Combination low dose sulphonylurea and DPP4 inhibitor have potent glucose effect through augmentation of beta cell function without increase in hypoglycaemia: a randomised crossover study. a randomised crossover study

Aims/Hypothesis: It is important to address our use of cheaper generic therapies as the global prevalence of type 2 diabetes (T2DM) will surpass 600 million by 2035. Negative aspects of SU may be avoided by their use at low dose. We have previously shown that 20mg standard release gliclazide reduces plasma glucose through augmentation of the classical incretin effect, increased beta-cell glucose sensitivity and late-phase incretin potentiation. We hypothesised that there would be potential synergy between low dose SU when given in combination with a DPP4i, without increased hypoglycaemia risk, and aimed to assess this in a randomised clinical trial.

Methods: 30 participants with T2DM (HbA1c <64 mmol/mol) treated with diet or metformin monotherapy were recruited to a single-centre, open-label, randomised crossover study. Participants completed four, 14-day study periods in a random order: control, gliclazide 20mg once daily (SU), sitagliptin 100mg (DPP4i), or combination (SUDPP4i). A 2-hour mixed meal tolerance test was conducted at the end of each block. Beta-cell function was assessed by modelling. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary end points included frequency of blood glucose <3mmol/l on continuous glucose monitoring, sub analysis by genotype (KNCJ11 E23K), and analysis by gender and body mass index.

Results: Linear mixed model estimates showed a potent additive, glucose lowering effect of low dose SU combination with DPP4. 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). Beta-cell glucose sensitivity (pmol min-1 m-2 mM-1) mirrored this additive effect: 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). Glucose time in range <3mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2 – 7) (p = 0.65). The increase in glucose sensitivity with sulphonylurea treatment was seen in men not women.

Conclusions: Combination low dose gliclazide with a DPP4i has potent glucose lowering effect through augmentation of beta cell function. Glucose reduction was achieved at gliclazide concentrations far below those achieved with standard therapeutic doses. A double-blind randomised controlled trial is merited to formalise efficacy and safety of this combination, which may avoid negative aspects of SU and provide pharmacoeconomic benefit in diabetes care.