For decades, adequate care for type 2 diabetes (T2D) has been in focus across the world [1]. American Diabetes Association (ADA) presented the standard guideline for diabetes annually. For diabetic complications, macroangiopathy and microangiopathy would be crucial problem, such as cerebral vascular accident (CVA), ischemic heart disease (IHD), and peripheral artery disease (PAD) [2,3]. Furthermore, recent development has been observed for new and useful oral hypoglycemic agents (OHAs) in diabetic practice and research [4]. Authors and collaborators have continued to present various reports for diabetic cases and research [5]. Among them, imeglimin (Twymeeg) has attracted attention for useful effective mechanism for increasing insulin secretion and decreasing insulin resistance through mitochondrial pathway [6]. 

 Regarding basic principle of therapy for T2D, nutritional treatment would be required. Formerly, calorie restriction (CR) was popular measure, and after that low carbohydrate diet (LCD) was begun by two doctors of Atkins and Bernstein [7,8]. Successively, Dietary Intervention Randomized Controlled Trial (DIRECT) Group has reported the comparison among CR, LCD and Mediterranean Diet (MD) [9]. It was the milestone for nutritional treatment. Authors have developed LCD in Japan from medical, economic and social points of view by several seminars, medical societies, and Japan LCD promoting association (JLCDPA) [10,11]. We have developed convenient measure of LCD as petite, standard and super LCD [12].

Our diabetic team has continued medical practice and research for various types of T2D patients. Among them, we have encountered an impressive T2D patient treated with imeglimin, who was found to have peripheral artery disease (PAD) this time. Her general situation and related perspectives will be described in this report.

Medical History

The patient is 60-year-old female with type 2 diabetes (T2D). She has not specific past history without obesity until 55 years old. She was diagnosed as T2D and treated by some oral hypoglycemic agents (OHAs) at another clinic. However, her glycemic variability was not improved, then she came to our diabetic department. Her HbA1c was 7.2% and weight was 84 kg in January 2022 (Figure 1). She started to take imeglimin (Twymeeg) 2000mg per day to normalize glucose control. HbA1c value was gradually decreased to 6.4% in August 2022. However, glycemic control has shown exacerbation again to 6.9% in December 2022. Then, she was added semaglutide (Rybelsus) from 3 mg to 7 mg a day. Her HbA1c was decreased to 6.4% in April 2023. For 9 months, her HbA1c showed some fluctuation from 6.4% to 6.8%.

Figure 1: Clinical Progress of the Case.

Physicals and Laboratory Exams

The physical examination in January 2022 revealed as follows: speech, consciousness, and vital signs were unremarkable. Negative findings were observed in the heart, lung, abdomen or neurological tests. She did not have any specific symptoms or signs. Her physique revealed height 151.0 cm, weight 84kg, and BMI 36.8 kg/m².

The data of biochemistry were summarized in Table 1. General findings showed elevated liver function test, due to fatty liver. Otherwise, renal, lipids or complete blood count (CBC) showed negative findings.

Table 1: Changes in Laboratory Data.

Her chest X-ray and electrocardiogram (ECG) results showed negative. She received the examination of pulse wave velocity (PWV, sphygmograph). General data showed that ankle brachial index (ABI) 0.93/0.66, and baPWV 1567/1346 for right /left. As a result, data of left ankle showed Mean Artery Pressure (%MAP) as 54% (normal <44%) and upstroke time (UT) as 250 ms (normal <179 ms) (Figure 2). The PWV in the left ankle showed decreased amplitude compared with ordinary situation. The result of brachial-ankle Pulse Wave Velocity (baPWV) showed 1567/1346 for right/left ankles) (Figure 3). The data of left ankle would be re-evaluated again in the next examination.

Figure 2: Results of Sphygmograph in Arm and Ankle.

Figure 3: Pulse Wave Velocity (PWV) Exam.

Ethical Standards

Current report is complied with ethic guideline for the Declaration of Helsinki. In addition, some commentaries were observed for the protected regulation for information. The principle was along with the ethical regulation in the clinical research and practice. Certain guidelines were valid from official presentation of Japanese Ministry. The governmental offices included for Ministry of Health, Labor and Welfare (MHLW) and Ministry of Education, Culture, Sports, Science Technology (MEXT). The authors et al. have established the ethic committee related to this case. It exists  in Kanaiso Hospital, Tokushima, Japan. It included main medical staffs and legal professional, which were the president of the hospital, physician, head nurse, pharmacist, nutritionist, and legal professional. These members fully discussed the case enough, and agreed for the protocol. The informed consent was taken from the patient by the document.

