Factors contributing to the clinical effectiveness of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: To investigate the effect of patient characteristics on imeglimin effectiveness in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Data were pooled from two randomized, placebo-controlled, 24-week, double-blind studies of imeglimin monotherapy in Japanese adults with type 2 diabetes mellitus, with the proportion of responders (glycated hemoglobin [HbA1c] < 7.0%) and sustained responders (i.e., achieved and maintained response) in the imeglimin 1,000 mg twice daily group calculated at each visit. Patient factors significantly (P < 0.05) correlated with response were explored through multivariate logistic regression. Subgroup analyses compared the efficacy of imeglimin in patients with a HbA1c improvement less than or equal to -0.3% (early responders) versus greater than -0.3% (early non-responders) at week 4. RESULTS: A total of 38.0% of imeglimin-treated patients and 7.2% of placebo-treated patients were responders (P < 0.001, number needed to treat = 4). The proportion of sustained responders at weeks 4, 8, 12, 16 and 20 was 10.6, 19.0, 24.0, 25.7 and 29.1%, respectively (>70% of responders at each visit). Improvements in HbA1c and fasting glucose were significantly greater in early responders versus early non-responders from week 4; between-group differences remained significant to week 24. Older age (odds ratio 1.09, 95% confidence interval 1.04-1.14; P < 0.001); treatment-naïve status vs previous treatment (odds ratio 3.70, 95% confidence interval 1.55-8.82; P = 0.003), and lower baseline HbA1c (odds ratio 0.06, 95% confidence interval 0.02-0.16; P < 0.001) predicted response. CONCLUSIONS: A significantly higher proportion of patients receiving imeglimin 1,000 mg twice daily monotherapy were responders versus placebo. Most (>70%) were sustained responders, suggesting that response is fairly predictable. Older age, treatment-naïve status and early treatment response significantly predicted imeglimin effectiveness.

C-peptide index at 2 h post-meal is a useful predictor of endogenous insulin secretory capacity and withdrawal from insulin therapy in subjects with type 2 diabetes.

AIMS: To evaluate the correlation between C-peptide index (CPI) at 2 h post-meal and endogenous insulin secretory capacity and to develop clinical models to predict the possibility of withdrawal from insulin therapy in patients with type 2 diabetes. METHOD: This was a single-centre retrospective study of patients with type 2 diabetes admitted to our hospital. Patients were divided into a withdrawal group (n = 72) and a non-withdrawal group (n = 75) based on whether they were able to withdraw from insulin therapy at discharge, and the correlation between CPI at 2 h after meal and diabetes-related parameters was evaluated. In addition, we created two clinical models to predict the possibility of withdrawal from insulin therapy using machine learning. RESULTS: The glycated haemoglobin values of the study participants were 87.8 ± 22.6 mmol/mo. The CPI at 2 h post-meal was 1.93 ± 1.28 in the non-withdrawal group and 2.97 ± 2.07 in the withdrawal group (p < 0.001). CPI at 2 h post-meal was an independent predictor of withdrawal from insulin therapy. In addition, CPI at 2 h post-meal was a better predictor than fasting CPI. Six factors associated with insulin therapy withdrawal (age, duration of diabetes, creatinine, alanine aminotransferase, insulin therapy until hospitalization, and CPI at 2 h post-meal) were used to generate two clinical models by machine learning. The accuracy of the generated clinical models ranged from 78.3% to 82.6%. CONCLUSION: The CPI at 2 h post-meal is a clinically useful measure of endogenous insulin secretory capacity under non-fasting conditions.

Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice. METHOD: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated. RESULTS: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. CONCLUSION: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.

Clinical findings of acute necrotizing esophagitis complicated by diabetic ketoacidosis.

