Effect of patient characteristics on the efficacy and safety of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus: A post‐hoc analysis of two randomized, placebo‐controlled trials

Katsuhiko Hagi; Kenji Kochi; Hirotaka Watada; Kohei Kaku; Kohjiro Ueki

doi:10.1111/jdi.14035

. 2023 Jun 1;14(9):1101–1109. doi: 10.1111/jdi.14035

Effect of patient characteristics on the efficacy and safety of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus: A post‐hoc analysis of two randomized, placebo‐controlled trials

Katsuhiko Hagi ^1,^✉, Kenji Kochi ¹, Hirotaka Watada ², Kohei Kaku ³, Kohjiro Ueki ⁴

PMCID: PMC10445191 PMID: 37264517

ABSTRACT

Aims/Introduction

Substantial variability in demographic and clinical characteristics exists among patients with type 2 diabetes mellitus, which may impact treatment. This post‐hoc analysis evaluated the efficacy and safety of imeglimin 1,000 mg twice daily (BID) monotherapy in type 2 diabetes mellitus patients according to demographic and clinical characteristics.

Materials and Methods

Data were pooled from two placebo‐controlled, 24 week, randomized, double‐blind studies in adults with type 2 diabetes mellitus. Outcomes (least squares mean [LSM] change in HbA1c from baseline to week 24, and safety) were analyzed according to subgroups based on demographics, clinical characteristics, and comorbidities.

Results

The difference in LSM change in HbA1c from baseline to week 24 was statistically significant for imeglimin vs placebo in all patient subgroups analyzed (P < 0.05 each), including demographics (age, body mass index), clinical characteristics (duration of type 2 diabetes mellitus, chronic kidney disease [CKD] stage, and prior medication use) and comorbidities (hypertension, dyslipidemia, risk of hepatic fibrosis and liver function parameter status). A statistically significant separation from placebo in HbA1c was observed at week 4 and maintained through week 24. No new safety concerns were identified with imeglimin in any patient subpopulations.

Conclusions

The efficacy and safety of imeglimin was demonstrated across patient subgroups, irrespective of baseline demographic and clinical characteristics. Our findings confirm the efficacy and safety of imeglimin across a broad spectrum of patients with type 2 diabetes mellitus.

Keywords: Imeglimin, Post‐hoc analysis, Type 2 diabetes

Substantial variability in the demographic and clinical characteristics exists among patients with type 2 diabetes mellitus, which may impact treatment. In this post‐hoc analysis, the efficacy of imeglimin was demonstrated across patient subgroups irrespective of baseline demographic and clinical characteristics, with a statistically significant separation from placebo in HbA1c observed at week 4 and maintained through week 24. No new safety concerns were identified with imeglimin in any patient subpopulations.

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INTRODUCTION

Type 2 diabetes mellitus is a widespread disease, affecting more than 500 million people worldwide ¹ . Prolonged hyperglycemia leads to serious macrovascular and microvascular complications, such as coronary heart disease, cerebrovascular disease, and diabetic retinopathy ² , ³ , ⁴ , ⁵ , which are the main causes of long‐term disability ⁶ and premature death ⁶ . In Japan, approximately 7.7% of the population has type 2 diabetes mellitus ⁷ , which accounts for up to 6% of total healthcare expenditure ⁸ , making it a national healthcare priority.

In addition to insulin therapy, several classes of antidiabetic drugs are routinely available for type 2 diabetes mellitus in Japan, including biguanides, sulfonylureas (SUs), alpha‐glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase‐4 (DPP‐IV) inhibitors, sodium glucose cotransporter‐2 (SGLT2) inhibitors, glinides, and glucagon‐like peptide‐1 (GLP‐1) receptor agonists ⁹ . However, these agents possess distinct mechanisms of action and adverse event (AE) profiles, which may influence drug selection. Current guidelines from the Japan Diabetes Society and others therefore recommend that the choice of glucose‐lowering therapy be individualized according to patient characteristics, such as age, comorbidities, and patient preference ¹⁰ , ¹¹ , ¹² .

Various patient characteristics have been shown to influence treatment efficacy in type 2 diabetes mellitus. For example, in a retrospective analysis of a GLP‐1 receptor agonist, semaglutide, in patients with type 2 diabetes mellitus, the reduction in HbA1c with oral semaglutide 14 mg (flexible dosing) was greater in patients with a higher baseline HbA1c (HbA1c >9.0%: −1.7% to −2.6%; HbA1c <8.0%: −0.7% to −1.2%), and Asian patients experienced greater reductions in HbA1c with oral semaglutide 14 mg (flexible dosing) (−1.5% to −1.8%) than other racial groups (−0.6% to −1.6%) ¹³ . However, treatment efficacy was not affected by age, duration of diabetes, and body mass index (BMI). In contrast, in a post hoc analysis of pooled data from six randomized, controlled trials in type 2 diabetes mellitus patients newly initiated on insulin glargine or neutral protamine Hagedorn (NPH), a greater reduction in HbA1c was observed in patients who had a body mass index (BMI) ≥30 kg/m² compared with a BMI <30 kg/m² ¹⁴ . The incidence of severe hypoglycemia was significantly lower in glargine vs NPH‐treated patients, but occurred primarily in the BMI <30 kg/m² group ¹⁴ . Given the evidence demonstrating that certain baseline clinical and demographic characteristics may negatively influence the efficacy and safety of certain treatments in type 2 diabetes mellitus, evaluation of the potential effect/s of various patient characteristics on the efficacy and safety of individual antidiabetic agents is warranted.

A number of new drugs have been approved for the management of type 2 diabetes mellitus in recent years, with more in development ¹⁵ . Imeglimin is a first‐in‐class oral diabetic agent, which possesses both a glucose‐dependent insulin production‐enhancing effect, as well as an insulin sensitivity‐improving effect ¹⁶ . In June 2021, imeglimin received its first approval for the treatment of type 2 diabetes mellitus in Japan ¹⁷ . A pivotal Phase 3 program (Trials of ImegliMin for Efficacy and Safety [TIMES]) has now been completed, which evaluated the efficacy and safety of imeglimin in Japanese patients with type 2 diabetes mellitus ¹⁸ , ¹⁹ , ²⁰ . Across these studies, imeglimin was associated with statistically significant reductions in HbA1c and a favorable safety and tolerability profile, including a lack of severe hypoglycemia ¹⁸ , ¹⁹ , ²⁰ .

