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

Abstract

Background/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.