Abstract
Aims/Introduction
This meta‐analysis aimed to evaluate the efficacy and safety/tolerability of imeglimin, a novel oral antihyperglycemic agent, administered as monotherapy and adjunctive therapy in patients with type 2 diabetes mellitus.
Materials and Methods
Parallel‐group randomized controlled trials comparing imeglimin with placebo in adults with type 2 diabetes mellitus were included. Risk ratios or weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated using random effects models. The primary outcome for efficacy was the change in glycated hemoglobin (HbA1c). Secondary outcomes included other efficacy‐related outcomes, specific adverse events, and changes in body weight and lipid parameters.
Results
Nine randomized controlled trials (n = 1,655) were included. When analyzed by dose, there was a significant difference in glycated hemoglobin (%) between imeglimin monotherapy and placebo at doses >1,000 mg twice daily (1,000 mg: studies N = 3, patients n = 517, WMD = −0.714, P < 0.001; 1,500 mg: N = 5, n = 448, WMD = −0.531, P = 0.020; 2,000 mg: N = 1, n = 149, WMD = −0.450, P = 0.005). Imeglimin adjunctive therapy significantly improved glycated hemoglobin over placebo at doses of 1,000 mg (N = 1, n = 214, WMD = −0.600, P < 0.001) and 1,500 mg (N = 2, n = 324, WMD = −0.576, P < 0.001). Subgroup analysis of the primary outcome showed that imeglimin was effective regardless of chronic kidney disease category, with studies carried out in Japan and in patients with lower body mass index showing a trend toward improved imeglimin efficacy. There were no significant differences between imeglimin and placebo in the risk of all‐cause discontinuation and the proportion of patients who presented with at least one adverse event.
Conclusions
Imeglimin is efficacious, safe, and well tolerated as monotherapy and adjunctive therapy.
Keywords: Imeglimin, Meta‐analysis, Type 2 diabetes mellitus
Imeglimin is a new oral hypoglycemic agent approved in Japan for the treatment of type 2 diabetes mellitus. We carried out a systematic review and meta‐analysis of randomized controlled trials comparing imeglimin with placebo to evaluate the efficacy, safety and tolerability of imeglimin as monotherapy and adjunctive therapy in adult patients with type 2 diabetes mellitus. The results showed that imeglimin was effective as a single agent and adjunctive therapy in this patient population, with good safety and tolerability.
INTRODUCTION
It is estimated that in 2017, 462 million individuals were affected by type 2 diabetes mellitus worldwide (prevalence rate 6,059 cases per 100,000 persons), which corresponds to approximately 6% of the global population 1 . By 2030, the global prevalence of type 2 diabetes mellitus is expected to increase to 7,079 cases per 100,000. In 2019, type 2 diabetes mellitus accounted for 1,472,900 deaths, with an age‐standardized mortality rate of 18.5 deaths per 100,000 2 . Type 2 diabetes mellitus is a leading cause of death worldwide from non‐communicable diseases, with a rising impact following its increasing prevalence 3 , 4 .
Type 2 diabetes mellitus is caused by the combined effect of the inability of insulin‐sensitive tissues to respond to insulin and insulin secretion deficiency by pancreatic β‐cells 5 , with both conditions leading to hyperglycemia. Although there are many antihyperglycemic drugs available on the market, there is no drug that is effective for both conditions.
Imeglimin is the world's first oral hypoglycemic agent that both stimulates insulin secretion in a glucose‐dependent manner and improves insulin sensitivity. Imeglimin was approved in Japan in June 2021 for use either as monotherapy or adjunctive therapy. The mode of action and pharmacological properties of imeglimin differ from those of other antihyperglycemic classes. Imeglimin targets mitochondrial bioenergetics 6 , improves mitochondrial function and regulates mitochondrial respiratory chain complex activities while decreasing the production of reactive oxygen species 7 . Imeglimin has also been shown to prevent the death of human endothelial cells without inhibiting mitochondrial respiration 8 , suggesting that it might have end‐organ protective effects. The cardioprotective effect of imeglimin has been shown in preclinical studies using murine models mimicking metabolic stress 6 , 9 . Imeglimin increases glucose‐stimulated insulin secretion by improving β‐cell glucose responsiveness in patients with type 2 diabetes mellitus, and has been shown to stimulate insulin secretion from β‐cells through the cyclic adenosine diphosphate ribose‐transient receptor potential channel and other pathways 10 , 11 , 12 . In a rodent model of diabetes, imeglimin improved insulin sensitivity, contributing to the normalization of glucose tolerance 7 . In addition, several studies have shown that imeglimin has a β‐cell‐protective effect 13 , 14 , 15 , 16 . Although imeglimin has similar effects to those of metformin in that they both inhibit glucose production in liver cells, their effects on the expression of some genes related to mitochondrial function differ 17 , 18 , 19 .
A previous meta‐analysis of randomized controlled trials (RCTs) evaluated the efficacy and safety of imeglimin versus placebo in patients with type 2 diabetes mellitus 20 ; however, this previous report had some limitations. The dose‐by‐dose analysis was inadequate, because the data for the 1,000‐ and 1,500‐mg twice daily (b.i.d.) groups were categorized as the high‐dose group, and the efficacy of each dose of 1,000 and 1,500 mg b.i.d. was unknown. Although there were data for imeglimin 2,000 mg b.i.d., the respective results were not shown. Regarding the incidence of adverse events, monotherapy and combination therapy studies were presented together. Finally, one RCT was missed during the literature search, and a total of eight trials were included in the meta‐analysis. Another meta‐analysis of RCTs evaluated the efficacy and safety of imeglimin versus placebo or other oral glucose‐lowering drugs 21 . However, only three studies were included in the analysis, which was carried out without separating one monotherapy trial and two combination trials. Furthermore, the outcomes evaluated only included glycated hemoglobin (HbA1c) and fasting glucose 21 .
The objective of the present meta‐analysis was to evaluate the efficacy, safety, and tolerability of imeglimin administered as monotherapy and adjunctive therapy in patients with type 2 diabetes mellitus.
MATERIALS AND METHODS
Inclusion criteria, search strategy, data extraction and outcomes
Randomized controlled trials comparing imeglimin with placebo in adults with type 2 diabetes mellitus were included in this meta‐analysis. It was carried out according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 22 .
A systematic literature review was carried out according to the PICO strategy (Patients: type 2 diabetes mellitus; Intervention: imeglimin; Comparator: placebo; and Outcome: efficacy and tolerability). To identify relevant studies, an electronic search was carried out without language restrictions using Embase, MEDLINE/PubMed, the Cochrane Library, the US National Institutes of Health clinical trials registry (http://www.clinicaltrials.gov) and University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR; http://www.umin.ac.jp/ctr/index.htm; last search: 13 March 2023), and using the following search terms: imeglimin; type 2 diabetes mellitus; and random, randomly or randomized. Details of the search strategy and types of study included are provided in Appendix S1. Additional eligible studies were also sought by a manual search of reference lists from relevant articles and reviews.
The search, inclusion and the selection of the criteria for each of the identified studies, and data extraction, were carried out independently by two reviewers (KH and MN). Discrepancies in the different coding forms were resolved by discussions between the reviewers. The methodological quality of the trials was also assessed using the Cochrane risk‐of‐bias criteria (Cochrane Collaboration, http://www.cochrane.org/) 23 .
Statistical analysis
The primary outcome for efficacy was HbA1c (change from baseline to study end) in the intention‐to‐treat population. The secondary outcomes included change from baseline in (1) fasting plasma glucose; (2) homeostasis model assessment‐insulin resistance (HOMA‐IR) index; (3) treatment response; (4) lipid parameters, including triglyceride, total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and high‐intensity lipoprotein cholesterol; (5) adverse events AEs; (6) premature study discontinuation due to any reason, inefficacy of treatment, and AEs; and (7) weight and body mass index (BMI). AEs were classified using Medical Dictionary for Regulatory Activities terminology version 20.1.
Weighted mean difference (WMD) or pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated using random effects models 24 . The reviewers extracted duplicated data in a spreadsheet, and any disagreement was resolved by discussion. The random effects model was applied for pooling studies using the inverse of variance weighting method. This conservative model was used to address the possibility that the underlying effects that differ across the studies and populations would be heterogeneous.
Relative risk values <1 show superiority of imeglimin for negative outcomes (including discontinuation due to any cause and incidence of any specific AE), whereas the opposite is true for the positive outcome (e.g., study‐defined treatment response). The number‐needed‐to‐treat for an additional beneficial outcome or for an additional harmful outcome was calculated when risk differences were significant.
