Pharmacogenomic study of the effects of saxagliptin on glucose control and hypoglycemic events

TY - JOUR

T1 - Pharmacogenomic study of the effects of saxagliptin on glucose control and hypoglycemic events

AU - Pilon, Marc Olivier

AU - de Denus, Simon

AU - Asselin, Géraldine

AU - Legault, Marc André

AU - Ngongang Kwandjang, Hervira Brenda

AU - Barhdadi, Amina

AU - Lemieux Perreault, Louis Philippe

AU - Valois, Diane

AU - Mongrain, Ian

AU - Haefliger, Carolina

AU - Paul, Dirk S.

AU - Pearson, Ewan R.

AU - Tardif, Jean Claude

AU - Dubé, Marie Pierre

N1 - Copyright: © The Author(s) 2026.

PY - 2026/3/26

Y1 - 2026/3/26

N2 - Background: Saxagliptin is a DPP-4 inhibitor widely used to manage type 2 diabetes, though genetic contributors to variability in response remain unclear. This study aimed to identify genetic variants associated with the efficacy and safety of saxagliptin using genome-wide association studies (GWAS) with data from randomized controlled trials.Methods: GWAS were conducted on glycated hemoglobin (HbA1c) levels and hypoglycemic events in saxagliptin-treated individuals from 12 phase II or III clinical trials. Additional exploratory traits included fasting glucose, weight, body mass index, systolic and diastolic blood pressure, heartbeat, and renal function. Primary analyses focused on participants of European ancestry, followed by analyses in the overall multi-ancestry cohort. Linear mixed models for continuous traits and Cox proportional hazards models for time-to-event analyses were used, including gene-by-sex and gene-by-treatment interactions. We also performed a transcriptome-wide association study (TWAS) to identify genes whose predicted expression is associated with the response to saxagliptin using the S-PrediXcan framework.Results: Among 1 016 European and 1 826 multi-ancestry saxagliptin-treated participants, no genome-wide significant associations were observed. Suggestive associations included rs2168426:T > C near UBE2E1 for HbA1c (p = 1.0 × 10⁻⁷) and rs138558907:C > T near CCSER2 for hypoglycemia (p = 6.1 × 10⁻⁸). Treatment interaction analyses showed a stronger rs2168426 effect on HbA1c among saxagliptin users compared with non-users (pint = 9.2 × 10⁻³). The TWAS revealed three genes that significantly associated with HbA1c in human tissues: OGFOD3 in aorta (p = 8.3 × 10⁻⁷), TBC1D3D in coronary artery (p = 3.3 × 10⁻⁶), and TYSND1 in amygdala (p = 3.9 × 10⁻⁶). In the multi-ancestry cohort, KDM7A in whole blood was significantly associated with HbA1c (p = 3.6 × 10⁻⁶).Conclusion: Larger, diverse studies are needed to identify pharmacogenomic determinants of responses to saxagliptin.

AB - Background: Saxagliptin is a DPP-4 inhibitor widely used to manage type 2 diabetes, though genetic contributors to variability in response remain unclear. This study aimed to identify genetic variants associated with the efficacy and safety of saxagliptin using genome-wide association studies (GWAS) with data from randomized controlled trials.Methods: GWAS were conducted on glycated hemoglobin (HbA1c) levels and hypoglycemic events in saxagliptin-treated individuals from 12 phase II or III clinical trials. Additional exploratory traits included fasting glucose, weight, body mass index, systolic and diastolic blood pressure, heartbeat, and renal function. Primary analyses focused on participants of European ancestry, followed by analyses in the overall multi-ancestry cohort. Linear mixed models for continuous traits and Cox proportional hazards models for time-to-event analyses were used, including gene-by-sex and gene-by-treatment interactions. We also performed a transcriptome-wide association study (TWAS) to identify genes whose predicted expression is associated with the response to saxagliptin using the S-PrediXcan framework.Results: Among 1 016 European and 1 826 multi-ancestry saxagliptin-treated participants, no genome-wide significant associations were observed. Suggestive associations included rs2168426:T > C near UBE2E1 for HbA1c (p = 1.0 × 10⁻⁷) and rs138558907:C > T near CCSER2 for hypoglycemia (p = 6.1 × 10⁻⁸). Treatment interaction analyses showed a stronger rs2168426 effect on HbA1c among saxagliptin users compared with non-users (pint = 9.2 × 10⁻³). The TWAS revealed three genes that significantly associated with HbA1c in human tissues: OGFOD3 in aorta (p = 8.3 × 10⁻⁷), TBC1D3D in coronary artery (p = 3.3 × 10⁻⁶), and TYSND1 in amygdala (p = 3.9 × 10⁻⁶). In the multi-ancestry cohort, KDM7A in whole blood was significantly associated with HbA1c (p = 3.6 × 10⁻⁶).Conclusion: Larger, diverse studies are needed to identify pharmacogenomic determinants of responses to saxagliptin.

KW - Genome-wide association studies

KW - HbA1c

KW - Hypoglycemic event

KW - Pharmacogenomics

KW - Saxagliptin

UR - https://www.scopus.com/pages/publications/105037763007

U2 - 10.1186/s12920-026-02348-z

DO - 10.1186/s12920-026-02348-z

M3 - Article

C2 - 41882721

AN - SCOPUS:105037763007

SN - 1755-8794

VL - 19

JO - BMC Medical Genomics

JF - BMC Medical Genomics

IS - 1

M1 - 72

ER -