Clinical epidemiology of the endoscopic, laparoscopic, and surgical resection of malignant gastric tumors in Japan, 2014-2021: a retrospective study using open data from a national claims database.

BACKGROUND: Gastric cancer is a common malignancy with a high incidence in East Asia. Gastric resection ranges from endoscopic resection to open total gastrectomy. However, nationwide data are lacking. METHODS: This observational study analyzed data from the publicly accessible National Database of Health Insurance Claims and Specific Health Checkups, which includes most national health insurance claims data in Japan. Trends in the types of resection performed for malignant gastric tumors between 2014 and 2021, patients' age and sex distributions, and regional disparities were investigated. RESULTS: The annual number of resections was highest in 2015 (109,000) and lowest in 2020 (90,000) after the COVID-19 pandemic. The proportion of endoscopic resections increased from 47% in 2014 to 57% in 2021 while that of total gastrectomies decreased from 17 to 10%. In 2021, 70% of patients who underwent resection were men. That year, 83.8% of all patients who underwent any type of gastric resection and 87.1% of those who underwent endoscopic submucosal dissection were aged ≥ 65 years. The annual incidence of gastric resection per million population was highest in Tottori (n = 1236) and lowest in Okinawa (n = 251). The proportion of endoscopic resections was highest in Miyagi (66%) and lowest in Aichi (45%) and that of open surgery was highest in Aomori (36%) and lowest in Wakayama (5%). CONCLUSIONS: Gastric malignancy is increasingly treated by endoscopic submucosal dissection rather than open total gastrectomy. However, regional disparities remain in resection type. Standardization of treatment and a more even distribution of specialists are needed.

Effects of sodium glucose cotransporter 2 inhibitors and pioglitazone on FIB-4 index in metabolic-associated fatty liver disease.

BACKGROUND: The antidiabetic drugs sodium glucose cotransporter 2 inhibitors (SGLT2is) and thiazolidinediones have beneficial effects on the liver dysfunction of patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus (T2DM). We aimed to determine the efficacy of these drugs for the treatment of liver disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and T2DM. METHODS: We undertook a retrospective study of 568 patients with MAFLD and T2DM. Of these, 210 were treating their T2DM with SGLT2is (n = 95), 86 with pioglitazone (PIO), and 29 with both. The primary outcome was the change in Fibrosis-4 (FIB-4) index between baseline and 96 weeks. RESULTS: At 96 weeks, the mean FIB-4 index had significantly decreased (from 1.79 ± 1.10-1.56 ± 0.75) in the SGLT2i group, but not in the PIO group. The aspartate aminotransferase to platelet ratio index, serum aspartate and alanine aminotransferase (ALT), hemoglobin A1c, and fasting blood sugar significantly decreased in both groups (ALT: SGLT2i group, -17 ± 3 IU/L; PIO group, -14 ± 3 IU/L). The bodyweight of the SGLT2i group decreased, but that of the PIO group increased (-3.2 kg and +1.7 kg, respectively). When the participants were allocated to two groups according to their baseline ALT (>30 IU/L), FIB-4 index significantly decreased in both groups. In patients taking pioglitazone, the addition of SGLT2i improved liver enzymes but not FIB-4 index for 96 weeks. CONCLUSIONS: Treatment with SGLT2i causes a larger improvement in FIB-4 index than PIO in patients with MAFLD over 96 weeks.

Postprandial Hyperlipidemia: Its Pathophysiology, Diagnosis, Atherogenesis, and Treatments.

