Introduction
For decade, authors and
co-researchers have continued clinical practice and research for
Atherosclerotic cardiovascular disease (ASCVD). They include hypertension, type
2 diabetes (T2D), ischemic heart disease (IHD), chronic kidney disease (CKD)
and other diseases [1]. In many patients with various medical problems, we have
managed certain pharmacological treatments. From lifestyle point of view,
nutritional treatment and exercise therapy would be necessary [2]. Consequently,
Bando Heart Clinic has continued providing educational lifestyle modification
for years. Among them, adequate amount of sodium would be recommended, which
are effective for the control of blood pressure and ASCVD [3]. For prevention
of ASCVD, predicting metabolic syndrome (MetS) has been crucial for identifying
the risk degree for patients and giving preventive interventions [4].
On the other hand, T2D has been
crucial medical and social problem across the world [5]. American Diabetes
Association (ADA) has announced the latest guideline for T2D in Jan 2023 [6].
As to diet therapy for T2D and obesity, the recommended method has been changed
from calorie restriction (CR) to low carbohydrate diet (LCD) [7]). Recent
studies have revealed various evidence of predominance of LCD [8]).
Furthermore, recent pharmacological development introduced novel oral
hypoglycemic agents (OHAs) and useful combination of OHAs. Among them, the
combined agent of vildagliptin/metformin (EquMet) showed clinical efficacy and
evidence from large studies of vildagliptin and metformin versus sequential
metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY) [8]. This
intensified prescription has brought paradigm shift in the diabetic therapy
across the world, which has been from ADA and European Association for the
Study of Diabetes (EASD) [9].
Authors and co-researchers have continued clinical practice and research for various ASCVD, in which T2D patients on EquMet were followed up 6 years [10]. In addition, another case on EquMet was analyzed in detail by high-technique radiological method of Curved Planar Reconstruction (CPR) [11]. Recently, we have experienced an impressive case who was treated by EquMet associated with several problems. Their general situation and related perspectives are described in this article.
Case Presentation
Medical History
The case is 71-year-old female patient with T2D and dyslipidemia for years. About 16 years ago, she was pointed out to have T2D, dyslipidemia, fatty liver, and obesity. She had been on OHAs for years, and HbA1c was around 7.8%. In 2016, she developed right back pain and hematuria, and then was diagnosed as right renal stone. The problem of urinary stone was excreted as itself after that. During 2017-2018, HbA1c decreased to 6.5% by the administration of luseogliflozin and EquMet. However, she complained of discomfort in the inguinal region. It was probably because of SGLT2-i intake every day. Then, the intake of luseogliflozin was decreased for every other day. After that, HbA1c value was elevated to some degree (Figure 1).
Figure 1: Clinical course of the case with HbA1c, laboratory data and treatment.
Figure 2: Consecutive ECG findings for 4 years.
Figure 3: Pilgrimage map of 88 temples in Shikoku Island, Japan.
Physical examination
Her physical examination in July 2019
showed in the following: Consciousness and conversation were normal. Vitals of
BP, pulse, respiration and SpO2 99% were in the normal range. Her head, neck,
lung and heart showed negative. Abdomen showed a little distended and soft with
unremarkable findings. Neurological examination was intact. Her physique showed
height 151 cm, weight 65 kg, BMI 28.5 kg/m2, and fat ratio of the
body 35.7% by the analysis of the apparatus InBody.
Several examinations
Laboratory exams in July 2019 were as
follows: TP 7.0 g/dL?T-Bil 0.5 mg/dL, AST 14 U/L, ALT 18 U/L, LDH 169 U/L,
GGT 12 U/L, CPK 87 U/L, Uric acid 2.8 mg/dL, BUN 16 mg/dL, Cre 0.47 mg/dL, eGFR
98.4 mL/min/1.73m2, Na 141 mEq/L, Cl 104 mEq/L, K 4.2 mEq/L, HDL 58
mg/dL, LDL 78 mg/dL, TG 106 mg/dL, T-Cho 151 mg/dL, LDL/HDL ratio 1.3, glucose
67 mg/dl, WBC 6000/?L, RBC 4.80 x 106 /?L, Hb 14.7 g/dL, Ht 45.8 %,
MCV 95.4 fL (80-98), MCH 30.6 pg (27-33), MCHC 32.1 g/dL (31-36), Plt 23.2x 104
/?L.
