Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide

Weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is heterogeneous across individuals, yet the genetic causes of this variation are not fully known. We integrated exome sequencing data with electronic health records within the Helix Research Network (n = 351,818). Here, we show that, among 13,725 GLP-1RA-treated adults, carriers of rare damaging GLP1R variants lose less weight with semaglutide than matched non-carriers but achieve a near-normal tirzepatide response. Carriers of rare variants in GIPR, which encodes the glucose-dependent insulinotropic polypeptide receptor, the second target of tirzepatide, also achieve normal weight loss responses. Our study demonstrates that rare GLP1R variants affect the response to semaglutide but not to tirzepatide. Rare GLP1R variants are shown to reduce weight loss with semaglutide but not tirzepatide, suggesting GLP1R genetic variation as a pharmacogenetic determinant of GLP-1 receptor agonist efficacy.

Authors

Institutions

Publication Details

Journal
Nature Metabolism
Published
2026-11-11
DOI
https://doi.org/10.1038/s42255-026-01656-z
Primary Topic
Diabetes Treatment and Management
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
article

Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide

Natalie Telis, Kent Shefchek, Chad R. Haldeman‐Englert, Douglas A. Stoller et al.
Nature Metabolism
Diabetes Treatment and Management
article

Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide

Natalie Telis, Kent Shefchek, Chad R. Haldeman‐Englert, Douglas A. Stoller, Jamie L. Renbarger, Nicole L. Washington, Amy Curry Sturm, William H. Lagarde, Kelly M. Schiabor Barrett, James F. Maher, Lisa M. McEwen, Matthew E. Levy, Joseph J. Grzymski, Steven Francis Powell, Daniel Philip Judge, C. Anwar A. Chahal, Pradyumna D. Phatak, Elizabeth T. Cirulli, Douglas A. Olson, Christopher N. Chapman, William Lee
article en

Abstract

Weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is heterogeneous across individuals, yet the genetic causes of this variation are not fully known. We integrated exome sequencing data with electronic health records within the Helix Research Network (n = 351,818). Here, we show that, among 13,725 GLP-1RA-treated adults, carriers of rare damaging GLP1R variants lose less weight with semaglutide than matched non-carriers but achieve a near-normal tirzepatide response. Carriers of rare variants in GIPR, which encodes the glucose-dependent insulinotropic polypeptide receptor, the second target of tirzepatide, also achieve normal weight loss responses. Our study demonstrates that rare GLP1R variants affect the response to semaglutide but not to tirzepatide. Rare GLP1R variants are shown to reduce weight loss with semaglutide but not tirzepatide, suggesting GLP1R genetic variation as a pharmacogenetic determinant of GLP-1 receptor agonist efficacy.

Nature Metabolism
St. Luke's University Health Network (US), Sanford Health (US), Cone Health (US), University of Nevada, Reno (US), Medical University of South Carolina (US), The Ohio State University Wexner Medical Center (US), Unity Health System (US), WakeMed (US), WellSpan Health (US), Parkview Health (US), TriHealth (US), Helix (United States) (US), HealthPartners (US), University of Nebraska Medical Center (US)
Diabetes Treatment and Management
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon