Detail Measurement of Pre-Prandial and Post-Prandial Blood Glucose during Imeglimin (Twymeeg) Treatment

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Introduction
Type 2 diabetes (T2D) is one of the most critical diseases affecting both developed and developing countries.HbA1c, pre-prandial glucose, and postprandial glucose are important factors for screening T2D [1].Additionally, the diagnosis, treatment, and monitoring of clinical progress in T2D cases are essential for making appropriate judgments [2].Therefore, diabetes care should be provided adequately in various situations worldwide [3] [4].Along with the standard method, adequate management should be provided for T2D patients [5].
Recently, effective oral hypoglycemic agents (OHAs) have been introduced to diabetic practice [6].They developed better glucose variability associated with improved safety situation such as dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter 2 inhibitor (SGLT2i).Among them, latest focus would be imeglimin (Twymeeg) as the novel OHA [7,8].It has the similar molecule for metformin, which has been the first-line agent for T2D [9].Imeglimin has been known for its clinical efficacy for monotherapy and also add-on therapy.Some large investigation was reported, that are Trials of IMeglimin for Efficacy and Safety (TIMES) [10].They include TIMES 1, 2 and 3 [11].From pharmaco-physiological point of view, imeglimin has dual effects for reducing insulin resistance and also increasing insulin secretion ability through various mechanism of mitochondria in the cell.
Authors and colleagues have developed diabetic team and continued diabetic practice and research so far [12].Their area includes low carbohydrate diet (LCD), Carbo-70g loading test, continuous glucose monitoring (CGM) associated with several OHA reports [13].We experienced an impressive T2D case who could check pre-prandial and post-prandial blood glucose perfectly for months.Consequently, the general progress and some perspectives are described concerning HbA1c and glucose variability in this article.

Presentation of Cases Medical History:
The patient is a 58-year-old female who has been working as a hospital nurse for many years.She had undergone three operations for posterior longitudinal ligament ossification about 10 years ago and occasionally took analgesic medication to manage the pain, including pregabalin, mecobalamin, rebamipide, esomeprazole magnesium hydrate, and azilsartan/amlodipine combined drug.Her medical history includes hypertension and posterior longitudinal ligament ossification.In early September 2022, she began experiencing slight nausea, dizziness, and a general feeling of unwellness.On September 12, she developed dyspnea, cold sweating, dizziness, and cold sensations in her hands and fingers.A laboratory blood test was conducted, which revealed a severe diabetic condition, with HbA1c at 11.1% and postprandial blood glucose at 395 mg/dL.She was diagnosed with type 2 diabetes (T2D).

Physicals and Various Exams:
On September 12, 2022, the patient's physical examination showed that she was alert and able to communicate clearly.Her vital signs were as follows: blood pressure was 150/96 mmHg, pulse rate was 84 beats per minute, oxygen saturation was 99%, and her respiration and body temperature were normal.There were no remarkable findings in her lung, heart, abdomen, and neurological examination.Additionally, her neurological tests were negative.Her current status showed no abnormalities in her lung, chest, and abdomen, and her neurological findings were intact.In terms of her body weight, she weighed 81kg ten years ago, and 79 kg in Sept 2022, with a gradual reduction of about 2kg.Her physique was measured as 153 cm in height and 79kg in weight, with a BMI of 33.7 kg/m 2 .
The data of the laboratory examination were in the following: HbA1c

Clinical Progress:
She was pointed out to have heavy level T2D on Sept 12, 2022 and then she was explained to start low carbohydrate diet (LCD) immediately and continue three months and to take Metformin 500 mg/day.Furthermore, she began to check pre-prandial and post-prandial blood glucose every day (Table -1 treatment.The combination of LCD, Metformin and Twymeeg was continued.Changes in HbA1c value showed 9.0% in 5 weeks, 6.7 % in 10 weeks and 5.9% in 15 weeks.As regards to the body weight, her weight was decreased from 79kg to 77kg for 4 months (Fig- 1).She did not suffer from any symptoms of gastrointestinal adverse effects (GIAEs) of Twymeeg.

