Introduction
From epidemiological point of view,
global burden of type 2 diabetes (T2D) has been increasing for decades [1]. The
elevation status of T2D will bring the increase of atherosclerotic
cardiovascular disease (ASCVD) such as cerebral vascular accident (CVA), coronary
heart disease (CHD) and peripheral artery disease (PAD) which are diabetic
macroangiopathy. Concerning the treatment of T2D, adequate judgement and
management has been presented by American Diabetes Association (ADA). ADA
announced the latest standard care method on January, 2024 [2]. Furthermore,
novel types of oral hypoglycemic agents (OHAs) have been introduced to medical
practice. Among them, imeglimin has attracted attention for its clinical
efficacy and functioning mechanism via mitochondria [3].
For T2D treatment, three main
principles have been known, which are nutrition, exercise and medicine. The
basic therapy would be adequate nutrition, where calorie restriction (CR) or
recent low carbohydrate diet (LCD) has been applied. When ingesting
carbohydrate, blood glucose always increase according to the amount of
carbohydrate [4]. From historical point of view, CR was formerly popular, and
after that LCD has been evaluated for its clinical efficacy [5]. Especially,
ketogenic LCD has also provided more actual effect through the energy
production of ketone bodies [6]. LCD was initiated by Doctors of Atkins and
Bernstein in western countries [7,8]. Successively, authors and collaborators
have begun LCD in Japan, and developed LCD measure clinically and socially
through Japan LCD promotion Association (JLCDPA) [9]. We have often educated many people and
patients with T2D and obesity for adequate method of LCD in the usual lives.
They are petite-LCD, standard-LCD and super-LCD, in which containing carbohydrate
amount would be 40%, 26% and 12%, respectively [10].
Combining adequate nutritional
treatment and pharmacological agents, T2D patients would be treated in
satisfactory manner than before [11]. Our diabetic research team has continued
holistic practice for patients with T2D, T1D, SPIDDM and life style-related
diseases for long [12]. We have informed actual LCD measures and treated T2D
patients with balanced daily treatment [13]. Recently, we have been in charge
of an impressive T2D case associated with various medical problems and
remarkable efficacy of imeglimin. In this article, general outline of the
patient and some perspectives are presented.
Case Presentation
Medical History
The reported case is a 75-year-old male with T2D, hypertension and other medical problems. He has taken several kinds of oral medicines for years. He has been treated in some departments of internal medicine, urology and dermatology. Concerning recent treatment of T2D, he was treated by pioglitazone until summer 2021 (Figure 1). After that, it was changed to glimepiride associated with the addition of EquMet. His HbA1c level increased to 8.5% in May 2023, and then he was started to take imeglimin (Twymeeg). Successively, HbA1c value has been acutely reduced as 7.6%, 7.1%, 6.5% and 6.2% for consecutive 4 months.
Figure 1: Clinical progress of the case.
Several Exams
During his clinical progress, his
laboratory results are summarized in Table 1. They have been stable, and
unremarkable changes were found. Chest X-ray was negative. Electrocardiogram
(ECG) showed ordinary sinus rhythm (OSR), in which Pulse 57/min, R-R interval
1.052 sec, P-R 0.169 sec. QRS 0.101 sec, QT 0.398 sec, axis -8 degree, SV1 0.79
mV, RV5 1.80 mV, R + S 2.59 mV (Figure 2). Findings are slight left axis
deviation and counter-clock rotation.
MRI and MRA examination
MRI and MRA exams were performed in
September, 2021(Figure 3). Selective atrophy of the hippocampus was somewhat
conspicuous and consistent with the characteristics of Alzheimer's disease (AZ)
[14,15]. Compared to the previous exam, small signal changes in the deep
cerebral white matter and subcortex were the same as before. There was no
significant difference in the low signal level adjacent to the dorsal side of
the left ventricular trigone on T2-weighted images, and no new vascular
disorders or lesions were observed.
The nodules within the trigone of the
bilateral lateral ventricles also have similar FLAIR hyperintensity under the
ependyma of the trigone. No new high signals found on DWI. MRA shows decreased
signal and irregularities in the left and right internal carotid arteries and left
middle cerebral artery. The origin of the left internal artery is also slightly
thin. These are about the same as the previous exam.
Ethical Standards
This case complied with standard
ethic guideline in Declaration of Helsinki [16]. Moreover, some comment is
found for the information regulation. The principle has been observed in
ethical rule as to medical practice and related research. Clinical various
problems for human being have been present. Important guidelines have been
valid from Japanese government, which are Ministry of Health, Labor and Welfare
(MHLW) and Ministry of Education, Culture, Sports, Science Technology (MEXT).
