Article Type : Short commentary
Authors : Bando H
Keywords : Imeglimin (Twymeeg); Oral hypoglycemic agent (OHA); Trials of IMeglimin for Efficacy and Safety (TIMES); Mitochondrial morphology; Lactic acidosis
A novel imeglimin (Twymeeg) was developed
as an oral hypoglycemic agent (OHA) in Japan. It has clinically dual action for
increasing insulin secretion and reducing insulin resistance, from Trials of
IMeglimin for Efficacy and Safety (TIMES) 1-3. For basic medicine, imeglimin
revealed reduction of apoptotic ?-cell death with reduced expression for
inflammation. Thus, imeglimin may increase insulin granules, bring beneficial
efficacy on ?-cell mitochondrial morphology and enhance directly insulin
secretion from ?-cell of the pancreas. Imeglimin has chemical moiety for
metformin. Compared with both agents using experiments of dog and mice, lactic
acidosis would be lower in imeglimin group.
In the light of common
disease across the world, non-communicable diseases (NCDs) have become crucial
problems [1]. Among them, type 2 diabetes (T2D) has brought medical, social and
pharmacological practice and research [2]. American Diabetes Association (ADA)
has announced standard guideline for diabetes in 2022 [3]. For the development
of oral hypoglycemic agents (OHAs) for T2D, effective kinds of meds are found
such as glucagon-like-peptide 1 receptor agonist (GLP1-RA) [4] and also
sodium–glucose cotransporter 2 inhibitor (SGLT2i) [5]. Recent topics of OHA would be novel
introduction of imeglimin as brand name of Twymeeg [6]. In this article, latest
information of imeglimin will be described.
Imeglimin has been
recently developed as OHA in Japan. Several large clinical trials of imeglimin
were reported for human subjects. They include Trials of IMeglimin for Efficacy
and Safety (TIMES) 1-3 [7]. A series of TIMES have shown clinical effect and
safety of long-term treatment and also its effectiveness of combined therapy of
other OHAs and insulin treatment [8,9]. The difference between imeglimin and
previous OHAs may be the existence of various mechanism of imeglimin. From
clinical point of view, imeglimin has clinically dual efficacy of increasing
insulin secretion function in response to glucose situation [10], and
decreasing insulin resistance that is similar to metformin [11]. It also shows
the preservation of the ?-cell mass and reduction of ?-cell apoptosis through
modulating the pathway of ER stress [12,13].
Furthermore, imeglimin
leads improving insulin sensitivity and also inhibiting glycogenesis [14]. As a
matter of fact, imeglimin was reported to prevent heart failure associated with
preserving the degree of ejection fraction [15], and to improve cardiac
impaired function in the case of rat experiment [16]. Concerning the function
of pancreas and liver, imeglimin can alleviate impaired function of
mitochondria in ?-cell and hepatocyte [14]. However, these phenomena are not
always observed, and then these mechanisms have been not fully apparent yet.
In actual medical
practice, imeglimin has been introduced for treating T2D patients and it has
been drawing most attention in also diabetic research. For recent report,
fundamental efficacy of imeglimin on ?-cell of pancreas was evaluated [17].
Firstly, single administration of imeglimin has strengthened insulin secretory
degree from ?-cell and reduced blood glucose in T2D mice (db/db). Moreover,
single imeglimin administration has augmented significant insulin secretion
that was responsive to glucose stimuli from ?-cell in non-diabetic mice (db/m).
Secondly, it enhanced insulin secretion and improved blood glucose variability
in diabetic mice (db/db) during GTT associated with imeglimin for 4 weeks. Using
electron microscope, imeglimin has brought beneficial efficacy on morphological
image of ?-cell mitochondria and more insulin granules in T2D and KK-Ay mice
[17]. For surprising results, imeglimin revealed reduction of apoptotic ?-cell
death that was found with reduced expression related with inflammation and
apoptosis of ?-cell. From mentioned above, imeglimin may enhance directly
insulin secretion from ?-cell, increase insulin granules, bring beneficial
efficacy on ?-cell mitochondrial morphology and decrease apoptotic ?-cell death
in T2D mice.
From pharmacological
action point of view, the detail mechanism of imeglimin was not completely
clear. However, it seems to be involved in the enhanced situation of
glucose-stimulated insulin secretion (GSIS). During the GSIS process, transient
receptor potential melastatin 2 (TRPM2) channel can be activated, and it can
promote the depolarization of plasma membrane as a non-selective cation channel
(NSCCs) in ?-cell of the pancreas [18]. In the experiments of wild-type and
TRPM2-knockout (KO) mice, imeglimin can promote the function through NSCC. This
is related to the releasing efficacy of insulin from ?-cell. Imeglimin causes
the activation of TRPM2 channels of ?-cell through the mechanism of NAD+ /cADPR
production that leads to GSIS potentiation. In addition, imeglimin contributes
to calcium mobilization through the amplificated pathway for insulin secretion
from ?- cell [14]. Concerning the categorization of OHAs, imeglimin become the
first agent for tetrahydrotriazine-containing class as glimins [19].
In the actual diabetic
practice, clinical efficacy of imeglimin was recently investigated [20]. The
protocol included 32 cases of T2D and detail measurement of blood glucose using
continuous glucose monitoring (CGM). These data were gathered for more than 4
weeks. As a result, imeglimin has improved significantly mean glucose levels
(from 159 mg/dL to 142 mg/dL, p<0.001), TIR (67.9% to 79.5%, p<0.001 and
TAR (29.4% to 17.9%, p < 0.001). Consequently, imeglimin can apparently
shift daily glucose profile to appropriate range in T2D cases, which indicates
better glycemic variability in a short period [20].
From pharmacokinetic
point of view, detail blood concentration of imeglimin was measured in two
groups of Jananese and Caucasian healthy individuals [21]. The methods included
two randomized placebo-controlled phase 1 clinical studies, in which single for
250-8000mg and multiple administration (500-2000mg twice a day) were included.
The half-lives (t1/2) showed dose-dependent manner and their means were 4.5-12
h in Japanese and 9.0-20 h for Caucasians. Exposures were similar between two
groups with <20% difference, but Japanese tended to have slightly higher
exposure value. From these results, imeglimin showed acceptable tolerability
profile and safety, associated with mild gastrointestinal adverse events
(GIAEs).
Imeglimin has molecular
similarity and chemical moiety for metformin, and has modulated the activity of
mitochondrial complex I [22]. Then, it may show a potential mechanism
concerning metformin-related lactate accumulation. Comparative studies were
conducted between imeglimin and metformin for experiments. For dog model with
major surgery, both agents were provided. As a result, only metformin caused
lactate accumulation with pH decrease leading to lactic acidosis with severe
state. For rat model with gentamycin-induced renal failure, only metformin
brought high lactatemia with high h+ concentrations leading to mortality of
higher amounts. Consequently, the results supposed that lactic acidosis by
imeglimin may be lower than that of metformin [22].
In summary, latest
information concerning imeglimin has been described for basic medicine and
clinical practice. Imeglimin as brand name Twymeeg may become a first-line
agent for T2D because of its dual mechanism and safety. This article becomes
hopefully a reference for future diabetic practice and research.