Given the existing evidence demonstrating that patient factors may modulate treatment response in type 2 diabetes mellitus ¹⁴ , ²¹ , ²² , we conducted a post‐hoc analysis to explore the effect of various baseline characteristics on the efficacy and safety of imeglimin in patients with type 2 diabetes mellitus. Data from two, similarly designed randomized, double‐blind, placebo‐controlled trials of imeglimin in type 2 diabetes mellitus were pooled and analyzed according to patient subgroups stratified by baseline demographic characteristics, clinical characteristics, and comorbidities. Concomitant hypertension, dyslipidemia, and prior medication use are also prevalent in patients with type 2 diabetes mellitus and may affect the efficacy and safety of future diabetes medication ²³ , ²⁴ , ²⁵ . Therefore, it is also clinically important to evaluate imeglimin in these subgroups.

MATERIALS AND METHODS

Data sources

Data were pooled from two similarly designed, randomized, double‐blind, placebo‐controlled trials of imeglimin in type 2 diabetes mellitus, the Phase 2b (protocol PXL008‐014; JAPIC number: JapicCTI‐153086) ²⁶ and Phase 3 (protocol PXL008‐018; JAPIC number: JapicCTI‐173769) ¹⁸ studies.

Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and were approved by the appropriate institutional review boards and regulatory agencies. Patients provided written informed consent to participate in each study.

Study design

Detailed information regarding study designs and eligibility have been published previously ¹⁸ , ²⁶ . Briefly, both studies consisted of a screening and drug washout period, followed by a 24 week double‐blind treatment period, and a 1 week safety follow‐up.

The Phase 2b study was a randomized (1:1:1:1), double‐blind, placebo‐controlled, parallel‐group, dose‐ranging study designed to evaluate the efficacy and safety of imeglimin monotherapy (500 mg, 1,000 mg or 1,500 mg twice daily [BID]) vs matched placebo in Japanese patients with type 2 diabetes mellitus. Eligible patients were Japanese adults aged ≥20 years who were either treatment‐naive or previously treated with one oral antidiabetic agent. The imeglimin 500 and 1,500 mg BID dosage groups were not included in this post‐hoc analyses because they are not within the recommended imeglimin dose range.

The Phase 3 study (TIMES 1) was a double‐blind, randomized (1:1), and parallel‐group study designed to evaluate the efficacy and safety of oral imeglimin (1,000 mg BID) or matched placebo in Japanese patients with type 2 diabetes mellitus over 24 weeks. Eligible patients were ≥20 years of age, had been treated with diet and exercise for ≥12 weeks, and had HbA1c levels between 7.0 and 10.0%.

In each trial, the primary efficacy endpoint was the change from baseline to week 24 in HbA1c.

Patients

Japanese patients aged 20–75 years in PXL008‐014 and ≥20 years of age in PXL008‐018 with type 2 diabetes mellitus were eligible if they were managed with diet and exercise, with or without a stable dose of a single oral antidiabetic agent for at least 12 weeks prior to screening, and an HbA1c of 7.0–10.0% (53–86 mmol/mol).

Key exclusion criteria included: insulin therapy or any injectable glucose‐lowering drugs in the 3 months (PXL008‐014) or 30 days (PXL008‐018) before screening; an estimated glomerular filtration rate (eGFR) (estimated with the Japanese MDRD equation [from the Japanese Modification of Diet in Renal Disease trial]) ²⁷ of <45 mL/min/1.73 m²; heart failure (New York Heart Association class III or IV); or any acute coronary or cerebrovascular events in the 24 weeks before screening.

Statistical analysis

Post‐hoc analyses were conducted in patient subgroups, according to selected demographic characteristics, clinical characteristics, and comorbidities. Subgroups were selected based on their potential association with clinical outcomes in type 2 diabetes mellitus. Demographic subgroups were stratified by age (<65 and ≥65 years) and BMI (≥25 kg/m² [overweight] and <25 kg/m² [non‐overweight]). Clinical characteristic subgroups were stratified by chronic kidney disease (CKD) glomerular filtration rate (GFR) stage (CKD G1: eGFR [mL/min/1.73 m²] ≥90; G2: eGFR <90–≥60; G3a: eGFR <60–≥45), duration of type 2 diabetes mellitus (<5; ≥5–<10; ≥10 years), and prior medication use (treatment naïve, DPP‐IV inhibitors, or other medication/s). Comorbidity subgroups were stratified by the presence or absence of hypertension and dyslipidemia, and risk of hepatic fibrosis (FIB‐4 index ≥1.3 or <1.3) and liver function abnormality parameter (total bilirubin ≥1.6 mg/dL; AST ≥1.25 × Upper Limit of Normal [ULN]; AST ≥50 IU; ALT ≥1.25 × ULN; ALT ≥50 IU; ALP ≥1.25 × ULN; gamma‐GTP ≥1.5 × ULN).

Given the similar study designs of the imeglimin type 2 diabetes mellitus clinical trials, patient‐level data were pooled to provide larger subgroups and improved power for post‐hoc analysis. The least‐squares mean (LSM) changes in HbA1c from baseline were analyzed for the 1,000 mg BID dose group vs placebo for patient subgroups using a mixed‐effects model for repeated measures with treatment group, study, visit, treatment by visit interaction as fixed effects, and baseline value as a covariate. The statistical significance of the LSM difference between imeglimin and placebo was determined at the 0.05 level. The incidence of adverse events in each treatment group was analyzed descriptively by the Preferred Term of the Medical Dictionary for Regulatory Activities, version 20.1.

All statistical analyses were performed using SAS® software version 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

A total of 362 patients (Phase 2b: imeglimin 1,000 mg BID, n = 74; placebo, n = 75; Phase 3: imeglimin, n = 106; placebo, n = 107) were included in the pooled analysis population. Baseline characteristics were similar between treatment groups (Table 1) with respect to age, duration of type 2 diabetes mellitus, HbA1c level, BMI, and eGFR.

Table 1.

