The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4.

Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1ß, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1ß and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.

FOXM1-CD44 Signaling Is Critical for the Acquisition of Regorafenib Resistance in Human Liver Cancer Cells.

Regorafenib is a multikinase inhibitor that was approved by the US Food and Drug administration in 2017. Cancer stem cells (CSCs) are a small subset of cancer-initiating cells that are thought to contribute to therapeutic resistance. The forkhead box protein M1 (FOXM1) plays an important role in the regulation of the stemness of CSCs and mediates resistance to chemotherapy. However, the relationship between FOXM1 and regorafenib resistance in liver cancer cells remains unknown. We found that regorafenib-resistant HepG2 clones overexpressed FOXM1 and various markers of CSCs. Patients with hepatocellular carcinoma also exhibited an upregulation of FOXM1 and resistance to regorafenib, which were correlated with a poor survival rate. We identified a close relationship between FOXM1 expression and regorafenib resistance, which was correlated with the survival of patients with hepatocellular carcinoma. Thus, a strategy that antagonizes FOXM1-CD44 signaling would enhance the therapeutic efficacy of regorafenib in these patients.

Low Dose of Lenvatinib Treatment for Patients of Radioiodine-Refractory Differentiated Thyroid Carcinoma - A Real-World Experience.

BACKGROUND: Lenvatinib treatment of 24 mg/day for radioiodine-refractory differentiated thyroid carcinoma (RRDTC) patients was almost intolerable, with high rates of dose reduction, interruption and discontinuation. Balancing treatment safety with disease risks remains challenging, and the appropriate dosage remains unclear in Asia. PATIENTS AND METHODS: A total of 65 RRDTC patients treated with lenvatinib were retrospectively collected from Oct. 2015 to Jun. 2020 from two medical centers of South Taiwan. The drug tolerability, treatment efficacy and clinical outcomes were analyzed. RESULTS: Different doses of lenvatinib were initiated but ultimately maintained with a median dose of 10 mg/day within the first 3 months. The disease control rate reached 89.2%, including 24.6% partial response and 64.6% stable disease. Disease progression occurred in 10.8% of patients and increased to 40.0% at the end. Eventually, the treatment dose achieved a median progression-free survival (PFS) of 26.1 months (95% CI: 17.1-NA) with overall survival (OS) not reached yet (24.1~NA). Overall, the 48-month PFS rate was 35.6% (95% CI: 18.5-68.4) and 48-month OS was 54.3% (95% CI: 41.2-71.7). The dose was tolerable with a dose reduction rate of 44.6%, dose interruption rate of 40.0% and fewer high-graded adverse events. The drug discontinuation rate was only 3.1%. However, RRDTC patients with bone metastasis or maximal dose exposure to RAI (≥600 mCi) may have less efficacy to the low maintenance dose treatment. CONCLUSION: Assessing treatment intensity, safety and efficacy, low-dose lenvatinib treatment was well tolerated by RRDTC patients and displayed acceptable drug efficacy and outcomes.

Therapeutic Strategies Targeting Tumor Suppressor Genes in Pancreatic Cancer.

The high mortality of pancreatic cancer is attributed to the insidious progression of this disease, which results in a delayed diagnosis and advanced disease stage at diagnosis. More than 35% of patients with pancreatic cancer are in stage III, whereas 50% are in stage IV at diagnosis. Thus, understanding the aggressive features of pancreatic cancer will contribute to the resolution of problems, such as its early recurrence, metastasis, and resistance to chemotherapy and radiotherapy. Therefore, new therapeutic strategies targeting tumor suppressor gene products may help prevent the progression of pancreatic cancer. In this review, we discuss several recent clinical trials of pancreatic cancer and recent studies reporting safe and effective treatment modalities for patients with advanced pancreatic cancer.

Use and effectiveness of dapagliflozin in patients with type 2 diabetes mellitus: a multicenter retrospective study in Taiwan.

