Comparison of canagliflozin and teneligliptin on energy intake and body weight in Japanese patients with Type 2 diabetes: a subanalysis of the CANTABILE study.

BACKGROUND: While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. METHODS: This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. RESULTS: Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. CONCLUSION: Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.

Risk Assessment for Cardiovascular Events using Achilles Tendon Thickness and Softness and Intima-Media Thickness in Familial Hypercholesterolemia.

AIMS: This was a retrospective cohort study that aimed to determine cutoff values for major adverse cardiovascular events (MACEs) in patients with heterozygous FH (HeFH) for Achilles tendon (AT) thickness (ATT) measured by ultrasonography (US-ATT) and radiography (Xp-ATT), AT softness, and intima-media thickness of carotid artery (C-IMT), and to examine the effectiveness of these values as well as AT calcification as indexes in assessing risk for MACEs. METHODS: The subjects were 391 clinically diagnosed HeFH patients. Kaplan-Meier curves were drawn based on the threshold values for the individual indexes calculated from ROC curves, and multivariate analysis was used to examine whether they were predictors of the development of MACEs. RESULTS: The median observation period was 1,239 days (700-1,827 days). Twenty-one subjects (5%) had MACEs during the observation period. The cutoff values for MACEs for US-ATT were 9.9 mm in males and 7.1 mm in females, and those for C-IMT were 1.6 mm in males and 1.5 mm in females. Subjects were classified into two groups according to whether they were above or below the cutoff values and presence of calcification, and we compared MACE rates between them. MACE rates were significantly increased in groups with AT thickening determined by ultrasonography (P＜0.001), AT softening (P＜0.001), presence of calcification in AT (P=0.016) and greater C-IMT (P＜0.001). However, classification according to Xp-ATT revealed no significant difference in MACE rate (P=0.112). CONCLUSIONS: These thresholds and examination for AT calcification will help in risk assessment for patients in Japanese FH practice and encourage stricter and more comprehensive management for patients who exceed the thresholds.

Effect of Luseogliflozin on Myocardial Flow Reserve in Patients with Type 2 Diabetes Mellitus (LUCENT-J Study).

INTRODUCTION: In patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors has been shown to reduce hospital admission rates for heart failure (HF). However, the multiple mechanisms hypothesized and investigated to explain the cardioprotection of SGLT2 inhibitors are not fully understood. OBJECTIVES: The effect of luseogliflozin on myocardial flow reserve (MFR) in patients with T2D (LUCENT-J) study aims to examine the effects of SGLT2 inhibitors on myocardial perfusion. METHODS: The LUCENT-J study is a prospective, single-center, randomized, two-arm, parallel-group, open-label (i.e., the radiology readers are blinded), active-controlled study. A cohort of 40 patients with T2D with no or stable (with no history of myocardial infarction and with or without previous percutaneous coronary intervention) coronary artery disease will be included. Patients will be randomized in a 1:1 ratio to luseogliflozin or control and treated for 24 weeks. The primary outcome is the change in MFR, as measured by 13N-ammonia positron emission tomography/computed tomography, from baseline to 24 weeks after treatment initiation. PLANNED OUTCOMES: The LUCENT-J study will elucidate the mechanisms of cardioprotection by SGLT2 inhibitors in patients with T2D. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs051220016).

Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial.

Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

The effect of continuous glucose monitoring-guided glycemic control on progression of coronary atherosclerosis in type 2 diabetic patients with coronary artery disease: The OPTIMAL randomized clinical trial.

