Standard of Care -2025 has been just announced from American Diabetes Association (ADA) on January 1, 2025 [1]. Basic treatment principle has been known, which are nutritional therapy, exercise and pharmacotherapy for years [2]. From the history of diabetic therapy, calorie restriction (CR) was formerly the standard measure, but recently, low carbohydrate diet (LCD) was been known and prevalent by the achievement of famous doctors of Atkins and Bernstein [3,4]. After that, LCD has been in focus for health care region and medical practice, and beneficial efficacy of LCD has attracted attention [5]. In contrast, authors et al. have started LCD in Japan and developed socially and medically through the activities of Japan LCD promotion association (JLCDPA) [6]. We have presented useful three methods of practical LCD, that are super-LCD, standard-LCD and petite-LCD [7]. Each way has calorie-ratio carbohydrate amount for 12%, 26% and 40%, respectively. Nowadays, applicable educational workshops and seminars have been developed [8,9].

Concerning pharmacotherapy of T2D, various types of oral hypoglycemic agents (OHAs) have been developed and used for long years [10]. Among them, recent topic include the novel OHA named imeglimin (Twymeeg). It was introduced to actual medical practice, that shows satisfactory medical efficacy. It has an impressive and novel mechanism through the mitochondrial route [11]. In other words, imeglimin would reduce insulin resistance and stimulate insulin secretion from pancreatic beta cell [12]. For clinical efficacy of imeglimin, large international research projects were conducted as the Trials of IMeglimin for Efficacy and Safety (TIMES) 1,2 and 3 [4,13]. As various research has been more reported, additional beneficial effects of imeglimin have been found [15].

Authors and collaborators have presented lots of diabetic papers so far [14]. Among them, some T2D cases revealed clinical effect by imeglimin (Twymeeg) [15]. Their HbA1c reduction showed more than expected, because the continuation of LCD and applicable OHA would contribute. Recently, an impressive case was found for clinical benefit of imeglimin, and then general clinical progress with related perspectives are described in this report.

We have experienced an impressive T2D patient who showed remarkable improvement by LCD and imeglimin, and describe general clinical progress and related perspective in this article.

History and Physicals

Current case is 64-year-old male with T2D. He has been the professional researcher and educator in the university hospital. As his past history, he was not detected remarkable diseases before. For recent 2 years, his HbA1c value showed the borderline level about 5.6-5.8%.

As a result of health check-up in June 2024, his HbA1c showed 6.0% with positive urine glucose. For past stature, his body weight was 58kg in 20 years old, and is 68kg at present. Regarding family history, his younger brother at the age of 60 years has been treated as slowly progressive insulin-dependent diabetes mellitus (SPIDDM).

He visited diabetes department in August, 2024. His physical exam showed in the following: consciousness, general movements and vital signs were unremarkable. His head, face, lung, heart, abdomen and neurological exams were normal. negative. His physique revealed height 167cm, weight 67kg, and BMI 24.0 kg/m².

Several Exams

The electrocardiogram (ECG) showed negative findings and chest X-ray was normal. The biochemistry exams for consecutive 4 data were summarized in Table 1. Among them, GGT and Triglyceride, and HbA1c showed the improvement. The results of 75gOGTT showed delayed hyperglycemia more than 200 mg/dL with slow and low response of insulin secretion (Figure 1). The insulinogenic index (IGI) showed 0.074.

Figure 1: Response of glucose and insulin for 75gOGTT Upper: blood glucose, lower: response of IRI.

1) before imeglimini 2) 3 month after imeglimin.

In December 2024, he received 75gOGTT. The response of glucose and insulin showed improvement in comparison with those in previous GTT 3 months ago. Between both data of 75gOGTT in Sep vs Dec, the value of IGI 0-30 was 0.074 vs 0.079 with similar value, but IGI 30-60 was 0.192 vs 0.987, respectively, with remarkable change (Figure 1).

This case underwent the pulse wave velocity (PWV) exam for evaluation of arteriosclerosis. The result showed unremarkable with normal shape of pulse wave (Figure 2a), % mean artery pressure (%MAP) in lower extremities 35% (<45), and upstroke time (UT) 131-134 ms (<179). The value of ankle-brachial index (ABI) revealed 1.14/1.02 (right/left) (0.9-1.3). The value of brachial-ankle pulse wave velocity (baPWV) showed 1566/1562 cm/sec (R/L), respectively (Figure 2b). These data are within normal range of 1400-1800 cm/sec, but higher than age-related standard blue line. The red line in Figure 2b indicates the standard curve of systolic 135 mmHg cases.