Subgroup analyses of the primary outcome were carried out (where ≥2 studies existed) with the aim of identifying potential moderators and methodological biases. Subgroup analyses included: (1) country, (2) BMI (≥30, <30, ≥25 and <25 kg/m2), and (3) chronic kidney disease (CKD) category (G1, estimated glomerular filtration rate ≥90 mL/min/1.73 m2; G2, 60–89 mL/min/1.73 m2; G3a, 45–59 mL/min/1.73 m2; G3b, 30–44 mL/min/1.73 m2; G4, 15–29 mL/min/1.73 m2; and G5, <15 mL/min/1.73 m2) 25 . Heterogeneity between studies was explored using the χ2‐test and I 2 statistics, with χ2 values of P < 0.05 and I 2 values of >50% showing significant heterogeneity 26 . Comprehensive Meta‐Analysis software, version 3 (Biostat Inc., Englewood, NJ, USA) was used for all two‐tailed analyses, with α = 0.05, and without adjustments for multiple comparisons.
RESULTS
Study characteristics
The search in Embase, MEDLINE/PubMed, Cochrane Library databases, clinicaltrials.gov and UMIN‐CTR yielded 74 potential studies. Two additional studies were identified by a manual search. A total of 67 studies were excluded, because they were not relevant or were duplicates (Figure 1). Altogether, nine studies 10 , 27 , 28 , 29 , 30 , 31 , 32 , 33 with 1,655 patients were included (mean age 58.5 ± 1.9 years; proportion of male patients 58.8 ± 13.1%; Table 1). One of the studies, PXL008‐008, has not been published (data on file). Sample sizes ranged from 33 to 382 participants. All RCTs included in the meta‐analysis used HbA1c as an outcome‐measuring tool to evaluate the effect of imeglimin in patients with type 2 diabetes mellitus.
Figure 1.
Flow diagram describing the search process. †Excluded for being clearly not relevant or a duplicate search result.
Table 1.
Characteristics of included studies
| Study/country | Randomly assigned patients | Blinding status/study design | Duration (weeks) | Inclusion criteria | Arms (n) | Mean age (years) | Male (%) | Baseline BMI | Baseline HbA1c (%) |
|---|---|---|---|---|---|---|---|---|---|
| Pirags 2012/Latvia | 128 | DB Monotherapy | 8 | Male and female patients with type 2 diabetes mellitus, treatment‐naïve or treated with antidiabetic monotherapy (MET or sulfonylurea), 18–70 years old, with a BMI 22–40 kg/m2, FPG 7.8–13.3 mmol/L at randomization, and HbA1c ≤10% at screening were eligible. | IME 500 mg BID (31) | 60.0 | 41.9 | 32.2 | 7.20 |
| IME 1,500 mg b.i.d. (31) | 59.4 | 38.7 | 32.4 | 7.35 | |||||
| MET 850 mg b.i.d. (33) † | [60.0] | [48.5] | [32.7] | [7.12] | |||||
| PBO (33) | 58.9 | 39.4 | 32.0 | 7.21 | |||||
| Fouqueray 2013/multiple countries | 156 | DB add‐on | 12 | Male and female patients with type 2 diabetes mellitus (N = 156), ≥18 to ≤70 years old, inadequately controlled (HbA1c ≥7.5%) by MET alone (1,500–2,000 mg/day, both inclusive) were included. Enrolled patients had received a stable dose of MET for at least 10 weeks before randomization and no other glucose‐lowering medication within 3 months prior to randomization. Most other therapeutic classes of concomitant medication were permitted. | IME 1,500 b.i.d. (78) | 56.2 | 62.8 | 32.6 | 8.50 |
| PBO (78) | 55.1 | 61.5 | 33.1 | 8.60 | |||||
| Fouqueray 2014/multiple countries | 170 | DB add‐on | 12 | Male and female patients, 18–75 years old, with a BMI of 20–40 kg/m2, and type 2 diabetes mellitus that was inadequately controlled by sitagliptin monotherapy at randomization (HbA1c ≥7.5%) were included in the double‐blind add‐on to sitagliptin treatment period with imeglimin or placebo. | IME 1,500 b.i.d. (82) | 57.5 | 50.0 | 32.0 | 8.47 |
| PBO (88) | 56.1 | 55.7 | 32.3 | 8.53 | |||||
| Pacini 2015/France | 33 | DB monotherapy | 1 | Male and female patients, 18–75 years old, with a BMI of 20–40 kg/m2 and type 2 diabetes mellitus that was naïve or treated with monotherapy including MET, DPP‐IV inhibitors, and alpha‐glucosidase inhibitors, and with HbA1c 6.0–8.0% were enrolled. | IME 1,500 b.i.d. (18) | 60.3 | 72.2 | 28.7 | 6.80 |
| PBO (15) | 60.5 | 80.0 | 30.3 | 6.76 | |||||
| Dubourg 2021a/Japan | 299 | DB monotherapy | 24 | Male and female Japanese patients with type 2 diabetes mellitus aged 20–75 years, with a BMI ≥18.5 kg/m2, who were on a diet and exercise regimen and were either treatment‐naïve (no antidiabetic agents for at least 12 weeks prior to screening) or receiving one oral antidiabetic agent (previously treated patients; dose unchanged for at least 12 weeks prior to screening), and with HbA1c 7.0–10.0% were enrolled. | IME 500 mg b.i.d. (75) | 58.7 | 65.3 | 25.2 | 7.89 |
| IME 1,000 mg b.i.d. (74) | 59.9 | 65.8 | 25.2 | 7.78 | |||||
| IME 1,500 mg b.i.d. (75) | 57.6 | 71.2 | 26.8 | 7.91 | |||||
| PBO (75) | 60.2 | 65.3 | 25.8 | 7.78 | |||||
| Dubourg 2021b/Japan | 213 | DB monotherapy | 24 | Japanese patients aged ≥20 years with type 2 diabetes mellitus treated with diet and exercise and with or without a stable dose of a single oral antidiabetic agent for ≥12 weeks prior to screening, and HbA1c 7.0–10.0% (53–86 mmol/mol). | IME 1,000 mg b.i.d. (106) | 62.2 | 84.0 | 25.66 | 7.99 |
| PBO (107) | 61.9 | 72.9 | 25.31 | 7.93 | |||||
| PXL008‐008/multiple countries | 382 | DB monotherapy | 24 | Male and female patients with type 2 diabetes mellitus aged 18–75 years, with BMI of 24–40 kg/m2, who were either treatment‐naïve (no antidiabetic agents for at least 12 weeks prior to screening) or treated with an oral antidiabetic monotherapy stable for at least 12 weeks, and with HbA1c 7.0–9.5% and 6.5–9.0% at screening for treatment naïve patients and for patients previously treated with oral antidiabetic monotherapy, respectively. | IME 500 mg b.i.d. (74) | 58.1 | 45.9 | 31.8 | 7.95 |
| IME 1,000 mg b.i.d. (79) | 58.5 | 31.6 | 31.4 | 8.09 | |||||
| IME 1,500 mg b.i.d. (74) | 58.1 | 39.2 | 32.0 | 7.89 | |||||
| IME 2,000 mg b.i.d. (74) | 59.0 | 39.2 | 31.0 | 8.04 | |||||
| PBO (81) | 58.2 | 45.7 | 30.5 | 7.76 | |||||
| Theurey 2022/multiple countries | 59 | DB monotherapy | 18 | Male or female type 2 diabetes mellitus patients aged 18–75 years, treated with MET monotherapy at stable dose (≥1,500 mg/day) for at least 12 weeks prior to screening, with HbA1c 6.8–9% at screening; 7.2–9.5% at pre‐randomization, and with a BMI of 25–40 kg/m2. | IME 1,500 b.i.d. (30) | 58.4 | 40.0 | 32.83 | 8.12 |
| PBO (29) | 54.3 | 55.2 | 32.91 | 8.14 | |||||
| Reilhac 2022/Japan | 215 | DB add‐on | 16 | (a) Japanese patients aged ≥20 years with type 2 diabetes mellitus who had inadequate glycemic control on insulin monotherapy in addition to diet and exercise for ≥12 weeks prior to randomization, and HbA1c 7.5% to <11.0% at screening visit and at pre‐randomization visit, or (b) Japanese patients aged ≥20 years with type 2 diabetes mellitus who had inadequate glycemic control on insulin in combination with only one oral hypoglycemic agent (oral hypoglycemic agent stable for ≥12 weeks prior to screening visit, and HbA1c 7.5–10.0% at screening visit). | IME 1,000 mg b.i.d. (108) | 59.3 | 61.1 | 25.2 | 8.74 |
| PBO (107) | 57.6 | 64.5 | 24.9 | 8.83 | |||||
|
Included RCTs = 9, n = 1,655 Region: Multiple countries (studies, N = 4; patients, n = 767), Japan (N = 3, n = 727), Latvia (N = 1, n = 128), France (N = 1, n = 33) Blinding status: DB (N = 9, n = 1,655) Study design: Monotherapy (N = 6, n = 1,114), Adjunctive therapy (N = 3, n = 541) Study duration: Mean = 15.44 ± 7.56 weeks (range 1–24) |
Mean age: 58.5 ± 1.9 years % male: 58.8 ± 13.1 Mean ± SD BMI (kg/m2): 29.7 ± 3.2 (n = 1,649), Asian: 25.5 ± 4.1 (n = 733), white: 32.0 ± 4.5 (n = 906), black or African American: 31.5 ± 4.7 (n = 8), native Hawaiian or other Pacific Islander: 28.8 (n = 1), other: 34.8 (n = 1) HbA1c (%): 7.97 ± 0.60 The number of patients per study: median = 170 (range 33–382) |
||||||||
Drug groups or numbers in square brackets were not used in any analysis, neither the primary one nor in a sensitivity analysis.
b.i.d., twice daily; BMI, body mass index; DB, double blind; DPP, dipeptidyl peptidase; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; IME, imeglimin; MET, metformin; PBO, placebo; RCT, randomized controlled trial; SD, standard deviation.