BACKGROUND: Continuous glucose monitoring (CGM) improves glycemic fluctuation and reduces hypoglycemic risk. Whether CGM-guided glycemic control favorably modulates coronary atherosclerosis in patients with type 2 diabetes (T2DM) remains unknown. METHODS: The OPTIMAL trial was a prospective, randomized, single-center trial in which 94 T2DM patients with CAD were randomized to CGM- or HbA1c-guided glycemic control for 48 weeks (jRCT1052180152). The primary endpoint was the nominal change in total atheroma volume (TAV) measured by serial IVUS. The secondary efficacy measure was the nominal change in maxLCBI4mm on near-infrared spectroscopy imaging. RESULTS: Among the 94 randomized patients, 82 had evaluable images at 48 weeks. Compared to HbA1c-guided glycemic control, CGM-guided control achieved a greater reduction in %coefficient of variation [-0.1 % (-1.8 to 1.6) vs. -3.3 % (-5.1 to -1.5), p = 0.01] and a greater increase in the duration with glucose between 70 and 180 mg/dL [-1.5 % (-6.0 to 2.9) vs. 6.7 % (1.9 to 11.5), p = 0.02]. TAV increased by 0.11 ± 1.9 mm3 in the HbA1c-guided group and decreased by -3.29 ± 2.00 mm3 in the CGM-guided group [difference = -3.4 mm3 (95%CI: -8.9 to 2.0 mm3), p = 0.22]. MaxLCBI4mm, increased by 90.1 ± 25.6 in the HbA1c-guided group and by 50.6 ± 25.6 in the CGM-guided group (difference = -45.6 (95%CI: -118.1 to 26.7) p = 0.21]. A post-hoc exploratory analysis showed a greater regression of maxLCBI4mm in the CGM-guided group [difference = 20.4 % (95%CI:1.3 to 39.5 %), p = 0.03]. CONCLUSIONS: CGM-guided control for 48 weeks did not slow disease progression in T2DM patients with CAD. A greater regression of lipidic plaque under CGM-guided glycemic control in the post-hoc analysis requires further investigation.

Diabetic microvascular complications predicts non-heart failure with reduced ejection fraction in type 2 diabetes.

AIMS: The relationship between diabetic microvascular complications and the incidence of two types of heart failure-heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] < 40%) and non-HFrEF (LVEF ≥ 40%)-in patients without prior heart failure has not been clarified. We herein examined the association between diabetic microvascular complications and HFrEF or non-HFrEF in patients with type 2 diabetes mellitus (T2DM) without prior heart failure. METHODS AND RESULTS: In this retrospective cohort study, we assessed the relationship between the presence of diabetic microvascular complications or severity of diabetic retinopathy (no apparent, non-proliferative and proliferative retinopathy) and nephropathy (normoalbuminuria, microalbuminuria, and macroalbuminuria) at baseline, with the primary outcome of first heart failure hospitalization classified as HFrEF or non-HFrEF in patients with type 2 diabetes mellitus without prior heart failure. Among 568 patients (69.2% males, mean age 66.2 ± 9.6 years), 70 experienced heart failure hospitalization (HFrEF: 24 and non-HFrEF: 46). Non-HFrEF hospitalization but not HFrEF hospitalization was significantly associated with the presence of diabetic microvascular complications. The incidence of non-HFrEF hospitalization was significantly higher in the proliferative retinopathy group than that in the no apparent retinopathy group (adjusted hazard ratio [HR] 2.96, 95% confidence interval [CI]: 1.09-6.83, P = 0.035) and in those with macroalbuminuria than in those with normoalbuminuria (adjusted HR 4.23, 95% CI: 2.24-7.85, P < 0.001) even after adjustment for age and sex. When non-HFrEF was classified into heart failure with mildly reduced ejection fraction (HFmrEF) (40% ≤ LVEF < 50%) and heart failure with preserved ejection fraction (HFpEF) (50% ≤ LVEF), HFmrEF and HFpEF hospitalizations were also found to be associated with the progression of retinopathy and nephropathy. CONCLUSIONS: In patients with T2DM without prior heart failure, non-HFrEF hospitalization was more closely associated with the progression of diabetic microangiopathy than HFrEF. The development of non-HFrEF may be mediated through a mechanism similar to that of microvascular complications in these patients.

First Case Report of Arrhythmogenic Right Ventricular Cardiomyopathy Showing Refractory Ventricular Tachycardia Induced by Thyroid Storm due to Graves' Disease.