This case is 60-year-old patient with T2D, obesity with BMI more than 35, dyslipidemia, hypertension, and other diseases. She has been administered for oral hypoglycemic agents (OHAs) and other agents, including metformin, canagliflozin, amlodipine, rosuvastatin. In addition, she was provided imeglimin (Twymeeg) from Jan 2023. This addition showed clinical effect for reduction of HbA1c satisfactory from 7.2% to 6.4% for 7 months. After that, the administration of oral semaglutide (Rybelsus) showed certain clinical effect of controlling HbA1c and body weight. She did not show apparent diabetic microangiopathy or macroangiopathy for years.

Current case showed remarkable clinical efficacy by Twymeeg. She presented no gastrointestinal adverse events (GI-AEs), such as diarrhea, nausea, constipation or abdominal discomfort [13]. As to imeglimin investigation, international research for Trials of IMeglimin for Efficacy and Safety (TIMES) 1,2,3 have been continued [14]. From these some results were presented as follows: single administration of imeglimin -0.46%, combination of administration of other agents for SGLT2-i -0.57%, DPP4-i -0.92%, metformin as biguanides -0.67%, and SU agents -0.56% [15]. This case has continued OHAs of metformin, imeglimin, SGLT2-i, and GLP-1RA. Consequently, this case had successful results by the combined OHAs.

This time, however, she was pointed out to have macroangiopathy of peripheral artery disease (PAD) [16]. She does not have apparent cerebrovascular accident (CVA) or coronary heart disease (CHD).  Concerning PAD, her ABI in the left ankle showed remarkably decreased value, and sphygmograph showed decreased amplitude associated with elevated  %MAP and UT. The value of brachial-ankle Pulse Wave Velocity (baPWV) for left ankles will be re-evaluated because of probable existing of PAD in left foot and leg. Currently, her obtained data in the left ankle suggested that bilateral femur artery may become partly occluded.

As regards to the judgment of baPWV data, standard range is less than 1400 cm/sec and the cut off value for arteriosclerosis is 1800cm/sec. In this case, baPWV cannot be analyzed for detail because of decreased ABI indicating the existence of PAD. Increased both %MAP and UT suggested the existence of stenosis and/or occlusion of blood vessels of left leg and foot [17]. Consequently, we have to pay attention to the data of ABI results. Since there are patients with PAD even with an ABI > 0.9, it is important to evaluate PWV and also detail forms of PWV in addition to the ABI.

Regarding the relationship of diabetes and PAD, various reports have been observed [18]. Some risk factors for PAD have been cumulative and numerous, such as age over 50, smoking, hypertension and T2D. Its prevalence reveals elevation with aging, in which rates are from 2.5% to 60% for people over 50 to those over 85. In diabetic cases, the prevalence was 11.2% associated with elevated TG, high-risk waist circumference, weak pulses and positive results of Edinburgh questionnaire. For diabetic cases with PAD, comprehensive management and proactive screening would be required for decreasing risks and improving outcomes [18].

During actual developing arteriosclerosis, PWV can present the degree of aggravation of the arteriosclerotic changes of lower extremities [19]. By observing the clinical process of ABI and/or CAVI, possible occlusion of arteries may be suggested [20]. The arteriosclerotic exacerbation in PAD can be prevented by lowering average blood glucose variability, decreasing mean amplitude of glucose excursions (MAGE), reduction of HbA1c, and controlling of body weight, lipids, and blood glucose [21].

Some limitation may be present for this case. Her medical problems persisted as T2D, obesity, hypertension without apparent arteriosclerotic changes. However, current evaluation showed probable existence of PAD. Then, the case is planned to proceed some necessary exams and treatments such as vascular analysis and anti-coagulants [22]. Furthermore, strict control of weight, glucose variability, blood pressure, lipids and others would be required in the successive course.

In summary, 60-year-old T2D female case was presented in this article. Clinical problems included PAD found recently, and future treatment strategies controlling glucose, lipids, BP and weight. We expect that this report will become useful reference for diabetic research and practice.

Conflict of interest

The authors declare no conflict of interest.

Funding

There was no funding received for this paper.

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