Type 2 Diabetes (T2D) Female Case with Clinical Efficacy of Vildaglipin, Metformin and Imeglimin

Bando H, Iwatsuki N, Okada M, Ogawa T, Sakamoto K and Hatakeyama S

Published on: 2024-05-06

Abstract

The current case is a 63-year-old female patient with Type 2 Diabetes (T2D) who was treated for oral hypoglycemic agents (OHAs). During 2019–2020, she was diagnosed with Bowen’s disease with skin problems in the inguinal region and a urinary tract infection (UTI). Then she discontinued SGLT-2i. In April 2022, HbA1c was increased to 8.1%, and then vildagliptin/metformin (EquMet) was begun with clinical effect. After HbA1c exacerbation in September 2022, imeglimin (Twymeeg) was added with a satisfactory effect of a 1.4% decrease for 10 months. Clinical progress will be followed up for related OHAs and other various factors with close attention.

Keywords

Oral Hypoglycemic Agents (OHAs); Bowen’s disease; Vildagliptin/metformin (EquMet); Imeglimin (Twymeeg); Japan LCD Promotion Asssociation (JLCDPA)

Introduction

For decades, type 2 diabetes (T2D) has been a crucial disease in light of medical, social, and economic problems. The American Diabetes Association (ADA) has announced the latest standard diabetic care measure in January 2024 [1]. The principle of adequate treatment for T2D would be mainly three measures: exercise/physical therapy, proper exercise, and medication of oral hypoglycemic agents (OHAs), insulin, and injectable agents.

As to exercise, adequate physical activity would be recommended as a routine method every day, where both aerobic training (AT) and resistance training (RT) are included [2,3]. Regarding diet therapy, the previous method was known as calorie restriction (CR). In recent years, however, a low-carbohydrate diet (LCD) has been evaluated as effective. LCD has been initiated in the medical care and health care fields by Atkins and Bernstein [4,5]. Successively, authors’ et al. began various educational LCD activities in Japan through the Japan LCD Promotion Association (JLCDPA) [6]. JLCDPA has presented three useful methods so far. They are petite LCD, standard LCD, and super LCD, where the carbo amount ratio would be 40%, 26%, and 12%, respectively [7]. The understanding of LCD has been more prevalent, and it will have beneficial effects for diabetes, obesity, and metabolic syndrome [8]. Such standard information about blood glucose and carbo count has been widely known [9].

Concerning pharmacological treatment for T2D, several novel OHAs have been developed and introduced in actual clinical practice. They include some combinations of OHAs, such as DPP4-i and metformin, in which vildagliptin (Equa) and metformin (Metgluco) are combined into vildagliptin/metformin (EquMet) [10]. These combined agents seem to be useful and clinically effective [11]. Furthermore, a recent topic includes the novel OHA as Imeglimin (Twymeeg). It attracts attention for its clinical functioning mechanism via the mitochondria pathway [12,13].

During our clinical practice and research, we experienced a meaningful female patient with T2D and Bowen’s disease, who revealed clinical improvement with EquMet and Twymeeg. Her general clinical progress and related perspectives will be described in this article.

Medical History

The current case is a 63-year-old female patient with T2D and other medical problems. She has been treated for T2D, or dyslipidemia, for about 8 years. She has been treated for some kinds of OHAs so far. During 2019–2020, her glucose variability remained rather stable, with HbA1c of about 6.8%. At that time, she was provided empagliflozin (Jardiance 10mg and 25 mg) as an SGLT-2i agent, but she had suffered from erythema in the inguinal region and a urinary tract infection. She visited dermatology in the university hospital, and then she received a skin biopsy. She was diagnosed with Bowen’s disease and skin problems. Then, she was advised to discontinue the SGLT-2i agent.

After 2021, her HbA1c became rather unstable, at more than 8% (Figure 1). In April 2022, HbA1c was increased to 8.1%, and then OHAs were changed to vildagliptin plus metformin (Equa plus Metformin, a combined agent of EquMet). After that, HbA1c decreased to 7.7% for 4 months. However, her HbA1c increased again to 8.8% in September 2022. Consequently, she was provided imeglimin (Twymeeg) 2000mg a day. As a result, HbA1c gradually decreased to 7.4% after about 10 months. She did not complain of skin problems or other adverse effects, such as gastroesophageal reflux disease (GERD).

Figure 1: Clinical Progress of the Case.

Physical Exam and Various Exams

For physical examination, she showed normal consciousness, speech, and behaviors. Her vitals, chest, and abdomen showed negative findings. The physique showed 141cm, 42.9 kg, and a BMI of 21.6 kg/m². As her usual lifestyle, she has been working regularly as hospital staff every day for years. The biochemical changes for 4 years are summarized in Table 1, in which remarkable abnormalities were not detected. Chest X-ray showed unremarkable, and ECG revealed within normal limit.

Table 1: Changes in Laboratory Data.

