Introduction
From bio-psycho-social points of
view, diabetes has become crucial problem worldwide [1]. Each country in
several regions has managed diabetic matters for long, such as European and
North American [2,3]. American Diabetes Association (ADA) has announced the
latest guideline for managing type 2 diabetes (T2D) in Jan 2024 [3]. Recent
topics include some types of novel oral hypoglycemic agents (OHAs) beneficial
for actual practice. Among them, imeglimin (Twymeeg) has been introduced with
pharmacological function mechanism through mitochondria pathway [4]. Authors’
et al have presented some reports of T2D patients with clinical efficacy by
imeglimin [5].
For T2D, basic principle for
treatment includes nutritional therapy, exercise continuation and medicine of OHA
or insulin. As diet method, calorie restriction (CR) was formerly usual
measure, but low carbohydrate diet (LCD) has been recently known with clinical
efficacy for T2D [5]. LCD was started in medical care and health care regions,
where two doctors of Atkins and Bernstein have contributed much through
educational books [6,7]. Successively, LCD was also initiated in Japan, in
which author’s collaborators have developed social movement of LCD via Japan
LCD promotion Association (JLCDPA) [8,9]. Our team has continued actual LCD
prevalence more by seminars, books and various presentations [10]. We have
recommended three types of useful LCD meals. They are petite LCD, standard LCD
and super LCD that include carbo amount ratio by calorie calculation as 40%, 26%
and 12%, respectively [11].
As we have continued diabetic
practice and research for various types of patients, a meaningful T2D male case
was present. He has suffered from T2D and diabetic macroangiopathy for long,
and showed remarkable clinical effect by imeglimin (Twymeeg) associated with
HbA1c decrease. Furthermore, he showed parallel improvement of HbA1c decrease
and improved arteriosclerosis in his clinical progress. His general outlines
and related clinical perspectives would be described in this article.
Presentation of Cases
Medical history
The patient is 68-year-old male with
T2D. He has past history of several clinical problems. He was diagnosed as T2D
in early 50s, dyslipidemia of elevated LDL and benign prostate hyperplasia
(BPH) in later 50s, and peripheral artery disease (PAD) and coronary heart
disease (CHD) in early 60s. Furthermore, he was pointed out to have nephropathy
in late 60s.
Clinical changes in HbA1c were shown
in Figure 1. He has been treated by T2D and glucose variability has been
unstable for years. Authors and collaborators have managed his total
therapeutic measures, including adequate nutritional therapy of low
carbohydrate diet (LCD), stable exercise daily habit, and administration of
oral hypoglycemic agents (OHAs). In response to these combined therapy, HbA1c
value in 2018 was gradually decreased from 8.0% to 5.7% for a year. His
diabetic situation had been satisfactory stable during 2019 and 2020 as keeping
low HbA1c value for 5.7%-6.6%. From spring 2021, his HbA1c was gradually
elevated, and then OHA was changed from pioglitazone to empagliflozin in summer
2021. After that, HbA1c was peaked to 7.5% in April 2023. Consequently,
imeglimin (Twymeeg) was started and then HbA1c was decreased to 6.2% for 5
months. His diabetic status has been now kept stable so far.
Physicals and laboratory exams
The physical examination in March
2023 revealed in the following: consciousness, speech and vital signs were in
the normal ranges. No remarkable changes were observed in the lung, heart,
abdomen, extremities or neurological exams. He did not complain of specific
symptoms or signs. His physique showed height 162.0 cm, weight 61.3 kg and BMI
23.4 kg/m2.
Table 1: Changes in laboratory data.
|
|
|
2019 |
2020 |
2021 |
2022 |
2023 |
2024 |
|
|
|
|
Oct |
Sept |
Apr |
Sep |
Mar |
Jan |
Units |
|
Liver |
|
|
||||||
|
|
AST |
33 |
31 |
28 |
24 |
24 |
39 |
(U/L) |
|
|
ALT |
45 |
36 |
35 |
31 |
31 |
47 |
(U/L) |
|
|
GGT |
50 |
43 |
45 |
36 |
36 |
45 |
(U/L) |
|
Renal |
|
|
||||||
|
|
UA |
6.1 |
6.2 |
6.0 |
5.9 |
5.7 |
(mg/dL) |
|
|
|
BUN |
20 |
22 |
23 |
28 |
30 |
(mg/dL) |
|
|
|
Cre |
1.00 |
1.06 |
1.05 |
|
0.87 |
1.06 |
(mg/dL) |
|
Lipids |
|
|
||||||
|
|
HDL |
76 |
66 |
64 |
59 |
73 |
69 |
(mg/dL) |
|
|
LDL |
86 |
87 |
103 |
81 |
89 |
106 |
(mg/dL) |
|
|
TG |
79 |
80 |
98 |
96 |
113 |
83 |
(mg/dL) |
|
CBC |
|
|
||||||
|
|
WBC |
51 |
46 |
53 |
50 |
(x10*2/?L) |
||
|
|
RBC |
423 |
404 |
455 |
435 |
(x10*4/?L) |
||
|
|
Hb |
13.1 |
12.3 |
13.8 |
13.3 |
(g/dL) |
||
|
|
PLT |
18.7 |
16.1 |
20.4 |
|
|
22.4 |
(x10*4/?L) |
The results of biochemistry exam for
6 years were summarized in (Table 1). They showed almost negative findings in
the liver and complete blood count (CBC), and some subnormal data in the renal
and lipids associated with several oral medicines for years.
