Acute Effect of Imeglimin Add-on Therapy on 24-h Glucose Profile and Glycemic Variability in Patients with Type 2 Diabetes Receiving Metformin

Over the past few decades, the biguanide derivative metformin has been the cornerstone of type 2 antidiabetic drugs due to its favorable pharmacokinetic and physicochemical characteristics as well as its capacity to significantly lower glycated hemoglobin (HbA1c) levels [1]. It might also be advantageous in the treatment of cancer and cardiovascular diseases [2]. However, metformin therapy is associated with an uncommon but potentially serious complication known as metformin-associated lactic acidosis [3].

Recently, imeglimin was launched as the first of a new tetrahydrotriazine-containing class of oral antidiabetic agents [4]. Chemically, imeglimin, which is synthesized from metformin, is a basic molecule and contains a triazine ring system [4, 5]. Metformin and imeglimin both modulate the respiratory chain complex activities through complex I inhibition, which restores mitochondrial dysfunction; however, imeglimin has a novel, unique, and dual mode of action due to its insulinotropic and insulin-sensitizing effects [4‒8]. Furthermore, the risk of lactic acidosis is markedly lower with imeglimin than with metformin [9]. Although metformin and imeglimin show some similarities in their chemical and pharmacological properties, including a similar mechanism of action, previous studies reported that addition of imeglimin to metformin further reduced HbA1c [10, 11]. These findings suggest that imeglimin may enhance insulin secretion and insulin sensitivity by a different mechanism than metformin and that this difference may play a role in the additional HbA1c-lowering effect of combination therapy. However, to date no studies have examined the acute effects of imeglimin on glycemic control in patients with type 2 diabetes receiving metformin. Continuous glucose monitoring (CGM) can provide information on 24-h mean blood glucose level, time in the glucose target range (TIR), and indices of glycemic variability. Therefore, the present study used (CGM) to investigate the acute effect of imeglimin add-on therapy on 24-h glucose levels and glycemic variability in patients with type 2 diabetes receiving metformin.

We enrolled 30 consecutive outpatients with type 2 diabetes inadequately controlled with metformin at the Japanese Red Cross Nasu Hospital (Otawara, Tochigi, Japan). Individuals with type 2 diabetes who were at least 20 years old, on stable therapy with one to three oral antidiabetic medications, such as metformin, with or without insulin for at least 3 months, and had a HbA1c level of 7.0%–12.0% were eligible to enroll. Imeglimin 1,000 mg twice daily was administered to all 30 patients.

A CGM device (FreeStyle Libre, Abbott Diabetes Care Inc., USA) was attached to each patient for 2 weeks. No additional antidiabetic medications were added, and the doses of insulin and antidiabetic medications did not change during the study period. The day CGM was started was defined as day 1. On day 8, treatment with imeglimin 2,000 mg/day was started. We compared the mean values of CGM parameters on day 4–6 (i.e., before starting treatment with imeglimin, defined as baseline) with those on day 11–13 (i.e., after starting treatment with imeglimin).

Main endpoints were the 24-h mean glucose level and TIR. As indexes of glycemic variability, standard deviation (SD) of the 24-h glucose level, coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGEs) were calculated from CGM. The percentage coefficient of variation (%CV) was calculated as follows: %CV = [(SD of glucose)/(mean glucose)] × 100. MAGE was calculated by taking the arithmetic mean of the increase or decrease in CGM values (from nadirs to peaks or vice versa) when both ascending and descending segments exceeded the value of 1 SD of the CGM values for the same 24-h period. We also recorded glucose levels within 1–3 h after each meal from CGM data. The glucose management indicator (GMI) was calculated with the following equation: GMI = 3.31 + 0.02392 × mean glucose in mg/dL [12]. The percentage of time with a glucose level between 70 and 180 mg/dL was used to calculate the TIR. The percentage of time with a glucose level below 70 mg/dL was called time below range, and the percentage of time with a glucose level above 180 mg/dL was called time above range.

