IDF21-0069 Beta-cell function and insulin resistance of type 2 diabetes patients on maximum doses of sulphonylurea-metformin

Abstract

Background: The sulphonylurea-metformin dual therapy is common among type 2 diabetes (T2D) patients before they are escalated to insulin, particularly in developing countries. Although oral therapy often has better acceptance among patients than injectables, the duration of which patients can remain on insulin secretagogues such as sulphonylureas depends on their pancreatic beta-cell function. Aim: In this study, we sought to investigate the factors associated with pancreatic beta-cell function and insulin resistance of type 2 diabetes patients on maximal sulphonylurea-metformin therapy. Method: Using a prospective multicentre design, patients meeting the inclusion criteria which were age 18 years and above, T2D for ≥ 1 year, treatment with maximum doses sulfonylurea-metformin combination for ≥ 1 year, and good adherence to treatment were recruited between September 2014 and March 2016, from seven out-patient clinics across Malaysia and followed up for 12 months. Exclusion criteria were renal impairment (eGFR < 30 ml/min/1.73m2), treatment with other antidiabetic agents, and comorbidities that could potentially confound glycemic parameters. Blood samples were taken at baseline for fasting insulin and fasting c-peptide which were used to construct the homeostatic model assessment of beta-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR). Results: A total of 401 subjects were included in the final analysis of which 44.4% were males. At baseline, their median HbA1c was 8.0% (7.2 – 9.3) (64.0 [55.0 – 78.0] mmol/mol). They also had a median duration of diabetes of 10.0 years (8.0 – 16.0). The median HOMA2-%B was 54.3% (35.2 – 80.1) while the median HOMA2-IR was 2.2 (1.5 – 3.0). A significant positive correlation was observed between BMI and HOMA2-%B (r=0.232, P<0.001). Majority of the subjects who presented with a HOMA2-%B > 50.0% had a diabetes duration of ≤ 10 years. A higher number of subjects who were taking gliclazide modified release (71.3%) had HOMA2-%B level > 50.0% followed by immediate release gliclazide (60.5%) although there were no significant differences among the different types of sulphonylureas in HOMA2-%B level (P=0.054). Increased BMI was significantly associated with increased HOMA2-IR (r=0.236, P<0.001) and there was also a significant positive correlation between waist circumference and HOMA2-IR of subjects (r=0.551, P<0.001). More than two-thirds (65.3%) of subjects failed to achieve the target HbA1c of < 7.0% (53 mmol/mol) at 12 months from baseline. Discussion: The attainment of target HbA1c among T2D patients on maximal sulphonylurea-metformin therapy is difficult despite them having higher pancreatic beta-cell function because they were also more obese and had increased insulin resistance. As sulphonylureas also induce weight increment which contributes to insulin resistance, monitoring the bodyweight of T2D patients upon sulphonylurea initiation is important to prevent excessive weight increase and failure to sulphonylurea therapy. Choosing gliclazide modified release over other sulphonylureas may preserve patients' beta-cell function better. Early combination with a third oral glucose-lowering agent instead of maximizing the dose of the sulphonylurea in sulphonylurea-metformin regimen can be considered when target glucose is not met. This would also probably delay the need to start patients on insulin therapy.