A summary of the risk of bias is shown in Table 2. The risk of bias was considered low or unclear in all domains, and no study scored high for risk of bias in any domain.
Table 2.
Risk of bias summary
| Study publication year | Random sequence generation | Allocation concealment | Blinding of participants and personnel | Blinding of outcome assessment | Incomplete outcome data addressed | Selective reporting | Other sources of bias | No. low‐risk ratings |
|---|---|---|---|---|---|---|---|---|
| Pirags 2012 | Unclear | Unclear | Low | Low | Low | Low | Low | 5 |
| Fouqueray 2013 | Unclear | Unclear | Low | Low | Low | Low | Low | 5 |
| Fouqueray 2014 | Unclear | Unclear | Low | Low | Low | Low | Low | 5 |
| Pacini 2015 | Unclear | Unclear | Low | Low | Low | Low | Low | 5 |
| Dubourg 2021a | Low | Low | Low | Low | Low | Low | Low | 7 |
| Dubourg 2021b | Low | Low | Low | Low | Low | Low | Low | 7 |
| PXL008‐008 | Unclear | Unclear | Low | Low | Low | Low | Unclear | 4 |
| Theurey 2022 | Unclear | Unclear | Low | Low | Low | Low | Unclear | 4 |
| Reilhac 2022 | Low | Low | Low | Low | Low | Low | Low | 7 |
Risk of bias summary: review of authors' judgments about each risk of bias item for each included study (“Low”: low risk of bias; “Unclear”: unclear risk of bias).
The quality of the RCTs in this systematic review was moderately satisfactory, and all included studies were double‐blind. The characteristics of all the included studies are shown in Table 1.
Efficacy
The analysis by dose when imeglimin was administered as monotherapy showed that imeglimin 500 mg b.i.d. did not significantly differ from placebo regarding HbA1c (studies N = 3, patients n = 366, P = 0.320). However, imeglimin 1,000 mg b.i.d. (N = 3, n = 517, WMD = −0.714, 95% CI −1.069 to −0.358, P < 0.001), 1,500 mg b.i.d. (N = 5, n = 448, WMD = −0.531, 95% CI −0.979 to −0.083, P = 0.020) and 2,000 mg b.i.d. (N = 1, n = 149, WMD = −0.450, 95% CI −0.763 to −0.137, P = 0.005) significantly improved HbA1c (Figure 2a and Table 3). The analysis by dose when imeglimin was administered as adjunctive therapy showed that both imeglimin 1,000 mg b.i.d. (N = 1, n = 214, WMD = −0.600, 95% CI −0.794 to −0.406, P < 0.001) and 1,500 mg b.i.d. (N = 2, n = 324, WMD = −0.576, 95% CI −0.851 to −0.302, P < 0.001) significantly improved HbA1c (Figure 2b and Table 3).
Figure 2.
Forest plot of the weighted mean difference (WMD) for changed glycated hemoglobin (%) by imeglimin dose (monotherapy) (a) and forest plot of the WMD for changed glycated hemoglobin (%) by imeglimin dose (adjunctive therapy) (b). b.i.d., twice daily; CI, confidence interval.
Table 3.
Summary of pooled results of the primary outcome (glycated hemoglobin, %) by dose
| Group | Dose (mg b.i.d.) | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | Effect size (95% CI) | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Lower limit | Upper limit | P‐value | I 2 | |||||||
| Monotherapy | 500 | 3 | 366 | −0.190 | −0.565 | 0.185 | 0.320 | 0.017 | 75.6 | 0.227 (ns) |
| 1,000 | 3 | 517 | −0.714 | −1.069 | −0.358 | <0.001 | 0.002 | 83.6 | 0.895 (0.302–1.488) | |
| 1,500 | 5 | 448 | −0.531 | −0.979 | −0.083 | 0.020 | 0.000 | 93.9 | 0.748 (0.426–1.071) | |
| 2,000 | 1 | 149 | −0.450 | −0.763 | −0.137 | 0.005 | — | — | 0.462 (0.136–0.789) | |
| Adjunctive therapy | 1,000 | 1 | 214 | −0.600 | −0.794 | −0.406 | <0.001 | — | — | 0.829 (0.549–1.108) |
| 1,500 | 2 | 324 | −0.576 | −0.851 | −0.302 | <0.001 | 0.172 | 46.4 | 0.626 (0.384–0.869) | |
The n values account for all patients included in the analysis (both in the imeglimin and placebo groups). Boldface indicates statistical significance. All analyses were two‐tailed with α set at 0.05 without adjustments for multiple comparisons. b.i.d., twice daily; CI, confidence interval; HbA1c, glycated hemoglobin; ns, not significant; WMD, weighted mean difference.
Efficacy by dose and duration of treatment
Table 4 shows a summary of the pooled results of the primary outcome (HbA1c) by dose and duration of treatment. When imeglimin was administered as monotherapy at a dose of 500 mg b.i.d., a significant improvement in HbA1c versus placebo was shown at 2, 4, 16 and 20 weeks; at a dose of 1,000 mg b.i.d., a significant improvement in HbA1c versus placebo was shown at 2, 4, 8, 12, 16, 18, 20 and 24 weeks; at a dose of 1,500 mg b.i.d., a significant improvement in HbA1c versus placebo was shown at 2, 3, 4, 6, 8, 12, 16, 18, 20 and 24 weeks; and at a dose of 2,000 mg b.i.d., a significant improvement in HbA1c versus placebo was shown at 3, 6, 12, 18 and 24 weeks. When imeglimin was administered as adjunctive therapy at a dose of 1,000 mg b.i.d., a significant improvement in HbA1c versus placebo was shown at 4, 8, 12 and 16 weeks, and when it was administered at 1,500 mg, a significant improvement in HbA1c versus placebo was shown at 4, 8 and 12 weeks.
Table 4.
