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[...]the risk of first admission for HF was 116.6 per 1,000 patient‐years in diabetes patients with HFpEF, and 155.4 per 1,000 patient‐years in diabetes patients with HFrEF. [...]compared with individuals without diabetes, the incidence of HHF was reported to be almost doubled in patients with diabetes independent of HFpEF or HFrEF (CHARM). Prevention of Heart Failure in the Treatment of Sodium–Glucose Cotransporter 2 Inhibitors Recently, a sodium–glucose cotransporter 2 inhibitor has shown unexpected cardiorenal benefits in large‐scale clinical trials among type 2 diabetes patients with either established cardiovascular diseases or multiple cardiovascular risk factors in the Empagliflozin Cardiovascular Outcome Event Trial in type 2 Diabetes Mellitus Patients‐Removing Excess Glucose (EMPA‐REG OUTCOME) study. [...]both women and/or older patients with diabetes have a higher risk for HFpEF. [...]a new approach to the diagnosis and treatment of HFpEF in diabetes will be an important area in clinical diabetes.

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes. SGLT2 inhibitors protect cardio‐renal outcomes through metabolic hemodynamic effects. SGLT2 inhibitors exert glucose‐deficiency metabolism in vivo. SGLLT2 inhibitors have ambivalent clinical characteristics.

Periodontal infection induces systemic inflammation; therefore, aggravating diabetes. Orally administered periodontal pathogens may directly alter the gut microbiota. We orally treated obese db / db diabetes mice using Porphyromonas gingivalis ( Pg ). We screened for Pg -specific peptides in the intestinal fecal specimens and examined whether Pg localization influenced the intestinal microbiota profile, in turn altering the levels of the gut metabolites. We evaluated whether the deterioration in fasting hyperglycemia was related to the changes in the intrahepatic glucose metabolism, using proteome and metabolome analyses. Oral Pg treatment aggravated both fasting and postprandial hyperglycemia ( P  < 0.05), with a significant ( P  < 0.01) increase in dental alveolar bone resorption. Pg -specific peptides were identified in fecal specimens following oral Pg treatment. The intestinal Pg profoundly altered the gut microbiome profiles at the phylum, family, and genus levels; Prevotella exhibited the largest increase in abundance. In addition, Pg -treatment significantly altered intestinal metabolite levels. Fasting hyperglycemia was associated with the increase in the levels of gluconeogenesis-related enzymes and metabolites without changes in the expression of proinflammatory cytokines and insulin resistance. Oral Pg administration induced gut microbiota changes, leading to entero-hepatic metabolic derangements, thus aggravating hyperglycemia in an obese type 2 diabetes mouse model.

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.

Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have shown beneficial effects on cardiometabolic risk factors (hemoglobin A1c, body mass index, systolic blood pressure) in patients with type 2 diabetes mellitus. We compared combined cardiometabolic effects of SGLT2i on hemoglobin A1c, body mass index and systolic blood pressure versus dipeptidyl peptidase‐4 inhibitors (DPP4i) in Japanese patients with type 2 diabetes mellitus. Materials and Methods This Japanese retrospective cohort study used the JMDC claims database. Patients newly treated with an SGLT2i (n = 18,936) or DPP4i (n = 55,484) were enrolled (January 2015–March 2020) and matched 1:1 using the propensity score. The primary end‐point was the proportion of patients achieving a composite outcome (i.e., simultaneous absolute/percent reduction in hemoglobin A1c ≥0.5%, body mass index ≥3% and systolic blood pressure ≥2 mmHg) 1 year after first SGLT2i or DPP4i prescription; Mantel–Haenszel common risk difference and its 95% confidence interval were estimated. Other end‐points included treatment persistence, with the associated hazard ratio calculated using the Cox proportional hazards model. Results After matching, patient characteristics were balanced (7,302 patients each). The proportion of patients achieving the composite outcome was significantly greater in patients receiving an SGLT2i than those receiving a DPP4i (31.0% [1,279/4,120] vs 12.9% [524/4,070], risk difference 18.6%, 95% confidence interval 16.3, 20.9, P < 0.001). Risk of treatment discontinuation was significantly lower in the SGLT2i group than in the DPP4i group (hazard ratio 0.85, 95% confidence interval 0.81, 0.90, P < 0.001). Conclusions In the present study, SGLT2i showed favorable cardiometabolic risk reduction and longer treatment persistence than DPP4i in Japanese patients with type 2 diabetes mellitus. In this large retrospective cohort study using a Japanese administrative database, the proportion of patients with type 2 diabetes mellitus achieving a simultaneous improvement in hemoglobin A1c, body mass index and systolic blood pressure was significantly greater in patients newly treated with a sodium–glucose cotransporter 2 inhibitor than those newly treated with a dipeptidyl peptidase‐4 inhibitor. Furthermore, sodium–glucose cotransporter 2 inhibitor treatment showed better treatment persistence than dipeptidyl peptidase‐4 inhibitor treatment.