Baseline demographics and clinical characteristics.

	Imeglimin 1000 mg BID (n = 180)	Placebo (n = 182)
Sex, male, n (%)	138 (76.7)	127 (69.8)
Age (years), mean (SD)	61.3 (9.8)	61.2 (9.9)
<65, n (%)	97 (53.9)	106 (58.2)
≥65, n (%)	83 (46.1)	76 (41.8)
HbA1c (%), mean (SD)	7.9 (0.7)	7.9 (0.7)
Type 2 diabetes mellitus duration (years), mean (SD)	7.1 (5.6)	6.9 (6.2)
Previous diabetes therapy, n (%)
Treatment‐naïve	109 (60.6)	111 (61.0)
DPP‐IV i	43 (23.9)	34 (18.7)
Other hypoglycemic agent	28 (15.6)	37 (20.3)
Body weight (kg), mean (SD)	69.7 (13.5)	69.7 (13.7)
BMI, (kg/m²), mean (SD)	25.5 (4.1)	25.5 (4.3)
<25, n (%)	90 (50.0)	95 (52.2)
≥25, n (%)	90 (50.0)	87 (47.8)
eGFR (MRMD, mL/min/1.73 m²), mean (SD)	73.6 (12.8)	71.5 (12.4)
CKD GFR stage, n (%)
G1	21 (11.7)	16 (8.8)
G2	131 (72.8)	137 (75.3)
G3a	28 (15.6)	29 (15.9)
Hypertension, n (%)
Yes	100 (55.6)	104 (57.1)
No	80 (44.4)	78 (42.9)
Dysplipidemia, n (%)
Yes	104 (57.8)	101 (55.5)
No	76 (42.2)	81 (44.5)
FIB‐4 index, n (%)
≥1.3	83 (46.1)	91 (50.0)
<1.3	97 (53.9)	91 (50.0)

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Percentages may not add up to 100 due to rounding.

BID, twice daily; BMI, body mass index; CKD, chronic kidney disease; DPP‐IV i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; FIB‐4, fibrosis‐4; HbA1c, glycated hemoglobin A1c; MDRD, Japanese Modification of Diet in Renal Disease.

In the overall population, the mean age was 61 years and 43.9% of patients were elderly (≥65 years). The mean HbA1c at baseline was 7.9%, the mean duration of type 2 diabetes mellitus was approximately 7 years, the mean eGFR was 71.5 mL/min/1.73 m², and 60.8% of patients were treatment‐naïve. The patient demographic data and disposition stratified by subgroup are summarized in Table S1.

Efficacy by patient subgroup

Demographic characteristics

The difference in LSM change from baseline to week 24 in HbA1c (%) was significant for imeglimin 1,000 mg BID vs placebo in all demographic subgroups defined by age and BMI (Figure 1).

HbA1c change from baseline in demographic subgroups. BID, twice daily; BMI, body mass index; HbA1c, glycated hemoglobin A1c; LS, least squares. ***P < 0.001 vs placebo (mixed model for repeated measures).

The difference in LSM change in HbA1c (%) from baseline to week 24 and associated 95% confidence interval (CI) was significantly in favor of imeglimin vs placebo for patients aged <65 years old (−0.87 [−1.111, −0.636], P < 0.001) and those aged ≥65 years old (−0.87 [−1.050, −0.695], P < 0.001). Similarly, the LSM difference (95% CI) for imeglimin vs placebo was statistically significant for patients in both weight categories, including non‐overweight (BMI <25 kg/m²: −0.90 [−1.037, −0.767], P < 0.001) and overweight (BMI ≥25 kg/m²; −0.83 [−1.088, −0.571], P < 0.001) patients.

Clinical characteristics

When efficacy was analyzed according to clinical characteristics, the difference in LSM change in HbA1c (%) from baseline to week 24 was also significantly greater for imeglimin‐ vs placebo‐treated patients across all subgroups defined by clinical characteristics (Figure 2).

Adjusted LSM differences (95% CI) for imeglimin vs placebo were similar in subgroups defined according to CKD GFR stage (G1 [eGFR ≥90]: −0.70 [−1.051, −0.343]; P < 0.001; G2 [eGFR ≥60–<90]: −0.96 [−1.152, −0.773]; P < 0.001; G3a [eGFR ≥45–<60]: −0.66 [−1.002, −0.315]; P < 0.001) and duration of type 2 diabetes mellitus (<5 years: −0.93 [−1.168, −0.683]; P < 0.001; ≥5–<10 years: −0.99 [−1.293, −0.693]; P < 0.001; ≥10 years: −0.70 [−0.943, −0.447]; P < 0.001).

When efficacy was assessed according to prior medication use, the difference in LSM change in HbA1c (%) from baseline to week 24 was significantly greater for imeglimin vs placebo in treatment naïve patients and in those who had received DPP‐IV inhibitor or an oral antihyperglycemic medication other than a DPP‐IV inhibitor up to 12 weeks prior to screening (Figure 2).

The LSM difference (95% CI) in favor of imeglimin was −0.83 (−1.003, −0.652; P < 0.001) for treatment naïve patients, −0.91 (−1.239, −0.580; P < 0.001) for patients who had previously been treated with a DPP‐IV inhibitor, and −1.03 (−1.468, −0.602; P < 0.001) for patients who had received medication other than a DPP‐IV inhibitor.

Comorbidities

The potential effect of comorbidities on the efficacy of imeglimin was explored in patients with hypertension, dyslipidemia, or those at risk of hepatic fibrosis, or with or without liver function parameter abnormalities. The LSM change in HbA1c (%) from baseline to week 24 was significantly greater for imeglimin vs placebo in all comorbidity subgroups (Figure 3).

HbA1c change from baseline in comorbidity subgroups. BID, twice daily; FIB‐4, the fibrosis 4; HbA1c, glycated hemoglobin A1c; LS, least squares. ***P < 0.001, **P < 0.01 vs placebo (mixed model for repeated measures).