Summary of pooled results of the primary outcome (glycated hemoglobin, %) by dose and duration of treatment
| Group | Dose (mg b.i.d.) | Study period in weeks | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | Effect size (95% CI) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Lower limit | Upper limit | P‐value | I 2 | ||||||||
| Monotherapy | 500 | 2 | 1 | 150 | −0.130 | −0.192 | −0.068 | <0.001 | — | — | 0.666 (0.337–0.995) |
| 3 | 1 | 152 | 0.010 | −0.144 | 0.164 | 0.899 | — | — | 0.021 (ns) | ||
| 4 | 1 | 150 | −0.170 | −0.266 | −0.074 | 0.001 | — | — | 0.566 (0.239–0.892) | ||
| 6 | 1 | 145 | −0.010 | −0.208 | 0.188 | 0.921 | — | — | 0.016 (ns) | ||
| 8 | 2 | 214 | −0.169 | −0.549 | 0.210 | 0.382 | 0.077 | 68.1 | 0.319 (ns) | ||
| 12 | 2 | 291 | −0.319 | −0.661 | 0.023 | 0.067 | 0.032 | 78.4 | 0.511 (ns) | ||
| 16 | 1 | 150 | −0.610 | −0.813 | −0.407 | <0.001 | — | — | 0.960 (0.622–1.298) | ||
| 18 | 1 | 135 | −0.160 | −0.455 | 0.135 | 0.288 | — | — | 0.183 (ns) | ||
| 20 | 1 | 150 | −0.590 | −0.818 | −0.362 | <0.001 | — | — | 0.828 (0.494–1.161) | ||
| 24 | 2 | 302 | −0.299 | −0.749 | 0.152 | 0.193 | 0.024 | 80.3 | 0.358 (ns) | ||
| 1,000 | 2 | 1 | 148 | −0.210 | −0.272 | −0.148 | <0.001 | — | — | 1.083 (0.738–1.428) | |
| 3 | 1 | 156 | −0.100 | −0.231 | 0.031 | 0.136 | — | — | 0.239 (ns) | ||
| 4 | 2 | 359 | −0.297 | −0.356 | −0.239 | <0.001 | 0.917 | 0.0 | 1.058 (0.837–1.279) | ||
| 6 | 1 | 149 | −0.120 | −0.310 | 0.070 | 0.215 | — | — | 0.203 (ns) | ||
| 8 | 2 | 359 | −0.565 | −0.651 | −0.479 | <0.001 | 0.946 | 0.0 | 1.358 (1.128–1.587) | ||
| 12 | 3 | 499 | −0.585 | −0.839 | −0.332 | <0.001 | 0.000 | 93.1 | 1.026 (0.300–1.751) | ||
| 16 | 2 | 350 | −0.810 | −0.928 | −0.692 | <0.001 | 0.811 | 0.0 | 1.444 (1.209–1.679) | ||
| 18 | 1 | 139 | −0.410 | −0.675 | −0.145 | 0.002 | — | — | 0.514 (0.176–0.852) | ||
| 20 | 2 | 347 | −0.870 | −1.000 | −0.741 | <0.001 | 0.606 | 0.0 | 1.414 (1.178–1.649) | ||
| 24 | 3 | 517 | −0.714 | −1.069 | −0.358 | <0.001 | 0.000 | 90.4 | 0.895 (0.302–1.488) | ||
| 1,500 | 1 | 1 | 30 | −0.030 | −0.112 | 0.052 | 0.471 | — | — | 0.263 (ns) | |
| 2 | 1 | 148 | −0.230 | −0.294 | −0.166 | <0.001 | — | — | 1.150 (0.802–1.498) | ||
| 3 | 1 | 149 | −0.260 | −0.409 | −0.111 | 0.001 | — | — | 0.561 (0.233–0.889) | ||
| 4 | 1 | 148 | −0.390 | −0.489 | −0.291 | <0.001 | — | — | 1.267 (0.914–1.620) | ||
| 6 | 1 | 142 | −0.390 | −0.582 | −0.198 | <0.001 | — | — | 0.671 (0.332–1.010) | ||
| 8 | 2 | 212 | −0.601 | −0.863 | −0.339 | <0.001 | 0.131 | 56.1 | 1.086 (0.208–1.963) | ||
| 12 | 2 | 288 | −0.726 | −1.088 | −0.365 | <0.001 | 0.019 | 81.7 | 1.156 (0.243–2.069) | ||
| 16 | 1 | 148 | −1.030 | −1.238 | −0.822 | <0.001 | — | — | 1.594 (1.224–1.964) | ||
| 18 | 2 | 190 | −0.605 | −0.851 | −0.360 | <0.001 | 0.944 | 0.0 | 0.701 (0.408–0.994) | ||
| 20 | 1 | 148 | −1.040 | −1.268 | −0.812 | <0.001 | — | — | 1.469 (1.106–1.832) | ||
| 24 | 2 | 297 | −0.826 | −1.188 | −0.464 | <0.001 | 0.073 | 68.8 | 0.947 (0.358–1.535) | ||
| 2,000 | 3 | 1 | 149 | −0.220 | −0.351 | −0.089 | 0.001 | — | — | 0.541 (0.214–0.869) | |
| 6 | 1 | 143 | −0.310 | −0.501 | −0.119 | 0.001 | — | — | 0.532 (0.198–0.866) | ||
| 12 | 1 | 140 | −0.490 | −0.759 | −0.221 | 0.000 | — | — | 0.604 (0.265–0.943) | ||
| 18 | 1 | 134 | −0.480 | −0.797 | −0.163 | 0.003 | — | — | 0.513 (0.169–0.858) | ||
| 24 | 1 | 149 | −0.450 | −0.763 | −0.137 | 0.005 | — | — | 0.462 (0.136–0.789) | ||
| Adjunctive therapy | 1,000 | 4 | 1 | 213 | −0.280 | −0.374 | −0.186 | <0.001 | — | — | 0.796 (0.517–1.075) |
| 8 | 1 | 212 | −0.510 | −0.649 | −0.371 | <0.001 | — | — | 0.990 (0.705–1.275) | ||
| 12 | 1 | 210 | −0.590 | −0.767 | −0.413 | <0.001 | — | — | 0.902 (0.618–1.186) | ||
| 16 | 1 | 214 | −0.600 | −0.794 | −0.406 | <0.001 | — | — | 0.829 (0.549–1.108) | ||
| 1,500 | 2 | 1 | 131 | −0.070 | −0.220 | 0.080 | 0.360 | — | — | 0.160 (ns) | |
| 4 | 2 | 291 | −0.220 | −0.406 | −0.034 | 0.021 | 0.078 | 67.8 | 0.482 (0.052–0.912) | ||
| 8 | 2 | 298 | −0.558 | −0.717 | −0.399 | 0.000 | 0.429 | 0.0 | 0.757 (0.335–1.178) | ||
| 12 | 2 | 324 | −0.576 | −0.851 | −0.302 | 0.000 | 0.172 | 46.4 | 0.626 (0.384–0.869) | ||
Boldface indicates statistical significance. All analyses were two‐tailed with α set at 0.05 without adjustments for multiple comparisons. b.i.d., twice daily; CI, confidence interval; HbA1c, glycated hemoglobin; ns, not significant; WMD, weighted mean difference.
Subgroup analysis of the primary outcome
The results of the subgroup analysis of the primary outcome (HbA1c) by country showed that HbA1c significantly improved with imeglimin compared with placebo regardless of the country, whereas the effect size tended to be larger in trials carried out in Japan than in trials carried out outside of Japan (Table 5a). The subgroup analysis of the primary outcome by baseline BMI showed that the effect of imeglimin tended to be slightly attenuated in patients with high BMI (Table 5b). The mean BMI was 25.5 ± 4.1 kg/m2 (n = 733) in the Asian population, whereas that in the non‐Asian population, it was 32.0 ± 4.5 kg/m2 for Whites (n = 906), 31.5 ± 4.7 kg/m2 for black or African Americans (n = 8), 28.8 kg/m2 for native Hawaiians or other Pacific Islanders (n = 1) and 34.8 kg/m2 for others (n = 1; Table 1). The mean BMI differed significantly between the Asian and non‐Asian populations (25.5 ± 4.1 vs 32.0 ± 4.5 kg/m2, respectively; P < 0.001). The subgroup analysis of the primary outcome by CKD category showed that imeglimin appeared to be effective regardless of CKD category (Table 5c).
Table 5.