Postprandial hyperlipidemia showing postprandial increases in serum triglyceride (TG) is associated with the development of atherosclerotic cardiovascular disease (ASCVD). To diagnose postprandial hyperlipidemia, the oral fat loading test (OFLT) should be performed; however, this test is very time-consuming and is difficult to perform. Elevated serum TG levels reflect an increase in TG-rich lipoproteins (TRLs), such as chylomicrons (CM), very low-density lipoproteins (VLDL), and their remnants (CM remnants [CMRs] and VLDL remnants [VLDLRs]). Understanding of elevation in CMR and/or VLDLR can lead us to understand the existence of postprandial hyperlipidemia. The measurement of apo B48, which is a constituent of CM and CMR; non-fasting TG, which includes TG content in all lipoproteins including CM and CMR; non-high-density lipoprotein cholesterol (non-HDL-C), which includes TRLs and low-density lipoprotein; and remnant cholesterol are useful to reveal the existence of postprandial hyperlipidemia. Postprandial hyperlipidemia is observed in patients with familial type III hyperlipoproteinemia, familial combined hyperlipidemia, chronic kidney disease, metabolic syndrome and type 2 diabetes. Postprandial hyperlipidemia is closely related to postprandial hyperglycemia, and insulin resistance may be an inducing and enhancing factor for both postprandial hyperlipidemia and postprandial hyperglycemia. Remnant lipoproteins and metabolic disorders associated with postprandial hyperlipidemia have various atherogenic properties such as induction of inflammation and endothelial dysfunction. A healthy diet, calorie restriction, weight loss, and exercise positively impact postprandial hyperlipidemia. Anti-hyperlipidemic drugs such pemafibrate, fenofibrate, bezafibrate, ezetimibe, and eicosapentaenoic acid have been shown to improve postprandial hyperlipidemia. Anti-diabetic drugs including metformin, alpha-glucosidase inhibitors, pioglitazone, dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide 1 analogues have been shown to ameliorate postprandial hyperlipidemia. Although sodium glucose cotransporter-2 inhibitors have not been proven to reduce postprandial hyperlipidemia, they reduced fasting apo B48 and remnant lipoprotein cholesterol. In conclusion, it is important to appropriately understand the existence of postprandial hyperlipidemia and to connect it to optimal treatments. However, there are some problems with the diagnosis for postprandial hyperlipidemia. Postprandial hyperlipidemia cannot be specifically defined by measures such as TG levels 2 h after a meal. To study interventions for postprandial hyperlipidemia with the outcome of preventing the onset of ASCVD, it is necessary to define postprandial hyperlipidemia using reference values such as IGT.

Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk.

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.

Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment.

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56-79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78-87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.

Hospitalization for urinary tract infections in Japan, 2010-2015: a retrospective study using a national inpatient database.

BACKGROUND: Urinary tract infections (UTI) are common and can have severe consequences. However, there are few recent large-scale studies about them. We aimed to determine the incidence of hospitalization for UTI and to elucidate patient characteristics, clinical practice, and clinical outcomes by drawing on a Japanese nationwide database. METHODS: This was a retrospective observational study using a national database that covers half the acute care inpatients in Japan. Patients aged ≥ 15 years who were hospitalized for UTI were eligible. We did not include patients with lower UTI such as cystitis. We investigated the annual number of patients hospitalized in Japan, those patients' characteristics, and risk factors for in-hospital mortality. RESULTS: We identified 232,396 eligible patients from 31 million records of discharge between April 2010 and March 2015. The average age was 73.5 years and 64.9% of patients were female. The estimated annual number of hospitalizations because of UTI was 106,508. The incidence was 6.8 per 10,000 for men and 12.4 for women. The median medical care cost was 4250 USD. In-hospital mortality was 4.5%. Risk factors of poor survival included male sex, older age, lower bed capacity, non-academic hospital, admission in winter, higher Charlson Comorbidity Index score, low body mass index, coma on admission, ambulance use, disseminated intravascular coagulation, sepsis, renal failure, heart failure, cerebrovascular diseases, pneumonia, malignancies, use of anti-diabetic drugs, and use of corticosteroid or immunosuppressive drugs. CONCLUSIONS: We found that older patients of both sexes accounted for a significant proportion of those hospitalized for UTI. The clinical and economic burden of UTI is considerable.

Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.

Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease.

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Beneficial Effects of Adiponectin on Glucose and Lipid Metabolism and Atherosclerotic Progression: Mechanisms and Perspectives.

Circulating adiponectin concentrations are reduced in obese individuals, and this reduction has been proposed to have a crucial role in the pathogenesis of atherosclerosis and cardiovascular diseases associated with obesity and the metabolic syndrome. We focus on the effects of adiponectin on glucose and lipid metabolism and on the molecular anti-atherosclerotic properties of adiponectin and also discuss the factors that increase the circulating levels of adiponectin. Adiponectin reduces inflammatory cytokines and oxidative stress, which leads to an improvement of insulin resistance. Adiponectin-induced improvement of insulin resistance and adiponectin itself reduce hepatic glucose production and increase the utilization of glucose and fatty acids by skeletal muscles, lowering blood glucose levels. Adiponectin has also ß cell protective effects and may prevent the development of diabetes. Adiponectin concentration has been found to be correlated with lipoprotein metabolism; especially, it is associated with the metabolism of high-density lipoprotein (HDL) and triglyceride (TG). Adiponectin appears to increase HDL and decrease TG. Adiponectin increases ATP-binding cassette transporter A1 and lipoprotein lipase (LPL) and decreases hepatic lipase, which may elevate HDL. Increased LPL mass/activity and very low density lipoprotein (VLDL) receptor and reduced apo-CIII may increase VLDL catabolism and result in the reduction of serum TG. Further, adiponectin has various molecular anti-atherosclerotic properties, such as reduction of scavenger receptors in macrophages and increase of cholesterol efflux. These findings suggest that high levels of circulating adiponectin can protect against atherosclerosis. Weight loss, exercise, nutritional factors, anti-diabetic drugs, lipid-lowering drugs, and anti-hypertensive drugs have been associated with an increase of serum adiponectin level.

