Abstract P635: Effect of Patient Characteristics and DPP4 genotype on Dipeptidyl Peptidase IV Activity and Inhibition by Sitagliptin

Dipeptidyl peptidase IV (DPP4) inhibitors are a class of oral antihyperglycemic agents commonly used to treat type 2 diabetes mellitus (T2DM). Evidence suggests that these medications also have cardiovascular effects. We tested the hypothesis that subject characteristics and genetic variability in DPP4 , the gene encoding DPP4, affect response to DPP4 inhibition with sitagliptin. We studied 56 subjects undergoing trials of sitagliptin therapy. DPP4 activity was measured during placebo and after sitagliptin and percent inhibition calculated. Subject characteristics were: 41.1% men (n=23), 19.6% African American (n=11), 30.4% with both T2DM and hypertension (HTN) (n=17), mean age 39.16±15.70 years, and mean BMI 26.71±6.24 kg/m 2 . Sitagliptin doses were 100mg daily for 4-7 days (n=31) or a single dose of 200mg (n=25). Baseline DPP4 activity decreased significantly with age (r=-0.36, p<0.01) and was lower in T2DM HTN (22.54±5.20 vs 26.08±5.88U in non-diabetics, p=0.02). There was no effect of gender, race, weight, or BMI on baseline or inhibited DPP4 activity in T2DM or non-T2DM. Baseline DPP4 activity was significantly lower in rs4664446 (p=0.03; lower activity GG). These characteristics were not significant in a multivariable model. During sitagliptin, DPP4 activity was significantly higher (13.06±5.56 vs 6.85±3.34U, p<0.01) and percent inhibition lower (43±13% vs 74 ±11.2%, p<0.01) in T2DM HTN. Inhibited DPP4 activity declined with age in non-diabetics but not in T2DM. The variant rs2909451 was significantly associated with DPP4 activity during sitagliptin (p<0.01; higher activity TT). In multivariable analysis, inhibited DPP4 activity was associated with T2DM (p=0.02), rs2909451 genotype (p<0.01), but not age (p=0.08) or sitagliptin dose regimen (p=0.24). Inhibition of DPP4 by sitagliptin is decreased in T2DM HTN. Future studies are needed to determine if DPP4 inhibitor dose should be increased in T2DM HTN.