Aims/Introduction Healthcare resource utilization (HCRU) and healthcare costs are important factors to consider when selecting appropriate treatment for type 2 diabetes mellitus. We compared the HCRU and healthcare costs of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) vs dipeptidyl peptidase‐4 inhibitors (DPP4i) in patients with type 2 diabetes mellitus in Japan. Materials and Methods This was a Japanese retrospective cohort study conducted using the JMDC Claims Database (January 1, 2015–December 31, 2021). Patients newly treated with an SGLT2i (31,872 patients) or a DPP4i (73,279 patients) were matched 1:1, using propensity score, after excluding patients without continuous SGLT2i or DPP4i prescriptions after the index date. HCRU and healthcare costs were compared between the treatment groups in the full cohort and subcohorts/subgroups of different baseline characteristics, including body mass index (BMI). Results After matching, patient characteristics were well balanced (17,767 patients each). Patients receiving an SGLT2i vs those receiving a DPP4i had significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM, and had shorter lengths of stay per hospitalization. Healthcare costs, including all‐cause overall healthcare costs PPPM and all‐cause hospitalization costs PPPM, were generally lower in patients receiving an SGLT2i than those receiving a DPP4i. Similar results were observed among patients with a higher BMI but not among patients with a lower BMI. Conclusions SGLT2i were associated with lower HCRU and healthcare costs than DPP4i, suggesting economic benefits with SGLT2i vs DPP4i in type 2 diabetes mellitus management. This large retrospective cohort study of type 2 diabetes mellitus conducted in Japan, using an administrative database, showed significantly lower numbers of hospitalizations per person per month (PPPM) and outpatient visits PPPM and shorter length of stay per hospitalization in patients newly treated with a sodium‐glucose cotransporter 2 inhibitor (SGLT2i) than those newly treated with a dipeptidyl peptidase‐4 inhibitor (DPP4i). All‐cause overall healthcare costs PPPM and all‐cause hospitalization costs PPPM were also generally lower in patients receiving an SGLT2i than those receiving a DPP4i. The results suggest economic benefits with SGLT2i vs DPP4i in the management of type 2 diabetes mellitus.

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (<30 mL/min/1.73 m2) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age‐dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. Conclusions During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively. Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate. During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced estimated glomerular filtration rate increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced estimated glomerular filtration rate without macroalbuminuria, respectively.

