Twice-daily imeglimin monotherapy is associated with significant improvements in HbA1c, confirming the efficacy, safety, and tolerability of this treatment compared with placebo, according to research published in Diabetes Care.
Through the phase 3, randomized, double-blind, parallel-group, multicenter TIMES 1 trial, French researchers sought to determine the safety, efficacy, and tolerability of twice-daily imeglimin 1,000 mg monotherapy compared with placebo in a cohort of Japanese patients with type 2 diabetes insufficiently controlled through diet and exercise.
Eligible participants were adults at least 20 years of age with T2D treated with diet and exercise, with or without a stable dose of a single oral antidiabetic agent for at least 12 weeks before screening and with an HbA1c of 7% to 10% (53-86 mmol/mol).
The primary efficacy endpoint was change in baseline HbA1c at 24 weeks vs placebo. Key secondary endpoints included the percentage of responders based on the following definitions: first, the percentage of patients who reached the target HbA1c of less than 7% (<53 mmol/mol) at week 24; and second, the percentage of patients with a relative decrease of ≥7% from baseline HbA1c at 24 weeks.
Exploratory endpoints included the percentage of patients who required rescue therapy and the change from baseline to 24 weeks in fasting plasma glucose levels and lipid parameters.
Eligible participants (n=107) were randomly assigned 1:1 to either a treatment (oral imeglimin 1000 mg twice daily) or placebo group. Baseline characteristics were similar between groups in terms of mean age (62 years; 46.9% ≥65 years), HbA1c, diabetes duration, body mass index (BMI), and estimated glomerular filtration rate (eGFR; mean, 71.31 mL/min/1.73/m2). The majority (71.8%) of patients were treatment naïve.
By week 24, HbA1c significantly decreased by 0.72% (95% CI, -0.86 to -0.58 [7.9 mmol/mol; 95% CI, -9.6 to -6.3]) in the imeglimin group, compared with a nonsignificant increase of 0.15% (95% CI, 0.01-0.29 [1.6 mmol/mol; 95% CI, 0.1-3.2]) in the placebo group (estimated treatment difference, -0.87%; 95% CI, -1.04 to -0.69 [9.5 mmol/mol; 95% CI, -11.4 to -7.5]). By week 24, HbA1c <7% (53 mmol/mol) was achieved by “significantly more patients” in the imeglimin group vs the placebo group (35.8% vs 7.5%). A relative decrease of ≥7% from baseline HbA1c was also achieved by significantly more patients in the imeglimin group (57.5% vs 11.3%).
Decrease in HbA1c was consistent across age groups; at 24 weeks, HbA1c decreased by 0.70% (7.7 mmol/mol) in those younger than 65 years and by 0.75% (8.2 mmol/mol) in the elderly. This decrease was also consistent across groups stratified by chronic kidney disease stage.
Among treatment naïve patients, week 24 HbA1c significantly decreased by 0.81% (8.9 mmol/mol) in the treatment group, compared with a 0.06% (0.7 mmol/mol) increase in the placebo group (estimated treatment difference, -0.87%; 95% CI, -1.97 to -0.67 [-9.5 mmol/mol; 95% CI, -11.7 to -7.3]). Among those who received previous treatment, HbA1c decreased significantly in the imeglimin group and increased by 0.33% (3.6 mmol/mol) with placebo.
All patients (5.7%) who required rescue therapy were in the placebo group.
No deaths were reported in either group, and both groups had a similar proportion of participants who reported any adverse events—most of which were of mild intensity. Five patients experienced serious adverse events. Four patients reported hypoglycemia group (imeglimin n=3), and no effects on blood pressure or body weight were reported. Total cholesterol and low-density lipoprotein cholesterol increased by 3.3% and 7.2% in the imeglimin group, but no other clinically relevant changes were seen in “other safety laboratory assessments, physical examination, or electrocardiograms.”
Study limitations include a lack of generalizability outside of this group of Japanese patients and the short study duration.
“Imeglimin monotherapy…was associated with substantial improvements in glycemic control that were superior to placebo,” the researchers concluded. “These results confirm efficacy, safety, and tolerability of imeglimin monotherapy in Japanese patients with type 2 diabetes.”
Disclosure: This clinical trial was supported by Sumitomo Dainippon Pharma and Poxel. Please see the original reference for a full list of authors’ disclosures.
Dubourg J, Gouqueray P, Thang C, Grouin J-M, Ueki K. Efficacy and safety of imeglimin monotherapy versus placebo in Japanese patients with type 2 diabetes (TIMES 1): A double-blind, randomized, placebo-controlled, parallel-group, multicenter phase 3 trial. Diabetes Care. 2021;44(4):952-959.