Low dose sulphonylurea plus DPP4 inhibitor lower blood glucose and enhance beta cell function without hypoglycaemia.

Abstract

Low dose sulphonylureas have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. To evaluate potential synergy between low dose sulphonylurea plus DPP4 inhibitor. Unblinded randomised crossover study. Clinical Research Centre, University of Dundee. 30 participants with T2DM (HbA1c < 64 mmol/mol) treated with diet or metformin. Participants completed four, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4i), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/l on continuous glucose monitoring, sub-analyses by genotype (KNCJ11 E23 K), gender and body mass index. SU combination with DPP4i showed additive effect on glucose lowering: Mean glucose AUC (mean 95% CI) (mmol/l) was: Control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (p < 0.001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2mM-1): Control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (p = 0.04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (p = 0.65). Low dose sulphonylurea plus DPP4i has potent glucose lowering effect through augmentation of beta cell function. A double-blind randomised controlled trial would formalise efficacy and safety of this combination, which may avoid negative aspects of SU.