Explosive Hypertrophy Development

Medical History

Current case is an 86-year-old man with arteriosclerotic diseases. He has been treated as T2D, dyslipidemia and cerebral arteriosclerosis for about 8 years. He visited internal medicine department and neurosurgery department in our hospital. His life style has been stable for long. He grows rice in the paddy fields, cultivates the fields to grow vegetables, and makes several flowers in his home garden. He continues to take walks every morning and evening, staying physically active throughout the year and maintaining sufficient strength in his legs and hips. His medication has been oral hypoglycemic agents (OHAs), atorvastatin and cilostazol (Figure 1).

Figure 1: Clinical progress of the case.

Several Examinations

Physical examinations in January 2023 revealed as follows: consciousness, vitals, and speech were within normal limits. His head, face, neck, lung, heart, abdomen and neurological findings revealed unremarkable. His physique showed height 157.7 cm, weight 52.1 kg and BMI 20.9 kg/m².

Biochemical exams were summarized in Table 1. They showed unremarkable results of liver, lipids, renal function and complete blood count (CBC). As fundamental exams, chest X-ray exam showed unremarkable, and electrocardiogram (ECG) revealed ordinary sinus rhythm with no specific ST-T changes.

Table 1: Changes in laboratory data.

		2022		2023		2024
		Feb	Jul	Jan	Aug	Feb	Units
Liver	AST	19	26	27	17	16	(U/L)
	ALT	24	35	28	14	13	(U/L)
	GGT	15	20	15	12	11	(U/L)
Lipids	HDL	66	64	58	58	61	(mg/dL)
	LDL	91	90	88	74	78	(mg/dL)
	TG	82	83	144	95	90	(mg/dL)
Renal	BUN	13	14	14	13	16	(mg/dL)
	Cre	0.79	0.88	0.8	0.75	0.76	(mg/dL)
	UA	4.4	5.3	5	4.7	4.6	(mg/dL)
CBC	WBC	5400	5900	5800	4900	5600	(x10*2/µL)
	RBC	455	440	457	394	410	(x10*4/µL)
	Hb	15.6	15.3	15.4	13.6	14.4	(g/dL)
	PLT	15.6	17.7	17.2	17.7	17.1	(x10*4/µL)

Blood pressure pulse wave (BPW) exam (plethysmography) was performed. The latest data was obtained in December 2023, in which ankle brachial index (ABI) was 1.14/1.19 (right/left, normal range 0.91-1.40), and Cardio-Ankle Vascular Index (CAVI) was 10.6/12.5 (R/L, 9.7+/- 0.9 for age), which showed rather above the standard range (Figure 2). As the reference of BPW, the standard values are from the previous report [13].

Figure 2: Plethysmography examination.

MRI and MRA Exam

Brain MRI and MRA examinations were performed in December 2022 and compared with those in January 2022 (Figure 3). Regarding MRI, brain atrophy and ventricular enlargement were almost the same as last time, and no major changes were observed in hippocampal atrophy. Similar findings include old infarcts in the right cerebellum and leukoaraiosis in deep white matter, including the corona radiata. Signal changes are also observed in the left and right basal ganglia and pons. No significant hyperintensity was observed on DWI.

Regarding MRA, tortuosity of the blood vessels was slightly noticeable and stenosis was observed at the M1/2 bifurcation of the right middle cerebral artery (MCA), but no major changes were observed from the previous time. The signal at other bifurcations is also slightly heterogeneous, suggesting general atherosclerotic changes.

Figure 3: Brain MRI and MRA.

Clinical Progress

For his impaired glucose variability, HbA1c was gradually increased in summer and autumn, 2022. In January 2023, HbA1c was elevated to 7.8%, and then novel OHA of imeglimin (Twymeeg) was started (Figure 1). HbA1c decreased to 7.1% for 2 months, and kept the same level for 2 months. Consequently, OHA was changed from linagliptin/metformin to vildagliptin/metformin (Equa + Metformin, EquMet). His glucose variability was improved for 4 months, and HbA1c was 6.7% in July, 2023. After that, his HbA1c has been maintained the same level.

