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

Abstract

AbstractAims/HypothesisIt 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.Methods30 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.ResultsLinear 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-1m-2mM-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.ConclusionsCombination 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.Research in ContextWhat is already known about this subject?Previous isoglycaemic clamp studies in low dose sulphonylureas established that 20mg of gliclazide augments the classical incretin effect, increases glucose sensitivity by 50% and late phase incretin potentiation.What is the key question?What is the effect of low dose sulphonylureas as monotherapy or in combination with a DPP4i on parameters of beta cell function following a mixed meal?What are the new findings?Low dose sulphonylureas have potent glucose lowering potential which is further enhanced by the addition of a DPP4i, without increasing hypoglycaemia.Modelling of beta cell function demonstrates that low dose sulphonylureas heighten the beta cell dose response which is further augmented by the presence of a DPP4i.Phenotypic differences in response are noted, with male participants showing additional effect of glucose sensitivity in response to sulphonylureas. This effect is not seen in women.Gliclazide standard release at 20mg produces a similar pharmacokinetic profile during mixed meal tolerance test to 30mg of modified release gliclazide.How might this impact on clinical practice in the foreseeable future?These results suggest that it is possible to modernise the use of two cheap, effective second-line treatments of type 2 diabetes mellitus through future production of a combined preparation of low dose gliclazide and a DPP4i. This combination has real potential as a safe, efficacious treatment which could bring pharmacoeconomic benefit to low- and middle-income countries worldwide.