Ethical Standards
The present report adheres to the ethical guidelines outlined in the Declaration of Helsinki and includes several commentaries on the protection of personal information.The principles of ethical clinical practice and research involving human subjects were followed, as outlined by guidelines proposed by the Japanese

Discussion
Concerning this case, three characteristic points are present in the following.They are i) Twimeeg was effective for improving glucose variability, ii) the case continued to check pre-prandial and post-prandial blood glucose vigorously, and iii) the relationship between blood sugar and HbA1c values becomes impressive matters, which are discussed in this order.
First, a 59-year-old female with underlying obesity developed T2D in September 2022.The diabetic condition was rapidly improved by LCD and administration of Twimeeg.About 10 years ago, she had multiple operations of ossification of the posterior longitudinal ligaments [14].This past history may be related with the persistence of obesity [15,16].Her body weight was slightly reduced due to the prescription of Twimeeg and LCD.Currently, her diabetic condition is stable, and it is expected that she will maintain her weight by continuing LCD in the future.
Second, she had been working as a hospital nurse for many years and had a thorough understanding and treatment of diabetes.Her LCD method was successfully continued at super-LCD [17].There are three levels of LCD, which are super-, standard-and petite-, in which carbohydrate content is 12%, 26%, and 40%, respectively [18].Furthermore, blood glucose was measured for pre-prandial and postprandial timing in each meal.She could continue for long period.According to her complete glucose measurement, important detail data for glucose variability were obtained.Consequently, this situation contributes the following third perspective.
Third, her blood glucose has been normalized in early period.At 5 weeks, HbA1c was 9.0%, but pre-prandial and post-prandial glucose was already normalized.During 5-15 weeks, HbA1c decreased to 9.0, 6.7 and 5.9%, while her glucose control was perfect.The same level of HbA1c 5.9% persisted for 15-20 weeks.Judging from these data, linearly decreasing HbA1c value may suggest the detail relationship of HbA1c and glucose variability [19].Such perspectives are described in the following.
The relationship between HbA1c and blood glucose has been known as Nathan's equation [20].That is [eAG (mg/dl) = (28.7 x HbA1c) -46.7, r 2 =0.84].Various studies have been continued for correlation of HbA1c, estimated average glucose (eAG) and fasting plasma glucose (FPG).Cases (n=1285) were analyzed for 3 groups of normal, high HbA1c and HbE, which were divided into subgroups (HbA1c ≤ 7%, or HbA1c >7%).As a result, strong correlation was found in these studies [21].Basic understanding has been known that HbA1c indicates average blood glucose value over last 120 days [19].For more correct data, detail glucose measurements for both of lower overnight period and postprandial peaks would be required.Some investigations showed that large ratio of HbA1c variation may be due to CGM glucose averages.
From the recent report, relationship of HbA1c and glycated albumin (GA) has been found [22].Data set (n=2461) were analyzed from 731 cases, and lots of cases were excluded such as low Hb, Alb or eGFR and patients with hemodialysis, malignancy, pregnancy, chronic liver disease, hyperthyroidism and steroid treatment.Consequently, 284 data set were analyzed.As a result, equation became that HbA1c = 0.216 × GA + 2.978 (R 2 = 0.5882, P < 0.001).
Individual variations are present in glucose uptake and RBC turnover, and a kinetic model was reported to show the different relationship of HbA1c and glucose level [23].As RBC turnover rate is 0.94 % per day, the standard RBC lifespan would be 106 days.For applying these data, laboratory HbA1c can be adjusted for standard RBC lifespan.It will bring more accurate biomarker of hyperglycemia associated with HbA1c [24].For type 1 diabetes (T1D) and T2D, RBC lifespan was investigated [25].Laboratory HbA1c and CGM data were evaluated for 6 months.The cases were 51 T1D and 80 T2D patients.As a result, mean (median) RBC lifespan was 94 (100) days in T1D, and 92 (100) days in T2D.For the detail data, mean (median) of absolute difference of adjusted HbA1c (a-HbA1c) and laboratory HbA1c (l-HbA1c) were 1.0 (0.4) % in T1D, and 1.4(0.5)% in T2D cases.Thus, T2D showed a little higher value.When RBC lifespan is less than 80 days, it showed 2% lower l-HbA1c than adjusted HbA1c.Such situation may bring miss-reading of accurate HbA1c value.On the other hand, when RBC lifespan is more than 130 days, it brings higher l-HbA1c than a-HbA1c [25].
Certain limitation may be present in this report.Current case is a nurse who could continue LCD and measurement of pre-prandial and post-prandial blood glucose perfectly.From this situation, detail relationship of HbA1c and blood glucose can be investigated.However, glucose variability is influenced by various factors, such as obesity, insulin secretion, insulin resistance, and so on.Then, further research and case accumulation would be required in the future.
In summary, this case report describes a 58-year-old female with T2D who carefully monitored her pre-and post-prandial glucose levels.Treatment with LCD and Twymeeg was successful in improving glucose variability, and the relationship between HbA1c and glucose variability was discussed.These findings provide valuable insights for future diabetic research.