A 48-year-old man who was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) due to a plakophilin 2 gene mutation developed acute both-sided heart failure with rapid atrial fibrillation and was hospitalized. After admission, sustained ventricular tachycardia, which was refractory to antiarrhythmic agents, occurred repeatedly, and required electrical cardioversion. He was diagnosed with thyroid storm due to Graves' disease, and treatment for hyperthyroidism was initiated. After the treatment, lethal arrhythmia did not reoccur, and biventricular heart failure ameliorated. To our best knowledge, this is the first report in English of a patient with ARVC showing refractory arrhythmia induced by thyroid storm due to Graves' disease.

Association between Achilles Tendon Softness and Atherosclerotic Cardiovascular Disease in Patients with Familial Hypercholesterolemia.

AIMS: Achilles tendon (AT) xanthomas are a specific physical finding of familial hypercholesterolemia (FH) and AT thickness has been used for its diagnosis and evaluation of its severity. Recently, we reported that the AT of FH patients was softer than that of non-FH patients and the combined use of a cut-off value for AT softness with that for AT thickness improved diagnostic accuracy. However, an association between AT softness and severity of atherosclerosis has not been reported. Accordingly, the present study aimed to investigate whether AT softness was associated with carotid atherosclerosis and presence of atherosclerotic cardiovascular disease (ASCVD) in FH. METHODS: The AT of 176 genetically diagnosed FH patients and 98 non-FH patients was examined to measure AT thickness and the elasticity index (EI) as an indicator for assessing AT softness using ultrasonography. RESULTS: Increased age was associated with AT softness, and overweight was negatively related to AT softness. There were significant inverse correlations between EI and maximum and mean intima-media thickness (IMT) within the common carotid artery only among FH patients. In multiple linear regression analysis, although the relationship between EI and mean IMT was attenuated, the association between EI and maximum IMT remained robust. In logistic regression analysis adjusted for age, sex and traditional cardiovascular risk factors (smoking history, presence of hypertension, presence of diabetes mellitus, overweight, LDL-cholesterol, HDL-cholesterol, and Log triglycerides), EI was associated with presence of ASCVD (Odds ratio per 1-SD increase, 0.37; 95% CI, 0.15 - 0.86; P=0.0252). CONCLUSION: The degree of lipid deposition in the AT of FH patients could be assessed by its thickness as well as its softness. AT softness is not only useful in diagnosing FH but is also associated with the severity of carotid atherosclerosis and presence of ASCVD. In addition, these findings suggest that AT softness would be helpful in risk assessment for FH patients.

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Comparison of efficacy between dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor on metabolic risk factors in Japanese patients with type 2 diabetes mellitus: Results from the CANTABILE study.

AIMS: The aim of this study was to compare the effectiveness of teneligliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, at reducing a composite outcome of three metabolic risk factors (obesity, hypertension, and dyslipidemia) in Japanese patients with type 2 diabetes mellitus (T2DM) and metabolic risks. METHODS: In this prospective, multicenter, open-label, randomized, parallel-group comparison study, 162 patients with T2DM and one or more metabolic risk factors were randomized into a teneligliptin or canagliflozin group and treated for 24 weeks. The primary endpoint was the composite percentage of subjects who experienced an improvement in at least one metabolic risk after 24 weeks of treatment. RESULTS: The primary endpoint was achieved significantly by more patients in the canagliflozin group than in the teneligliptin group (62.2% vs. 31.3%, p = 0.0004). A ≥ 3% body weight loss was also achieved by significantly more participants in the canagliflozin group than in the teneligliptin group (55.9% vs. 10.5%, p < 0.0001). CONCLUSIONS: This study showed canagliflozin to be more effective at reducing metabolic risks than teneligliptin. In Japanese patients with T2DM and metabolic risk factors, SGLT2 inhibitors may be superior to DPP-4 inhibitors at controlling multiple metabolic risk.

Glucose Fluctuation and Severe Internal Carotid Artery Siphon Stenosis in Type 2 Diabetes Patients.