Aims/Introduction Glucagon, a peptide hormone produced from proglucagon, is involved in the pathophysiology of diabetes. Plasma glucagon levels are currently measured by sandwich enzyme‐linked immunosorbent assay (ELISA), but the currently used sandwich ELISA cross‐reacts with proglucagon‐derived peptides, thereby providing incorrect results in subjects with elevated plasma proglucagon‐derived peptide levels. We aimed to develop a more broadly reliable ELISA for measuring plasma glucagon levels. Materials and Methods A new sandwich ELISA was developed using newly generated monoclonal antibodies against glucagon. After its validation, plasma glucagon levels were measured with the new ELISA and the currently used ELISA in subjects who underwent laparoscopic sleeve gastrectomy (LSG) and in outpatients with suspected glucose intolerance. The ELISA results were compared with those from liquid chromatography‐high resolution mass (LC‐HRMS) analysis, which we previously established as the most accurate measuring system. Results The new ELISA has high specificity (<1% cross‐reactivities) and high sensitivity (a lower range of 0.31 pmol/L). Plasma glucagon values in the subjects who underwent laparoscopic sleeve gastrectomy and some outpatients with suspected glucose intolerance differed between the new ELISA and the currently used ELISA. These subjects also showed markedly high plasma glicentin levels. Despite the elevated plasma glicentin levels, the new ELISA showed better positive correlation with LC‐HRMS than did the currently used ELISA. Conclusions The new ELISA enables more accurate measurement of plasma glucagon than the currently used ELISA, even in subjects with elevated proglucagon‐derived peptide levels. It should be clinically useful in elucidating the pathophysiology of individual diabetic patients. A new glucagon sandwich enzyme‐linked immunosorbent assay (ELISA) has been developed that enables highly reliable measurement. The new ELISA provided much more reliable glucagon values than the currently used ELISA even in the subjects with elevated plasma proglucagon‐derived peptide levels. This new ELISA should be clinically useful in elucidating the pathophysiology of individual diabetic patients.

Aims/Introduction To evaluate the benefit of sodium–glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase‐4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history. Materials and Methods This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus (n = 625,739) who were new users of an SGLT2i (n = 57,070; 9.1%) or DPP4i (n = 568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all‐cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups. Results Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283–0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481–0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613–0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history. Conclusions In this real‐world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history. Patients with type 2 diabetes mellitus have increased risk of developing cardiovascular events, and death. The present study using a Japanese administrative database has demonstrated that the use of sodium–glucose cotransporter 2 inhibitors is associated with a significant reduction in the risk of hospitalization for heart failure, all‐cause death, and the composite of hospitalization for heart failure or all‐cause death, compared with dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes mellitus, particularly in those without a history of cardiovascular disease.

To improve prognosis, it is important to predict the incidence of renal failure and cardiovascular disease in type 2 diabetic patients before the progression to advanced nephropathy. We investigated the predictive effects of urinary liver-type fatty acid-binding protein (L-FABP), which is associated with renal tubulointerstitial damage, in renal and cardiovascular prognosis. Japanese type 2 diabetic patients (n = 618) with serum creatinine ≤1.0 mg/dL and without overt proteinuria were enrolled between 1996 and 2000 and followed up until 2011. Baseline urinary L-FABP was measured with an enzyme-linked immunosorbent assay. The primary end points were renal and cardiovascular composites (hemodialysis, myocardial infarction, angina pectoris, stroke, cerebral hemorrhage, and peripheral vascular disease). The secondary renal outcomes were the incidence of a 50% decline in estimated glomerular filtration rate (eGFR), progression to an eGFR <30 mL/min/1.73 m(2), and the annual decline rate in eGFR. During a 12-year median follow-up, 103 primary end points occurred. The incidence rate of the primary end point increased in a stepwise manner with increases in urinary L-FABP. In Cox proportional hazards analysis, the adjusted hazard ratio in patients with the highest tertile of urinary L-FBAP was 1.93 (95% CI 1.13-3.29). This relationship was observed even when analyzed separately in normoalbuminuria and microalbuminuria. Patients with the highest tertile of urinary L-FABP also demonstrated a higher incidence of the secondary renal outcomes. Our results indicate that urinary L-FABP may be a predictive marker for renal and cardiovascular prognosis in type 2 diabetic patients without advanced nephropathy.