As physiological exams in 2019, chest X-P was
negative and electrocardiogram (ECG) showed normal axis, pulse 63 /min,
ordinary sinus rhythm (OSR), and no remarkable ST-T changes. Regarding annual
check of ECG, the results during 2019-2022 are shown in Figure 2. For latest 4
years, she did not develop unremarkable cardiovascular complaints, symptoms or
signs.
The examination of carotid
echocardiogram was performed in 2019. As a result, no plaque was found and no
significant change was observed as a whole. The value of intima media thickness
(IMT) was 0.78 mm and 0.70 mm in right and left carotid artery, respectively.
Clinical course
This case has continued various
behaviors and trials for diabetic treatments. They include three categories as
nutritional, exercise and medicine during 2020-2023. Regarding diet therapy,
she likes to eat rice, fruits, cakes, beer and so on. Then, our nutritionists
always give lectures for adequate diet therapy. As to exercise therapy, she
states that she always takes a walk around the house. Actually, her diet and
exercise treatments seemed to be unsatisfactory.
One impressive episode for exercise
therapy was observed. Japan has 4 main islands, which are Hokkaido, Honshu,
Shikoku and Kyushu. The word “Shi+koku” means four + country, state, or
prefecture. Tokushima is one of these 4 prefectures (Figure 3). Shikoku has
pilgrim journey course visiting 88 consecutive temples, which takes 40 days for
walking for 1400km. The important points would be that i) walking for long distance,
ii) staying at cheap pilgrim lodgings, iii) interacting with other pilgrims for
deep communication, and iv) thinking about our whole lives and relationship of
other people with appreciation. She attended the pilgrim journey, but it was
incomplete. The reason was that she moved by car and stayed high-class hotel
with comfortable travel.
Concerning pharmacotherapy, she
continued rosuvastatin as anti-hypercholesterolemia, and EquMet, Luseogliflozin
and glimepiride for OHAs. Her body weight has been almost stable for years.
Several biomarkers for liver, renal, lipid and diabetes were followed up for 5
years, and these data were almost stable (Figure 1).
Ethical standards
This case report is complied with the
ethic guideline in Declaration of Helsinki. Furthermore, some commentaries are
based on the regulation for adequate personal information. These principles
would be observed in the ethical rule as to clinical practice and research. As
related, some medical problems of human are present. The certain guideline has
been from Japanese government, which are Ministry of Education, Culture,
Sports, Science Technology and Ministry of Health, Labor and Welfare. The
authors and collaborators have established ethical committee regarding this
case. It was present in Bando Heart Clinic, Tokushima city, Japan. The
committee has included the hospital director, physician, nurse, pharmacist,
nutritionist, laboratory specialist and legal professional. We have discussed
in satisfactory manner concerning current protocol and have agreed for the
protocol. The informed consent was taken from the case by the written document.
Discussion
This case is 71-year-old female
patient with T2D and other problems. Some medical problems include i)
relationship among renal stone, diabetes and medication of OHA and sodium
glucose cotransporter 2inhibitor (SGLT2-i), ii) incomplete diet therapy and iii)
inadequate exercise therapy. From these points of view, some perspectives are
described in this order.
First, this case has history of renal
stone, and medication of EquMet and SGLT2-i in 2017. The HbA1c decreased to
6.5% in 2018. This effect may be by both agents. During 2018-2023, several
biomarkers showed almost stable. From her clinical course, the relationship of
renal stone and SGLT2-i will be discussed. The close relationship exists among
gout, diabetes, insulin resistance, cardiometabolic risk and kidney disease
[12]. From recent study, SGLT2-i can contribute risk reduction of gout for T2D
patients. SGLT2-i is known to exert favorable efficacy in decreasing uric acid
(UA) level. For its mechanism, SGLT2-i increases glucose excretion in urine,
associated with probably inhibiting glucose transport 9 (GLUT9)-mediated UA
reabsorption in the collecting duct [13]. It will result in elevated UA
excretion that is in exchange for the reabsorption of glucose. Elevated
UA is associated with impaired beta cell function and insulin acts to decrease
the excretion of UA [14]. Furthermore, elevated UA is observed with higher risk
of hypertension, CVD, CKD and Metabolic syndrome (Met-S). Thus, clinical effect
of SGLT2-i would be investigated for the relationship of CV events, glucose and
UA levels.