The impact of glucose fluctuation on intracranial artery stenosis remains to be elucidated. This study aimed to investigate the association between glucose fluctuation and intracranial artery stenosis. This was a cross-sectional study of type 2 diabetes mellitus (T2DM) patients equipped with the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories) between February 2019 and June 2020. Glucose fluctuation was evaluated according to the standard deviation (SD) of blood glucose, coefficient of variation (%CV), and mean amplitude of glycemic excursions (MAGE). Magnetic resonance angiography was used to evaluate the degree of intracranial artery stenosis. Of the 103 patients, 8 patients developed severe internal carotid artery (ICA) siphon stenosis (≥70%). SD, %CV, and MAGE were significantly higher in the severe stenosis group than in the non-severe stenosis group (<70%), whereas there was no significant intergroup difference in the mean blood glucose and HbA1c. Multivariable logistic regression analysis adjusted for sex showed that SD, %CV, and MAGE were independent factors associated with severe ICA siphon stenosis. In conclusion, glucose fluctuation is significantly associated with severe ICA siphon stenosis in T2DM patients. Thus, glucose fluctuation can be a target of preventive therapies for intracranial artery stenosis and ischemic stroke.

A Prospective Longitudinal Study on the Relationship Between Glucose Fluctuation and Cognitive Function in Type 2 Diabetes: PROPOSAL Study Protocol.

INTRODUCTION: Although the risk of dementia among patients with type 2 diabetes mellitus (T2DM) is double that of those without T2DM, the mechanism remains to be elucidated and the glycemic goal to prevent progression of cognitive impairment is unclear. Results from cross-sectional studies suggest that glucose fluctuations are associated with impairment of cognitive function among T2DM patients. Therefore, the aim of the longitudinal study described here is to evaluate the relationships between glucose fluctuation indexes assessed by continuous glucose monitoring (CGM) and cognitive function among elderly patients with T2DM. METHODS: This will be a prospective, single-center, 2-year longitudinal study in which a total of 100 elderly patients with T2DM showing mild cognitive impairment (MCI) will be enrolled. Glucose fluctuations, assessed using the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories), and results of cognitive tests, namely the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale (ADAS), will be evaluated at baseline, 1-year visit and 2-year visit. The primary endpoint is the relationships between indexes of glucose fluctuation and change in MoCA and ADAS scores. Secondary endpoints are the relationships between the indexes of glucose fluctuation or cognitive scores and the following: indexes representing intracranial lesions obtained by magnetic resonance imaging and angiography of the head; Geriatric Depression Scale score; Apathy Scale score; carotid intima-media thickness assessed by echography; inflammatory markers; fasting glucose; glycated hemoglobin; blood pressure; and the development of cardiovascular and renal events. PLANNED OUTCOMES: The current study is scheduled for completion in June 2022. The results could lead to the elucidation of novel glycemic goals to prevent the progression of cognitive impairment and/or of relationships between glucose fluctuations and cognitive function among T2DM patients. The findings of the study will be reported in publications and conference presentations. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000038546).

Effect of tofogliflozin on cardiac and vascular endothelial function in patients with type 2 diabetes and heart diseases: A pilot study.

Recent studies have shown that sodium-glucose cotransporter 2 inhibitors decrease the risk of heart failure in patients with type 2 diabetes. However, the precise mechanisms of action of these drugs are not well understood. In the present study, we evaluated the effect of treatment with tofogliflozin for 6 months on cardiac and vascular endothelial function in 26 patients with type 2 diabetes and heart diseases. Tofogliflozin treatment significantly decreased left ventricular end-diastolic dimensions and significantly increased flow-mediated vasodilation. Although E/e' did not significantly change after treatment, the decrease observed in the E/e' ratio was significantly correlated with the increase in acetoacetic acid and 3-hydroxybutyrate levels. These results suggest that sodium-glucose cotransporter 2 inhibitor might improve left ventricular dilatation and vascular endothelial function in patients with type 2 diabetes. Furthermore, it is suggested that the elevation of ketone bodies induced by sodium-glucose cotransporter 2 inhibitors might contribute to a protective effect in left ventricular diastolic dysfunction.