Figure 2: Findings of pulse wave velocity (PWV).

a: negative findings in the lower extremities.

b: arteriosclerosis is found for current age.

He had a tendency towards mild diabetes for several years, and recently his HbA1c level was found to be elevated. As a basic treatment, he started dietary therapy. Specifically, he was advised to continue a standard low-carbohydrate diet (LCD). In addition, he started taking 2000 mg/day of imeglimin (Twymeeg) in September 2024. His weight gradually decreased, reaching 62 kg in December 2024. He achieved a weight loss of 6 kg in 4 months. In 2024, HbA1c also decreased to 5.9%, and apparent decrease data were found in the liver function and lipid markers (Table 1).

Table 1: Changes in laboratory data and GTT.

Regarding the arteriosclerosis in this case, there was no significant change in the electrocardiogram or chest X-ray, and the results of PWV showed rather developed arteriosclerosis compared to the age [17]. This is probably due to the progression of macroangiopathy caused by mild diabetes over the past few years [18]. In addition, since it is affected by hypertension, baPWV may be a useful screening tool for early detection of cardiac abnormalities in untreated hypertensive patients [19].

In this case, a 75gOGTT was performed before and 3 months after administration of Twymeeg, and clinical marker of IGI was compared. As a result, there was no change in IGI 0-30min, but IGI 30-60 min showed a 5-fold increase. We have similar previous reported 2 years ago in our same hospital. The case was a 61-year-old T2D male treated by Twymeeg in a similar progress, with comparison of IGI before and after of Twymeeg administration [20]. In the previous case, IGI 0-30 was initially 0.03 and remained unchanged at 0.03. However, the IGI 30-60 was initially 0.09, and then doubled to 0.17. In contrast, the present case showed that its value increased 5-fold, where similar phenomenon were observed.

From animal experiment of diabetic mice, imeglmin may miligate accumulation of dysfunctional mitochondria via mitophagy, and may bring preserving beta-cell function leading to improvement of glucose variability in T2D [21]. Regarding the responses of blood glucose and insulin for GTT, impressive data during administration of imeglimin were found that is currently unpublished. The protocol included the Goto-Kakizaki (GK) rat, that is a model of T2D. It was produced originally by selective inbreeding for a hyperglycemic trait. The characteristic point would be that they have insulin resistance and an insulin secretory defect. There are two groups for unmedicated GK rats (Unmed) and GK rats administered Imeglimin for 4 weeks (Imeg). They received GTT and glucose and insulin level were compared from 0-120 minutes. As a result, Imeg group showed significantly lower glucose at 20, 30, and 60 minutes compared with Unmed group. Insulin secretion levels tended to be higher at 10, 20, and 30 minutes in Imeg group, but no significant differences were observed. Further investigation of insulin and blood glucose responses for GTT will be expected.

Current case was provided only imeglimin (Twymeeg), and remarkable clinical effect was observed. By the data of international studies of TIMES 1, 2, 3, clinical responses for monotherapy and also combined therapy were reported [22]. They showed 0.46% in monotherapy, 0.56% in SU, 0.67% in biguanide, 0.57% in SGLT2-i and 0.92% in DPP4-i [23]. Current case showed remarkable benefit for weight reduction, decrease in abdominal circumference, and somewhat decrease in HbA1c. They seem to be additional effects by the continuation of LCD, imeglimin and regular lifestyle.

Some limitation may be present in this case. He has complex pathophysiology of T2D and arteriosclerosis, which may cause mal-circulation leading to clinical exacerbation [24,25]. General situation will be carefully followed with close attention.

In summary, 64-year old male case with T2D and arteriosclerosis was introduced with some discussion. It is expected that current report will become useful reference for future diabetic research and practice.

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

Funding: There was no funding received for this paper.

1. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes - 2025. 2025; 48: S207–S238.
2. Currenti W, Losavio F, Quiete S, Alanazi AM, Messina G, Polito R, et al. Comparative Evaluation of a Low-Carbohydrate Diet and a Mediterranean Diet in Overweight/Obese Patients with Type 2 Diabetes Mellitus: A 16-Week Intervention Study. Nutrients. 2023; 16: 95.
3. Atkins and Robert. Atkins' New Carbohydrate Gram Counter. M. Evans and Company.1996.
4. Bernstein RK. Dr. Bernstein's Diabetes Solution. Little, Brown and company. New York.1997.
5. Sindler D, Kastovska B, Dostal T, Cipryan L, Elavsky S. The effects of carbohydrate-restricted diet on psychological outcomes: a systematic review of randomized controlled trials. Nutr Rev. 2024; 82: 228-239.
6. Muneta T, Hayashi M, Nagai Y, Matsumoto M, Bando H, et al. Ketone Bodies in the Fetus and Newborn During Gestational Diabetes and Normal Delivery. Int J Diabetes. 2023; 5: 157-163.
7. Bando H, Ebe K. Beneficial and Convenient Method of Low Carbohydrate Diet (LCD) as Petite, Standard and Super LCD. Asp Biomed Clin Case Rep. 2023; 7: 1-4.
8. Ebe K, Wood M, Bando H. American Diabetes Association (ADA) Standards of Care-2025: Sustained Euglycemia on Low-Carbohydrate Diet (LCD). Int J Case Rep Clin Image. 2024; 6: 237.
9. Wood M, Bando H, Ebe K. American Diabetes Association Standards of Care 2025: New Recommendations for Diabetes Self-Management Education and Support. Int J Endocrinol Diabetes. 2024; 7: 181.
10. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes - 2025. Diabetes Care Decr. 2024; 48: S181-S206
11. Yanai H, Adachi H, Hakoshima M, Katsuyama H. Glucose-Lowering Effects of Imeglimin and Its Possible Beneficial Effects on Diabetic Complications. Biology (Basel). 2023; 12: 726.
12. Bando H. Dual action mechanism of insulin resistance and insulin secretion by imeglimin for diabetic treatment. Diabetes Res Open J. 2022; 8: e1-e3.
13. Reilhac C, Dubourg J, Thang C, Grouin JM, Fouqueray P, Watada H. Efficacy and safety of imeglimin add-on to insulin monotherapy in Japanese patients with type 2 diabetes (TIMES 3): A randomized, double-blind, placebo-controlled phase 3 trial with a 36-week open-label extension period. Diabetes Obes Metab. 2022; 24: 838-848.
14. Kawahito A, Bando H, Kato Y, Yamashita H, Kato Y. Beneficial Recognition of Glucose Variability for Adequate Lifestyle by Continuous Glucose Monitoring (CGM). Asp Biomed Clin Case Rep. 2024; 7: 88-94.
15. Kawata T, Bando H, Kato Y, Yamashita H, Kato Y, Ogura K. Improvement of HbA1c, Weight and Fatty Liver by Short Treatment of Imeglimin (Twymeeg). Asp Biomed Clin Case Rep. 2024; 7: 30-35.
16. General Assembly of the World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent. 2014; 81: 14-18.
17. Wu JH, Wang R, Jia XJ, Lu N, Lu Q, Yin FZ, et al. The risk factors of early arterial stiffness in type 2 diabetes without diabetic macroangiopathy. Int J Diabetes Dev Ctries. 2024; 44: 271–277.
18. Bando H, Okada M, Iwatsuki N, Ogawa T, Sakamoto K. Parallel Improvement of HbA1c and Arteriosclerosis during Clinical Progress for Diabetic Patient. SunText Rev Endocrine Care. 2024; 4: 121.
19. Kwak S, Kim HL, In M, Lim WH, Seo JB, Kim SH, et al. Associations of Brachial-Ankle Pulse Wave Velocity With Left Ventricular Geometry and Diastolic Function in Untreated Hypertensive Patients. Front Cardiovasc Med. 2021; 8: 647491.
20. Urasaki H, Bando H, Kobayashi H, et al. Improved insulin resistance and glucose variability by super-low carbohydrate diet. Diabetes Res Open J. 2022; 8: 11-17.
21. Aoyagi K, Nishiwaki C, Nakamichi Y, Yamashita SI, Kanki T, Ohara-Imaizumi M. Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice. Sci Rep. 2024; 14: 6178.
22. Dubourg J, Fouqueray P, Thang C, Grouin JM, Ueki K. Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients with Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial. Diabetes Care. 2021; 44: 952-959.
23. Dubourg J, Fouqueray P, Quinslot D, Grouin JM, Kaku K. Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52-week, open-label, multicentre phase 3 trial. Diabetes Obes Metab. 2021; 24: 609-619.
24. Bruun K, Mortensen MB. Rethinking atherosclerotic cardiovascular disease prevention in the era of expanding therapies: could plaque stabilization reduce the need for lifelong treatments and polypharmacy? Curr Opin Cardiol. 2025; 40: 50-55.
25. Wood M, Bando H, Ebe K. Increased Saturated Fat Intake Decreases LDL-Cholesterol in Individual with Lean Mass Hyper-Responder (LMHR) Phenotype. Int J Case Rep Clin Image. 2025; 7: 238.