AIMS/INTRODUCTION: To investigate the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) who initiated dapagliflozin in real-world practice in Taiwan. MATERIALS AND METHODS: In this multicenter retrospective study, adult patients with T2DM who initiated dapagliflozin after May 1st 2016 either as add-on or switch therapy were included. Changes in clinical and laboratory parameters were evaluated at 3 and 6 months. Baseline factors associated with dapagliflozin response in glycated hemoglobin (HbA1c) were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 1,960 patients were eligible. At 6 months, significant changes were observed: HbA1c by -0.73% (95% confidence interval [CI] -0.80, -0.67), body weight was -1.61 kg (95% CI -1.79, -1.42), and systolic/diastolic blood pressure by -3.6/-1.4 mmHg. Add-on dapagliflozin showed significantly greater HbA1c reduction (-0.82%) than switched therapy (-0.66%) (p = 0.002). The proportion of patients achieving HbA1c <7% target increased from 6% at baseline to 19% at Month 6. Almost 80% of patients experienced at least 1% reduction in HbA1c, and 65% of patients showed both weight loss and reduction in HbA1c. Around 37% of patients had at least 3% weight loss. Multivariate logistic regression analysis indicated patients with higher baseline HbA1c and those who initiated dapagliflozin as add-on therapy were associated with a greater reduction in HbA1c. CONCLUSIONS: In this real-world study with the highest patient number of Chinese population to date, the use of dapagliflozin was associated with significant improvement in glycemic control, body weight, and blood pressure in patients with T2DM. Initiating dapagliflozin as add-on therapy showed better glycemic control than as switch therapy.

Stemness regulation of the adrenal mixed corticomedullary tumorigenesis-a case-control study.

Mixed corticomedullary tumor is an adrenal tumor intermixed with cortical and medullary cells. It is extremely rare with unclear tumorigenesis. We reported a 32-year-old female, manifested with typical Cushing's syndrome and hypertension, to be diagnosed with right huge adrenal mixed corticomedullary tumor (8.8 cm). Right adrenalectomy was done to document the tumor intimately admixed with adrenal cortical adenoma and pheochromocytoma by biochemistry and immunohistochemistry. A case-control study was designed to explore the tumorigenesis of mixed corticomedullary tumor by whole exome sequencing. Expression of the stemness markers was controlled by a tissue array of 80 adrenal tumors. Overall, 1559 identical variants coexisted in parts of adrenal cortical adenoma and pheochromocytoma, which mainly (85.8%) originated from germline mutations. These enriched mutations were engaged in stemness control, coherent with substantial expression of the stemness markers (SOX2, CD44 and OCT4) in both parts. The differential stemness expressions were demonstrated in other adrenal tumors as well. The germline mutations were also enriched in signaling involving cancer proliferation, hypoxia inducible factor-1, focal adhesion and extracellular matrix receptor interaction. Somatic mutations affecting mitogen-activated protein kinase signaling, glycolysis and the citrate cycle were found in some tumor elements. This is the first study to verify the rare mixed corticomedullary tumor by molecular and genetic evidence to link with its phenotype. Germline mutations involving the stemness regulation and cancer proliferative signaling may drive intermixed tumor formation. Somatic mutations related to glycolysis and the citrate cycle may contribute to greater tumor outgrowth.

Clinical application of the ultrasound-guided fine needle aspiration for thyroglobulin measurement to diagnose lymph node metastasis from differentiated thyroid carcinoma-literature review.

Papillary thyroid carcinoma (PTC) generally has a good prognosis, but disease recurs in 25% to 30% of PTC patients and significantly reduces the survival rate. Lymph node metastasis (LNM) is reported in 20% to 50% of PTC patients, mainly in the neck, and 20% originates from recurrence. LNM of papillary thyroid carcinoma are a plausible prognostic factor to determine disease recurrence. Currently, fine needle lymph node aspiration for cytology (LN-FN-cytology) is the best modality to diagnose LNM but is limited by diagnostic sensitivity and sample error. Fine needle lymph node aspiration for thyroglobulin measurement (LN-FNA-Tg) could offer a reliable and quantitative diagnostic method for LNM. The combination of LN-FNA-cytology and LN-FNA-Tg could achieve almost 100% diagnostic sensitivity and specificity for LNM. Both treatment guidelines of the American Thyroid Association and European Thyroid Association recommend LN-FNA-Tg to diagnose LNM after total thyroidectomy. Diagnostic accuracy of the LN-FNA-Tg depends on optimal equipment, scanning protocol, skill, and experience of operators. Normal saline is mainly used for aspiration needle wash-out and buffer solution. And radioimmunoassay or immunoradiometric assay are widely used for the LN-FNA-Tg measurement. So far, there is no consensus about the diagnostic threshold of LN-FNA-Tg for positive LNM, but high LN-FNA-Tg, especially higher than 10 ng/mL, strongly favors LNM.