Acute necrotizing esophagitis (ANE) is a rare and potentially life-threatening complication of diabetic ketoacidosis (DKA). While its association with DKA is established, specific clinical characteristics that predict ANE in DKA patients remain less understood. This study aimed to identify these characteristics by analyzing data from 30 DKA patients admitted from January 2018 to September 2022. Seven patients in this study presented with ANE, forming the ANE group. The remaining 23 constituted the non-ANE group. We compared the clinical parameters and computed tomography (CT) between the groups. The mean age of participants was 57.7 ± 20.4 years, and their mean HbA1c was 11.1 ± 3.3%. Notably, ethanol intake was significantly higher in the ANE group (44.4 ± 25.4 g/day) compared to the non-ANE group (6.8 ± 14.0 g/day; p = 0.013). Additionally, sodium-glucose transport protein 2 inhibitor use was significantly more prevalent in the ANE group (p = 0.013). Gastrointestinal symptoms were also significantly more pronounced in the ANE group, with vomiting occurring in 85.7% of patients compared to only 13.0% in the non-ANE group. Admission CT scans revealed further distinguishing features, with the ANE group showing significantly higher rates of esophageal wall thickening, intra-esophageal effusion, and calcification of the celiac artery origin (p < 0.0001, 0.0038, 0.0038, respectively). In conclusion, our study suggests that heavy alcohol consumption and strong gastrointestinal symptoms in DKA patients warrant a heightened suspicion of ANE. Early consideration of CT or upper gastrointestinal endoscopy is recommended in such cases.

The impact of grip strength, waist circumference, and body mass index on Hemoglobin A1c value: Cross-sectional study using outpatient clinical data in Japanese elderly patients with type 2 diabetes mellitus.

AIM: Grip strength (GS) as a surrogate for muscular strength, waist circumference (WC) as a surrogate marker of visceral fat, and body mass index (BMI) as a surrogate marker of obesity should also be considered markers for the management of risks associated with type 2 diabetes mellitus (T2DM). However, in terms of the management of T2DM in elderly patients, the accentuated heterogeneity of sarcopenic change might modify the associations between those factors and glycemic control. In this cross-sectional study, we aimed to clarify the impact of GS, WC, and BMI on hemoglobin A1c (HbA1c) in elderly Japanese patients with T2DM. METHODS: GS, WC, and BMI were measured in 327 patients. Odds ratios (ORs) and 95% confidence intervals (CIs) for good glycemic control (HbA1c < 7.0%) were investigated to analyze the three variables as numerical values by dividing them into tertiles. All results were expressed after adjustment was made for the confounders of age, sex, and number of diabetes medications being used by the study participants. RESULTS: The ORs of GS, WC, and BMI for well-controlled HbA1c were 1.056 (95% CI, 1.016-1.098), 0.986 (95% CI, 0.960-1.013), and 1.032 (95% CI, 0.959-1.111), respectively. The OR of 3.726 (95% CI, 1.831-7.581) in the high tertile for GS was significantly higher than the OR in the low tertile, and no differences were observed among the tertiles for WC and BMI. CONCLUSIONS: Based on that result, GS was found to have more potential as an effective marker of glycemic control than WC or BMI among elderly Japanese patients with T2DM. Geriatr Gerontol Int 2024; 24: 410-414.

Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ.

BACKGROUND: Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic ß-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). METHODS: ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. RESULTS: Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. CONCLUSIONS: Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

The impact of handgrip strength and waist circumference on glycemic control: Prospective, observational study using outpatient clinical data in Japanese patients with type 2 diabetes mellitus.

INTRODUCTION: Loss of muscle mass and the accumulation of visceral fat are known risk factors for the deterioration of glycemic control in type 2 diabetes mellitus. This study looked at the effects of such factors on glycemic control in Japanese patients with type 2 diabetes mellitus in the form of handgrip strength (HGS) and waist circumference (WC). MATERIALS AND METHODS: In this prospective, observational study, 233 patients with type 2 diabetes mellitus and a HbA1c level of ≥7.0% were followed for around 1 year, during which time they were studied for an understanding of the association between handgrip strength, waist circumference, and glycemic control (HbA1c <7.0%). Hazard ratios (HRs) and 95% confidence intervals (CIs) for glycemic control improvement by Cox hazards models were analyzed for handgrip strength and waist circumference. RESULTS: Compared with the low tertile, patients in the middle and high tertiles of handgrip strength when adjustment was carried out for waist circumference were 2.117 (1.142-3.924) and 4.670 (2.526-8.632), respectively. The HRs of patients in the middle and high tertiles of WC when adjustment was made for HGS were 0.442 (0.269-0.725) and 0.339 (0.191-0.604), respectively. Within the low, middle, and high HGS tertiles, the HRs for WC were 0.863 (0.797-0.934), 0.940 (0.899-0.982), and 1.009 (0.984-1.035), respectively, although the HRs for HGS within each WC tertile remained significant. CONCLUSIONS: Handgrip strength and waist circumference demonstrated independent associations for glycemic control, but the effect of waist circumference appeared to be at least partially canceled out by increased handgrip strength. The data suggest that handgrip strength might help to mitigate the negative impact of waist circumference on glycemic control.