Subgroup analysis of the primary outcome (glycated hemoglobin, %). (a) By country; (b) By baseline body mass index; (c) By baseline chronic kidney disease category
| (a) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Country | Group | Dose (mg b.i.d.) | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | Effect size (95% CI) | ||
| Lower limit | Upper limit | P‐value | I 2 | ||||||||
| Japan | Monotherapy | 500 | 1 | 150 | −0.520 | −0.774 | −0.266 | <0.001 | — | — | 0.656 (0.328–0.985) |
| 1,000 | 2 | 360 | −0.895 | −1.050 | −0.741 | <0.001 | 0.670 | 0.0 | 1.197 (0.973 to 1.422) | ||
| 1,500 | 1 | 148 | −1.000 | −1.258 | −0.742 | <0.001 | — | — | 1.250 (0.898–1.602) | ||
| Adjunctive therapy | 1,000 | 1 | 214 | −0.600 | −0.794 | −0.406 | <0.001 | — | — | 0.829 (0.549–1.108) | |
| Europe and the USA | Monotherapy | 500 | 2 | 216 | −0.010 | −0.259 | 0.238 | 0.935 | 0.597 | 0.0 | 0.016 (ns) |
| 1,000 | 1 | 157 | −0.290 | −0.595 | 0.015 | 0.062 | — | — | 0.298 (ns) | ||
| 1,500 | 4 | 300 | −0.396 | −0.764 | −0.028 | 0.035 | <0.001 | 86.4 | 0.609 (0.377–0.841) | ||
| 2,000 | 1 | 149 | −0.450 | −0.763 | −0.137 | 0.005 | — | — | 0.462 (0.136–0.789) | ||
| Adjunctive therapy | 1,500 | 2 | 324 | −0.576 | −0.851 | −0.302 | <0.001 | 0.172 | 46.4 | 0.626 (0.384–0.869) | |
| France | Monotherapy | 1,500 | 1 | 30 | −0.030 | −0.112 | 0.052 | 0.471 | — | — | 0.263 (ns) |
| Latvia | Monotherapy | 500 | 1 | 64 | 0.080 | −0.337 | 0.497 | 0.707 | — | — | −0.094 (ns) |
| 1,500 | 1 | 64 | −0.420 | −0.752 | −0.088 | 0.013 | — | — | 0.620 (0.118–1.122) | ||
| Multiple countries | Monotherapy | 500 | 1 | 152 | −0.060 | −0.369 | 0.249 | 0.704 | — | — | 0.062 (ns) |
| 1,000 | 1 | 157 | −0.290 | −0.595 | 0.015 | 0.062 | — | — | 0.298 (ns) | ||
| 1,500 | 2 | 206 | −0.627 | −0.888 | −0.366 | <0.001 | 0.972 | 0.0 | 0.658 (0.377–0.939) | ||
| 2,000 | 1 | 149 | −0.450 | −0.763 | −0.137 | 0.005 | — | — | 0.462 (0.136–0.789) | ||
| Adjunctive | 1,500 | 2 | 324 | −0.576 | −0.851 | −0.302 | <0.001 | 0.172 | 46.4 | 0.626 (0.384–0.869) | |
| (b) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline mean BMI | Group | Dose (mg b.i.d.) | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | Effect size (95% CI) | ||
| Lower limit | Upper limit | P‐value | I 2 | ||||||||
| BMI <25 kg/m2 | Monotherapy | 500 | 2 | 84 | −0.674 | −0.977 | −0.371 | <0.001 | 0.907 | 0.0 | 0.953 (0.499–1.407) |
| 1,000 | 3 | 193 | −0.948 | −1.121 | −0.775 | <0.001 | 0.865 | 0.0 | 1.521 (1.184–1.859) | ||
| 1,500 | 2 | 71 | −1.521 | −2.593 | −0.449 | 0.005 | 0.131 | 56.1 | 1.711 (1.160–2.263) | ||
| 2,000 | 1 | 11 | −0.810 | −2.015 | 0.395 | 0.188 | — | — | 0.798 (ns) | ||
| Adjunctive therapy | 1,000 | 1 | 116 | −0.770 | −0.993 | −0.547 | <0.001 | — | — | 1.255 (0.857–1.653) | |
| 1,500 | 1 | 9 | 0.040 | −1.252 | 1.332 | 0.952 | — | — | −0.043 (ns) | ||
| BMI 25 to <30 kg/m2 | Monotherapy | 500 | 2 | 108 | −0.299 | −0.629 | 0.031 | 0.076 | 0.405 | 0.0 | 0.332 (ns) |
| 1,000 | 3 | 192 | −0.732 | −1.031 | −0.432 | <0.001 | 0.155 | 46.3 | 0.986 (0.384–1.587) | ||
| 1,500 | 4 | 148 | −0.562 | −1.254 | 0.130 | 0.111 | <0.001 | 91.5 | 0.647 (ns) | ||
| 2,000 | 1 | 59 | −0.750 | −1.240 | −0.260 | 0.003 | — | — | 0.795 (0.256–1.334) | ||
| Adjunctive therapy | 1,000 | 1 | 79 | −0.520 | −0.839 | −0.201 | 0.001 | — | — | 0.723 (0.265–1.181) | |
| 1,500 | 2 | 78 | −0.768 | −1.167 | −0.369 | <0.001 | 0.219 | 33.8 | 1.056 (0.505–1.607) | ||
| BMI ≥30 kg/m2 | Monotherapy | 500 | 2 | 110 | −0.021 | −0.395 | 0.353 | 0.912 | 0.659 | 0.0 | 0.020 (ns) |
| 1,000 | 3 | 132 | −0.356 | −0.712 | 0.000 | 0.050 | 0.419 | 0.0 | 0.348 (ns) | ||
| 1,500 | 4 | 161 | −0.305 | −0.561 | −0.049 | 0.020 | 0.166 | 40.9 | 0.578 (0.262–0.895) | ||
| 2,000 | 1 | 79 | −0.240 | −0.685 | 0.205 | 0.290 | — | — | 0.238 (ns) | ||
| Adjunctive therapy | 1,000 | 1 | 19 | −0.040 | −1.091 | 1.011 | 0.941 | — | — | 0.035 (ns) | |
| 1,500 | 2 | 230 | −0.602 | −0.836 | −0.368 | <0.001 | 0.276 | 15.7 | 0.716 (0.354–1.079) | ||
| (c) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CKD category | Group | Dose (mg b.i.d.) | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | Effect size (95% CI) | ||
| Lower limit | Upper limit | P‐value | I 2 | ||||||||
| CKD G1 (eGFR ≥90 mL/min/1.73 m2) | Monotherapy | 500 | 2 | 84 | 0.013 | −0.360 | 0.386 | 0.946 | 0.917 | 0.0 | −0.020 (ns) |
| 1,000 | 3 | 105 | −0.576 | −0.892 | −0.260 | <0.001 | 0.425 | 0.0 | 0.744 (0.121–1.366) | ||
| 1,500 | 4 | 144 | −0.352 | −0.735 | 0.032 | 0.072 | 0.014 | 71.7 | 0.548 (0.211–0.885) | ||
| 2,000 | 1 | 64 | −0.710 | −1.216 | −0.204 | 0.006 | — | — | 0.700 (0.187–1.214) | ||
| Adjunctive therapy | 1,000 | 1 | 30 | −0.530 | −0.973 | −0.087 | 0.019 | — | — | 0.858 (0.109–1.608) | |
| 1,500 | 2 | 235 | −0.537 | −0.781 | −0.292 | <0.001 | 0.230 | 30.7 | 0.677 (0.359–0.995) | ||
| CKD G2 (eGFR 60–89 mL/min/1.73 m2) | Monotherapy | 500 | 2 | 186 | −0.359 | −0.876 | 0.158 | 0.174 | 0.050 | 74.0 | 0.418 (ns) |
| 1,000 | 3 | 345 | −0.719 | −1.199 | −0.239 | 0.003 | 0.001 | 86.7 | 0.938 (0.125–1.751) | ||
| 1,500 | 4 | 208 | −0.543 | −1.172 | 0.086 | 0.091 | <0.001 | 92.8 | 0.823 (0.287–1.360) | ||
| 2,000 | 1 | 71 | −0.060 | −0.509 | 0.389 | 0.793 | — | — | 0.062 (ns) | ||
| Adjunctive therapy | 1,000 | 1 | 184 | −0.620 | −0.840 | −0.400 | <0.001 | — | — | 0.816 (0.515–1.117) | |
| 1,500 | 2 | 89 | −0.669 | −1.007 | −0.330 | <0.001 | 0.550 | 0.0 | 0.738 (0.152–1.325) | ||
| CKD G3a (eGFR 45–59 mL/min/1.73 m2) | Monotherapy | 500 | 2 | 32 | −0.207 | −0.996 | 0.582 | 0.607 | 0.167 | 47.6 | 0.264 (ns) |
| 1,000 | 3 | 67 | −0.646 | −0.959 | −0.333 | <0.001 | 0.820 | 0.0 | 0.967 (0.448–1.485) | ||
| 1,500 | 2 | 31 | −1.187 | −1.733 | −0.642 | <0.001 | 0.589 | 0.0 | 1.545 (0.733–2.357) | ||
| 2,000 | 1 | 14 | −1.270 | −2.099 | −0.441 | 0.003 | — | — | 1.605 (0.400–2.809) | ||
Boldface indicates statistical significance. All analyses were two‐tailed with α set at 0.05 without adjustments for multiple comparisons. b.i.d., twice daily; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; ns, not significant; WMD, weighted mean difference. [Correction added on 18 October 2023, after first online publication: In Table 5(a), the Dose (mg b.i.d) in Latvia was amended from “1,000” to “1,500”.]
Secondary outcomes
A summary of the pooled results of secondary continuous outcomes are shown in Table 6. Secondary efficacy outcomes, including BMI, bodyweight, fasting proinsulin‐to‐insulin ratio, fasting plasma glucose, glycated albumin, homeostatic model assessment of β‐cell function (HOMA‐β), LDL‐C and quantitative insulin check index 34 , showed a significant difference with imeglimin versus placebo.
Table 6.