His chest X-ray and electrocardiogram
(ECG) revealed negative results. As he has received several times of pulse wave
velocity (PWV, sphygmograph) exams until now (Figure 2). Among them, changes in
the cardio-ankle vascular index (CAVI) were summarized in Figure 3. It showed
rather stable CAVI for years, but the value was lower in 2019 and 2020 for two
years. Concerning ankle brachial index (ABI), obtained data showed almost stable during 0.80 –
0.90 bilaterally for these period.
Ethical standards
This report was complied with ethical guideline for the previous Declaration of Helsinki [12]. Moreover, certain commentaries were found as the protection regulation for information. The principle has been along with the ethic regulation for the clinical practice and research for the human. Some guidelines are found as the official announcement of Japanese Ministry. The information has been from Ministry of Health, Labor and Welfare (MHLW) and Ministry of Education, Culture, Sports, Science Technology (MEXT) of Japan. The authors and co-researchers have set up the ethic committee for this case, which is present in Sakamoto Hospital, Kagawa, Japan. It has medical staffs and legal people, where hospital director, doctors, nurse, pharmacist, dietician, and legal professional person. The members have discussed the protocol in satisfactory manner, and have agreed for the research. We have taken the informed consent by the document of the patient.
Figure 1: Clinical progress of the case.
Figure 2: Pulse wave velocity (PWV) exam.
Figure 3: Changes in cardio-ankle vascular index (CAVI).
Discussion
Current case has been 68-year-old
patient with T2D, hypertension, dyslipidemia and other diseases. He has been
provided for OHAs and anti-hypertensive agents (AHAs) for years, including
linagliptin, metformin, voglibose, rosuvastatin, cilostazol and aspirin.
Furthermore, he has taken imeglimin (Twymeeg) which showed clinical efficacy
for decreasing HbA1c. He showed the existence of diabetic macroangiopathy for
CVD and PAD, as well as microangiopathy of nephropathy. He has rather long
history of diabetes, and then such patient tends to have macro-and
micro-angiopathy [13].
Due to the developed
arteriosclerosis, pulse wave velocity (PWV, sphygmograph) showed the developed
degree of arteriosclerosis [14]. When observing CAVI values of right leg, the
results during 2016 to 2018 showed 8.4-9.4 [15]. After that, it showed
decreased values of 7.5 and 6.6 during 2019-2020. Interestingly, HbA1c levels
showed satisfactory glucose control of 5.7%- 6.6% during 2019-2020. This
parallel phenomenon results may suggest the evidence of clinical importance of
strict control of glucose variability, and the possibility of improving
arteriosclerosis by lowering average blood glucose and mean amplitude of
glucose excursions (MAGE) [16].
Consequently, current case has
peripheral artery disease (PAD), in which he has been already provided
anti-coagulant agents for years [17]. In the light of presence of T2D and
moderate arteriosclerosis, the case will be required to be followed with close
attention for several regular examination. Regarding the study of CV risk, 885
diabetic patients were studied for HbA1c, lipid profile, BP, eGFR and
medication [2]. Average data were HbA1c 7.1%, BP 134/80 mmHg, BMI 32.3,
hypertension 83%, obesity 64.6%, intake of metformin 87%, statin agents 67%.
Average LDL values showed in the three categories of very high, high, moderate
risk as 107mg/dL, 113 mg/dL, and 124 mg/dL, respectively. These factors are
involved in various glucose-lowering treatment and CV risk-modifying therapies,
and then LDL value is not necessarily related with risk degree of
arteriosclerosis.
As to his clinical progress, HbA1c
has been rather unstable until 2022. By the additional prescription of
imeglimin (Twymeeg), HbA1c was rapidly decreased 1.3% for 5 months [18]. This
remarkable clinical effect may be from pharmacological mechanism for decreasing
insulin resistance and increasing insulin secretion [19]. As imeglimin has
shown beneficial effect, it will hopefully contribute useful diabetic therapy
from now [20].
This case did not feel any
gastrointestinal adverse events (GI-AEs), such as nausea, constipation,
diarrhea, abdominal discomfort or pain [19]. For imeglimin studies, large
research of Trials of IMeglimin for Efficacy and Safety (TIMES) 1,2 and 3 were
internationally conducted [21]. Clinical effects were reported in the
following: only imeglimin administration 0.46%, DPP4-i 0.92%, SGLT2-i 0.57%,
sulfonyl urea (SU) 0.56%, and biguanide 0.67% [22]. Current case had combined
OHAs of DPP4-i, SGLT2-I, metformin and imeglimin. Thus, safe and satisfactory
effect were observed.
There may be some limitation in this
article. This case presented clinical efficacy for imeglimin, but current case
showed clinical effect by imeglimin, but other factors may be involved in the
pharmacological response. Diabetes is always influenced by various factors, and
then his clinical progress is required to be followed in the future [23,24].
In summary, 68-year-old T2D case was
presented in this report. In addition, some perspectives are introduced for
arteriosclerosis and novel imeglimin. We hope that it will become a beneficial
reference for diabetic practice.
Conflict of Interest
The authors declare no conflict of
interest.
Funding
There was no funding received for
this paper.
References
7.
Atkins
and Robert. Dr. Atkins' New Carbohydrate Gram Counter. M. Evans and Company.
1996.
8.
Bernstein
RK. Dr. Bernstein's Diabetes Solution. Little, Brown and company, New York.
1997.
18.
Association for
Research into Arterial Structure and Physiology (ARTERY), the European Society
of Hypertension Working Group on Large Arteries, European Cooperation in
Science and Technology (COST) Action VascAgeNet, North American Artery Society,
ARTERY LATAM, Pulse of Asia, and Society for Arterial
Stiffness—Germany-Austria-Switzerland (DeGAG). 2024 Recommendations for
Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices.
Hypertension. 2024; 81: 183-192.