Usefulness of Once-Weekly GLP-1 Receptor Agonist Semaglutide on Glycemic Control in Subjects with Type 2 Diabetes Mellitus: Switching from the Same Class Dulaglutide in a Retrospective Observation Study.

Recently, the development of once-weekly incretin-based injections dulaglutide and semaglutide has drawn a great deal of attention. This study is aimed at comparing the efficacy of once-weekly GLP-1 receptor activator (GLP-1RA) dulaglutide and semaglutide on glycemic control and several metabolic parameters in patients with type 2 diabetes mellitus. We compared various clinical parameters between before and after switching from dulaglutide to semaglutide in "study 1" (pre-post comparison) and set the control group using propensity score matching method in "study 2." In "study 1," six months after the switching, HbA1c was significantly reduced from 8.2% to 7.6% and body mass index was also decreased from 30.4 kg/m2 to 30.0 kg/m2. Such effects were more pronounced in subjects whose glycemic control was poor. In "study 2," after 1 : 1 propensity score matching, glycemic control and body weight management were improved in the switching group compared with the dulaglutide continuation group. In this study including obese subjects with poor glycemic control, switching dulaglutide to semaglutide showed more beneficial effects on both glycemic and weight control irrespective of age, body weight, and diabetes duration. Therefore, we should bear in mind that it would be better to start using a relatively new once-weekly GLP-1RA semaglutide in clinical practice, especially in obese subjects with poor glycemic control with other GLP-1RAs.

Pathology of Ketoacidosis in Emergency of Diabetic Ketoacidosis and Alcoholic Ketoacidosis: A Retrospective Study.

This study is aimed at examining which factors are useful for the diagnosis and distinction of ketoacidosis. We recruited 21 diabetic ketoacidosis (DKA) and alcoholic ketoacidosis (AKA) patients hospitalized in Kawasaki Medical School General Medical Center from April 2015 to March 2021. Almost all patients in this study were brought to the emergency room in a coma and hospitalized. All patients underwent blood gas aspiration and laboratory tests. We evaluated the difference in diagnosis markers in emergencies between DKA and alcoholic ketoacidosis AKA. Compared to AKA patients, DKA patients had statistically higher values of serum acetoacetic acid and lower values of serum lactate, arterial blood pH, and base excess. In contrast, total ketone bodies, ß-hydroxybutyric acid, and ß-hydroxybutyric acid/acetoacetic acid ratio in serum did not differ between the two patient groups. It was shown that evaluation of each pathology such as low body weight, diabetes, liver dysfunction, and dehydration was important. It is important to perform differential diagnosis for taking medical histories such as insulin deficiency, alcohol abuse, or starvation as the etiology in Japanese subjects with DKA or AKA. Moreover, it is important to precisely comprehend the pathology of dehydration and alcoholic metabolism which would lead to appropriate treatment for DKA and AKA.

Reductions in liver enzymes are associated with anti-hyperglycaemic and anti-obesity effects of tofogliflozin in people with type 2 diabetes: Post-hoc analyses.

