A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E–Deficient Mice

ObjectivesThe aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).BackgroundThe new class of anti–type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.MethodsEndothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E–deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.ResultsDFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10−4 mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).ConclusionsA DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium

Impact of Reduced Renal Function on the Glucose-Lowering Effects of Luseogliflozin, a Selective SGLT2 Inhibitor, Assessed by Continuous Glucose Monitoring in Japanese Patients with Type 2 Diabetes Mellitus

INTRODUCTION: We investigated the impact of reduced renal function on 24-h glucose variability in Japanese patients with type 2 diabetes mellitus (T2DM) treated with luseogliflozin. METHODS: In this double-blind, placebo-controlled, crossover study, 37 Japanese patients with T2DM [glycated hemoglobin (HbA1c) 7.0–10.0%] and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m(2) were randomized into two groups in which patients first received luseogliflozin then placebo, or vice versa, for 7 days each. Twenty-four-hour glucose variability was measured on day 7 in each period and was compared among patients divided into three groups according to their baseline eGFR (mL/min/1.73 m(2)): normal (≥90; n = 13; normal group), normal-to-mildly reduced renal function (≥75 to <90; n = 12; normal–mild group), and mild-to-moderately reduced renal function (<75; n = 9; mild–moderate group). RESULTS: The mean [95% confidence interval (CI)] placebo-subtracted 24-h cumulative urinary glucose excretion (g) was 82.1 (72.7, 91.5), 82.5 (73.4, 91.5), and 62.2 (51.2, 73.3); the placebo-subtracted 24-h mean glucose concentration (mg/dL) was −24.39 (−32.53, −16.26), −28.28 (−39.35, −17.22), and −11.53 (−23.93, 0.86); and the placebo-subtracted peak postprandial glucose (mg/dL) was −26.9 (−46.9, −6.9), −38.1 (−59.6, −16.6), and 1.5 (−25.5, 28.4) in the normal, normal–mild, and mild–moderate groups, respectively. The mean lowest glucose concentrations (placebo vs. luseogliflozin, mg/dL) decreased to similar levels in the normal (115.4 vs. 93.4), normal–mild (121.0 vs. 97.9), and mild–moderate (104.0 vs. 91.1) groups. CONCLUSION: This post hoc subanalysis revealed that although mild-to-moderately reduced renal function attenuated the glucose-lowering effects of luseogliflozin on peak postprandial glucose, it did not attenuate the effects of luseogliflozin on fasting glucose. These findings may explain the smaller increase in urinary glucose excretion in these patients relative to patients with normal renal function or normal-to-moderately reduced renal function. Further studies may be needed to examine these findings in large populations of patients with T2DM and reduced renal function. TRIAL REGISTRATION: JapicCTI-142548. FUNDING: Taisho Pharmaceutical Co., Ltd. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0291-z) contains supplementary material, which is available to authorized users

Sex Differences in the Renal Function Decline of Patients with Type 2 Diabetes

Aims. We aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus (T2DM), focusing on the differences in the risk factors at early stage of renal dysfunction. Methods. A clinic-based retrospective longitudinal study (follow-up duration: 8.1±1.4 years) was conducted to assess the sex differences in the annual estimated glomerular filtration rate (eGFR) change in 344 (247 male and 97 female) Japanese T2DM patients. The sex differences in the risk factors of annual eGFR decline were subjected to linear regression analyses. Results. The mean annual eGFR change was -3.5±2.7%/year in females and -2.0±2.2%/year in males (P<0.001). Baseline retinopathy and proteinuria were significantly associated with a larger eGFR decline, irrespective of sex, while HbA1c and LDL-cholesterol levels were significantly associated with an eGFR decline in females only. Interactive effects were observed between sex and the HbA1c, LDL-cholesterol, retinopathy, or proteinuria levels on the annual eGFR decline. Conclusions. The increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with T2DM. Our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage, especially in females

HbA1c and telemedicine during COVID-19

Aims/Introduction: To investigate whether the COVID-19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. Materials and Methods: In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. Results: The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician–patient interaction and the impossibility of consultation and examination were cited as sources of concern. Conclusions: Our data suggest that glycemic control did not deteriorate during the COVID-19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine

Cys34-cysteinylated human serum albumin is a sensitive plasma marker in oxidative stress-related chronic diseases

The degree of oxidized cysteine (Cys) 34 in human serum albumin (HSA), as determined by high performance liquid chromatography (HPLC), is correlated with oxidative stress related pathological conditions. In order to further characterize the oxidation of Cys34-HSA at the molecular level and to develop a suitable analytical method for a rapid and sensitive clinical laboratory analysis, the use of electrospray ionization time-of-flight mass spectrometer (ESI-TOFMS) was evaluated. A marked increase in the cysteinylation of Cys34 occurs in chronic liver and kidney diseases and diabetes mellitus. A significant positive correlation was observed between the Cys-Cys34-HSA fraction of plasma samples obtained from 229 patients, as determined by ESI-TOFMS, and the degree of oxidized Cys34-HSA determined by HPLC. The Cys-Cys34-HSA fraction was significantly increased with the progression of liver cirrhosis, and was reduced by branched chain amino acids (BCAA) treatment. The changes in the Cys-Cys34-HSA fraction were significantly correlated with the alternations of the plasma levels of advanced oxidized protein products, an oxidative stress marker for proteins. The binding ability of endogenous substances (bilirubin and tryptophan) and drugs (warfarin and diazepam) to HSA purified from chronic liver disease patients were significantly suppressed but significantly improved by BCAA supplementation. Interestingly, the changes in this physiological function of HSA in chronic liver disease were correlated with the Cys-Cys34-HSA fraction. In conclusion, ESI-TOFMS is a suitable high throughput method for the rapid and sensitive quantification of Cys-Cys34-HSA in a large number of samples for evaluating oxidative stress related chronic disease progression or in response to a treatment

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049