A positive family history of hypertension might be associated with an accelerated onset of type 2 diabetes: Results from the National Center Diabetes Database (NCDD-02).

Type 2 diabetes, which is characterized by a combination of decreased insulin secretion and decreased insulin sensitivity, can be delayed or prevented by healthy lifestyle behaviors. Therefore, it is important that the population in general understands their personal risk at an early age to reduce their chances of ever developing the disease. A family history of hypertension is known to be associated with insulin resistance, but the effect of a family history of hypertension on the onset of type 2 diabetes has not well been examined. We performed a retrospective study examining patient age at the time of the diagnosis of type 2 diabetes by analyzing a dataset of 1,299 patients (1,021 men and 278 women) who had been diagnosed as having type 2 diabetes during a health checkup. The mean ± standard deviation of the patient age at the time of the diagnosis of diabetes was 49.1 ± 10.4 years for patients with a family history of hypertension and 51.8 ± 11.4 years for patients without a family history of hypertension (p < 0.001). A multivariate linear regression analysis showed a significant association between a family history of hypertension and a younger age at the time of the diagnosis of type 2 diabetes, independent of a family history of diabetes mellitus and a male sex, suggesting that a positive family history of hypertension might be associated with the accelerated onset of type 2 diabetes.

[Diagnosis of Secondary Hyperlipidemia due to Diabetes].

Among secondary hyperlipidemia, dyslipidemia due to diabetes is common and important. Hyperlipidemia due to diabetes is divided into hypertriglyceridemia due to diabetic ketoacidosis (diabetic lipemia) and dyslipidemia due to relative insulin deficiency/insulin resistance in type 2 diabetes (diabetic dyslipidemia). Elevation of chylomicron due to the inactivation of lipoprotein lipase (LPL) induced by insulin deficiency is characteristic of diabetic lipemia, which is promptly ameliorated by insulin therapy. The characteristic lipo- protein profile for diabetic dyslipidemia involves elevations of VLDL, IDL, and small dense LDL and a reduc- tion of HDL. Relative insulin deficiency or insulin resistance induces the activation of hormone-sensitive lipase, reduced degradation of apoB100, increased microsomal triglyceride (TG) transfer protein, and inactivation of LPL and activation of hepatic TG lipase, which induce diabetic dyslipidemia. Diabetic dyslipidemia is a markedly ath- erogenic state, which should be carefully managed. [Review].

Development of diabetes in a familial amyotrophic lateral sclerosis patient carrying the I113T SOD1 mutation. Case Report.

Familial amyotrophic lateral sclerosis (ALS) are caused by the mutations in the copper (Cu) / zinc (Zn) superoxide dismutase 1 (SOD1) gene. SOD1 has been reported to play a critical role in glucose metabolism in yeast and cell models, and mice. However, effects of SOD1 for glucose metabolism in humans remain unknown. A 72-year-old woman was admitted to our hospital due to hyperglycemia. She showed severe muscle atrophy and visceral fat accumulation due to ALS. Her serum free fatty acids levels elevated and serum Cu and Zn levels decreased. Her two younger brothers and aunt were also diagnosed as having ALS, and DNA sequence analysis revealed the presence of the I113T SOD1 mutation. She may have developed diabetes due to SOD1 dysfunction by the I113T SOD1 mutation, and severe insulin resistance induced by ALS. The I113T SOD1 mutation may be the causative factor for diabetes as well as familial ALS.

Prevalence and in-hospital mortality of gastrostomy and jejunostomy in Japan: a retrospective study with a national administrative database.

BACKGROUND: PEG is widely used; however, large-scale data for PEG have been lacking. OBJECTIVE: To estimate the prevalence of placement of gastrostomy and jejunostomy tubes and to elucidate the patient background characteristics and their associations with in-hospital mortality. DESIGN: A retrospective analysis of the Japanese administrative claims database. SETTING: Japanese acute-care hospitals. PATIENTS: A total of 64,219 patients who underwent gastrostomy or jejunostomy tube insertion between July and December, 2007 to 2010, were identified among 11.6 million discharge records. INTERVENTION: Placement of gastrostomy and jejunostomy tubes. MAIN OUTCOME MEASUREMENTS: In-hospital mortality and the associated risk factors. RESULTS: The mean age was 77.4 years; >90% of patients were aged >60 years. Cerebrovascular disease and pneumonia were the most frequently recorded diagnoses, followed by neuromuscular disease and dementia. The estimated annual number of gastrostomy and jejunostomy placements in Japan ranged from 96,000 to 119,000. The in-hospital mortality was 11.9%, and the significantly associated risk factors were male sex, older age, placement of a jejunostomy tube, urgent admission, hospital with lower bed capacity, the presence of malignancy, miscellaneous diseases, pneumonia, heart failure, renal failure, chronic liver diseases, pressure sores and sepsis, and occurrence of peritonitis and/or GI perforation, GI hemorrhage, and intra-abdominal hemorrhage. LIMITATIONS: Retrospective investigation of administrative database. CONCLUSION: Our large-scale data revealed the current status of gastrostomy tube placement in Japan. This can contribute to individual decision-making and the public consensus regarding artificial nutritional support in the elderly.