Summary of pooled results of secondary continuous outcomes
| Outcomes | Group | Dose (mg b.i.d.) | Studies (N) | Patients (n) | WMD | 95% CI | P‐value | Heterogeneity | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Lower limit | Upper limit | P‐value | I 2 | |||||||
| Adiponectin (μg/mL) | Monotherapy | 500 | 1 | 64 | −0.140 | −1.583 | 1.303 | 0.849 | — | — |
| 1,500 | 1 | 64 | −0.180 | −1.329 | 0.969 | 0.759 | — | — | ||
| Apolipoprotein A (mg/dL) | Monotherapy | 500 | 1 | 64 | 5.000 | −6.516 | 16.52 | 0.395 | — | — |
| 1,500 | 1 | 64 | 0.700 | −9.804 | 11.20 | 0.896 | — | — | ||
| Adjunctive therapy | 1,500 | 1 | 141 | −4.300 | −9.984 | 1.384 | 0.138 | — | — | |
| Apolipoprotein B (mg/dL) | Monotherapy | 500 | 1 | 64 | 7.690 | −1.990 | 17.37 | 0.119 | — | — |
| 1,500 | 1 | 64 | 4.100 | −6.678 | 14.88 | 0.456 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 303 | −1.397 | −5.834 | 3.039 | 0.537 | 0.341 | 0.0 | |
| BMI (kg/m2) | Monotherapy | 500 | 3 | 351 | 0.218 | 0.040 | 0.395 | 0.016 | 0.614 | 0.0 |
| 1,000 | 3 | 496 | 0.038 | −0.079 | 0.156 | 0.524 | 0.439 | 0.0 | ||
| 1,500 | 4 | 406 | 0.220 | 0.054 | 0.385 | 0.009 | 0.794 | 0.0 | ||
| 2,000 | 1 | 155 | −0.110 | −0.423 | 0.203 | 0.492 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 212 | 0.265 | 0.123 | 0.407 | <0.001 | — | — | |
| 1,500 | 2 | 308 | −0.089 | −0.412 | 0.234 | 0.591 | 0.117 | 59.4 | ||
| Bodyweight (kg) | Monotherapy | 500 | 3 | 351 | 0.531 | 0.071 | 0.992 | 0.024 | 0.591 | 0.0 |
| 1,000 | 3 | 496 | 0.084 | −0.228 | 0.397 | 0.597 | 0.372 | 0.0 | ||
| 1,500 | 4 | 392 | 0.662 | 0.239 | 1.085 | 0.002 | 0.905 | 0.0 | ||
| 2,000 | 1 | 155 | −0.290 | −1.039 | 0.459 | 0.448 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 212 | 0.710 | 0.324 | 1.096 | <0.001 | — | — | |
| 1,500 | 2 | 322 | −0.234 | −1.172 | 0.704 | 0.625 | 0.075 | 68.5 | ||
| C‐peptide (nmol/L) | Monotherapy | 500 | 3 | 366 | 0.029 | −0.020 | 0.078 | 0.248 | 0.463 | 0.0 |
| 1,000 | 3 | 499 | 0.016 | −0.015 | 0.048 | 0.299 | 0.358 | 2.7 | ||
| 1,500 | 5 | 444 | 0.022 | −0.022 | 0.066 | 0.326 | 0.630 | 0.0 | ||
| 2,000 | 1 | 149 | 0.059 | −0.053 | 0.171 | 0.303 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 324 | −0.050 | −0.122 | 0.021 | 0.170 | 0.507 | 0.0 | |
| C‐peptide‐to‐fasting plasma glucose ratio | Adjunctive therapy | 1,500 | 1 | 168 | 0.020 | −0.008 | 0.048 | 0.158 | — | — |
| Fasting insulin (μIU/mL) | Monotherapy | 500 | 3 | 366 | 0.792 | −0.997 | 2.581 | 0.385 | 0.255 | 26.8 |
| 1,000 | 3 | 517 | 0.671 | −0.172 | 1.514 | 0.119 | 0.358 | 2.6 | ||
| 1,500 | 5 | 442 | 1.049 | −0.560 | 2.658 | 0.201 | 0.029 | 62.9 | ||
| 2,000 | 1 | 149 | 2.530 | −0.813 | 5.873 | 0.138 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 324 | −0.582 | −2.076 | 0.911 | 0.445 | 0.763 | 0.0 | |
| Fasting plasma glucagon (ng/L) | Monotherapy | 1,500 | 2 | 67 | 7.558 | −17.85 | 32.96 | 0.560 | — | — |
| Fasting proinsulin (pmol/L) | Monotherapy | 500 | 1 | 150 | 1.093 | −2.760 | 4.946 | 0.578 | — | — |
| 1,000 | 1 | 148 | −1.172 | −5.012 | 2.668 | 0.550 | — | — | ||
| 1,500 | 3 | 219 | −3.166 | −8.290 | 1.959 | 0.226 | 0.186 | 40.5 | ||
| Fasting proinsulin‐to‐C‐peptide ratio | Monotherapy | 500 | 1 | 150 | 0.002 | −0.026 | 0.030 | 0.899 | — | — |
| 1,000 | 3 | 510 | 0.000 | −0.001 | 0.000 | 0.077 | 0.981 | 0.0 | ||
| 1,500 | 2 | 296 | −0.002 | −0.022 | 0.017 | 0.814 | 0.972 | 0.0 | ||
| 2,000 | 1 | 148 | −0.003 | −0.030 | 0.025 | 0.849 | — | — | ||
| Fasting proinsulin‐to‐insulin ratio | Monotherapy | 500 | 2 | 281 | −0.034 | −0.156 | 0.087 | 0.581 | 0.248 | 24.9 |
| 1,000 | 3 | 493 | −0.014 | −0.059 | 0.032 | 0.555 | 0.038 | 69.3 | ||
| 1,500 | 4 | 345 | −0.031 | −0.061 | −0.001 | 0.045 | 0.398 | 0.0 | ||
| 2,000 | 1 | 149 | −0.019 | −0.051 | 0.013 | 0.243 | — | — | ||
| Adjunctive therapy | 1,500 | 1 | 167 | −39.53 | −165.5 | 86.39 | 0.538 | — | — | |
| Fibrinogen (g/L) | Monotherapy | 500 | 1 | 64 | 0.240 | −0.195 | 0.675 | 0.280 | — | — |
| 1,500 | 1 | 64 | −0.330 | −0.760 | 0.100 | 0.133 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 300 | −0.014 | −0.225 | 0.198 | 0.897 | 0.701 | 0.0 | |
| Fasting plasma glucose (mmol/L) | Monotherapy | 500 | 3 | 366 | −0.342 | −0.724 | 0.039 | 0.079 | 0.505 | 0.0 |
| 1,000 | 3 | 517 | −0.998 | −1.455 | −0.542 | <0.001 | 0.121 | 52.7 | ||
| 1,500 | 5 | 448 | −1.207 | −1.528 | −0.886 | <0.001 | 0.399 | 1.3 | ||
| 2,000 | 1 | 149 | −0.616 | −1.344 | 0.112 | 0.097 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | −0.480 | −1.118 | 0.158 | 0.140 | — | — | |
| 1,500 | 2 | 316 | −1.094 | −1.614 | −0.575 | <0.001 | 0.408 | 0.0 | ||
| Free fatty acids (mmol/L) | Monotherapy | 500 | 1 | 64 | 0.060 | −0.072 | 0.192 | 0.371 | — | — |
| 1,500 | 1 | 64 | 0.060 | −0.097 | 0.217 | 0.453 | — | — | ||
| Glycated albumin (%) | Monotherapy | 500 | 1 | 150 | −2.330 | −3.508 | −1.152 | <0.001 | — | — |
| 1,000 | 1 | 148 | −4.110 | −5.301 | −2.919 | <0.001 | — | — | ||
| 1,500 | 1 | 148 | −4.230 | −5.422 | −3.038 | <0.001 | — | — | ||
| HDL cholesterol (mmol/L) | Monotherapy | 500 | 3 | 366 | −0.021 | −0.069 | 0.028 | 0.407 | 0.920 | 0.0 |
| 1,000 | 3 | 499 | 0.013 | −0.064 | 0.089 | 0.746 | 0.029 | 71.8 | ||
| 1,500 | 4 | 404 | −0.002 | −0.045 | 0.042 | 0.944 | 0.547 | 0.0 | ||
| 2,000 | 1 | 149 | 0.020 | −0.054 | 0.094 | 0.595 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | −0.032 | −0.084 | 0.020 | 0.227 | — | — | |
| 1,500 | 2 | 315 | −0.017 | −0.064 | 0.030 | 0.485 | 0.374 | 0.0 | ||
| HOMA‐β | Monotherapy | 500 | 2 | 302 | 8.521 | 2.355 | 14.69 | 0.007 | 0.860 | 0.0 |
| 1,000 | 3 | 517 | 8.040 | 4.390 | 11.69 | <0.001 | 0.421 | 0.0 | ||
| 1,500 | 4 | 367 | 8.414 | 0.869 | 15.96 | 0.029 | 0.311 | 16.1 | ||
| 2,000 | 1 | 149 | 310.3 | −4.755 | 625.4 | 0.054 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 234 | −3.025 | −9.625 | 3.575 | 0.369 | 0.711 | 0.0 | |
| HOMA‐IR | Monotherapy | 500 | 3 | 362 | 0.469 | −0.239 | 1.178 | 0.194 | 0.579 | 0.0 |
| 1,000 | 3 | 517 | 0.007 | −0.411 | 0.425 | 0.976 | 0.499 | 0.0 | ||
| 1,500 | 5 | 428 | −0.449 | −1.451 | 0.552 | 0.379 | 0.062 | 55.3 | ||
| 2,000 | 1 | 149 | 0.358 | −1.106 | 1.822 | 0.632 | — | — | ||
| Adjunctive therapy | 1,500 | 2 | 234 | −0.433 | −1.725 | 0.859 | 0.511 | 0.819 | 0.0 | |
| HOMA‐IS | Monotherapy | 500 | 1 | 60 | 7.000 | −1.713 | 15.71 | 0.115 | — | — |