All participants gave written informed consent to participate in the study, which was approved by the Institutional Review Board of the Japanese Red Cross Nasu Hospital (Approval No. 2022-12). The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN: 000051451).

The mean (SD) or the median and interquartile range are used to express the results. The Student’s paired t test or unpaired t test was used to analyze group differences, and the Wilcoxon matched pairs test or Mann-Whitney U test was used to evaluate differences in nonparametric data. Linear regression analysis or the Spearman’s rank method was used to determine correlations. To identify independent factors influencing the changes in the 24-h mean glucose following imeglimin treatment, multivariate analysis was carried out. A p value of less than 0.05 was regarded as statistically significant.

The baseline characteristics of the patients are shown in Table 1. The mean age was 60.5 ± 13.6 years; mean body mass index, 25.0 ± 3.53; mean fasting plasma glucose, 170.3 ± 84.4 mg/dL; and mean HbA1c, 8.1 ± 1.3%. Ten patients (33%) were receiving insulin. The mean metformin dose at baseline was 992 mg/day.

CGM revealed a significant reduction in postprandial and 24-h mean glucose following imeglimin add-on treatment (Fig. 1; Table 2). TIR increased significantly after treatment with imeglimin (from 69.9 ± 23.9% to 80.6 ± 21.0%, p < 0.0001), and time above range decreased significantly (Table 2). After treatment with imeglimin, the SD of 24-h glucose decreased significantly (from 41.6 ± 13.6 mg/dL to 32.8 ± 11.6 mg/dL, p < 0.0001; Table 2), as did the CV (from 25.8% ± 5.8%–23.4% ± 5.6%, p = 0.0002). In addition, MAGE decreased significantly (from 103.3 ± 34.8 mg/dL to 82.9 ± 31.2 mg/dL, p < 0.0001; Table 2).

Next, we evaluated correlations between changes in 24-h mean glucose or the SD of 24-h glucose after treatment with imeglimin and baseline clinical variables (Table 3). Changes (i.e., reductions) in 24-h mean glucose after treatment with imeglimin were positively correlated with TIR at baseline (Table 3), whereas changes (i.e., reductions) in 24-h mean glucose after treatment with imeglimin were negatively correlated with duration of diabetes, serum high-density lipoprotein (HDL)-cholesterol (r = −0.3859, p = 0.0352; Fig. 2a), 24-h mean glucose and SD at baseline. Only baseline HDL cholesterol was negatively correlated with SD of 24-glucose after treatment with imeglimin (r = −0.4015, p = 0.0309; Fig. 2b).

In a model that explained 88% (R² = 0.776) of the variation in the changes (i.e., reductions) in 24-h mean glucose after treatment with imeglimin, multivariate logistic regression analysis showed that duration of diabetes (β = −0.516, p = 0.012), serum HDL cholesterol (β = −0.651, p = 0.001), baseline 24-h mean glucose (β = −0.692, p < 0.001), and insulin use (β = 0.586, p = 0.003) was independent determinants of the reduction in 24-h mean glucose after treatment with imeglimin (Table 4).

We next analyzed the effects of imeglimin on 24-h mean glucose in the two groups depending on whether patients received medication (SGLT2i, GLP-1RA, or insulin) or not. We found no significant difference in mean 24-h mean glucose after treatment with imeglimin in patients with or without each drug. However, 24-h mean glucose levels after treatment with imeglimin tended to be higher in insulin users than non-users (151.0 ± 33.3 vs. 129.6 ± 28.9 mg/dL, p = 0.0703).

In this study, we found that imeglimin acutely decreased 24-h mean glucose levels and postprandial glucose levels and increased TIR in patients with type 2 diabetes receiving metformin. Additionally, we observed a significant reduction in the CV and the SD of 24-h glucose (two glycemic variability indices) following imeglimin treatment. This is the first study to look at the acute effects of imeglimin add-on therapy on patients with type 2 diabetes taking metformin’s 24-h glucose levels and glycemic variability as measured by CGM. The study confirmed previous findings that imeglimin has additive effects to metformin [10, 11]. A previous study with CGM also showed that a 4-week short-term treatment with imeglimin clearly shifted daily glucose profiles into an appropriate range in Japanese patients with type 2 diabetes, although it did not find any improvement in SD or MAGE [13].

