Akihiro Honda

Pioglitazone Decreases Coronary Artery Inflammation in Impaired Glucose Tolerance and Diabetes Mellitus : Evaluation by FDG-PET/CT Imaging

OBJECTIVES The aim of this study was to compare the effect of pioglitazone with glimepiride on coronary arterial inflammation with serial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) angiography. BACKGROUND Recent studies have shown that FDG-PET combined with CT is a reliable tool to visualize and quantify vascular inflammation. Although pioglitazone significantly prevented the progression of coronary atherosclerosis and reduced the recurrence of myocardial infarction in patients with type 2 diabetes mellitus (DM), it remains unclear whether pioglitazone could attenuate coronary artery inflammation. METHODS Fifty atherosclerotic patients with impaired glucose tolerance or type 2 DM underwent determination of blood chemistries, anthropometric and inflammatory variables, and FDG-PET/CT angiography, and then were randomized to receive either pioglitazone or glimepiride for 16 weeks. Effects of the treatments on vascular inflammation of the left main trunk were evaluated by FDG-PET/CT angiography at baseline and end of the study. Vascular inflammation of the left main trunk was measured by blood-normalized standardized uptake value, known as a target-to-background ratio. RESULTS Three patients dropped out of the study during the assessment or treatment. Finally, 25 pioglitazone-treated patients and 22 glimepiride-treated patients (37 men; mean age: 68.1 ± 8.3 years; glycosylated hemoglobin: 6.72 ± 0.70%) completed the study. After 16-week treatments, fasting plasma glucose and glycosylated hemoglobin values were comparably reduced in both groups. Changes in target-to-background ratio values from baseline were significantly greater in the pioglitazone group than in the glimepiride group (-0.12 ± 0.06 vs. 0.09 ± 0.07, p = 0.032), as well as changes in high-sensitivity C-reactive protein (pioglitazone vs. glimepiride group: median: -0.24 [interquartile range (IQR): -1.58 to -0.04] mg/l vs. 0.08 [IQR: -0.07 to 0.79] mg/l, p = 0.031). CONCLUSIONS Our study indicated that pioglitazone attenuated left main trunk inflammation in patients with impaired glucose tolerance or DM in a glucose-lowering independent manner, suggesting that pioglitazone may protect against cardiac events in patients with impaired glucose tolerance or DM by suppressing coronary inflammation. (Anti-Inflammatory Effects of Pioglitazone; NCT00722631).

Effects of pioglitazone on visceral fat metabolic activity in impaired glucose tolerance or type 2 diabetes mellitus.

CONTEXT Excess visceral fat is associated with chronic systemic inflammation and cardiovascular complications. Pioglitazone has been reported to variably influence visceral fat volume; however, its effect on metabolic activity of the visceral fat remains uncharacterized. OBJECTIVE The aim of this study was to assess the effects of pioglitazone on glucose metabolism of fat tissue by using (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and computed tomography imaging. DESIGN, SETTING, AND PARTICIPANTS FDG-PET and computed tomography imaging were performed in 56 patients with impaired glucose tolerance or type 2 diabetes mellitus; lipid and glycemic profiles and inflammatory biomarkers were obtained in all patients. These patients were randomized to treatment with either pioglitazone or glimepiride for 16 weeks. MAIN OUTCOME MEASURES The metabolic activity of the visceral fat tissues as assessed by FDG uptake was expressed as a target-to-background ratio (TBR) of blood-normalized standardized uptake value. RESULTS The study was completed in 32 pioglitazone-treated and 21 glimepiride-treated patients (40 men and 13 women; mean age, 67.7 ± 8.1 y; body mass index, 25.0 ± 3.6 kg/m(2); glycated hemoglobin, 6.78 ± 0.70%). Both treatments were well-tolerated and comparably improved glycemic control. At baseline, visceral fat exhibited a higher TBR value than subcutaneous fat (0.55 ± 0.14 vs 0.30 ± 0.07, P < .001). Pioglitazone, but not glimepiride, significantly decreased the visceral fat volume (130.5 ± 53.0 to 122.1 ± 51.0 cm(2), P = .013) and TBR values (0.57 ± 0.16 to 0.50 ± 0.11, P = .007). Neither pioglitazone nor glimepiride treatment showed any effect on the volume or TBR values of subcutaneous fat. After 16 weeks of treatment with pioglitazone, reduction in visceral fat TBR was correlated to the increase in high-density lipoprotein cholesterol levels. CONCLUSIONS Our study indicated that pioglitazone decreased the visceral fat volume and its metabolic activity in patients with impaired glucose tolerance or type 2 diabetes mellitus. The beneficial effects of pioglitazone on visceral fat may be independent of its glucose-lowering effect.

