Introduction
Various
metabolic diseases have been prevalent and giving impact on public health in
the world [1]. Among them, major diseases include type 2 diabetes (T2D),
obesity, overweight, hypertension, fatty liver, and so on [2]. Adequate
nutritional therapy would be required for the fundamental treatment of these
diseases. Recent treatments for T2D and obesity include low carbohydrate diet
(LCD), where long discussion was observed between LCD and calorie restriction
(CR) [3]. LCD has been more known and popular associated with elevated
understanding for LCD [4]. The ratio of US people applying LCD become twice in
the latest decade. Some nutritional studies for daily meal were conducted, in
which 57% of LCD performer were female and mean age was 48-67 years old [5].
Furthermore,
several novel oral hypoglycemic agents (OHAs) have been introduced for diabetic
practice and research. American
Diabetes Association (ADA) has played the main role of diabetic management so
far, and has announced standard treatment guideline in Jan 2023 [6]. The
feature of T2D includes the decrease of beta-cell mass and increase of insulin
resistance. This mechanism is involved in mitochondrial dysfunction [7].
Recently, imeglimin has been a novel OHA that has molecular similarity with metformin
and possesses a unique mechanism of targeting mitochondrial bioenergetics [8].
It can decrease reactive oxygen species (ROS) production, and increase
mitochondrial integrity and function, and improve the function and structure of
endoplasmic reticulum (ER) [9]. Associated with large studies, imeglimin
(Twymeeg) has shown beneficial glucose-lowering effects for diabetic various
complications in T2D patients.
Authors and our clinical team continued actual medical practice and research for years [10]. A variety case reports have been presented concerning continuous glucose monitoring (CGM), meal tolerance test (MTT), LCD and treatment experiences with several OHAs [11]. Among them, beneficial effect of imeglimin (Twymeeg) has been found [12]. Recently, we experienced a T2D patient who was treated by Twymeeg associated with clinical efficacy. Its general clinical course and related perspectives will be described in this article.
History and Physicals
Current case is 64-year-old male patient with obesity, T2D and dyslipidemia. When he was 20 years old, his body weight was 49 kg. When he was 61 years old in January 2021, he was pointed out to show hyperglycemia with HbA1c 9.4% and elevated weight 69kg (Figure 1).
Figure 1: Clinical Progress with Hba1c, Weight and Treatment.
Figure 2: Mechanocardiogram and Sphygmogram.
At
that time, his physique showed 157cm, 69kg and BMI 28.0. He was introduced to
our diabetes department, and he was advised to start super-low carbohydrate
diet (LCD) immediately. Super-LCD means 12% of carbohydrate intake of total
calory per day. Carbohydrate amount in his meal was restricted with continuous
diet advise and therapy. His LCD treatment was successful, because he showed
decrease of HbA1c from 9.4% to 6.6% and weight reduction from 69 kg to 64 kg
for 5 months. Then, his diet therapy became standard LCD, in which carbohydrate
intake was 26% in his total calory per day. His glucose variability and weight
had been slowly worse until November 2022. His HbA1c was increased to 7.4% with
weight 71kg in December 2022.
Several exams
Obtained
laboratory data in November 2022 was in the following: HbA1c 7.2%,
post-prandial blood glucose 276 mg/dL, AST 15 U/L, ALT 11 U/L, GGT 41 U/L, ChE
303 U/L (213-501), uric acid 6.1 mg/dL, Cr 0.90 mg/dL, BUN 12 mg/dL, LDL 138
mg/dL, HDL 45 mg/dL, post-prandial TG 375 mg/dL. WBC 7200 /?L, RBC 4.05 x 106
/?L, Hb 12.6 g/dL, Ht 38.4 %, MCV 94.8 fL, MCH 31.1 pg, MCHC 32.8 %, Plt 34.7 x
104 /?L. Chest X-P revealed
unremarkable, and electrocardiogram (ECG) showed within normal limits with no
specific ST-T changes. He received the examination of mechanocardiogram and
sphygmogram for arteriosclerosis (Figure 2). As the result, the ankle brachial index?ABI?
showed 1.02/1.06 in bilateral sides of right/left, respectively. The result of brachial-ankle pulse wave velocity (baPWV) showed
1564/1649 in right/left foot, which was 1SD higher than average degree of age.