AIMS: How the pathology of type 2 diabetes (T2D), including hyperglycaemia and obesity, affects liver enzymes has not been clinically demonstrated. Thus, we compared time courses of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) with those of fasting plasma glucose (FPG) and body weight (BW) during treatment with the SGLT2 inhibitor tofogliflozin for T2D. MATERIALS AND METHODS: We post-hoc analysed preexisting data on 1046 people with T2D administered tofogliflozin or placebo for 24 weeks in four tofogliflozin studies. First, time courses of percent changes in variables during the intervention were analysed using a mixed effect model to explore the similarity of the time courses and to evaluate time-treatment interactions. Second, clinical factors related to the percent changes in GGT and ALT were clarified using multivariate analyses. RESULTS: GGT levels and FPG values rapidly and significantly decreased via tofogliflozin as early as week 4, with decreases maintained until week 24. Conversely, BW and ALT decreased progressively until week 24. Time courses of FPG (p = .365, time-treatment interaction) and GGT (p = .510) reductions were parallel between tofogliflozin and placebo from weeks 4 to 24, while BW and ALT reductions (p < .001, respectively) were not. Reductions in GGT at week 24 were associated with reductions in FPG and BW at week 24, whereas ALT reductions were only associated with reductions in BW. CONCLUSIONS: Reductions in GGT and ALT were associated with the anti-hyperglycaemic and anti-obesity effects of tofogliflozin, respectively, in people with T2D. Therefore, GGT and ALT may be surrogate markers for hyperglycaemia and obesity in T2D.

Structural and functional differences in auto-antibody positive compared to auto-antibody negative hypothyroid patients with chronic thyroiditis.

Most primary hypothyroidism in adults is caused by chronic thyroiditis. Autoantibodies such as anti-thyroglobulin antibody (TgAb) and anti-thyroid peroxidase antibody (TPOAb) are involved in the pathogenesis of chronic thyroiditis. On the other hand, the clinical features of antibody-negative hypothyroidism are not clear. In this study, we aimed to determine the prevalence of thyroid-related autoantibodies in patients with primary hypothyroidism and to evaluate the differences in thyroid structure between antibody-positive and antibody-negative hypothyroidism. Among 804 patients who attended Kawasaki Medical School Hospital for thyroid hormone abnormalities or thyroid gland enlargement between January 1, 2010 and December 31, 2021, 237 patients with primary hypothyroidism who underwent thyroid antibody measurement and thyroid ultrasound examination were included. Participants were divided into groups according to antibody positivity/negativity, and differences in antibody positivity and thyroid structure were evaluated. In this study, 34.6% of patients had antibody-negative hypothyroidism. The positive rate of each antibody was 62.0% for TgAb and 49.4% for TPOAb. The participants with antibody-positive hypothyroidism had significantly larger thyroid gland on thyroid ultrasound examination (p < 0.05). Thyroid-stimulating hormone was significantly higher in participants with antibody-positive compared to antibody-negative hypothyroidism. The present study reveals a positive rate of thyroid-related autoantibodies in patients with hypothyroidism and the differences in thyroid structure between patients with and without antibodies. This study clearly show that the prevalence of antibody-negative chronic thyroiditis is quite high among hypothyroid patients, although this point needs confirmation by further investigations. The data in this study would be useful for the treatment of antibody-negative hypothyroid patients.

Comprehensive Search for GPCR Compounds which Can Enhance MafA and/or PDX-1 Expression Levels Using a Small Molecule Compound Library.

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as ß-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic ß-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of ß-cell glucose toxicity in the future.

Efficacy, safety and tolerability of imeglimin in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

AIMS/INTRODUCTION: This meta-analysis aimed to evaluate the efficacy and safety/tolerability of imeglimin, a novel oral antihyperglycemic agent, administered as monotherapy and adjunctive therapy in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Parallel-group randomized controlled trials comparing imeglimin with placebo in adults with type 2 diabetes mellitus were included. Risk ratios or weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated using random effects models. The primary outcome for efficacy was the change in glycated hemoglobin (HbA1c). Secondary outcomes included other efficacy-related outcomes, specific adverse events, and changes in body weight and lipid parameters. RESULTS: Nine randomized controlled trials (n = 1,655) were included. When analyzed by dose, there was a significant difference in glycated hemoglobin (%) between imeglimin monotherapy and placebo at doses >1,000 mg twice daily (1,000 mg: studies N = 3, patients n = 517, WMD = -0.714, P < 0.001; 1,500 mg: N = 5, n = 448, WMD = -0.531, P = 0.020; 2,000 mg: N = 1, n = 149, WMD = -0.450, P = 0.005). Imeglimin adjunctive therapy significantly improved glycated hemoglobin over placebo at doses of 1,000 mg (N = 1, n = 214, WMD = -0.600, P < 0.001) and 1,500 mg (N = 2, n = 324, WMD = -0.576, P < 0.001). Subgroup analysis of the primary outcome showed that imeglimin was effective regardless of chronic kidney disease category, with studies carried out in Japan and in patients with lower body mass index showing a trend toward improved imeglimin efficacy. There were no significant differences between imeglimin and placebo in the risk of all-cause discontinuation and the proportion of patients who presented with at least one adverse event. CONCLUSIONS: Imeglimin is efficacious, safe, and well tolerated as monotherapy and adjunctive therapy.

