Reduced Weight Gain with Pioglitazone vs Vildagliptin in CREBRF rs373863828 A-allele Carriers: Insights from the WORTH Trial

Zanetta LL Toomata,1,2 Yannan Jiang,3,4 Rui Qian Yeu,5 Rebecca Brandon,6 Ry Yves Tweedie-Cullen,1,2 Norma Nehren,7 Glenn Doherty,8 Huti Watson,9 Kerry A Macaskill-Smith,10 Megan Leask,2,11,12 Tony R Merriman,12,13 Ryan Paul,2,14 Troy L Merry,2,15 Peter R Shepherd,2,16 Rinki Murphy1,2 1Department of Medicine, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New Zealand; 2Maurice Wilkins Centre for Molecular Biodiscovery, the University of Auckland, Auckland, New Zealand; 3Department of Statistics, Faculty of Sciences, the University of Auckland, Auckland, New Zealand; 4National Institute for Health Innovation, School of Population Health, the University of Auckland, Auckland, New Zealand; 5Te Whatu Ora Te Toka Tumai Auckland, Auckland District Health Board, Auckland, New Zealand; 6Defence Health Centre, Waiouru, New Zealand; 7Te Hiku Hauora, Kaitaia, Northland District Health Board, Kaitaia, New Zealand; 8Tongan Health Society, Auckland, New Zealand; 9Ngāti Porou Oranga Trust (A Māori Health Provider), Te Puia Springs, Gisborne, New Zealand; 10Fairfield Medical Centre, Hamilton, New Zealand; 11Department of Biochemistry, University of Otago, Dunedin, New Zealand; 12Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; 13Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand; 14Te Huataki Waiora School of Health, University of Waikato, Waikato, New Zealand; 15Discipline of Nutrition, University of Auckland, Auckland, New Zealand; 16Department of Molecular Medicine and Pathology, School of Medical Sciences, the University of Auckland, Auckland, New ZealandCorrespondence: Zanetta LL Toomata, Email [email protected] Rinki Murphy, Email [email protected]/Objectives: This subgroup analysis of a randomised, open-label, two-period crossover trial in Aotearoa New Zealand (February 2019 to March 2020) assessed whether the glucose-lowering effects of vildagliptin, vs pioglitazone varied by the CREBRF (p.Arg457Gln) rs373863828 genotype.Methods: Adults with type 2 diabetes and HbA1c > 58 mmol/mol (> 7.5%) received either pioglitazone (30 mg) or vildagliptin (50 mg) for 16 weeks, then switched medications for another 16 weeks. Differences in HbA1c between treatments (pioglitazone vs vildagliptin) were tested for an interaction with CREBRF rs373863828 A-allele carrier status and controlling for baseline HbA1c using linear mixed models. Secondary endpoints included weight, systolic blood pressure, and diabetes treatment satisfaction.Results: Participants with the AA/AG genotype had a higher baseline weight than those with the GG genotype (121.4 kg vs 106.6 kg, respectively; p< 0.01). No significant difference in achieved HbA1c was found based on A-allele carrier status (0.43 mmol/mol; 95% CI − 4.83, 5.69; p=0.87). Among Māori and Pacific participants with the A-allele, a smaller weight difference was observed after pioglitazone vs vildagliptin compared to those with the GG genotype (interaction effect − 1.66 kg; 95% CI − 3.27, − 0.05; p=0.04).Conclusion: CREBRF rs373863828 A-allele carriers show a similar HbA1c-lowering response to pioglitazone vs vildagliptin compared to non-carriers but exhibit less weight gain with pioglitazone, despite having significantly higher baseline weights.Keywords: pioglitazone, vildagliptin, CREBRF, pharmacogenetics, precision medicine, stratified drug response