Least‐squares mean differences (95% CI) in favor of imeglimin vs placebo were statistically significant in both patients with (−0.94 [−1.120, −0.751]; P < 0.001) and without (−0.83 [−1.087, −0.573]; P < 0.001) hypertension. Similarly, the LSM differences (95% CI) for imeglimin vs placebo were statistically significant in both patients with (−0.97 [−1.186, −0.745]; P < 0.001) and without (−0.78 [−0.994, −0.565]; P < 0.001) dyslipidemia and those at risk of hepatic fibrosis (FIB‐4 index ≥1.3: −0.79 [−0.984, −0.595]; P < 0.001) and without the risk of fibrosis (FIB‐4 index <1.3: −0.98 [−1.219, −0.741]; P < 0.001). LSM changes in HbA1c (%) from baseline to week 24 were significantly greater in patients receiving imeglimin compared with placebo, both for patients with and without liver function parameter abnormalities. The difference in LSM change between imeglimin and placebo was −0.71 [−1.155, −0.272] for patients with liver function parameter abnormality (P = 0.002) and −0.91 [−1.074, −0.747] for those without (P < 0.001).

Figures S1 show the LSM change from baseline in HbA1c over the 24 week study period for the imeglimin and placebo groups according to demographics, clinical characteristics, and comorbidity subgroups, respectively. Statistically significant LSM differences (95% CI) in favor of imeglimin vs placebo were observed at each time point across demographic (age and BMI), clinical characteristic (CKD subgroups [with the exception of CKD G1 at week 4]), duration of type 2 diabetes mellitus, and prior medication use, and comorbidity (hypertension, dyslipidemia, risk of hepatic fibrosis, liver function parameter status [with abnormality/without abnormality]) subgroups. Reductions in HbA1c were rapid and continued over the course of the study for the imeglimin group and were similar across subgroups, with a trend towards greater LSM changes in the ≥65 year, BMI <25 kg/m², CKD G2 and G3a, and treatment naïve subgroups.

Safety by patient subgroup

The incidence of adverse events for the imeglimin and placebo groups according to demographic, clinical characteristics and comorbidity subgroups are presented in Tables S2–S4, respectively. The incidence of adverse events was generally similar between treatment groups and across subgroups. There was a trend towards a slightly higher incidence of serious adverse events (SAEs) in the imeglimin group (n = 8, 4.4%) compared with placebo (n = 2, 1.1%). The SAEs in the imeglimin group included clavicle fracture, femur fracture, radius fracture, bladder cancer, prostate cancer, solid pseudopapillary tumor of the pancreas, bradycardia, ileus, and spondylitic myelopathy (n = 1, 0.6%, each), none of which were considered related to the study drug. The SAEs in the placebo group included meniscus injury (n = 1, 0.5%) and lower limb fracture (n = 1, 0.5%). One death (metastatic pancreatic carcinoma) occurred during the study in the imeglimin group, but was not related to the study drug. When analyzed according to specific subgroups, the incidence of SAEs in the imeglimin group was higher in patients aged ≥65 years, patients with CKD G2, patients with type 2 diabetes mellitus duration ≥10 years, those previously treated with a DPP‐IV inhibitor, patients without liver function parameter abnormality, and those with hypertension (Tables S2–S4).

Nasopharyngitis was the most common adverse event across all subgroups, occurring with a higher incidence in the imeglimin group compared with placebo. The incidence of nasopharyngitis in the imeglimin group was generally similar across patient subgroups, with a few exceptions (Tables S2–S4).

Other adverse events that occurred with an incidence of ≥5% in the imeglimin group were hypoglycemia (7.1%) and diarrhea (6.3%). The incidence of hypoglycemia in the imeglimin group was low overall, but was numerically higher in patients aged <65 years vs ≥65 years, patients with a BMI ≥25 kg/m² vs <25 kg/m², patients with CKD G3a and G1 vs G2 disease, patients with a type 2 diabetes mellitus duration ≥10 years vs <5 years and ≥5–<10 years, and treatment naïve patients vs those previously treated with a DPP‐IV inhibitor or other antihyperglycemic agent, patients with liver function parameter abnormality vs without liver function parameter abnormality, and those without hypertension vs with hypertension.

DISCUSSION

In the present study, we demonstrated the broad efficacy and safety of imeglimin across Japanese patients with type 2 diabetes mellitus, irrespective of baseline demographic characteristics, clinical characteristics, and comorbidities. The present post‐hoc analyses investigated the effect of various patient characteristics on the efficacy and safety of imeglimin using pooled data from two, similarly designed, randomized, double‐blind, placebo‐controlled trials of imeglimin in Japanese patients with type 2 diabetes mellitus. Our results show that imeglimin monotherapy was consistently more effective than placebo, with statistically significant reductions in HbA1c (%) in favor of imeglimin across prespecified subgroups, including age, BMI, CKD GFR stage, duration of type 2 diabetes mellitus, prior medication used, and whether patients had presence or absence of diabetes‐associated comorbidities, including hypertension, dyslipidemia, risk of hepatic fibrosis and those with/without liver function parameter abnormality. Given that type 2 diabetes mellitus spans a diverse patient population with differing demographics and clinical characteristics, it is important to ensure that the medications used to treat type 2 diabetes mellitus are universally and consistently effective. Our study demonstrates the efficacy of imeglimin monotherapy across a broad spectrum of type 2 diabetes mellitus patients, irrespective of these factors. These results extend upon previous findings demonstrating the overall efficacy of imeglimin in patients with type 2 diabetes mellitus ¹⁸ , ¹⁹ , ²⁰ , ²⁶ .

Type 2 diabetes mellitus is a heterogeneous disease with myriad clinical symptoms, frequent comorbidities, and variable responses to treatment. Characterization of the efficacy and safety of pharmacologic treatments across specific patient subgroups with type 2 diabetes mellitus is valuable to allow therapeutic interventions to be tailored to those patients who will derive the greatest benefit. For example, hypertension, obesity, and dyslipidemia comorbidities are highly prevalent in type 2 diabetes mellitus (74–83% ²⁸ , ²⁹ , ³⁰ , ³¹ , 86–91% ³⁰ , ³² , 85–93% ³⁰ , ³¹ , respectively) and their presence is associated with increased severity ³³ and mortality ³⁴ , ³⁵ , ³⁶ of type 2 diabetes mellitus and decreased treatment success ¹⁴ , ²³ , ³⁷ , including worsened insulin resistance ²³ , ³⁸ , the need for more intensive therapy ³⁹ , and progression of macrovascular and microvascular complications ⁴⁰ , ⁴¹ . In view of evidence showing that comorbidities can influence treatment outcomes in type 2 diabetes mellitus, it is important to note that, in our analyses, imeglimin was consistently effective in patients with and without hypertension, dyslipidemia, hepatic fibrosis, and liver function parameter abnormality.