Comparison of clinical efficacy and safety of weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in Japanese patients with type 2 diabetes: Randomized, parallel-group, multicentre, open-label trial (COMING study).

AIM: To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. METHODS: In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. RESULTS: HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. CONCLUSIONS: This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

Simple standing test without furosemide is useful in the diagnosis of primary aldosteronism.

Primary aldosteronism (PA) is a well-known cause of secondary hypertension. We have long performed the simple standing test in patients with PA. On the other hand, there are few reports on the usefulness of the simple standing test in PA. This study is a single-center, retrospective, observational study. A total of 173 patients with hypertension or adrenal tumor admitted to Kawasaki Medical School were included. Eighty patients who met the exclusion criteria were excluded, and 31 patients without PA (non-PA), 26 patients with unilateral PA, and 36 patients with bilateral PA were included in the study. The simple standing test was performed after 120 min of standing or sitting followed, and the aldosterone/renin ratio (ARR) and percentage of increase plasma aldosterone concentration (%increase of PAC) was calculated. The mean ARR in the simple standing test in unilateral PA (1143 (528-2200)) and bilateral PA subjects (521 (374-765)) were significantly higher compared to non-PA subjects (152 (102-240)) (p < 0.0001, p = 0.0013, respectively). The percentage increase of PAC after standing loading was significantly lower in unilateral PA subjects (110 (96-140)) compared to non-PA subjects (187 (155-244)) (p = 0.0003), with no difference between non-PA and bilateral PA subjects (p = 0.99). The cutoff value of the ARR in the simple standing test for diagnosis of PA in this study was 364 (AUC = 0.948, sensitivity = 83.8%, specificity = 93.5%, false positive rate = 3.7%, false negative rate = 25.6%, p < 0.001), which was not inferior to the diagnostic performance of the captopril loading test. The diagnostic performance of the simple standing test for PA was not inferior to that of the captopril loading test. The percentage increase of PAC in unilateral PA subjects was significantly lower compared to bilateral PA subjects. These results demonstrate the usefulness of the simple standing test, which can be performed simultaneously with general screening tests of PA.

Immune checkpoint inhibitor-induced hypothyroidism predicts treatment response in Japanese subjects.

Background: Immune checkpoint inhibitors (ICIs) cause a variety of immune-related adverse events (irAEs). Among them, thyroid dysfunction is most frequently observed. Patients with irAEs have higher survival rates than those without irAEs, but there is no certainty as to whether the degree of thyroid dysfunction is associated with treatment response or survival with ICIs. Method: This is a single-center, retrospective, observational study. The study included 466 patients who received ICI at Kawasaki Medical School Hospital from September 1, 2014, to May 31, 2022 and evaluated the degree of abnormal thyroid function and survival and remission rates after treatment with ICIs. Primary hypothyroidism of less than 10 µIU/mL TSH was classified as grade 1, and primary hypothyroidism requiring more than 10 µIU/mL TSH or levothyroxine as grade 2-4. Result: The mean age of the study participants was 68.2 ± 10.3 years, and the percentage of male participants was 72.6%. The frequency of ICI-induced thyroid dysfunction in the study participants was 28.2%. TSH levels were significantly higher in Grade 1 and Grades 2-4 when treated with ICI compared to NTF (p<0.0001). The survival rate at 1 year after ICI administration was significantly higher with 64.9% for grade 1 and 88.9% for grades 2-4 compared to 52.1% for NTF (p<0.0001). Cancer stage at the time of ICI administration did not differ among the groups (p=0.68). Nevertheless, the remission rate assessed by RECIST criteria was significantly higher in grades 2-4 compared to NTF (p<0.0001). Conclusion: ICI-induced thyroid dysfunction was significantly correlated with survival, mean observation time, and treatment remission rate. It is important to monitor thyroid hormone levels regularly in patients receiving ICIs.