Medical Problems
From
mentioned clinical course and laboratory exams associated with previous history
and medication, his current medical problems in December 2022 can be summarized
as follows:
#1
Obesity (BMI 28.8)
#2
T2D (HbA1c 7.4%)
#3
Hypertension (Amlodipine)
#4
Dyslipidemia (LDL 138 mg/dL)
Clinical Progress
In
December 2022, his glucose variability became exacerbation as HbA1c 7.4% and
increased weight 71kg. Then, we have decided to provide imeglimin (Twymeeg) for
T2D. Consequently, his HbA1c was improved from 7.4% to 6.4% for 5 months,
associated with weight reduction from 71kg to 65kg. During this period, the
case visited regularly once per month. He stated that the appetite was
moderately suppressed, and he was satisfied with eating small amounts. He did
not change the degree of carbohydrate restriction as continuous same balance of
meal content. As a whole, general amount of food intake was reduced. The
changes in HbA1c and weight were apparent with linear improvement. This
clinical progress seemed to be effective by the administration of Twymeeg.
Ethical standards
The
case is complied with the ethical standard guideline of Declaration of
Helsinki. Further, some comments were along with the usual regulation for
personal information. This principle has been associated with the ethical rules
for medical research and actual practice for human. Several guidelines were
references from the official presentation of the Japanese government. These
perspectives were from the Ministry of Health, Labor and Welfare, and also the
Ministry of Education, Culture, Sports, Science Technology. The authors and
collaborators established our ethical committee about this research. It exists
in Kanaiso Hospital, Komatsushima, Tokushima, Japan. The committee has several
required members, including the hospital president, physicians, radiologist,
head nurse, pharmacist, nutritionist and legal professional. These members
discussed in a satisfactory manner for this case, and agreed the protocol.
Informed consent by written document was obtained from the case.
Discussion
As
regards to the current case, several medical and characteristic problems are in
the following. They are obesity, T2D, hypertension, dyslipidemia, clinical
response of LCD and pharmacological response of imeglimin (Twymeeg). In these
perspectives, some points would be discussed, which are i) LCD, ii) imeglimin,
iii) relationship among related atherosclerotic cardiovascular disease (ASCVD).
First,
super-LCD method was so effective, and then he has the improvement of HbA1c
from 9.4% to 6.6% for 5 months, associated with 5kg weight reduction. Authors
and collaborators have continued LCD movement from medically and socially
points of view. Three representative types of LCD were proposed and prevalent,
which are petite-LCD, standard-LCD and super-LCD. They include carbohydrate
ratio involvement as 40%, 26% and 12%, respectively [13]. These developments
were conducted by our group of Japan LCD promotion association (JLCDPA). We
have reported significant efficacy of super-LCD for thousands of patients with
obesity and T2D. The results of weight reduction more than 10% was found in
26%, and more than 5% was found in about 58% [14]. From these medical effects,
LCD seems to become one of the useful nutritional methods for obesity and T2D.
Second,
the case presented clinically rapid and remarkable improvement by imeglimin.
The results showed the decrease of HbA1c 1.0% and weight 6kg for 6 months.
During this period, he did not change his actual diet method, which are
standard-LCD style. Imeglimin showed mega clinical studies in many countries,
which were Trials of IMeglimin for Efficacy and Safety (TIMES) 1,2 and 3 [15].
From the reported results, clinically average HbA1c decrease was in the
following: monotherapy -0.46%, add-on therapy of biguanides -0.67%, DPP4-i
-0.92%, SGLT2i -0.57%, alfa-glucosidase inhibitor -0.70% from TIMES 2 [16].
Imeglimin has been known to have mechanism via mitochondrial pathway [17]. The
characteristic results can be observed between GLP-1RA and DPP4-i. They have common
pathway for pharmacological function, but both results were different as -0.12%
vs -0.92% [18]. Consequently, the difference might bring the crucial key to
uncover apparent mechanism of imeglimin [19].
Third,
current case showed gradually decreased LDL-C level for the treatment period.
For mega studies of imeglimin concerning the relationship of LDL-C and
imeglimin, systematic review and meta-analysis of randomized clinical trials
(RCTs) were conducted. It included 8 reports with 1555 T2D cases, where the
data were from Cochrane Library, Pubmed, Google Scholoar, Web of Science and
Wiley. General effects revealed significant HbA1c decrease after administration
of imeglimin. In contrast, it did not show significant impairment concerning
HOMA-IR, HDL-C, triglyceride, LDL-C, which were p > 0.05 [20].
There
are some limitations in current article. This case has been treated for LCD and
imeglimin, where certain effective results were found in the clinical progress.
However, various factors may be involved in the progress. Then, future
situation would be carefully followed up, where we can evaluate some related
biomarkers or factors.
In
summary, current case is 64-year-old male patient associated with obesity and
T2D. He showed remarkable clinical effect by the administration of imeglimin
(Twymeeg). Some discussion and perspective were described in this article, and
future progress will be observed. Current report is hopefully evaluated to be
useful in the future diabetic research and practice.
Conflict of Interest
The authors declare no conflict of interest.
FundingThere was no funding received for this paper.
References