Clinical and Biochemical Factors Associated With Area and Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT

CONTEXT Body fat distribution and inflammation may play a role in metabolic derangements and cardiovascular disease in obesity. OBJECTIVE The aim of this study is to investigate clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues (VAT and SAT). PARTICIPANTS (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography imaging was performed in 251 consecutive subjects (62.6 ± 9.3 y) for risk screening. MAIN OUTCOME MEASURES We examined which clinical, anthropometric, metabolic, and inflammatory variables including advanced glycation end products (AGEs) and pigment epithelium-derived factor (PEDF) were independently associated with area and metabolic activity in VAT and SAT. Adipose tissue area was determined with computed tomography, whereas metabolic activity was assessed by (18)F-fluorodeoxyglucose uptake expressed as a target to background ratio (TBR) of blood-normalized standardized uptake. RESULTS Serum levels of AGEs and PEDF were 9.81 ± 3.21 U/mL and 14.0 (range 10.8-17.7) μg/mL, respectively. Although the area in VAT and SAT was associated with waist circumference and sex, each adipose tissue area and TBR had different metabolic risk profiles. The TBR value in VAT was higher than that in SAT. In a multiple stepwise regression analysis, AGEs and medication for hypertension were independently associated with VAT TBR (R(2) = 0.102), whereas medication for diabetes, mean intima-media thickness, AGEs, and PEDF were the independent correlates of SAT TBR (R(2) = 0.132). CONCLUSIONS The present study demonstrated that area and metabolic activity in VAT and SAT could be differently regulated, suggesting the involvement of AGEs and PEDF in adipose tissue inflammation.

Molecular imaging of vascular inflammation.

Atherosclerosis and its thrombotic complications represent the major cause of morbidity and mortality in the industrialized countries. Despite recent advances in the diagnosis and management of cardiovascular disease, a substantial number of patients still die from acute coronary syndromes. Recently, atherosclerotic plaque composition rather than the degree of arterial stenosis has been shown to reflect the plaque vulnerability, thus contributing to the pathogenesis of cardiovascular disease. Vulnerable plaques have a large lipidrich necrotic core, a thin-fibrous cap and numerous inflammatory cells. Among them, macrophage activation plays a central role in vascular inflammation and plaque instability within the atherosclerosis, being strongly involved in acute coronary syndromes. Various morphologic features of plaque vulnerability have been described by computed tomography angiography, magnetic resonance imaging, intravascular ultrasound, and optical coherence tomography. Molecular imaging is the tool best suited for identifying metabolically active macrophages. Indeed, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) is capable of identifying and quantifying vascular inflammation characterized by macrophage activation within the atherosclerotic plaques. So, FDG-PET might be a feasible clinical tool for detecting vulnerable plaques and evaluating the efficacy of drugs in plaque instability. In this paper, we review the clinical utility of FDG-PET imaging in identifying patients at risk of plaque rupture and resultantly prone to cardiovascular disease.