		2020	2021		2022	2023	Units
		Feb	Apr	Oct	Mar	Apr	Units
Liver	AST	13	14	21	19	13	(U/L)
	ALT	13	12	13	13	8	(U/L)
	GGT	18	12	13	14	11	(U/L)
Lipids	HDL	-	56	60	63	-	(mg/dL)
	LDL	-	91	83	99	-	(mg/dL)
	TG	-	65	69	66	-	(mg/dL)
Renal	BUN	23	14	18	15	20	(mg/dL)
	Cre	0.63	0.59	0.68	0.74	0.54	(mg/dL)
	UA	5.1	4.4	4.8	5.0	4.1	(mg/dL)
CBC	WBC	73	61	55	58	-	(x10*2/μL)
	RBC	523	476	461	495	-	(x10*4/μL)
	Hb	15.5	13.9	13.4	14.1	-	(g/dL)
	PLT	39.1	34.4	31.8	36.2	-	(x10*4/μL)

A blood pressure pulse wave test (plethysmography) was conducted (Figure 2). As a result, the cardio-ankle vascular index (CAVI) was 8.1/8.0 (-8.9) and the ankle brachial pressure index (ABI) was 1.01/1.02 (0.91–1.40) for right/left side, respectively. Blood pressure showed 127/84 mmHg in the right arm and 128/81 mmHg in the right ankle, respectively. A remarkable abnormality was not detected in the peripheral arteries of her extremities.

Figure 2: Finding of Plethysmography.

Ethical Considerations

This case study was managed according to the standard ethics for the Declaration of Helsinki [14]. In addition, some commentary was also applied from the Ethical Guidelines for Research for Humans, which are accompanied by Good Clinical Practice (GCP). The authors established an ethical committee in the hospital. Several professional staff members were included, such as the hospital director, physician, registered head nurse, pharmacist, dietician, and legal professional. The committee had enough discussion in adequate manners and concluded the agreements for the protocol. The informed consent by written document was obtained from the patient.

Discussion

In this article, the case showed some medical problems. She had previously had T2D and dyslipidemia for years, and Bowen’s disease with skin problems for recent years. During the treatment, SGLT-2i was discontinued, and after that, her diabetic variability became rather unstable in 2021 and 2022.

As a characteristic aspect, this case has Bowen’s disease in the inguinal region. She was diagnosed and treated in the dermatology department of the university hospital. There was a possibility that the SGLT-2i agent may become the trigger of Bowen’s disease, but certain evidence cannot be detected for the relationship. For middle-aged and elderly people, various skin problems with nails and hair have been observed [15]. Among them, some diseased states have a relationship with diabetes mellitus, Bowen’s disease, acanthosis, and so on [16]. As to diabetes, malignant pathology may be recognized as the common cause of death [17]. It has been known that about 1.2 folds of higher risk exist for diabetic patients. It may be the increased mean amplitude of glycemic excursions (MAGE), that will bring more oxidative stress, certain inflammation, and endothelial dysfunction. When the treatment for large MAGE is not successful, the patient will show increased amplitude glycemic variability (GV). Such a situation would cause poor outcomes with various complications [18].

Short-term blood glucose measurement and control cannot present small glycemic excursions for the diabetic patient. However, long term GV with various glycemic data can detect glycemic variability and suggest changes in HbA1c [19,20]. In addition, the development of macro-/micro-angiopathy may be supposed to be associated with the clinical progress of T2D and T1D [21]. From several previous investigations, no specific or direct relationship can be found between diabetes and the existence of Bowen’s disease [22].

The current case has been treated as T2D for years, and diabetic control has been improved by the administration of Vildagliptin/Metformin (EquMet) and Imeglimin (Twymeeg) for the past 2 years. T2D has been evaluated for adequate various OHAs so far. Among them, the combination of Metformin and dipeptidyl-peptidase 4 inhibitors (DPP4-i) has been prevalent, and the combined OHA of vildagliptin/metformin (Equa/Metgluco, EquMet) has been convenient and effective [23]. For its large clinical investigation, the vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY) study has been conducted in international areas [10]. This agent shows the benefits of twice-daily administration. This intensified medication method seems to suppress increased blood glucose during the day and night [24]. Useful medication would provide a novel paradigm shift for clinical treatment [25]. ADA and the European Association for the Study of Diabetes (EASD) include commentary about the combined therapeutic measure [23].

The current case showed HbA1c reduction from 8.8% to 7.4% for 10 months with the addition of imeglimin 2000 mg/day. The dose amount was standard, and some reports showed HbA1c reductions of about 0.5–1.0% by single administration [26,27]. In addition, add-on therapy (AOT) has been reported, where combined DPP4-i caused a decrease in HbA1c of 0.6-0.65% [27]. In the previous TIMES study, single and combined therapy with imeglimin for 1 year showed the following results [28]. As the mean HbA1c decreased, 0.46% for single administration of imeglimin, 0.85% for alfa-GI, 0.56% for sulfonyl urea, 0.70% for glinide, 0.88% for thiazolidine, 0.57% for SGLT2-i, 0.92% for DPP4-i, and 0.12% for GLP-1RA. In the TIMES 3 study, combined therapy of insulin and imeglimin showed a 0.63% decrease. As DPP-4i and GLP-1RA show a pharmacologically common pathway, clinical efficacy revealed different results of 0.92% and 0.12%. Further clinical and basic development will be expected concerning the functioning mechanism via mitochondria [29].

Certain limitations would be present in this report. The current patient has several problems and treatments for T2D, Bowen’s disease, EquMet, Twymeeg, and so on. Mutual relationships among T2D, SGLT-2i, urinary infection, and Bowen’s disease were not apparent. Clinical efficacy would come, at least in part, from OHAs, but other factors such as social, diet, exercise, and lifestyle may be involved. Some novel OHAs and combined agents have been introduced to clinical practice, and close attention will be required in the future.

In conclusion, a 63-year-old female with T2D showed improvement in glucose variability with EquMet and Twymeeg. It is expected that this article will become a 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.

International Journal of Endocrinology and Diabetes