Both the glucose-lowering medications metformin and imeglimin have complementary modes of action when it comes to the pathophysiologic flaws in type 2 diabetes [4]. The results of our CGM findings support the benefits of combining imeglimin with metformin in patients with type 2 diabetes, irrespective of diabetes duration. Imeglimin, a medication currently under investigation in the USA and approved in Japan, is a novel, first-in-class medication with a mechanism that is currently understood to provide glycemic control by targeting multiple pathways [11, 14, 15]. Pirags et al. [16] demonstrated that 3,000 mg daily of imeglimin and 1,700 mg daily of metformin showed similar effects in people with type 2 diabetes, suggesting that metformin may be stronger than imeglimin when administered at the same dose. We speculate that replacing metformin with imeglimin at the same dose might cause a slight deterioration of glycemic control.

The mechanisms responsible for the acute effects of imeglimin add-on therapy on 24-h glucose levels and glycemic variability evaluated by CGM in patients with type 2 diabetes on metformin remain to be determined. An animal study showed that administration of a single dose of imeglimin lowered blood glucose levels and increased plasma insulin levels during an oral glucose tolerance test in both C57BL/6 and KK-Ay mice, models that closely resemble human type 2 diabetes [17]. Evaluation of isolated islets from these models suggested that imeglimin acutely and directly enhances glucose-stimulated insulin secretion (without having any effect in low glucose conditions). An in vitro study demonstrated that imeglimin amplifies glucose-stimulated insulin release from human diabetic islets via a distinct mechanism of action [18]. Another study showed that combination of imeglimin with metformin increases β-cell mass by promoting β-cell proliferation and inhibiting β-cell apoptosis in db/db mice because imeglimin treatment for 7 days raised the insulin secretory response to high glucose, as assessed by both the first- and the second-phase insulin secretion rate [6], suggesting that subacute treatment with imeglimin may improve β-cell function in patients with type 2 diabetes. These findings indicate that imeglimin may improve glycemic control by acutely and directly enhancing glucose-stimulated insulin secretion in patients inadequately controlled by metformin. In actuality, despite sharing a chemical moiety with biguanides, imeglimin is not listed by the World Health Organization as a biguanide; rather, it is placed under the heading “Other Drugs Used in Diabetics.”

While the mechanisms of action of metformin and imeglimin appear to be similar in type 2 diabetes, there are some distinct mechanisms of action for imeglimin [8]. For example, imeglimin competitively inhibits liver mitochondrial complex I and reduces the force of the respiratory chain and without changing cellular flux, or the rate at which oxygen is consumed, whereas metformin non-competitively inhibits liver mitochondrial complex I and reduces both the force of the respiratory chain and cellular flux (i.e., it decreases the oxygen consumption rate) [4‒8]. Furthermore, unlike imeglimin, metformin also inhibits the activity of mitochondrial glycerol-3-phosphate dehydrogenase [19]. Imeglimin provides a novel approach to the treatment of type 2 diabetes because of its unique dual mode of insulin resistance and/or insulin secretion, i.e., it has both insulinotropic and insulin-sensitizing effects [6‒8, 14, 15]. WHO classifies imeglimin as glimin, not biguanide. Imeglimin hydrochloride (TWYMEEG^®; hereafter referred to as imeglimin) is thus an orally administered, first-in-class glimin. Numerous preclinical (in vitro) and clinical (in vivo and human) investigations have discovered that imeglimin’s two functions are accomplished by mitochondrial bioenergetics in the liver, muscle, and pancreatic β cells [4, 8, 20].