To assess whether prior treatment for type 2 diabetes mellitus influenced the efficacy of imeglimin in the present analyses, patient subgroups were also stratified according to their recent treatment history. Reductions in HbA1c were comparable among patients who were treatment‐naïve prior to randomization and those who had received prior treatment with an antihyperglycemic agent for type 2 diabetes mellitus. Taken together, these findings demonstrate that, not only is imeglimin effective in treatment‐naïve patients, but treatment with imeglimin following discontinuation of other treatment also does not appear to compromise efficacy. Collectively, these results highlight the efficacy of imeglimin across the lifespan of type 2 diabetes mellitus, with potential utility as an early‐line treatment, and also later in the disease course following the failure of other agents, irrespective of patient background factors.

Overall, the incidence of adverse events was generally similar between imeglimin and placebo groups, and across subgroups. Nasopharyngitis was the most common adverse event reported with imeglimin across all subgroups in our study, which was consistent with the pivotal TIMES 2 and TIMES 3 Phase 3 clinical trials ¹⁹ , ²⁰ . There was a trend towards a higher incidence of SAEs in the imeglimin group compared with placebo overall, as well as within some subgroups in patients treated with imeglimin. However, no SAEs were considered related to study treatment and the small sample size in some of the subgroups precluded meaningful comparisons from being drawn. Other common adverse events occurring with a ≥ 5% incidence were hypoglycemia and diarrhea, which occurred at a similar proportion to those reported in the TIMES 2 study in Japanese patients ¹⁹ . Interestingly, no elderly (aged ≥65 years) patients developed hypoglycemia in our study, which is in contrast to the wealth of evidence demonstrating an increased risk of hypoglycemia in this patient population ⁴² , and warrants further investigation. No new safety signals were identified during our study and common adverse events reported were in keeping with the known safety profile of imeglimin ¹⁸ , ¹⁹ , ²⁰ .

Although study data were collected prospectively, the reported analyses were carried out post hoc and therefore subject to potential biases inherent to such analyses. For example, the sample size of some patient subgroups was relatively small, which may increase statistical variability. Further, for many parameters, clinically meaningful cut‐offs were either not available or would have provided too small a sample size after assessment of eligibility criteria. In these cases, patient subgroups were defined using a median cut‐off; although this method provided subgroups of equivalent size, the clinical relevance of these cut‐offs may be uncertain.

Nevertheless, in this post hoc analyses of two, similarly designed, randomized, controlled trials, imeglimin 1,000 mg BID consistently improved glycemic control in all patient subgroups, irrespective of differences in baseline demographics and clinical characteristics, pointing to broad efficacy across patients with type 2 diabetes mellitus. Although studies of other pharmacotherapies have shown that some clinical characteristics and comorbidities can influence treatment effects in type 2 diabetes mellitus ¹⁴ , ²¹ , ⁴³ , imeglimin was consistently effective in patients with various demographic and clinical characteristics, with or without the presence of comorbidities. These findings build upon the wealth of clinical evidence demonstrating the efficacy and safety of imeglimin for the treatment of type 2 diabetes mellitus ¹⁸ , ¹⁹ , ²⁰ , ²⁶ , and additionally confirm the broad efficacy and safety of imeglimin in type 2 diabetes mellitus. Given these findings, imeglimin may be a particularly attractive option in clinical practice, where a broad spectrum of patients with diverse demographic and clinical characteristics is typically seen.

DISCLOSURE

KH and KK (Kochi) are employees of Sumitomo Pharma Co., Ltd. HW has received honoraria for lectures for Mitsubishi Tanabe Pharma, Sumitomo Pharma, Sanwa Kagaku, Takeda Pharmaceuticals, Sanofi, Kowa, MSD, Nippon, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, Ono Pharmaceutical, Astellas Pharma, Kyowa Kirin, Terumo, Taisho Pharmaceutical, Abbott, and Kissei Pharmaceutical, and research activities for Takeda Pharmaceuticals, Nippon, Boehringer Ingelheim, Kissei Pharmaceutical, Novo Nordisk, Mitsubishi Tanabe Pharma, Lifescan Japan, Kyowa Kirin, Sumitomo Pharma, Eli Lilly, Teijin Pharma, Taisho Pharmaceutical, Abbott, Daiichi Sankyo, Astellas, Ono Pharmaceutical Co. Ltd, Sanofi, MSD, Soiken Inc., Sanwa Kagaku, and Kowa. KK (Kaku) has been an advisor to Sanwa Kagaku, and received honoraria for lectures from Astellas, AstraZeneca, Daiichi Sankyo, Kowa, Sumitomo Pharma Co. Ltd, MSD, Ono Pharmaceutical Co. Ltd, Sanwa Kagaku, Novo Nordisk, Nippon Boehringer Ingelheim, Eli Lilly Japan, Taisho Pharmaceutical, Takeda Pharmaceuticals and Mitsubishi Tanabe Pharma, and received scholarship grants from Nippon, Boehringer Ingelheim, Taisho Pharmaceutical and Kowa. KU has received honoraria for lectures from AstraZeneca, Taisho Pharmaceutical, Novo Nordisk, Sumitomo Pharma, Kowa, Mitsubishi Tanabe Pharma, and Ono Pharmaceutical; research grants from Sumitomo Pharma, Novo Nordisk, Eli Lilly Japan, Sanofi, Abbott Japan, MSD and Nippon Boehringer Ingelheim; and scholarship grants from Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Pharma, Takeda Pharmaceuticals and Sanofi.

Registry and the registration no. of the study/trial: This post hoc analysis was conducted using data from the Phase 2b (JAPIC number: JapicCTI‐153086; registration date: December 17, 2018) ²⁶ and Phase 3 (JAPIC number: JapicCTI‐173769; registration date: June 10, 2019) ¹⁸ studies.