The authors et al. set up the ethical committee about current case study. It
existed in Kanaiso hospital, Komatsushima, Japan. The committee consists of
several hospital staffs. They are the president of the hospital, physician,
registered nurse, pharmacist, nutritionist, and legal professional. These
members have discussed the protocol with satisfactory situation. The required informed
consent has been taken from the case with written document.
Discussion
This case is a 78-year-old man who is
characterized by T2D, as well as hypertension, coronary heart disease (CHD),
cerebral vascular accident (CVA), dementia, urological and dermatological
disease, and digestive health problems. Thus, he has various diabetic
macroangiopathy, in which several medical treatments would be required [11].
His current situation seems polypharmacy, but his general condition has been
stable.
Medical problems and related
pharmacotherapy would be summarized in the following. They are
#1 T2D: EquMet (Equa and Metformin),
imeglimin (Twymeeg), Glimepiride,
#2 hypertension: cilnidipine,
#3 hyperuricemia: silodosin,
#4 dementia: galantamine
hydrobromide,
#5 CHD: bisoprolol fumarate,
#6 CVA: aspirin,
#7 androgenetic alopecia (AGA):
dutasteride,
#8 reflux esophagitis (RE):
famotidine,
#9 constipation: magnesium oxide
Figure
2:
Electrocardiogram.
Figure 3: Brain MRI and MRA.
a:
MRI finding
b: MRA finding
Main medical problem in this case
would be T2D associated with hypertension, hyperuricemia, CHD, CVA
(#1,2,3,5,6). Further, he had dementia (#4) that is related with
arteriosclerosis (#1,2,3,5,6). For anti-hypertensive agent (AHA), cilnidipine
(#2) has been compared with amlodipine for years [17]. The former shows a
little stronger effect for protecting renal function associated with
hypertension than the latter [18]. There would be possible relationship between
dementia and AGA (#4, #7) [19]. Dutasteride is known to have some adverse
effect for recognition level [20]. By sensitivity analyses, younger cases and
those with alopecia showed higher odd ratio of cognitive dysfunctions [21]. For
GI tract complaints, these are possibly related to diabetic neuropathy and
gastrointestinal adverse effect (GIAE) of imeglimin (Twymeeg) (#1, 8, 9). This
case did not feel GI problems after starting Twymeeg.
Regarding actual treatment, some
points are found corresponding to his clinical situation. It is known that
SGLT2-i has some benefits for T2D, cardiovascular system and renal function. We
have considered to give SGLT2-i to this case. On the other hand, certain
disadvantage of SGLT2-i is present, such as increased urine output and higher
risk of dehydration. In this case, mild dementia is observed in daily life,
associated with prostate enlargement, frequent urination, slight CVA, and higher
risk of dehydration in summer [22]. For these reasons, SGLT2-i was not
administered. Our medical team will pay attention to these medical problems in
his clinical progress.
From a prospective observational
investigation, diabetic patients show 43% higher risk for Alzheimer disease
(AZ), 43% higher of all kinds of dementia, and 91% higher of vascular dementia
in comparison with those without diabetes [23]. In a well-known large study of
Hisayama study, Japan. For 15-year study, diabetic people tended to have
increased AZ, vascular dementia and all kinds of dementia compared with those
of normal glucose tolerance [24]. This case was provided imeglimin (Twymeeg)
and other OHAs, who showed remarkable clinical effect. HbA1c value was reduced
in short period. By the data of international studies of Trials of IMeglimin
for Efficacy and Safety (TIMES) 1, 2, 3, clinical response for monotherapy and
combined therapy was reported [25]). They are 0.46% in monotherapy, 0.67% in
biguanide, 0.92% in DPP4-i, 0.57% in SGLT2-i, and 0.56% in SU [26].
There is limitation in this article.
Observed clinical effect would be due to Twymeeg, other OHAs and continued LCD.
However, other related factors may be present, which are involved in the daily
life of the patient. Consequently, this case will be followed up with close
attention.
In summary, 75-year-old T2D male
patient was described in this case report. It showed clinical effectiveness of
glucose variability. We hope that this document will be some reference for
clinical research in the future.
Conflict of Interest
The authors declare no conflict of interest.
Funding
There was no funding received for this paper.
References
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Permana H,
Soetedjo NNM, Yanto TA, Tendean M, Hariyanto TI, Suastika K. Different doses of
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Atkins and Robert.
Dr. Atkins' New Carbohydrate Gram Counter. M. Evans and Company. 1996.
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Bernstein RK. Dr.
Bernstein's Diabetes Solution. Little, Brown and company, New York. 1997.
16)
General Assembly
of the World Medical Association. World Medical Association Declaration of
Helsinki: ethical principles for medical research involving human subjects. J
Am Coll Dent. 2014; 81: 14-18.