A double-blind, Randomized controlled trial on glucose-lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase-4 inhibitor therapy: REFIND study

Abstract

Aims: To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to patients with type 2 diabetes mellitus (T2DM) with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy.

Materials and methods: In this phase 4, multicentre, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycaemic control, expressed as the difference in mean glycated haemoglobin levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin.

Results: At week 24, the mean glycated haemoglobin levels were 6.87 ± 0.54% and 6.68 ± 0.46% in low-dose and standard-dose lobeglitazone groups, respectively (p = .031). The between-group difference was 0.18% (95% confidence interval 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36 ± 2.23 kg) than in the low-dose group (0.50 ± 1.85 kg) at week 24. The changes in HOMA-IR, lipid profile and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, oedema and hypoglycaemia) occurred more frequently in the standard-dose group.

Conclusions: Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in patients with T2DM.

Keywords: antidiabetic drugs; beta-cell function; glycaemic control; thiazolidinediones; type 2 diabetes.

FIGURE 1

Patient allocation. FAS, full analysis set

FIGURE 2

Comparing efficacy outcomes between the low‐dose and the standard‐dose group after 24 weeks from baseline. A, Mean HbA1c level (%). B, Changes to HbA1c level (%). C, Changes to body weight (kg). D, Changes to serum adiponectin level (μg/ml). *p < .05, **p < .001; 24 weeks versus baseline. HbA1c, glycated haemoglobin

FIGURE 3

Comparison of efficacy outcomes between the low‐dose and the standard‐dose groups after 24 weeks from baseline (continued). A, Proportion of patients achieving target HbA1c <7%. B, Changes to HOMA‐IR. C, Changes to lipid profiles (mg/dl). D, Changes to Liver enzyme level (U/L). *p < .05, **p < .001; 24 weeks versus baseline. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high‐density lipoprotein; HOMA‐IR, homeostatic model assessment of insulin resistance; LDL, low‐density lipoprotein

FIGURE 4

Subgroup analysis. Mean changes of HbA1c (%) from baseline to the end of treatment (24 weeks) in patient subgroups defined by sex, BMI (<25 or ≥25 kg/m²), age (<60 or ≥ 60 years), baseline HbA1c values (<8 or ≥8 %) and duration of T2DM (<10 or ≥ 10 years). BMI, body mass index; HbA1c, glycated haemoglobin; T2DM, type 2 diabetes mellitus.