The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL).

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are high-risk subjects who more frequently have micro- and macrovascular diseases including coronary artery disease (CAD). Since impaired glycemic homeostasis directly influences the formation and propagation of atherosclerotic plaques, optimal management of glycemic status is required for the prevention of diabetic atherosclerosis. Continuous glucose monitoring (CGM) provides not only average glucose level but also the degree of glucose fluctuation and hypoglycemia. Given the association of glycemic variability with diabetic macrovascular diseases, CGM-based glycemic management could favorably modulate glycemic fluctuation, thereby potentially modifying atheroma burden in T2DM subjects. To test this hypothesis, the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL) study has been designed (Japan Registry of Clinical Trials: jRCT1052180152, University Hospital Medical Information Network Clinical Trial Registry UMIN000036721). METHODS: The OPTIMAL is a single-center, randomized trial to evaluate the efficacy of CGM-based glycemic control on atheroma progression in T2DM patients with CAD by using serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. A total of 90 eligible subjects will be randomized 1:1 into two groups to receive either CGM-based glycemic control or HbA1c-baded glycemic management. Coronary angiography and NIRS/IVUS imaging is repeated at the end of the assigned treatment period. RESULTS: The primary endpoint is the normalized absolute change in total atheroma volume (TAV) from baseline to 12 months. The secondary endpoints include (I) the absolute change in percent atheroma volume, (II) the percent change in lipid core burden index, (III) the change in coefficient variance measured by CGM, (IV) the change in atherogenic markers (high-density lipoprotein functionality, proprotein convertase subxilisin/kexin type 9 and fatty-acid binding proteins), and (V) the frequency of hypoglycemia. Safety will also be evaluated. CONCLUSIONS: The collaboration of CGM use with serial NIRS/IVUS imaging will enable to compare atheroma progression rate under CGM-based glycemic management and HbA1c-based approach.

Efficacy of visceral fat estimation by dual bioelectrical impedance analysis in detecting cardiovascular risk factors in patients with type 2 diabetes.

BACKGROUND: Visceral fat area (VFA) is a good surrogate marker of obesity-related disorders, such as hypertension, dyslipidemia and glucose intolerance. Although estimating the VFA by X-ray computed tomography (CT) is the primary index for visceral obesity, it is expensive and requires invasive radiation exposure. Dual bioelectrical impedance analysis (BIA) is a simple and reliable method to estimate VFA; however, the clinical usefulness of dual BIA remains unclear in patients with type 2 diabetes (T2D). METHODS: We estimated the VFAs by dual BIA and CT in 98 patients with T2D and assessed anthropometric parameters, blood test results, and the presence of comorbid hypertension and dyslipidemia. We compared the correlation between the VFAs examined by dual BIA and CT. Furthermore, we performed the receiver operating characteristic (ROC) analyses for the VFAs to detect the presence of comorbid hypertension and/or dyslipidemia with T2D, which are major comorbidities of visceral obesity, and estimated the area under the curve (AUC). RESULTS: The measurement error between the VFAs by dual BIA and CT was significantly higher among patients with brain natriuretic peptide (BNP) ≥ 100 pg/mL than those with BNP < 100 pg/mL (39.2% ± 31.1% vs. 24.1% ± 18.6%, P < 0.05). After excluding patients with BNP ≥ 100 pg/mL, the VFA by dual BIA significantly correlated with the VFA by CT (r = 0.917; P < 0.0001). The AUC in the ROC analysis for the VFA by dual BIA to detect the presence of comorbid hypertension and/or dyslipidemia with T2D was almost equivalent to that for the VFA by CT. CONCLUSIONS: In patients with T2D without elevated BNP > 100 pg/mL as indicator for fluid accumulation interfering with BIA, estimation of the VFA by dual BIA significantly correlated with that by CT and also detected comorbid hypertension and/or dyslipidemia with T2D equivalent to those detected by CT. Hence, dual BIA could be an alternative to CT as a standard method for estimating the VFA in patients with diabetes.

