Introduction
Type 2 diabetes (T2D) has been crucial disease from medical, social and
economic points of view worldwide [1]. On Jan 2023, American Diabetes
Association (ADA) presented latest "Standards of Care in Diabetes"
[2]. The purpose of diabetic therapy would be maintaining the same QOL and
ordinary health as healthy people for reducing various macro- and
micro-angiopathy [3]. In recent years, various oral hypoglycemic agents (OHAs)
have been developed and introduced to actual medical practice [4]. They have
shown satisfactory clinical efficacy for improving glucose variability, such as
sodium–glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like-peptide 1
receptor agonist (GLP1-RA), dipeptidyl peptidase-4 inhibitor (DPP-4i), and
other agents [5]. Among them, imeglimin (Twymeeg) is in focus for beneficial
dual effects [6,7].
As regards to imeglimin, it shows the similar molecule with metformin
[8]. Metformin has been known for the first-line medicine of T2D for long over
the world [9]. Metformin can be used for monotherapy and also for combined
therapy with other OHA or insulin [10]. It is indeed that imeglimin has similar
molecule with metformin, but both OHAs are often used for combination therapy.
The characteristic prescription method includes the twice medication per day.
From pharmacological point of view, imeglimin has been provided for T2D
associated with clinical efficacy until now [11].
Furthermore, recent topic for effective diabetic treatment includes the
changes in the perspectives for diabetic treatment. Stepwise therapy was
previously rather common. But early combination therapy is recently evaluated
as longer-lasting positive efficacy. Among them, combination therapy of
vildagliptin and metformin has shown beneficial treatment protocol [12]. Related
to the combination of vildagliptin/metformin (EquMet), VERIFY study has been
known, which stands for Vildagliptin Efficacy in combination with metfoRmIn for
earlY treatment of type 2 diabetes. It was conducted for 254 multi centers in
34 countries, as a randomized, double-blind, parallel-group investigation
against newly-diagnosed T2D patients [13]. The compared results showed that
significant decrease of initial therapy failure was found in combined group for
5 years, in comparison with monotherapy group (hazard ratio, HR =0.51). For
adverse effects, approaches in both groups showed unremarkable problems.
Consequently, earlier start of combined treatment of vildagliptin/metformin can
give greater and also durable longer-acting beneficial efficacy in comparison
with previous metformin monotherapy. In
addition, EquMet is prescribed twice daily, where clinical efficacy of
decreasing blood glucose can be observed from midnight to early morning.
Authors have diabetic team group and reported clinical research for
years. The content includes meal tolerance test (MTT), Carbo-70g test for
breakfast, low carbohydrate diet (LCD), continuous glucose monitoring (CGM) and
pharmacological diabetic treatment [14,15]. Clinical effects of Twymeeg were
reported for several T2D cases [16]. Furthermore, lots of T2D patients treated
with EquMet for 6 years were analyzed for the seasonal changes [17]. We have recently experienced impressive
patient who had the treatment of both of EquMet and Twymeeg. Its general
clinical progress as well as some perspectives will be described in this
article.
Presentation of Case
Medical history
The presented case is 59-year-old female with obesity and Type 2 diabetes
(T2D). She has been obese for long years, and was previously diagnosed as T2D in
5 years ago. She has been on several oral hypoglycemic agents (OHAs) until now.
Her HbA1c has been almost stable around 6.0-6.7% for years (Figure 1). Her
blood pressure has been increased about 2 years ago. After that, she has been
provided anti-hypertensive agent (AHA), and her BP has been stable until now.
Physicals and
various exams
Her physical examination showed the following condition in Jan 2022. Her
consciousness is alert, conversation and speech are normal, her vital signs are
within normal limits, BP 132/80 mmHg. Her lung, chest and abdomen were
negative, and neurological findings were intact. Her physique showed 151cm in
height, 84.1kg in weight and BMI 36.8 kg/m2.