Ethical Considerations

The present study was performed in accordance with the ethical principles based on the Declaration of Helsinki (Amendment, Fortaleza, and Oct 2013). It was also complied with the Ethical Guidelines for Medical Research Involving Human Subjects (partial amendment, 2017). There was important guideline from Japanese government that are from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science Technology. The authors’ et al. set up the ethical committee for current case. It exists in Sakamoto hospital, Kagawa, Japan. The committee included necessary hospital staffs. They were the president of the hospital, physicians, pharmacist, head nurse, nutritionist, and legal professional. These members discussed the protocol sufficiently, and the informed consent by written document was taken from the patient.

This case was 86-year-old elderly men with T2D, hypertension, dyslipidemia and cerebral arteriosclerosis. His life style has been stable for adequate diet, exercise and pharmacological treatment for years. His stature has been stable and rather slender with BMI 20.9 kg/m². He had continued to have OHAs of linagliptin, metformin and voglibose. His HbA1c has increased to 7.8%, and then imeglimin (Twymeeg) was initiated [14]. Clinical efficacy of lowering HbA1c, and pre-/post-prandial glucose has been known for imeglimin. In addition of EquMet, his clinical progress showed satisfactory clinical efficacy for improving glucose variability [15]. As to diabetic microangiopathy and macroangiopathy, he has not suffered from apparent symptoms or signs in the light of diabetic complication. From plethysmograph and brain MRI and MRA, he was proved to have some degree of arteriosclerosis of brain vessels and lower extremities. Judging from his current general status, rather stable physiological situation would be persisted, although he has light degree of T2D, dyslipidemia and brain arteriosclerosis.

During this period, he did not feel any gastrointestinal adverse events (GI-AEs) such as nausea, vomiting, diarrhea or constipation [16]. Regarding imeglimin, there was large international research of Trials of IMeglimin for Efficacy and Safety (TIMES) 1, 2 and 3 [17]. Among them, clinical effects in monotherapy and combined therapy have been described. They are monotherapy -0.46%, DPP4-i -0.92%, SGLT2-i -0.57%, SU -0.56%, and biguanide -0.67% [18]. These data were analyzed from for 6-12 months of continuing OHAs. In the current case, remarkable medical efficacy was found for only 2 months after starting imeglimin. The reason for this speedy improvement would be from his lifestyle in the daily life. Before exacerbation of HbA1c value, he tended to have more carbohydrate amount a day. When initiating novel OHA of imeglimin, he seemed to decrease daily amount of carbohydrate, because he has good understanding of health care and medical treatments.

Authors and collaborators have continued diabetic practice and research for different patients [19]. Among several reports, similar case with arteriosclerosis was reported by effective therapy of EquMet [20,21]. We have analyzed lots of diabetic patients with the administration of EquMet for several years [22]. When EquMet are given twice a day, clinical efficacy was more than other DPP4-i agent once a day. Regarding this benefit, research-oriented evidence has been found for suppressing daily glucose fluctuation for 24 hours [23]. It showed satisfactory suppression of glucose variability during night by intake the EquMet at evening. The current case showed remarkable HbA1c reduction by EquMet. It would be due to pharmacological combined mechanism of vildagliptin and metformin as twice administration. It is beneficial point compared with other DPP4-i agents with once daily administration.

There were large international studies for the combination OHA of vildagliptin and metformin, which were VERIFY [5]. VERIFY studies included 34 countries for multi-centered investigation [24]. In comparison with other types of OHAs, EquMet revealed the beneficial data. They were significant decreased value of mean amplitude of glycemic excursions (MAGE) [23]. These characteristics would be originated from pharmaceutical mechanism of providing twice a day.

Certain limitations exist in this case report. Medical efficacy for diabetic practice may be involved in various factors. They include the efficacy of vildagliptin, metformin, imeglimin and other OHAs. Moreover, nutritional situation such as continuing LCD should be also considered. Thus, this case will be kept for careful following up from OHA and clinical progress points of view.

In summary, 86-year-old T2D elderly was presented in current report. It described efficacy of combined OHAs, and presented some perspectives of arteriosclerosis, diabetes, pharmaceutical characteristics. It is expected that this report becomes meaningful reference for future diabetic practice.

Conflict of interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

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Abstract:

Discussion

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