Familial Hypercholesterolemia and Lipoprotein Apheresis.

Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.

Effect of linagliptin on oxidative stress markers in patients with type 2 diabetes: a pilot study.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used for the treatment of type 2 diabetes and have been previously shown to prevent diabetic renal injury via various mechanisms, including the attenuation of oxidative stress. Therefore, we hypothesized that linagliptin, a DPP-4 inhibitor, attenuates oxidized stress and diabetic renal injury. METHODS: In total, 30 patients with type 2 diabetes who were undergoing treatment with linagliptin (5 mg) during the 3-month study period were enrolled. Oxidative stress markers [serum malondialdehyde-modified LDL (MDA-LDL) and urinary 8-hydroxydeoxyguanosine (8-OHdG)], an inflammatory marker (high-sensitive CRP), urinary albumin excretion, estimated GFR, and a urinary tubulointerstitial injury marker [urinary liver-type fatty acid-binding protein (L-FABP)] were evaluated at baseline and after 3 months of treatment. RESULTS: Following linagliptin treatment, serum MDA-LDL, serum HbA1c, and urinary L-FABP levels significantly decreased, while urinary 8-OHdG tended to decrease. In contrast, 1,5-AG levels increased, and high-sensitive CRP and urinary albumin excretion remained unchanged. CONCLUSION: In this study, we demonstrated that linagliptin partially attenuated oxidative stress. We also demonstrated that linagliptin treatment reduced urinary L-FABP excretion, suggesting that renal tubule-interstitial injury may be attenuated by linagliptin (UMIN 000015308).

Outcome Prediction in Acute Stroke Patients by Continuous Glucose Monitoring.

BACKGROUND: The purpose of this study was to examine the relationships between glucose parameters obtained by continuous glucose monitoring and clinical outcomes in acute stroke patients. METHODS AND RESULTS: Consecutive patients with acute ischemic stroke or intracerebral hemorrhage within 24 hours after onset were included. A continuous glucose monitoring device (iPro2) was attached for the initial 72 hours after emergent admission. Eight glucose parameters were obtained from continuous glucose monitoring: maximum, minimum, mean, and SD of blood glucose levels, as well as area under the curve more than 8 mmol/L of blood glucose, distribution time more than 8 mmol/L of blood glucose, coefficient of variation (%CV), and presence of time less than 4 mmol/L over 72 hours. The primary outcome measure was death or dependency at 3 months (modified Rankin Scale score ≥3). One hundred patients with acute ischemic stroke (n=58) or intracerebral hemorrhage (n=42) were included. Blood glucose levels varied between 5.2±1.4 and 11.4±3.2 mmol/L over 72 hours, with area under the curve more than 8 mmol/L of blood glucose of 0.7±1.4 min×mmol/L, distribution time more than 8 mmol/L of blood glucose of 31.7±32.7%, coefficient of variation of 15.5±5.4%, and presence of hypoglycemia in 20% of overall patients. Mean glucose level (adjusted odds ratio, 1.60, 95% confidence interval, 1.12-2.28/1 mmol/L), area under the curve more than 8 mmol/L of blood glucose (2.13, 1.12-4.02/1 min×mmol/L), and distribution time more than 8 mmol/L of blood glucose (1.25, 1.05-1.50/10%) were related to death or dependency for overall patients, as well as for acute ischemic stroke patients (2.05, 1.15-3.65; 2.38, 1.04-5.44; 1.85, 1.10-3.10, respectively). CONCLUSIONS: High mean glucose levels, distribution time more than 8 mmol/L of blood glucose, and areas under the curve more than 8 mmol/L of blood glucose during the initial 72 hours of acute stroke were associated with death or dependency at 3 months.

Adipocyte-specific expression of C-type natriuretic peptide suppresses lipid metabolism and adipocyte hypertrophy in adipose tissues in mice fed high-fat diet.

C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high-fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP-VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid ß-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity.