Modernising the Use of Sulphonylureas in Type 2 Diabetes Mellitus

Abstract

Objectives: The aim of this thesis is to modernise the use of sulphonylureas (SU), in type 2 diabetes mellitus (T2DM). The hypothesis is that low dose SU will prime beta-cells to the effect of endogenous incretins and promote incretin-mediated insulin secretion, thus avoiding hypoglycaemia. Furthermore, that low dose SU will have enhanced efficacy when used in combination with a DPP4 inhibitor (DPP4i).

Methods: Two clinical studies recruited patients with T2DM, controlled with diet or metformin monotherapy, HbA1c <64 mmol/mol and normal renal and hepatic function.

Firstly, LOGIC Study (n=20) utilised paired oral glucose tolerance tests (OGTT) and isoglycaemic intravenous glucose infusions (IIGI) to demonstrate the incretin effect in the presence and absence of low dose gliclazide.
 
Secondly, the SSS Study (n=30) was an open-label randomised cross-over study utilising multiple mixed meal tolerance tests to establish the effect of low dose SU alone on beta cell function, or in combination with a DPP4i.
 
Finally, a population-based cohort study of individuals in Tayside and Fife receiving insulin or SU (n=27186) aimed to determine the rate and clinical predictors of SU-induced severe hypoglycaemia (SH) using a fixed effect Poisson regression model with time-dependent co-variates.

Results: In LOGIC Study, 20mg of gliclazide reduced mean plasma glucose during the OGTT (Control 12.01 ± 2.2, Gliclazide 10.8 ± 2.0 mmol/l (p=0.0006)) (Mean ± SEM), augmented the classical Incretin Effect INSULIN by 20% (Control 35.5 (27.3, 61.2), Gliclazide 55.0 (34.8 – 72.8) (p<0.05)) (Median (LQ, UQ)), and increased glucose sensitivity by 50% (Control 22.61 ± 3.94, Gliclazide 33.11 ± 7.83 (p=0.01)). Beta-cell modelling showed incretin potentiation to be significant in late-phase (Control 0.92 ± 0.05, Gliclazide 1.29 ± 0.14 (p=0.04)).

The SSS Study showed combination low dose gliclazide with a DPP4i has potent additive glucose lowering effect (Control 11.5 (10.7 – 12.3), DPP4 10.2 (9.4 – 11.1), SU 9.7 (8.9 – 10.5), SUDPP4 8.7 (7.9 – 9.5) mmol/l (p<0.001) (Mean (95% CI)). This was mirrored in progressive increase of glucose sensitivity (pmol min-1 m-2 mM-1) (Control 71.5 (51.1 – 91.9), DPP4 75.9 (55.7 – 96.0), SU 86.3 (66.1 – 106.4), SUDPP4 94.1 (73.9 – 114.3) (p=0.04 SUDPP4 only)). Glucose reduction was achieved with gliclazide concentrations far below those achieved with standard therapeutic doses (~600ng/ml, 20mg gliclazide).

In the population-based cohort study, male gender was found to be protective of SH in patients receiving SU. Increasing age, duration of diabetes, creatinine, along with lower HbA1c and BMI were found to be associated with increased risk of SH. Modified release gliclazide was found to be the safest SU. A validated prediction tool has been created to estimate individual risk of SH.

Conclusion: The work in this thesis has shown that low dose gliclazide is a potent glucose lowering agent and augments the classical incretin effect. Beta-cell function is further enhanced in combination with a DPP4i. The incidence rate of SH associated with SU is low and could be lessened through precision prescribing of modified release preparations through a clinical prediction tool.

Date of Award	2022
Original language	English
Awarding Institution	University of Dundee
Supervisor	Ewan Pearson (Supervisor) & Rory McCrimmon (Supervisor)