Vascular Inflammation Evaluated by [18F]-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Is Associated With Endothelial Dysfunction

Objective—Endothelial dysfunction is an initial step in atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans because of the lack of diagnostic modality to noninvasively evaluate vascular inflammation. We assessed the relationship between endothelial function and vascular inflammation evaluated by [18F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging. Approach and Results—We examined endothelial function and vascular inflammation by flow-mediated dilation (FMD) of the brachial artery and [18F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging of carotid arteries, respectively, in 145 subjects (95 men and 50 women; mean age, 61.8±9.5 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target:background ratio (TBR). We investigated whether absolute changes from baseline of %FMD after antihypertensive treatment for 6 months (&Dgr;%FMD) were correlated with those of TBR in 33 drug-naive patients with essential hypertension. Multiple logistic regression analysis revealed that age (odds ratio, 1.767 for 10-year increase), male sex (odds ratio, 0.434), low-density lipoprotein-cholesterol (odds ratio, 1.630 for 26-mg/dL increase), and TBR values (odds ratio, 1.759 for 0.2 increase) were independently associated with %FMD in 145 patients. There was an inverse correlation between &Dgr;%FMD and &Dgr;TBR; &Dgr;TBR was a sole independent associate of &Dgr;%FMD in hypertensive patients (r=−0.558; P<0.001). Conclusions—The present study showed that vascular inflammation in the carotid arteries evaluated by [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography was one of the independent correlates of decreased %FMD, thus suggesting the association of vascular inflammation with endothelial dysfunction in humans.

Positive correlation between malondialdehyde-modified low-density lipoprotein cholesterol and vascular inflammation evaluated by 18F-FDG PET/CT

OBJECTIVE The purpose of this study was to investigate the relationship between serum levels of malondialdehyde-modified low-density lipoprotein cholesterol (MDA-LDL) and vascular inflammation evaluated by fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT). METHODS/RESULTS The study involved 106 consecutive patients (75 males and 31 female, mean age 62.5 ± 7.7 years) who visited our hospital for cardiovascular risk screening and underwent carotid ultrasonography, (18)F-FDG PET/CT, complete history, physical examinations, and determination of blood chemistry including high-sensitivity C-reactive protein (hsCRP), asymmetric dimethylarginine (ADMA), and MDA-LDL. Vascular inflammation, was measured as blood-normalized standardized (18)F-FDG uptake value, known as the target-to-background ratio (TBR) of carotid arteries. Univariate and multiple stepwise regression analyses were performed for determining independent correlates of carotid TBR values. Median MDA-LDL, mean carotid TBR values and carotid intima-media thickness (IMT) were 127.5 (IQR 92.0-147.8) U/l, 1.55 ± 0.22, and 0.72 ± 0.15 mm, respectively. Univariate analysis revealed that carotid TBR values positively correlated with MDA-LDL (p = 0.043) and carotid IMT (p = 0.049). Multiple stepwise regression analysis demonstrated that MDA-LDL (p = 0.043) and carotid IMT (p = 0.038) were independently associated with carotid TBR values. CONCLUSION The present study reveals that serum levels of MDA-LDL are independently associated with vascular inflammation evaluated by (18)F-FDG PET/CT. Circulating MDA-LDL may be a more useful clinical biomarker for vascular inflammation within the atherosclerotic plaques than hsCRP or ADMA.

Anagliptin, A Dipeptidyl Peptidase-4 Inhibitor Ameliorates Arterial Stiffness in Association with Reduction of Remnant-Like Particle Cholesterol and Alanine Transaminase Levels in Type 2 Diabetic Patients