Informed consent: Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and were approved by the appropriate institutional review boards and regulatory agencies. Patients provided written informed consent to participate in each study.

Animal studies: Not applicable.

Supporting information

Table S1 | Patient demographic data and disposition by subgroups

Table S2 | Adverse events in demographic subgroups

Table S3 | Adverse events in subgroups according to clinical characteristics

Table S4 | Adverse events in subgroups according to comorbidity status

Figure S1 | HbA1c change from baseline according to demographic subgroups

Figure S2 | HbA1c change from baseline according to clinical characteristics

Figure S3 | HbA1c change from baseline according to comorbidity status

Click here for additional data file.^{(983.3KB, docx)}

ACKNOWLEDGMENTS

This analysis was funded by Sumitomo Pharma Co., Ltd. All authors participated in the writing, editing, and critical revision for intellectual content, and approval of the final version of this manuscript. All authors met ICMJE authorship criteria and agree to be accountable for all aspects of the work. Neither honoraria nor payments were made for authorship. Medical writing support was provided by Jordana Campbell, BSc, CMPP of inScience Communications, Springer Healthcare. This medical writing assistance was funded by Sumitomo Pharma Co., Ltd. We thank Yuriko Kobayashi and Emi Matsukawa, who are contract programmers of Sumitomo Pharma Co., Ltd, for their excellent technical support.

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2. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008; 26: 77–82. [Google Scholar]
3. Kosiborod M, Gomes MB, Nicolucci A, et al. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol 2018; 17: 150. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Ergul A, Kelly‐Cobbs A, Abdalla M, et al. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 2012; 12: 148–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Pantalone KM, Hobbs TM, Wells BJ, et al. Clinical characteristics, complications, comorbidities and treatment patterns among patients with type 2 diabetes mellitus in a large integrated health system. BMJ Open Diabetes Res Care 2015; 3: e000093. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Khan MAB, Hashim MJ, King JK, et al. Epidemiology of type 2 diabetes – global burden of disease and forecasted trends. J Epidemiol Glob Health 2020; 10: 107–111. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Sengoku T, Ishizaki T, Goto Y, et al. Prevalence of type 2 diabetes by age, sex and geographical area among two million public assistance recipients in Japan: a cross‐sectional study using a nationally representative claims database. J Epidemiol Comm Health 2022; 76: 391–397. [DOI] [PubMed] [Google Scholar]
8. Neville SE, Boye KS, Montgomery WS, et al. Diabetes in Japan: a review of disease burden and approaches to treatment. Diabetes Metab Res Rev 2009; 25: 705–716. [DOI] [PubMed] [Google Scholar]
9. Bouchi R, Sugiyama T, Goto A, et al. Retrospective nationwide study on the trends in first‐line antidiabetic medication for patients with type 2 diabetes in Japan. J Diabetes Investig 2022; 13: 280–291. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Araki E, Goto A, Kondo T, et al. Japanese clinical practice guideline for diabetes 2019. J Diabetes Investig 2020; 11: 1020–1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Davies MJ, D'Alessio DA, Fradkin J, et al. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498. [DOI] [PubMed] [Google Scholar]
12. Draznin B, Aroda VR, Bakris G, et al. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2022. Diabetes Care 2022; 45(Suppl 1): S125–s43. [DOI] [PubMed] [Google Scholar]
13. Aroda VR, Bauer R, Christiansen E, et al. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab 2022; 24: 1338–1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Porcellati F, Lin J, Lucidi P, et al. Impact of patient and treatment characteristics on glycemic control and hypoglycemia in patients with type 2 diabetes initiated to insulin glargine or NPH: a post hoc, pooled, patient‐level analysis of 6 randomized controlled trials. Medicine 2017; 96: e6022. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Shah N, Abdalla MA, Deshmukh H, et al. Therapeutics for type‐2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021; 12: 20420188211042145. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Hallakou‐Bozec S, Vial G, Kergoat M, et al. Mechanism of action of imeglimin: a novel therapeutic agent for type 2 diabetes. Diabetes Obes Metab 2021; 23: 664–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Lamb YN. Imeglimin hydrochloride: first approval. Drugs 2021; 81: 1683–1690. [DOI] [PubMed] [Google Scholar]
18. Dubourg J, Fouqueray P, Thang C, et al. 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: 952–959. [DOI] [PubMed] [Google Scholar]