| 1,500 | 1 | 61 | −3.200 | −13.54 | 7.140 | 0.544 | — | — | ||
| hsCRP (mg/L) | Monotherapy | 500 | 3 | 351 | 1.229 | −1.323 | 3.781 | 0.345 | 0.451 | 0.0 |
| 1,000 | 3 | 499 | 0.107 | −1.282 | 1.496 | 0.880 | 0.410 | 0.0 | ||
| 1,500 | 4 | 400 | 0.582 | −0.796 | 1.959 | 0.408 | 0.677 | 0.0 | ||
| 2,000 | 1 | 149 | 3.820 | −0.464 | 8.104 | 0.081 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | 0.761 | −0.724 | 2.246 | 0.315 | — | — | |
| 1,500 | 2 | 324 | −0.735 | −2.128 | 0.658 | 0.301 | 0.384 | 0.0 | ||
| Insulin‐to‐fasting plasma glucose ratio | Adjunctive therapy | 1,500 | 1 | 168 | 0.020 | −0.160 | 0.200 | 0.827 | — | — |
| LDL cholesterol (mmol/L) | Monotherapy | 500 | 3 | 366 | 0.167 | 0.016 | 0.317 | 0.031 | 0.893 | 0.0 |
| 1,000 | 3 | 499 | 0.201 | 0.092 | 0.310 | <0.001 | 0.846 | 0.0 | ||
| 1,500 | 4 | 404 | 0.185 | 0.012 | 0.358 | 0.036 | 0.292 | 19.7 | ||
| 2,000 | 1 | 149 | 0.321 | 0.079 | 0.563 | 0.009 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | 0.079 | −0.071 | 0.229 | 0.303 | — | — | |
| 1,500 | 2 | 286 | 0.023 | −0.155 | 0.201 | 0.802 | 0.349 | 0.0 | ||
| Leptin (ng/mL) | Monotherapy | 500 | 1 | 64 | 1.300 | −1.358 | 3.958 | 0.338 | — | — |
| 1,500 | 1 | 64 | −0.650 | −3.325 | 2.025 | 0.634 | — | — | ||
| PAI‐1 (ng/mL) | Monotherapy | 500 | 1 | 64 | −5.300 | −39.77 | 29.17 | 0.763 | — | — |
| 1,500 | 1 | 64 | 13.30 | −28.36 | 54.96 | 0.532 | — | — | ||
| Adjunctive therapy | 1,500 | 1 | 143 | −6.430 | −14.27 | 1.415 | 0.108 | — | — | |
| QUICKI | Monotherapy | 500 | 1 | 152 | −0.001 | −0.009 | 0.007 | 0.814 | — | — |
| 1,000 | 2 | 369 | 0.006 | 0.000 | 0.013 | 0.044 | 0.405 | 0.0 | ||
| 1,500 | 2 | 200 | 0.003 | −0.005 | 0.011 | 0.469 | 0.595 | 0.0 | ||
| 2,000 | 1 | 149 | 0.000 | −0.008 | 0.008 | 1.000 | — | — | ||
| Total cholesterol (mmol/L) | Monotherapy | 500 | 3 | 351 | 0.104 | −0.056 | 0.264 | 0.202 | 0.687 | 0.0 |
| 1,000 | 3 | 481 | 0.183 | 0.056 | 0.311 | 0.005 | 0.346 | 5.8 | ||
| 1,500 | 4 | 388 | 0.117 | −0.174 | 0.407 | 0.431 | 0.060 | 59.6 | ||
| 2,000 | 1 | 149 | 0.243 | −0.057 | 0.543 | 0.113 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | 0.056 | −0.123 | 0.235 | 0.541 | — | — | |
| 1,500 | 2 | 318 | −0.029 | −0.240 | 0.182 | 0.788 | 0.465 | 0.0 | ||
| tPA (ng/mL) | Monotherapy | 500 | 1 | 64 | −2.400 | −9.296 | 4.496 | 0.495 | — | — |
| 1,500 | 1 | 64 | −1.600 | −3.965 | 0.765 | 0.185 | — | — | ||
| Adjunctive therapy | 1,500 | 1 | 141 | −1.030 | −2.208 | 0.148 | 0.087 | — | — | |
| Triglycerides (mmol/L) | Monotherapy | 500 | 3 | 366 | −0.167 | −0.370 | 0.035 | 0.105 | 0.797 | 0 |
| 1,000 | 3 | 499 | −0.024 | −0.200 | 0.151 | 0.787 | 0.613 | 0 | ||
| 1,500 | 5 | 447 | −0.081 | −0.257 | 0.095 | 0.366 | 0.662 | 0 | ||
| 2,000 | 1 | 149 | −0.090 | −0.411 | 0.231 | 0.583 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 209 | 0.111 | −0.111 | 0.333 | 0.327 | — | — | |
| 1,500 | 2 | 321 | −0.173 | −0.491 | 0.145 | 0.286 | 0.452 | 0.0 | ||
| Waist circumference (cm) | Monotherapy | 500 | 3 | 351 | 0.029 | −0.724 | 0.783 | 0.939 | 0.336 | 8.4 |
| 1,000 | 3 | 496 | −0.108 | −0.799 | 0.584 | 0.761 | 0.210 | 35.9 | ||
| 1,500 | 4 | 406 | 0.123 | −0.446 | 0.692 | 0.672 | 0.527 | 0.0 | ||
| 2,000 | 1 | 155 | −0.100 | −1.201 | 1.001 | 0.859 | — | — | ||
| Adjunctive therapy | 1,000 | 1 | 212 | 0.540 | −0.206 | 1.286 | 0.156 | — | — | |
| 1,500 | 2 | 322 | −0.356 | −1.846 | 1.133 | 0.639 | 0.062 | 71.2 | ||
Boldface indicates statistical significance. All analyses were two‐tailed with α set at 0.05 without adjustments for multiple comparisons. b.i.d., twice daily; BMI, body mass index; CI, confidence interval; HDL, high‐density lipoprotein; HOMA‐β, homeostatic model assessment of β‐cell function; HOMA‐IR, homeostasis model assessment‐insulin resistance; HOMA‐IS, homeostasis model assessment‐insulin secretion; hsCRP, high‐sensitivity C‐reactive protein; LDL, low density lipoprotein; PAI‐1, plasminogen activator inhibitor‐1; QUICKI, quantitative insulin check index; tPA, tissue plasminogen activator; WMD, weighted mean difference.
A summary of the pooled results of secondary dichotomous outcomes is shown in Table S1. Secondary dichotomous outcomes, including treatment response (HbA1c <7.0%, ≥0.5% decrease and relative decrease ≥7%) and discontinuation due to lack of efficacy, showed a significant difference with imeglimin versus placebo. The numbers‐needed‐to‐treat for an additional beneficial outcome were as low as single‐digit values.
Tolerability
There were no significant differences between imeglimin and placebo regarding tolerability‐related outcomes, including all‐cause discontinuations and discontinuations due to AEs (Table S1).
Safety
There were no significant differences between imeglimin and placebo regarding safety‐related outcomes, including the proportion of patients who presented with at least one AE and severe AEs (Table S1).
Adverse events by system organ class
The risk of diarrhea was significantly greater in patients who received imeglimin 1,500 mg b.i.d. as monotherapy vs placebo (N = 3, n = 369, RR 4.862, 95% CI 1.042–22.69, P = 0.044; Table S1). There were no significant differences between imeglimin and placebo regarding other gastrointestinal disorders. Regarding metabolism and nutrition disorders, the risk of hyperglycemia was lower with imeglimin 1,000 mg b.i.d. administered as monotherapy vs placebo (RR 0.272, heterogeneity P = 0.037, I 2 = 69.6). The proportion of patients requiring rescue medication for hyperglycemia was significantly lower with imeglimin 1,500 mg b.i.d. administered as monotherapy vs placebo (N = 3, n = 360, RR 0.086, 95% CI 0.021–0.353, P = 0.001).
There were no significant differences between imeglimin and placebo regarding AEs related to infections and infestations; musculoskeletal and connective tissue disorders; nervous system disorders; reproductive system and breast disorders; injury, poisoning and procedural complications; skin and subcutaneous tissue disorders; general disorders and administration site conditions; respiratory, thoracic and mediastinal disorders; cardiac disorders; vascular disorders; ear and labyrinth disorders; eye disorders; hepatobiliary disorders; renal and urinary disorders; neoplasms benign, malignant and unspecified; investigations; and endocrine disorders.