Several reports are found for the
relationship between SGLT2-i and risk of gout for T2D. When analyzing seven
adequate papers, 34% reduction risk was found for developing gout for T2D
patients [15]. In order to assess the relationship of SGLT2-i and gout,
nationwide health registry was used for 3 years. From the data of 42 thousand
person-years follow-up, SGLT2-i vs GLP1-RA users showed 4.1 vs 7.0 events per
1000 person years. It shows hazard ratio (HR) of 0.58 [16]. Using US National
administrative data, association between SGLT2-i and gout incidence was studied
for T2D. Totally 714 cases were analyzed for with/without SGLT2-i
administration [17]. As a result, 38% reduction was observed between them.
Consequently, SLGT2 inhibitors may show beneficial efficacy for T2D patients at
gout risk.
Furthermore, this case was provided
EquMet that is combined agent for vildagliptin and metformin. It shows
beneficial glucose-lowering effect all day long [18], and international
evidence was shown from Vildagliptin Efficacy in combination with metfoRmIn For
earlY treatment of type 2 diabetes (VERIFY) studies [8].
Second, this patient has been advised
many times by a registered dietitian in out clinic. The concept of the
fundamental diet would be on daily 1600 kcal, less than 6g/day of salt, 65g/day
of protein, 30g of fat and composition (P/S ratio 1.5) [19]. One of the reasons
why the long-term guidance could not produce results is that the patient liked
fruits and sweets, often snacked between meals, and inevitably ate relatively
large amounts of sugar. CR has historically been the standard way for guidance
on diabetes. Bernstein and others, however, have been known broadly, and LCD
has been recognized more. Recent data have been found from the Japan
Multi-Institutional Collaborative Cohort (J-MICC) Study, and more detailed data
are expected in the future [20].
Regarding diet therapy for T2D,
systematic review was performed for carbohydrate-later meal pattern (CLMP) and
meal sequence [21]. It included 230 cases from 8 trials. Detail review did not
show significant difference for blood glucose, HbA1c, GLP-1 and insulin levels.
However, eating fast habit may lead elevated risk for diabetes and obesity. The
latest study is to investigate meal sequence and eating speed for 18 healthy
cases [22]. The method included three patterns, which are slow or fast eating,
carbohydrate first or vegetable first, test meal or vegetables. Consequently,
eating vegetable first brought suppressed post-prandial glucose elevation and
insulin secretion.
Third, adequate exercise therapy for
diabetes has been in discussion for actual medical practice. For comparative
study of aerobic and anaerobic activities, T2D patients were investigated [23].
After exercise for 30 minutes, aerobic exercise brought glucose reduction to
9.4 mmol/L after 120 minutes. In contrast, anaerobic exercise brought no
changed glucose as 12.6 mmol/L. Thus, post-prandial glucose decrease can be
expected by aerobic exercise.
This case states that she has daily
habit of going out for walk 2-3 times a week for 20-30 minutes. However, this
exercise level is not enough, and then clinical efficacy cannot be expected. On
the other hand, walking for several hours in the picnic or visiting several
temples for pilgrim for weeks can contribute much for aerobic exercise.
Furthermore, Tokushima has world-known international Awa-dance Festival in
August 12-15 every year [24]. All dancers from amateur to professional team and
from elementary school children to elderly or patients with dementia can have
continuous dance for some hours [25]. Such exercise can contribute much for
health and fun, without giving much loading to each person.
Some limitation may be present in
this report. The case showed HbA1c reduction by OHAs, which was at least in
part by EquMet, SGLT2-i or other factors. She cannot continue effective
nutritional treatment or exercise therapy that are related with adequate
lifestyle. Further educational advice by medical staff would be expected and continuous
follow-up will be required.
In summary, current article is the
presentation of 71-year-old case with T2D. She presented several clinical
problems, where our medical staff will manage adequately for her improving
lifestyle. General description and various perspectives will hopefully become
useful reference for future diabetic practice.
Conflict of Interest
The authors declare no conflict of interest.
Funding
There was no funding received for this paper.
References
3.
Bando M. Medical
Book: Blood Pressure Can Be Lowered, Antihypertensive Drugs Can Be Stopped -
Cardiovascular Surgeon's Hypertension Management Techniques. Wani Books, 2013.
Tokyo, Japan.
25.
Sakurai H, Hanyu
H. Frailty and sarcopenia in patients with dementia. Jap Soc Vasc Cognit
Impairment. 2020; 6: 4-11.