Article Type : Research Article
Authors : Iwatsuki N, Bando H, and Okada M
Keywords : Oral hypoglycemic agents (OHAs); Imeglimin; type 2 diabetes mellitus (T2DM); Glucose-stimulated insulin secretion (GSIS); Treatment-emergent adverse events (TEAEs); American Diabetes Association (ADA)
Latest Standards of Medical Care in
Diabetes was presented in January 2022. Among oral hypoglycemic agents (OHAs),
imeglimin has been topic for a novel agent for type 2 diabetes mellitus (T2DM).
Pharmacologically, imeglimin is a cyclic molecule including triazine ring. It
has both pharmacological mechanism of increased insulin action and elevation of
glucose-stimulated insulin secretion (GSIS). Clinically, it showed HbA1c
reduction for 0.46% by monotherapy and 0.56-0.92% by combined therapy with
other OHAs. From compared administration of 500mg, 1000mg and 1500mg, 1000mg
twice doses would be adequate. No remarkable
treatment-emergent adverse events (TEAEs) were found for treatment of
imeglimin.
For useful guideline, the Standards of Medical Care in
Diabetes was presented on Jan 1, 2022 from American Diabetes Association (ADA)
[1]. The number of patients with diabetes mellitus (DM) has been increasing,
particularly in developing countries compared with developed countries [2]. DM
has brought various impaired function including microvascular and macrovascular
angiopathy. These chronic multifaced situation will give many patients
remarkable physical detriment. From recent statistics, 463 million diabetic
patients have been present in the world, and 90% of them show T2DM [3].
Concerning the pathophysiology of T2DM, both of decreased insulin secretion and
increased insulin resistance (IR) are involved in the onset and exacerbation.
IR means the impairment of adequate response to insulin leading to disturbed
metabolic homeostasis. For these pathologies, mitochondria in the cell are
involved in the impaired mechanisms of T2DM and IR. IR may affect mitochondrial
function, and liver and skeletal muscle have high impact on glucose homeostasis
for whole body [4].
From pharmacological point of view, some anti-diabetic
agents for improving IR have been used until now. Phenformin and metformin are
well-known biguanide agents which were provided to T2DM for reducing IR [5].
Phenformin was withdrawn from the market due to lactic acidosis. In contrast,
metformin has been still widely prescribed as first-in-class agent for T2DM. It
is one of the most prevalent oral hypoglycemic agents (OHAs), and it seems to
have desirable pharmacokinetics. Metformin-induced lactic acidosis has been
very rare, unless the patient has severe impaired renal or hepatic function. As
related to metformin, a novel molecule for OHA has been produced for imeglimin
by Poxel and Sumitomo Dainippon Pharma in Japan [6]. It is fundamentally basic
small molecule like metformin. In contrast, it is a cyclic molecule including a
triazine ring, which is unlike metformin. For the product of imeglimin, it can
be synthesized from metformin as a precursor agent through single step chemical
reaction [5]. From recent report, imeglimin improve the function of
mitochondria. When provided by combined these two agents, it will contribute
better glycemic control for T2DM [7].
Imeglimin will become possibly a first-in-class OHA
with higher evaluation. Some phase-3 trials were completed with satisfactory
evidence of clinical efficacy and safety. It has dual action mechanism for its
characteristics. They are i) increased insulin action associated with probable
inhibition of hepatic glucose output and increase of insulin signaling in both
of muscle and liver, ii) elevation of glucose-stimulated insulin secretion
(GSIS) associated with beta-cell mass preservation [8]. From molecular and cellular points of view,
its mechanism would involve the improvement of mitochondrial dysfunction, which
are commonly found for pathogenesis of T2DM. As a whole, imeglimin seems to
have a key for impaired cellular energy metabolism observed in T2DM. These
potentials of action mode may be unique and different from previous
categorization, such as sulphonylureas, biguanides and glucagon-like peptide-1
receptor agonists (GLP-1Ras). For the first agent in a novel category of OHA,
the effect and safety of imeglimin was investigated. It was conducted for
double-blind, randomized, parallel-group, placebo-controlled study as phase 3
trial in 30 multi-center research in Japan [9]. The subjects were patients with
T2DM for HbA1c 7-10% (n=106), and control cases (n=107). Methods were randomly
provided to either imeglimin or matched placebo for 6 months. As a result, the
adjusted mean difference of change of HbA1c at 6 months was -0.87% (95% CI
-1.04 to -0.69, p<0.0001). Regarding adverse effects associated with reports
?1 adverse event, imeglimin group vs placebo group showed 44.3% vs 44.9%,
respectively. From these, imeglimin significantly improved glucose variability
with safety profile compared with placebo.
Concerning OHA for T2DM, it is important to
investigate the pharmacokinetic (PK) characteristics for renal function,
chronic kidney disease (CKD), diabetic kidney disease (DKD) and renal failure.
Imeglimin has mainly excretion without changed metabolism through the kidneys
[10]. The recommended dose was studied by area under the curve (AUC) for analyzed
data of blood concentration. As a result, 500mg provided twice daily are
adequate for patients with eGFR 15-45 mL/min/1.73 m2, and 1000mg
provided twice a daily are suitable for eGFR > 45 mL/min/1.73 m2.
Further investigation will be required in the case of 1500 mg twice daily in
the future. By searching for randomized controlled trials (RCTs) of imeglimin
studies, meta-analysis was conducted [11]. The method included the analysis of
PubMed, Google Scholar, Cochrane Library Wiley and Scopus until April 2021. The
report was summarized from 8 studies of 1555 subjects. Results included the comparison of imeglimin
group and control group. Significantly lower values of HbA1c and blood glucose
were found in imeglimin group. On the other hand, no significant differences
were observed about LDL-C, HDL-C, TG and homeostasis model assessment-insulin
resistance (HOMA-IR). Imeglimin will be widely used in clinical practice, where
a several research would be necessary for monotherapy and combination therapy
of imeglimin [9].
Clinical effect of imeglimin for lowering HbA1c was
investigated for half year [12]. Subjects included 299 T2DM cases, they were
divided into some groups with different doses. At 6 months, HbA1c decrease
compared with that of placebo was -0.52%, -0.94% and -1.00% for imeglimin as
500mg x 2, 1000mg x 2, and 1500 mg x 2, respectively. From marginal increase
between 1000mg and 1500mg, 1000mg administration twice a day was selected for
subsequent phase studies. Regarding treatment-emergent adverse events (TEAEs),
the result was 68.0%, 62.2%, 73.3%, 68.0% for subjects provided imeglimin as
500mg, 1000mg, 1500 mg and placebo, respectively. Successively, 52-week study
was reported for efficacy of imeglimin for monotherapy and combined therapy
with other agents [13]. The cases were 714 T2DM patients. Combined agents
included biguanide, DPP4-I, GLP1-RA, SGLT2i, glinide and alfa-GI. No remarkable
TEAEs, physical or laboratory exams were found. After 52 weeks, HbA1c was
decreased 0.46% by monotherapy, and 0.56-0.92% by combined therapy. Most
effective reduction of 0.92% was found by imeglimine and DPP4i. Thus, imeglimin
of monotherapy and combined therapy seemed to be effective.
In summary, imeglimin as novel OHA category was
described. It seems to be prescribed more in the diabetic practice. Further
research will be expected for pharmacological mechanism and clinical efficacy.
The author declares no conflict of interest.
There was no funding received for this paper.