Laboratory exam revealed the follow results: HbA1c 7.0%, post-prandial
blood glucose 208 mg/dL, RBC 5.84 x 106 /?L, Hb 15.6 g/dL, Ht 52.0
%, MCV 89.0 fL (80-98), MCH 26.7 pg (27-33), MCHC 30.0 g/dL (31-36), WBC
8200/?L, Plt 25.4 x 104 /?L, AST 18 U/L, ALT 23 U/L, ?-GT 23 U/L,
Uric Acid 7.2 mg/dL, BUN 24 mg/dL, Cre 0.88 mg/dL, HDL 46 mg/dL, LDL 154 mg/dL,
TG 252 mg/dL.
Chest X-P revealed negative findings. Electrocardiogram (ECG) showed
pulse 72/min, ordinary sinus rhythm, and no specific ST-T changes. She received
detail test of mechanocardiogram and also sphygmogram. The results showed as
follows: Bilateral ankle brachial index?ABI?in
right/left were 1.12/1.18, respectively. The values of brachial-ankle pulse
wave velocity (baPWV) in right/left showed 1352/1458, respectively (Figure 2).
When analyzed the detail values of upstroke time (UT) and % mean arterial
pressure (%MAP), they were in normal range.
Clinical course
HbA1c level was increased to 7.0% in Jan 2022, and then the medication
was changed for more effective treatment. She started to have the combined
medicine of vildagliptin/metformin (EquMet) from Jan 2022 (Figure 1).
After that, HbA1c value was decreased for several months. However, HbA1c
increased to 6.9% in Nov 2022 again. For effective administration of OHA, she
was provided to begin imeglimin (Twymeeg) from Nov 2022. Her glucose
variability was improved, and HbA1c was decreased to 6.3% in Jan 2023. As to
the changes in body weight, it was 84kg in Mar 2022, and it decreased to 78kg
in Feb 2023. She did not complain of any gastro-intestinal adverse effects (GIAEs)
for EquMet or Twymeeg.
Ethical standards
This case report was complied with the standard ethic guideline that was
previously presented in Helsinki Declaration. Moreover, some commentary was
associated with the protection regulation concerning personal information. This
principle was along with the ethical rules against usual clinical practice and
research for human beings. Certain guideline is presented from Japanese
Ministry. This information is related with the Ministry of Health, Labor and
Welfare and Ministry of Education, Culture, Sports, Science Technology. Current
authors have established our ethical committee about this research that was
present at Kanaiso Hospital in Tokushima, Japan. It contains medical and also
legal personnels that has the president, physicians, surgeon, pharmacist, head
nurse, dietitian and legal professional. These members discussed in thorough
manner concerning the case, and agreed for current protocol.
Discussion
Concerning this case, the characteristic point was the combined treatment
of Twymeeg and EquMet. From the introduction of Twymeeg to clinical practice,
the usefulness of EquMet was re-evaluated again. The reason includes i) both
meds are given twice a day at morning and night, ii) hypoglycemic effects can
be expected during midnight to early morning, iii) this combination actually
includes actually three kinds of OHA, which are biguanide, DPP4-I and
imeglimin. For the current case, HbA1c value was improved by Twymeeg as 0.6%
for 3 months. Imeglimin was chosen for dual efficacy of decreasing insulin
resistance and elevating insulin secretion [18]. She did not feel any symptoms
of gastro-intestinal adverse events (GIAE) [19]. As to imeglimin, multi-center
studies were found, which are Trials of IMeglimin for Efficacy and Safety
(TIMES) 1,2,3 [20]. Among them clinical
effect was analyzed for monotherapy and combination therapy. Reduction of HbA1c
was 0.46% for monotherapy, 0.56% for sulfonyl urea, 0.67% for biguanides, 0.85%
for alpha-glucosidase and 0.92% for DPP4-i [21]. In contrast, combined therapy
with GLP-1RA showed only 0.12% decrease of HbA1c. From these data, different
mechanism may be present concerning mitochondria function that is related to
DPP4-i and GLP-1RA [22].