Case Report: Repeated esophageal obstruction in a patient with type 3C diabetes mellitus.

Although diabetic neuropathy is a well-known cause of gastrointestinal motility disorders, it is rare that diabetic neuropathy brings about esophageal obstruction. Here, we report a case with Type 3C diabetes mellitus (DM) lasting over 15 years and repeated esophageal obstruction resulting in chicken-meat-induced esophageal obstruction and candidiasis. This case highlights the importance of management of DM to prevent the development of complications such as diabetic neuropathy and associated symptoms.

Effect of patient characteristics on the efficacy and safety of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus: A post-hoc analysis of two randomized, placebo-controlled trials.

AIMS/INTRODUCTION: Substantial variability in demographic and clinical characteristics exists among patients with type 2 diabetes mellitus, which may impact treatment. This post-hoc analysis evaluated the efficacy and safety of imeglimin 1,000 mg twice daily (BID) monotherapy in type 2 diabetes mellitus patients according to demographic and clinical characteristics. MATERIALS AND METHODS: Data were pooled from two placebo-controlled, 24 week, randomized, double-blind studies in adults with type 2 diabetes mellitus. Outcomes (least squares mean [LSM] change in HbA1c from baseline to week 24, and safety) were analyzed according to subgroups based on demographics, clinical characteristics, and comorbidities. RESULTS: The difference in LSM change in HbA1c from baseline to week 24 was statistically significant for imeglimin vs placebo in all patient subgroups analyzed (P < 0.05 each), including demographics (age, body mass index), clinical characteristics (duration of type 2 diabetes mellitus, chronic kidney disease [CKD] stage, and prior medication use) and comorbidities (hypertension, dyslipidemia, risk of hepatic fibrosis and liver function parameter status). A statistically significant separation from placebo in HbA1c was observed at week 4 and maintained through week 24. No new safety concerns were identified with imeglimin in any patient subpopulations. CONCLUSIONS: The efficacy and safety of imeglimin was demonstrated across patient subgroups, irrespective of baseline demographic and clinical characteristics. Our findings confirm the efficacy and safety of imeglimin across a broad spectrum of patients with type 2 diabetes mellitus.

Efficacy and safety of pemafibrate in patients with hypertriglyceridemia in clinical settings: A retrospective study.

BACKGROUND AND AIMS: Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings. METHODS AND RESULTS: We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved. CONCLUSION: In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.

Safety and effectiveness of empagliflozin in clinical practice as monotherapy or with other glucose-lowering drugs in Japanese patients with type 2 diabetes: subgroup analysis of a 3-year post-marketing surveillance study.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin are increasingly prescribed as initial glucose-lowering drugs for type 2 diabetes (T2D), based on their cardiorenal benefits. However, information regarding the safety and the effectiveness of monotherapy with SGLT2 inhibitors in routine clinical practice is limited. RESEARCH DESIGN AND METHODS: We analyzed data from a prospective, 3-year, post-marketing surveillance study of empagliflozin in Japan. We evaluated adverse drug reactions (ADRs) (the primary endpoint) and glycemic effectiveness with or without other glucose-lowering drugs. RESULTS: 7931 T2D patients were treated with empagliflozin. At baseline, mean age was 58.7 years, 63.0% were male, and 1835 (23.14%) were not receiving other glucose-lowering drugs. ADRs occurred in 141 (7.68%) and 875 (14.62%) patients initiating empagliflozin as monotherapy or combination therapy, respectively. The most frequent ADRs of special interest with empagliflozin as monotherapy or combination therapy were urinary tract infections (0.82% and 1.14% of patients, respectively) and excessive/frequent urination (0.65%, 1.50%). At last observation, glycated hemoglobin level was reduced by a mean of 0.78% with empagliflozin monotherapy (from baseline mean of 7.55%) and 0.74% with combination therapy (baseline 8.16%). CONCLUSIONS: Empagliflozin is well tolerated and effective in clinical practice in Japan when initiated as monotherapy or combination therapy.