19. Dubourg J, Fouqueray P, Quinslot D, et al. Long‐term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): a 52‐week, open‐label, multicentre phase 3 trial. Diabetes Obes Metab 2022; 24: 609–619. [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Reilhac C, Dubourg J, Thang C, et al. Efficacy and safety of imeglimin add‐on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): a randomized, double‐blind, placebo‐controlled phase 3 trial with a 36‐week open‐label extension period. Diabetes Obes Metab 2022; 24: 838–848. [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Komatsu M, Watada H, Kaneko S, et al. Efficacy and safety of the fixed‐ratio combination of insulin degludec and liraglutide by baseline glycated hemoglobin, body mass index and age in Japanese individuals with type 2 diabetes: a subgroup analysis of two phase III trials. J Diabetes Investig 2021; 12: 1610–1618. [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Yoo JH, Cho YK, Lee J, et al. Clinical efficacy and parameters affecting the response to dulaglutide treatment in patients with type 2 diabetes: a retrospective, real‐world data study. Diabetes Ther 2019; 10: 1453–1463. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607. [DOI] [PubMed] [Google Scholar]
24. McAdam‐Marx C, Bellows BK, Unni S, et al. Determinants of glycaemic control in a practice setting: the role of weight loss and treatment adherence (The DELTA Study). Int J Clin Pract 2014; 68: 1309–1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Zaman Huri H, Chai LL. Drug‐related problems in type 2 diabetes mellitus patients with dyslipidemia. BMC Public Health 2013; 13: 1192. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Dubourg J, Ueki K, Grouin JM, et al. Efficacy and safety of imeglimin in Japanese patients with type 2 diabetes: a 24‐week, randomized, double‐blind, placebo‐controlled, dose‐ranging phase 2b trial. Diabetes Obes Metab 2021; 23: 800–810. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Imai E, Horio M, Nitta K, et al. Modification of the modification of diet in renal disease (MDRD) study equation for Japan. Am J Kidney Dis 2007; 50: 927–937. [DOI] [PubMed] [Google Scholar]
28. Baskar V, Kamalakannan D, Holland MR, et al. The prevalence of hypertension and utilization of antihypertensive therapy in a district diabetes population. Diabetes Care 2002; 25: 2107–2108. [DOI] [PubMed] [Google Scholar]
29. Comaschi M, Coscelli C, Cucinotta D, et al. Cardiovascular risk factors and metabolic control in type 2 diabetic subjects attending outpatient clinics in Italy: the SFIDA (survey of risk factors in Italian diabetic subjects by AMD) study. Nutr Metab Cardiovasc Dis 2005; 15: 204–211. [DOI] [PubMed] [Google Scholar]
30. Jelinek HF, Osman WM, Khandoker AH, et al. Clinical profiles, comorbidities and complications of type 2 diabetes mellitus in patients from United Arab Emirates. BMJ Open Diabetes Res Care 2017; 5: e000427. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Ohsugi M, Eiki JI, Iglay K, et al. Comorbidities and complications in Japanese patients with type 2 diabetes mellitus: retrospective analyses of J‐DREAMS, an advanced electronic medical records database. Diabetes Res Clin Pract 2021; 178: 108845. [DOI] [PubMed] [Google Scholar]
32. Daousi C, Casson IF, Gill GV, et al. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 2006; 82: 280–284. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Hurst C, Thinkhamrop B, Tran HT. The association between hypertension comorbidity and microvascular complications in type 2 diabetes patients: a nationwide cross‐sectional study in Thailand. Diabetes Metab J 2015; 39: 395–404. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease. Hypertension 2001; 37: 1053–1059. [DOI] [PubMed] [Google Scholar]
35. Mulnier HE, Seaman HE, Raleigh VS, et al. Mortality in people with type 2 diabetes in the UK. Diabet Med 2006; 23: 516–521. [DOI] [PubMed] [Google Scholar]
36. Eeg‐Olofsson K, Cederholm J, Nilsson PM, et al. Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia 2009; 52: 65–73. [DOI] [PubMed] [Google Scholar]
37. Gill GV, Woodward A, Pradhan S, et al. Intensified treatment of type 2 diabetes – positive effects on blood pressure, but not glycaemic control. QJM 2003; 96: 833–836. [DOI] [PubMed] [Google Scholar]
38. Wondmkun YT. Obesity, insulin resistance, and type 2 diabetes: associations and therapeutic implications. Diabetes Metab Syndr Obes 2020; 13: 3611–3616. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Wilding JPH. Medication use for the treatment of diabetes in obese individuals. Diabetologia 2018; 61: 265–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Gao S, Zhang H, Long C, et al. Association between obesity and microvascular diseases in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2021; 12: 719515. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Mancia G. Blood pressure and glucose control in patients with diabetes. Am J Hypertens 2007; 20(S1): 3S–8S. [Google Scholar]
42. Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgrad Med 2019; 131: 241–250. [DOI] [PubMed] [Google Scholar]
43. Breznoscakova D, Pallayova M. Bipolar disorder and type 2 diabetes mellitus: a bidirectional relationship. Eur J Psychiatry 2022; 36: 152–162. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1 | Patient demographic data and disposition by subgroups