In order to assess the effect of vildagliptin and metformin (Vil/Met), study was conducted for the comparative method. Using databases of RCTs for combined treatment of Vil/Met, 8533 cases from 11 RCTs were analyzed [23].
Figure 1: Clinical
progress of changes in HbA1c and weight.
Figure 2: The results of sphygmogram and mechanocardiogram.The method was the comparison for combination of Vil/Met and monotherapy of metformin (?1500mg/day). For the degree of evidence, the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach was applied. As a result, combination therapy showed significantly higher effect of HbA1c decrease as mean differences (MD) = -0.59. Total adverse events (AEs) were similar (Relative Ratio, RR = 0.98).
For comparison of clinical effect on diabetic initial therapy,
administration of combination and/or monotherapy of Vil/Met was conducted [24].
The method included 4 groups, which are i) Vil + Met 50 mg + 1000 mg twice
daily), ii) Vil + Met 50 mg + 500 mg twice), iii) Vil (50 mg twice) or iv) Met
(1000 mg twice). As a result, HbA1c decrease for 24 weeks was 1.8%, 1.6%, 1.1%
and 1.4%, respectively. When baseline HbA1c was higher (>10%), HbA1c
reduction was 3.2%, 2.7%, 1.5% and 2.6%, respectively. Consequently,
treatment-naïve diabetic patients showed superior effect of combined higher
dose of Vil/Met compared with lower dose and monotherapies.
In addition, the report on vildagliptin was found in vivo study. Against
diabetic rats, administration of vildagliptin has shown improved learning and
memory ability, which was continued for 2 months [25]. For newly-diagnosed T2D
patients (n=100), compared study was performed. The fundamental treatment was
administrating Metformin, and add-on therapy was conducted [26]. The two groups
were Met + glimepiride vs Met + vildagliptin. As a result, change in HbA1c value
was 8.14 to 6.98 % vs 8.33 to 6.99%, respectively. Clinical efficacy was the
same, but the latter did not show any reverse effect or hypoglycemic episode,
indicating superior evaluation for 24 weeks.
The impressive research was recently found concerning administration of
Met and/or Vil for streptozotocin-induced diabetic rats [27]. The protocol
included 5 groups of Wistar rats (each n=10), and they were separated as i)
control group (C), ii) diabetic control group (D), treated with iii) Met (DM),
iv) vildagliptin (DV) and v) combined Met/Vil (DMV). They were treated 15 days
and received some exams such as urination behavior and an open field test. For
this test, staying in the center space means less anxiety, and staying in the
periphery beside the wall means much anxiety. As a result, urination number was
elevated in the D, DM, and DV in comparison with that of C, and was decreased
in DMV in comparison with diabetic groups. From the open field evaluation,
staying time in the center was i) lower in D and DM compared with C
(p<0.05), and ii) remarkable higher in DMV compared with other groups
(p<0.01). It suggests that combined therapy (Met+Vil) may contribute
decreased anxiety, and that single Met or Vil may not be so effective.
For these results, gamma aminobutyric acid (GABA) may be involved in the
mechanism. GABA has been an inhibitory
neurotransmitter. When the expression or its receptor (named GABAA receptor) is
decreased, it can cause anxiety situation [28]. Metformin has anxiolytic-like
efficacy by changing the expression of GABAA receptors [29]. Furthermore, Metformin reduced anxiety by
decreasing BCAA which regulates tryptophan, which is possible reason leading to
anxiety [30].
Limitation may exist in the current report. Clinical efficacy of EquMet
and Twymeeg was analyzed. Some factors can influence each other, such as taken
carbohydrate amount, exercise situation and mutual medication relationship.
Further evaluation would be required by following up the clinical progress in
the future. In summary, a patient with obesity and T2D was reported accompanied
by the combined OHA therapy. Accumulation of case analyses will contribute the
development of diabetic research and adequate practice. This article becomes
hopefully a useful reference data in the future.