baseline in body weight, fasting insulin, estimates of insulin sensitivity (HOMA2-IR), and proportion of participants achieving body weight reduction thresholds (≥ 10% to ≥ 30%) at Week 72 were assessed using MMRM or logistic regression for categorical measures using the efficacy analysis set.

Results
Mean baseline age was 47 years, 63% were female, BMI was 40 kg/m2, and HbA1c was 5.86%. At Week 72, mean HbA1c reduction was significantly greater with tirzepatide vs semaglutide (-0.60% vs -0.48%; estimated treatment difference [ETD; 95% CI] -0.12% [−0.18, −0.06]; p < 0.001). A greater proportion of tirzepatide-treated participants reverted to normoglycemia (89.9%) vs semaglutide (76.2%). Mean percent body weight reduction was significantly greater with tirzepatide (−21.5% vs -14.5%; ETD −7.1% [−9.1, −5.0]; p < 0.001). Greater improvements in fasting insulin and HOMA2-IR were observed with tirzepatide vs semaglutide (p < 0.001).

Conclusion
In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants with obesity and prediabetes at baseline reverted to normoglycemia compared with semaglutide. Greater improvements in glycemia, estimates of insulin sensitivity and body weight were also observed with tirzepatide.

Original language	English
Number of pages	10
Journal	Journal of Endocrinological Investigation
Early online date	20 Apr 2026
DOIs	https://doi.org/10.1007/s40618-026-02895-3
Publication status	Published (in print/issue) - 20 Apr 2026

Bibliographical note

Data Availability Statement

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

Funding

This work is supported by Eli Lilly and Company.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Tirzepatide
Prediabetes
SURMOUNT-5
Semaglutide
Clinical trial
Obesity
Post hoc analysis

Access to Document

10.1007/s40618-026-02895-3Licence: CC BY

s40618-026-02895-3Final published version, 1 MBLicence: CC BY

Cite this

Galindo, R. J., Aronne, L. J., Horn, D. B., Miras, A. D., Dunn, J. P., Cao, D., Lee, C. J., Karanikas, C. A., Heine, R. J., Falcon, B. L., & Dimitriadis, G. K. (2026). Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5. Journal of Endocrinological Investigation. https://doi.org/10.1007/s40618-026-02895-3

@article{419bb5aa857a4449a1dbd6c86843754b,

title = "Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5",

abstract = "Background Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D. Purpose Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5. Methods Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4\%, were included in this analysis. Change from baseline in HbA1c, proportion of participants achieving normoglycemia (i.e., HbA1c < 5.7\% and FSG < 100 mg/dL), percent change from baseline in body weight, fasting insulin, estimates of insulin sensitivity (HOMA2-IR), and proportion of participants achieving body weight reduction thresholds (≥ 10\% to ≥ 30\%) at Week 72 were assessed using MMRM or logistic regression for categorical measures using the efficacy analysis set. Results Mean baseline age was 47 years, 63\% were female, BMI was 40 kg/m2, and HbA1c was 5.86\%. At Week 72, mean HbA1c reduction was significantly greater with tirzepatide vs semaglutide (-0.60\% vs -0.48\%; estimated treatment difference [ETD; 95\% CI] -0.12\% [−0.18, −0.06]; p < 0.001). A greater proportion of tirzepatide-treated participants reverted to normoglycemia (89.9\%) vs semaglutide (76.2\%). Mean percent body weight reduction was significantly greater with tirzepatide (−21.5\% vs -14.5\%; ETD −7.1\% [−9.1, −5.0]; p < 0.001). Greater improvements in fasting insulin and HOMA2-IR were observed with tirzepatide vs semaglutide (p < 0.001). Conclusion In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants with obesity and prediabetes at baseline reverted to normoglycemia compared with semaglutide. Greater improvements in glycemia, estimates of insulin sensitivity and body weight were also observed with tirzepatide.",

keywords = "Tirzepatide, Prediabetes, SURMOUNT-5, Semaglutide, Clinical trial, Obesity, Post hoc analysis",

author = "Galindo, \{Rodolfo J\} and Aronne, \{Louis J\} and Horn, \{Deborah B\} and Miras, \{Alexander D\} and Dunn, \{Julia P\} and Dachuang Cao and Lee, \{Clare J\} and Karanikas, \{Chrisanthi A\} and Heine, \{Robert J\} and Falcon, \{Beverly L\} and Dimitriadis, \{Georgios K\}",