BACKGROUND Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a therapeutic target for type 2 diabetes (T2DM). Arterial stiffness, a predictor of future cardiovascular events and all-cause mortality, is augmented in these patients. However, effects of DPP-4 inhibitors on arterial stiffness remain unknown. In this study, we compared effects of anagliptin, an inhibitor of DPP-4 on arterial stiffness evaluated by cardio-ankle vascular index (CAVI) with those of an equipotent glucose-lowering agent, glimepiride in patients with T2DM. METHODS The study involved 50 consecutive outpatients (33 males and 17 females; mean age of 72.5±9.5 years) who visited our hospitals for a risk-screening test or treatment for T2DM. They underwent complete history and physical examination, and determination of blood chemistry and anthropometric variables, and then were randomized to receive either anagliptin (n=26) or glimepiride (n=24) for 6 months. RESULTS After 6-months treatment, fasting plasma glucose and HbA1c values were comparably reduced in both groups. Anagliptin, but not glimepiride treatment significantly decreased low-density lipoprotein cholesterol, malondialdehyde-modified LDL, remnant-like particle (RLP) cholesterol, CAVI, alanine transaminase (ALT), γ-glutamyl transferase and visceral fat volume. In multiple regression analysis, absolute changes from baseline of RLP cholesterol and ALT after anagliptin treatment for 6 months (ΔRLP cholesterol and ΔALT) were independently correlated with ΔCAVI (R2=0.445). CONCLUSION The present study suggests that anagliptin may exert a beneficial effect on arterial stiffness in patients with T2DM, which is independent of its blood glucose-lowering property. Anagliptin may ameliorate arterial stiffness partly via reduction of RLP cholesterol and improvement of liver function.

Switching Dipeptidyl Peptidase-4 Inhibitors to Tofogliflozin, a Selective Inhibitor of Sodium-Glucose Cotransporter 2 Improves Arterial Stiffness Evaluated by Cardio-Ankle Vascular Index in Patients with Type 2 Diabetes: A Pilot Study

BACKGROUND We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients. METHODS Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin. RESULTS At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI. CONCLUSION The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.

FDG-PET/CT images during 5 years before acute aortic dissection.

Since 2008, a 64-year-old man has regularly taken cancer-screening tests by combined computed tomography (CT) and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan at his own expenses ( Panels A1–A8 ). Three weeks before the last PET/CT scan (10 December 2013), he suffered from chest pain extending to his neck. The serial PET/CT scans indicated that his aortic arch has progressively enlarged ( Panels A1–A3 ; white arrowheads and A9 ; diameter of aortic arch) and that aortic FDG …

Serum levels of pigment epithelium-derived factor (PEDF) are inversely associated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans

BACKGROUND We have previously found that advanced glycation end products (AGEs) stimulate the proteolytic cleavage of dipeptidyl peptidase-4 (DPP-4) from plasma membranes, and circulating AGE levels are independently correlated with serum DPP-4 values. Since pigment epithelium-derived factor (PEDF), one of the adipocytokines, inhibits the AGEs-induced insulin resistance and vascular damage, it is conceivable that besides AGEs, PEDF might also regulate soluble DPP-4 levels. In this study, we addressed the issue. STUDY DESIGN AND METHODS The study involved 188 subjects (123 males and 65 females; mean age of 61.1±9.2) who visited our hospital for a risk-screening test or treatment for cardiovascular disease. They underwent complete history and physical examinations, and determination of blood chemistry and anthropometric variables, including visceral and subcutaneous fat areas. Serum levels of DPP-4 and PEDF levels were examined by enzyme-linked immunosorbent assay. RESULTS Median (interquartile range) serum levels of DPP-4 and PEDF were 466.6 (400.2-545.1) ng/mL and 14.0 (10.6-17.0) μg/mL, respectively. Multiple stepwise regression analysis revealed that female (p<0.001), aspartate aminotransferase (p<0.001), glycated hemoglobin (p<0.001) and PEDF (inversely, p=0.020) were independently associated with DPP-4 levels (R(2)=0.267). CONCLUSION We found here for the first time that serum PEDF levels were one of the independent correlates of circulating DPP-4 levels in humans. Since DPP-4 could impair insulin action and evoke vascular damage, our present study suggests that insulin-sensitizing and atheroprotective properties of PEDF might be ascribed partly to its inhibitory actions on DPP-4.