DISCUSSION
To our knowledge, this is the first study investigating the efficacy, safety and tolerability of imeglimin by means of a systematic review and meta‐analysis in which imeglimin was administered as monotherapy and adjunctive therapy, and dose levels were evaluated separately after integrating all RCTs carried out to date. This meta‐analysis provides a comprehensive evidence‐based overview of both the efficacy and safety/tolerability profiles of imeglimin for use in patients with type 2 diabetes mellitus, and the findings support the efficacy of imeglimin in this patient population. This study showed the superiority of imeglimin over placebo in changes from baseline in efficacy‐related measures, such as HbA1c, fasting blood glucose, glycated albumin, HOMA‐β and treatment–response rate.
The pooled analysis of HbA1c by dose confirmed that imeglimin significantly improved HbA1c when administered as monotherapy (1,000, 1,500 and 2,000 mg b.i.d.: WMD = −0.714, −0.531 and −0.450; P < 0.001, 0.020 and 0.005, respectively) and adjunctive therapy (1,000 and 1,500 mg b.i.d.: WMD = −0.600 and −0.576, respectively; both P < 0.001). Considering the clinically significant efficacy findings and that the numbers‐needed‐to‐treat for an additional beneficial outcome were as low as single‐digit values, there might be no dose–dependency. In addition, based on the analysis results by duration of treatment, a statistically significant improvement was shown in the primary efficacy outcome (HbA1c) as early as the second week after the start of treatment with imeglimin versus placebo.
Whether or not to include imeglimin in a treatment plan cannot be decided based only on efficacy. Therefore, a comprehensive meta‐analysis of the safety and tolerability outcomes of RCTs of imeglimin was also carried out. There was no significant difference in treatment discontinuation rates, discontinuations due to AEs, the incidence of at least one AE and the incidence of serious AEs with imeglimin compared with placebo. These results suggest that imeglimin was generally well tolerated.
The only AE that occurred at a significantly higher incidence in imeglimin‐treated patients versus placebo‐treated patients was diarrhea in the monotherapy group when administered at 1,500 mg BID. However, the number‐needed‐to‐treat for an additional harmful outcome for this event was 49, suggesting that the influence of imeglimin was minor.
The present analysis showed increases in bodyweight, BMI and LDL‐C with imeglimin compared with placebo. However, the WMDs in the placebo group were several hundred grams for bodyweight, <0.3 points for BMI and <0.33 mmol/L (only observed in the monotherapy group) for LDL‐C, suggesting that the influence of imeglimin was minor. In addition, it was found that imeglimin had almost no influence on abdominal circumference.
A significant difference in HOMA‐β was observed between imeglimin and placebo, indicating that imeglimin improves HOMA‐β levels, but there was no significant difference in HOMA‐IR. It is possible that HOMA‐β increased (i.e., improved) because of the β‐cell‐protective effect and insulin secretion‐stimulating action of imeglimin. In addition to improving insulin resistance, imeglimin has a stimulatory effect on insulin secretion. When calculating HOMA‐IR, fasting insulin is included in the numerator and the calculation might have masked the insulin‐sensitizing effect of imeglimin, which has an insulin‐elevating effect. In fact, the insulin sensitivity indices derived from the oral glucose tolerance test Stumvoll (P = 0.001) and Matsuda (not significant) index were reported to be improved with imeglimin versus placebo 32 .
In addition, the results of the subgroup analysis suggest that the effects of imeglimin might vary depending on both BMI and racial differences; imeglimin might be less effective for patients with a high BMI. A previous study that compared ethnic differences in the glucose‐lowering efficacy of another hypoglycemic agent with an enhancing effect on glucose‐stimulated insulin secretion, dipeptidyl peptidase‐4 inhibitors, found a greater glucose‐lowering effect in Asian versus non‐Asian participants 35 . It is possible that differences in BMI between different ethnic groups might mediate the HbA1c‐lowering efficacy of dipeptidyl peptidase‐4 inhibitors, as well as other hypoglycemic agents, such as imeglimin. The present findings suggest that imeglimin might be more suitable for an Asian population with type 2 diabetes mellitus, as Asian patients tend to have a lower BMI than white patients 36 , 37 . The results of the subgroup analysis also suggest that imeglimin is effective regardless of the CKD category.
The present study had several strengths. First, this meta‐analysis was the first to comprehensively examine the efficacy, safety and tolerability of imeglimin in patients with type 2 diabetes mellitus while carrying out a separate analysis for monotherapy and adjunctive therapy and for each dose level of imeglimin. Second, we evaluated the outcomes of continuous and dichotomous variables for efficacy, and carried out an intention‐to‐treat analysis for all measurement results. Finally, this meta‐analysis was carried out with relatively consistent methods and quality measures across studies, and in study populations with a relatively small risk of bias.
The present study also had some limitations. First, the number of RCTs available for this study was limited, with only nine RCTs being included in this study. In addition, subgroup analyses by dose and other factors included even fewer RCTs. Therefore, the results presented in this study might not have sufficient power and should be interpreted with caution. Second, the duration of treatment was relatively short (up to 24 weeks, with a mean duration of 15.4 weeks). Given that type 2 diabetes mellitus is a lifelong chronic disease, longer‐term studies are needed to confirm the long‐term efficacy and safety of imeglimin. Third, there were interstudy variations in sample characteristics and study characteristics (e.g., ranging from phase II to phase III trials and use of different dose levels of imeglimin). It is possible that interstudy variations might have created so much heterogeneity that a meta‐analysis was not advisable, or at least that some studies were not suitable to have been pooled. It will be necessary to carry out long‐term clinical studies with a larger sample size to clarify the therapeutic effects of imeglimin.
In conclusion, this meta‐analysis of placebo‐controlled RCTs supports the efficacy, safety and tolerability of imeglimin, a novel antihyperglycemic agent. The main effect of imeglimin was observed at ≥1,000 mg b.i.d. when administered as either monotherapy or adjunctive therapy, and an increased risk of AEs and hypoglycemia was not observed.
DISCLOSURE
KH and MN are employees of Sumitomo Pharma Co., Ltd. HW has received fees for medical writing support from Novo Nordisk; grants from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Pfizer Japan, Sanofi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical and Terumo; and speaker fees from Astellas Pharma, AstraZeneca, Eli Lilly Japan, Fujifilm Pharma, Kissei Pharmaceutical, Kowa Pharmaceutical, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma and Takeda Pharmaceutical. KK has received grants from Nippon Boehringer Ingelheim, Taisho Pharmaceutical and Mitsubishi Tanabe Pharma; consulting fees from Sanwa Kagaku Kenkyusho; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Taisho Pharmaceutical, Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Pharma, Elli Lily Japan, Kowa and Novo Nordisk Pharma. KU has received grants from Boehringer Ingelheim, Mitsubishi Tanabe, Sumitomo Pharma, Sanofi, Novo Nordisk, Kyowa‐Kirin, Ono Pharmaceutical and Takeda Pharmaceutical; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordisk, Mitsubishi Tanabe, AstraZeneca, Eli Lilly, Ono Pharmaceutical, Sumitomo Pharma, Kowa, Daiichi Sankyo, Taisho Pharmaceutical, Boehringer Ingelheim and Bayer; and has participated in a Data Safety Monitoring Board or Advisory Board for Abbott, Kyowa‐Kirin, Bayer, Terumo, AstraZeneca, Eli Lilly, Sumitomo Pharma, Mitsubishi Tanabe and Novo Nordisk. HW, KK and KU are Editorial Board members of Journal of Diabetes Investigation, and co‐authors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication.
Approval of the research protocol: N/A.
Informed consent: N/A.
Registry and the registration no. of the study/trial: The study protocol was registered at OSF on 2022‐03‐27 (https://osf.io/t2nuw/).
Animal studies: N/A.
DATA AVAILABILITY
The datasets used in the current analysis are available from the corresponding author upon reasonable request.
Supporting information
Appendix S1 | Supplementary methods. Search strategy and types of study included.
Table S1 | Summary of pooled results of secondary dichotomous outcomes.
ACKNOWLEDGMENTS
This study was funded by Sumitomo Pharma Co., Ltd. The authors thank Michelle Belanger, MD, of Edanz, Japan, for providing medical writing support, which was funded by Sumitomo Pharma Co., Ltd., Japan, through EMC K.K., Japan, in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp‐2022).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1 | Supplementary methods. Search strategy and types of study included.
Table S1 | Summary of pooled results of secondary dichotomous outcomes.
Data Availability Statement
The datasets used in the current analysis are available from the corresponding author upon reasonable request.