Renal Function Improvement With Glucagon-Like Peptide-1 Receptor Agonist in a Patient With Type 2 Diabetes.

Diabetic kidney disease (DKD) includes hypertensive nephrosclerosis, aging, obesity, and atherosclerosis-related renal diseases, in addition to classical diabetic nephropathy. Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been approved for diabetic and non-diabetic patients at risk of chronic kidney disease progression. As the main mechanism for SGLT2i-mediated improvement of renal function, the normalization of tubulo-glomerular feedback (TGF) has been proposed. Enhanced TGF and resulting glomerular hypertension are observed in diabetic patients, and SGLT2is normalize TGF, reducing the intraglomerular pressure, which may reduce albuminuria and improve renal function. A type 2 diabetic patient with DKD complicated with hypertensive nephrosclerosis, whose renal function was deteriorated by SGLT2i and improved by glucagon-like peptide-1 receptor agonists (GLP-1RAs), was presented. In patients with hypertensive nephrosclerosis such as this case, the normalization of TGF by SGLT2i may further reduce afferent arteriolar blood flow which may worsen glomerular ischemia, resulting in deterioration of renal function. GLP-1RAs have no effect on TGF and have multiple effects to improve vascular endothelial function, which may be associated with an improvement in renal function in this patient.

Real-world effectiveness of imeglimin in patients with type 2 diabetes: A retrospective longitudinal study in Japan.

OBJECTIVE: To examine the real-world effects of imeglimin on glycemic control and other metabolic factors in patients with type 2 diabetes (T2DM). METHODS: A retrospective longitudinal study was conducted based on a chart review. We recruited patients with T2DM who took imeglimin continuously for at least 3 months. Data on various metabolic parameters were collected at the first prescription of imeglimin and at 3, 6 and 12 months after the initiation of imeglimin. Statistical comparisons were performed using paired t-tests. RESULTS: 68 patients were eligible for this study. HbA1c decreased by 0.7 % at 3 months, 1.1 % at 6 months and 1.0 % by 12 months after the initiation of imeglimin. The decreases in HbA1c were observed regardless of age, gender, body mass index, duration of diabetes, renal function and concomitant use of hypoglycemic agents. There were also significant decreases in body weight, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and non-HDL-C during imeglimin treatment. CONCLUSIONS: This is the first report showing the long-term effects of imeglimin in a real-world setting. We confirmed the glucose-lowering effects of imeglimin. Furthermore, favorable effects of imeglimin on body weight and serum lipids were also suggested.

Retrospective Longitudinal Observational Study on the Long-Term Effects of Sodium-Glucose Cotransporter-2 Inhibitors on the Development of Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetic Japanese Patients.

Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

The Significance of Endothelial Dysfunction in Long COVID-19 for the Possible Future Pandemic of Chronic Kidney Disease and Cardiovascular Disease.

Various symptoms have been reported to persist beyond the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is referred to as long coronavirus disease 19 (long COVID-19). Over 65 million individuals suffer from long COVID-19. However, the causes of long COVID-19 are largely unknown. Since long COVID-19 symptoms are observed throughout the body, vascular endothelial dysfunction is a strong candidate explaining the induction of long COVID-19. The angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2, is ubiquitously expressed in endothelial cells. We previously found that the risk factors for atherosclerotic cardiovascular disease (ASCVD) and a history of ASCVD raise the risk of severe COVID-19, suggesting a contribution of pre-existing endothelial dysfunction to severe COVID-19. Here, we show a significant association of endothelial dysfunction with the development of long COVID-19 and show that biomarkers for endothelial dysfunction in patients with long COVID-19 are also crucial players in the development of ASCVD. We consider the influence of long COVID-19 on the development of chronic kidney disease (CKD) and ASCVD. Future assessments of the outcomes of long COVID-19 in patients resulting from therapeutic interventions that improve endothelial function may imply the significance of endothelial dysfunction in the development of long COVID-19.

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.