note = "{\textcopyright} The Author(s) 2026",

year = "2026",

month = apr,

day = "20",

doi = "10.1007/s40618-026-02895-3",

language = "English",

journal = "Journal of Endocrinological Investigation",

issn = "1720-8386",

publisher = "Springer International Publishing",

}

TY - JOUR

T1 - Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5

AU - Galindo, Rodolfo J

AU - Aronne, Louis J

AU - Horn, Deborah B

AU - Miras, Alexander D

AU - Dunn, Julia P

AU - Cao, Dachuang

AU - Lee, Clare J

AU - Karanikas, Chrisanthi A

AU - Heine, Robert J

AU - Falcon, Beverly L

AU - Dimitriadis, Georgios K

PY - 2026/4/20

Y1 - 2026/4/20

N2 - Background Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D. Purpose Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5. Methods Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4%, were included in this analysis. Change from baseline in HbA1c, proportion of participants achieving normoglycemia (i.e., HbA1c < 5.7% and FSG < 100 mg/dL), percent change from baseline in body weight, fasting insulin, estimates of insulin sensitivity (HOMA2-IR), and proportion of participants achieving body weight reduction thresholds (≥ 10% to ≥ 30%) at Week 72 were assessed using MMRM or logistic regression for categorical measures using the efficacy analysis set. Results Mean baseline age was 47 years, 63% were female, BMI was 40 kg/m2, and HbA1c was 5.86%. At Week 72, mean HbA1c reduction was significantly greater with tirzepatide vs semaglutide (-0.60% vs -0.48%; estimated treatment difference [ETD; 95% CI] -0.12% [−0.18, −0.06]; p < 0.001). A greater proportion of tirzepatide-treated participants reverted to normoglycemia (89.9%) vs semaglutide (76.2%). Mean percent body weight reduction was significantly greater with tirzepatide (−21.5% vs -14.5%; ETD −7.1% [−9.1, −5.0]; p < 0.001). Greater improvements in fasting insulin and HOMA2-IR were observed with tirzepatide vs semaglutide (p < 0.001). Conclusion In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants with obesity and prediabetes at baseline reverted to normoglycemia compared with semaglutide. Greater improvements in glycemia, estimates of insulin sensitivity and body weight were also observed with tirzepatide.

AB - Background Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D. Purpose Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5. Methods Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4%, were included in this analysis. Change from baseline in HbA1c, proportion of participants achieving normoglycemia (i.e., HbA1c < 5.7% and FSG < 100 mg/dL), percent change from baseline in body weight, fasting insulin, estimates of insulin sensitivity (HOMA2-IR), and proportion of participants achieving body weight reduction thresholds (≥ 10% to ≥ 30%) at Week 72 were assessed using MMRM or logistic regression for categorical measures using the efficacy analysis set. Results Mean baseline age was 47 years, 63% were female, BMI was 40 kg/m2, and HbA1c was 5.86%. At Week 72, mean HbA1c reduction was significantly greater with tirzepatide vs semaglutide (-0.60% vs -0.48%; estimated treatment difference [ETD; 95% CI] -0.12% [−0.18, −0.06]; p < 0.001). A greater proportion of tirzepatide-treated participants reverted to normoglycemia (89.9%) vs semaglutide (76.2%). Mean percent body weight reduction was significantly greater with tirzepatide (−21.5% vs -14.5%; ETD −7.1% [−9.1, −5.0]; p < 0.001). Greater improvements in fasting insulin and HOMA2-IR were observed with tirzepatide vs semaglutide (p < 0.001). Conclusion In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants with obesity and prediabetes at baseline reverted to normoglycemia compared with semaglutide. Greater improvements in glycemia, estimates of insulin sensitivity and body weight were also observed with tirzepatide.

KW - Tirzepatide

KW - Prediabetes

KW - SURMOUNT-5

KW - Semaglutide

KW - Clinical trial

KW - Obesity

KW - Post hoc analysis

UR - https://pure.ulster.ac.uk/en/publications/419bb5aa-857a-4449-a1db-d6c86843754b

UR - https://www.scopus.com/pages/publications/105036167336

U2 - 10.1007/s40618-026-02895-3

DO - 10.1007/s40618-026-02895-3

M3 - Article

C2 - 42002673

SN - 1720-8386

JO - Journal of Endocrinological Investigation

JF - Journal of Endocrinological Investigation

ER -

Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this