In the current study, we demonstrated for the first time that in patients with type 2 diabetes taking metformin, changes in the 24-h mean glucose following treatment with imeglimin (2,000 mg/day) were negatively correlated with baseline serum levels of HDL cholesterol. Additionally, multivariate regression analysis demonstrated that the reductions in 24-h mean glucose following imeglimin treatment were independently correlated with the baseline serum HDL cholesterol level. Thus, in type 2 diabetes patients taking metformin, higher HDL cholesterol levels may be linked to a better response to imeglimin. Moreover, following treatment with imeglimin (2,000 mg/day), there was a negative correlation between changes in the SD of 24-h glucose and the baseline serum level of HDL cholesterol, suggesting that high serum HDL cholesterol may be associated with an improvement in 24-h mean glucose and glycemic variability by acute effects of imeglimin. On the other hand, insulin use may be associated with a worse response to imeglimin in patients with type 2 diabetes on metformin (Table 4), suggesting that patients with markedly impaired endogenous insulin secretion may not respond well to imeglimin.

The mechanisms by which higher baseline serum HDL cholesterol level is related to a better response of 24-h mean glucose and glycemic variability in imeglimin add-on therapy in patients with type 2 diabetes receiving metformin are unclear. In people with type 2 diabetes, low serum HDL cholesterol levels are associated with metabolic syndrome, insulin resistance, and low serum adiponectin [21]. Low serum adiponectin also is closely related to insulin resistance [22]. Imeglimin has direct effects not only on pancreatic β cells to amplify glucose-stimulated insulin secretion but also on liver and muscle to enhance insulin action [4]. Several studies showed that this dual action is rendered through mitochondrial bioenergetics in the pancreatic β cells, liver, and muscle [4, 23, 24]. However, the mechanism by which imeglimin improves insulin sensitivity in the muscle and liver is not fully understood. A prior study found that imeglimin directly and acutely activates β-cell insulin secretion in awake rodents without altering hepatic insulin sensitivity, body composition, or energy expenditure [25]. Thus, the main action of imeglimin may be associated with amplification of glucose-stimulated insulin secretion rather than improvement of insulin resistance. Because high serum HDL cholesterol may reflect less obesity and less insulin resistance in people with type 2 diabetes, imeglimin may improve 24-h mean glucose and glycemic variability predominantly by increasing glucose-stimulated insulin secretion. Imeglimin appears to be less effective for insulin resistance in obese patients with type 2 diabetes. Since serum cholesterol levels, including HDL cholesterol, are affected by liver function, liver function may modify the effectiveness of imeglimin. However, there are no studies that have investigated the effects of imeglimin on glycemic control in diabetic patients with moderate to severe liver dysfunction.

This study has some limitations; one major limitation was the lack of a control group. We cannot conclude that the relationship between high serum HDL cholesterol levels and a better response to treatment is specific for imeglimin and does not apply to other classes of antidiabetic drugs. The lack of a control group also meant that we could compare only levels before and after addition of imeglimin. In addition, the improvement of the glucose profile after imeglimin administration might have been influenced by lifestyle modifications triggered by the add-on medication. Another limitation is that there was a high degree of heterogeneity in the use of other oral antidiabetic medications at baseline, leading to possible cofounding.

The present study showed that add-on therapy with imeglimin to metformin acutely reduces 24-h glucose levels and improves glycemic variability in patients with type 2 diabetes. A higher serum HDL cholesterol is associated with a better response to the acute effects of imeglimin on 24-h glucose levels and glycemic variability in patients with type 2 diabetes receiving metformin.

We wish to thank all medical staffs of our department for their kind assistance.

The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN: 000051451).

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

The present study was not funded.

Yasutake Shinohara, Yusuke Kamiga, Teruo Jojima, and Yoshimasa Aso contributed to the study design, data collection, and drafting of the manuscript; Shintaro Sakurai, Toshie Iijima, Takuya Tomaru, Ikuo Akutsu, Teruo Inoue, and Isao Usui contributed to the discussion and reviewed the manuscript; Isao Usui reviewed and edited the manuscript; and Yasutake Shinohara, Teruo Jojima, and Yoshimasa Aso analyzed the data and wrote, reviewed, and edited the manuscript.

The data that support the findings of this study are available from the corresponding author, upon reasonable request.