Table S2 | Adverse events in demographic subgroups

Table S3 | Adverse events in subgroups according to clinical characteristics

Table S4 | Adverse events in subgroups according to comorbidity status

Figure S1 | HbA1c change from baseline according to demographic subgroups

Figure S2 | HbA1c change from baseline according to clinical characteristics

Figure S3 | HbA1c change from baseline according to comorbidity status

Click here for additional data file.^{(983.3KB, docx)}

[jdi14035-bib-0001] 1. Kaiser A, Zhang N, Pluijm WVD. Global prevalence of type 2 diabetes over the next ten years (2018–2028). Diabetes 2018; 67(Suppl 1): 202. [Google Scholar]

[jdi14035-bib-0002] 2. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008; 26: 77–82. [Google Scholar]

[jdi14035-bib-0003] 3. Kosiborod M, Gomes MB, Nicolucci A, et al. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol 2018; 17: 150. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0004] 4. Ergul A, Kelly‐Cobbs A, Abdalla M, et al. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 2012; 12: 148–158. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0005] 5. Pantalone KM, Hobbs TM, Wells BJ, et al. Clinical characteristics, complications, comorbidities and treatment patterns among patients with type 2 diabetes mellitus in a large integrated health system. BMJ Open Diabetes Res Care 2015; 3: e000093. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0006] 6. Khan MAB, Hashim MJ, King JK, et al. Epidemiology of type 2 diabetes – global burden of disease and forecasted trends. J Epidemiol Glob Health 2020; 10: 107–111. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0007] 7. Sengoku T, Ishizaki T, Goto Y, et al. Prevalence of type 2 diabetes by age, sex and geographical area among two million public assistance recipients in Japan: a cross‐sectional study using a nationally representative claims database. J Epidemiol Comm Health 2022; 76: 391–397. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0008] 8. Neville SE, Boye KS, Montgomery WS, et al. Diabetes in Japan: a review of disease burden and approaches to treatment. Diabetes Metab Res Rev 2009; 25: 705–716. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0009] 9. Bouchi R, Sugiyama T, Goto A, et al. Retrospective nationwide study on the trends in first‐line antidiabetic medication for patients with type 2 diabetes in Japan. J Diabetes Investig 2022; 13: 280–291. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0010] 10. Araki E, Goto A, Kondo T, et al. Japanese clinical practice guideline for diabetes 2019. J Diabetes Investig 2020; 11: 1020–1076. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0011] 11. Davies MJ, D'Alessio DA, Fradkin J, et al. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61: 2461–2498. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0012] 12. Draznin B, Aroda VR, Bakris G, et al. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2022. Diabetes Care 2022; 45(Suppl 1): S125–s43. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0013] 13. Aroda VR, Bauer R, Christiansen E, et al. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab 2022; 24: 1338–1350. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0014] 14. Porcellati F, Lin J, Lucidi P, et al. Impact of patient and treatment characteristics on glycemic control and hypoglycemia in patients with type 2 diabetes initiated to insulin glargine or NPH: a post hoc, pooled, patient‐level analysis of 6 randomized controlled trials. Medicine 2017; 96: e6022. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0015] 15. Shah N, Abdalla MA, Deshmukh H, et al. Therapeutics for type‐2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021; 12: 20420188211042145. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0016] 16. Hallakou‐Bozec S, Vial G, Kergoat M, et al. Mechanism of action of imeglimin: a novel therapeutic agent for type 2 diabetes. Diabetes Obes Metab 2021; 23: 664–673. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0017] 17. Lamb YN. Imeglimin hydrochloride: first approval. Drugs 2021; 81: 1683–1690. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0018] 18. Dubourg J, Fouqueray P, Thang C, et al. 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: 952–959. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0019] 19. Dubourg J, Fouqueray P, Quinslot D, et al. Long‐term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): a 52‐week, open‐label, multicentre phase 3 trial. Diabetes Obes Metab 2022; 24: 609–619. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0020] 20. Reilhac C, Dubourg J, Thang C, et al. Efficacy and safety of imeglimin add‐on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): a randomized, double‐blind, placebo‐controlled phase 3 trial with a 36‐week open‐label extension period. Diabetes Obes Metab 2022; 24: 838–848. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0021] 21. Komatsu M, Watada H, Kaneko S, et al. Efficacy and safety of the fixed‐ratio combination of insulin degludec and liraglutide by baseline glycated hemoglobin, body mass index and age in Japanese individuals with type 2 diabetes: a subgroup analysis of two phase III trials. J Diabetes Investig 2021; 12: 1610–1618. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0022] 22. Yoo JH, Cho YK, Lee J, et al. Clinical efficacy and parameters affecting the response to dulaglutide treatment in patients with type 2 diabetes: a retrospective, real‐world data study. Diabetes Ther 2019; 10: 1453–1463. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0023] 23. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0024] 24. McAdam‐Marx C, Bellows BK, Unni S, et al. Determinants of glycaemic control in a practice setting: the role of weight loss and treatment adherence (The DELTA Study). Int J Clin Pract 2014; 68: 1309–1317. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0025] 25. Zaman Huri H, Chai LL. Drug‐related problems in type 2 diabetes mellitus patients with dyslipidemia. BMC Public Health 2013; 13: 1192. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0026] 26. Dubourg J, Ueki K, Grouin JM, et al. Efficacy and safety of imeglimin in Japanese patients with type 2 diabetes: a 24‐week, randomized, double‐blind, placebo‐controlled, dose‐ranging phase 2b trial. Diabetes Obes Metab 2021; 23: 800–810. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0027] 27. Imai E, Horio M, Nitta K, et al. Modification of the modification of diet in renal disease (MDRD) study equation for Japan. Am J Kidney Dis 2007; 50: 927–937. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0028] 28. Baskar V, Kamalakannan D, Holland MR, et al. The prevalence of hypertension and utilization of antihypertensive therapy in a district diabetes population. Diabetes Care 2002; 25: 2107–2108. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0029] 29. Comaschi M, Coscelli C, Cucinotta D, et al. Cardiovascular risk factors and metabolic control in type 2 diabetic subjects attending outpatient clinics in Italy: the SFIDA (survey of risk factors in Italian diabetic subjects by AMD) study. Nutr Metab Cardiovasc Dis 2005; 15: 204–211. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0030] 30. Jelinek HF, Osman WM, Khandoker AH, et al. Clinical profiles, comorbidities and complications of type 2 diabetes mellitus in patients from United Arab Emirates. BMJ Open Diabetes Res Care 2017; 5: e000427. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0031] 31. Ohsugi M, Eiki JI, Iglay K, et al. Comorbidities and complications in Japanese patients with type 2 diabetes mellitus: retrospective analyses of J‐DREAMS, an advanced electronic medical records database. Diabetes Res Clin Pract 2021; 178: 108845. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0032] 32. Daousi C, Casson IF, Gill GV, et al. Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 2006; 82: 280–284. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0033] 33. Hurst C, Thinkhamrop B, Tran HT. The association between hypertension comorbidity and microvascular complications in type 2 diabetes patients: a nationwide cross‐sectional study in Thailand. Diabetes Metab J 2015; 39: 395–404. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0034] 34. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease. Hypertension 2001; 37: 1053–1059. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0035] 35. Mulnier HE, Seaman HE, Raleigh VS, et al. Mortality in people with type 2 diabetes in the UK. Diabet Med 2006; 23: 516–521. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0036] 36. Eeg‐Olofsson K, Cederholm J, Nilsson PM, et al. Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia 2009; 52: 65–73. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0037] 37. Gill GV, Woodward A, Pradhan S, et al. Intensified treatment of type 2 diabetes – positive effects on blood pressure, but not glycaemic control. QJM 2003; 96: 833–836. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0038] 38. Wondmkun YT. Obesity, insulin resistance, and type 2 diabetes: associations and therapeutic implications. Diabetes Metab Syndr Obes 2020; 13: 3611–3616. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0039] 39. Wilding JPH. Medication use for the treatment of diabetes in obese individuals. Diabetologia 2018; 61: 265–272. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0040] 40. Gao S, Zhang H, Long C, et al. Association between obesity and microvascular diseases in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2021; 12: 719515. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jdi14035-bib-0041] 41. Mancia G. Blood pressure and glucose control in patients with diabetes. Am J Hypertens 2007; 20(S1): 3S–8S. [Google Scholar]

[jdi14035-bib-0042] 42. Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgrad Med 2019; 131: 241–250. [DOI] [PubMed] [Google Scholar]

[jdi14035-bib-0043] 43. Breznoscakova D, Pallayova M. Bipolar disorder and type 2 diabetes mellitus: a bidirectional relationship. Eur J Psychiatry 2022; 36: 152–162. [Google Scholar]

PERMALINK

Effect of patient characteristics on the efficacy and safety of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus: A post‐hoc analysis of two randomized, placebo‐controlled trials

Katsuhiko Hagi

Kenji Kochi

Hirotaka Watada

Kohei Kaku

Kohjiro Ueki