Electronegative low-density lipoprotein of patients with metabolic syndrome induces pathogenesis of aorta through disruption of the stimulated by retinoic acid 6 cascade.

AIMS/INTRODUCTION: Electronegative low-density lipoprotein (L5) is the most atherogenic fraction of low-density lipoprotein and is elevated in people with metabolic syndrome (MetS), whereas the retinol-binding protein 4 receptor (stimulated by retinoic acid 6 [STRA6]) cascade is disrupted in various organs of patients with obesity-related diseases. Our objective was to investigate whether L5 from MetS patients capably induces pathogenesis of aorta through disrupting the STRA6 cascade. MATERIAL AND METHODS: We examined the in vivo and in vitro effects of L5 on the STRA6 cascade and aortic atherogenic markers. To investigate the role of this cascade on atherosclerotic formation, crbp1 transfection was carried out in vitro. RESULTS: This study shows that L5 activates atherogenic markers (p38 mitogen-activated protein kinases, pSmad2 and matrix metallopeptidase 9) and simultaneously suppresses STRA6 signals (STRA6, cellular retinol-binding protein 1, lecithin-retinol acyltransferase, retinoic acid receptor-α and retinoid X receptor-α) in aortas of L5-injected mice and L5-treated human aortic endothelial cell lines and human aortic smooth muscle cell lines. These L5-induced changes of the STRA6 cascade and atherogenic markers were reversed in aortas of LOX1-/- mice and in LOX1 ribonucleic acid-silenced human aortic endothelial cell lines and human aortic smooth muscle cell lines. Furthermore, crbp1 gene transfection reversed the disruption of the STRA6 cascade, the phosphorylation of p38 mitogen-activated protein kinases and Smad2, and the elevation of matrix metallopeptidase 9 in L5-treated human aortic endothelial cell lines. CONCLUSIONS: This study shows that L5 from MetS patients induces atherogenic markers by disrupting STRA6 signaling. Suppression of STRA6 might be one novel pathogenesis of aorta in patients with MetS.

Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.

BACKGROUND: The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION: Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION: Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.

GREATER LOW-DENSITY LIPOPROTEIN CHOLESTEROL VARIABILITY INCREASES THE RISK OF CARDIOVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS.

Objective: Variability in lipid levels has been associated with poor cardiovascular outcomes in patients with coronary artery disease. The aim of this study was to investigate whether low-density lipoprotein cholesterol (LDLC) variability can be used to predict cardiovascular events in patients with type 2 diabetes mellitus (DM). Methods: A total of 5,354 patients with type 2 DM were enrolled in this study. Cardiovascular events including peripheral arterial disease, coronary artery disease, stroke, and cardiovascular death were defined as the study endpoints, and standard deviations of lipid levels were used to define intra-individual lipid variability. Results: Univariate Cox proportional hazards analysis showed that LDL-C standard deviation (hazard ratio [HR] = 1.016; 95% confidence interval [CI] = 1.006 to 1.022; P<.001) was associated with a higher risk of cardiovascular events. Multivariate Cox proportional hazards analysis showed that an increase in LDL-C standard deviation significantly increased the risk of cardiovascular events (HR = 1.063; 95% CI = 1.025 to 1.102; P = .01). Kaplan-Meier analysis of cardiovascular event-free survival showed that the patients in tertiles 2 and 3 of the standard deviation of LDL-C had worse cardiovascular event-free survival compared to those in tertile 1. Conclusion: Variability in LDL-C could predict cardiovascular events in the patients with type 2 DM in this study. Abbreviations: CAD = coronary artery disease; CI = confidence interval; CVD = cardiovascular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; KMUHRD = Kaohsiung Medical University Hospital Research Database; LDL-C = low-density lipoprotein cholesterol; SD = standard deviation; UACR = urine albumin to creatinine ratio.

Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System.

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.

A subanalysis of Taiwanese patients from ODYSSEY South Korea and Taiwan study evaluating the efficacy and safety of alirocumab.

BACKGROUND: Alirocumab can provide significant reductions in low-density lipoprotein cholesterol (LDL-C). However, data regarding its efficacy and safety in Asians are limited. METHODS: A subgroup analysis of Taiwanese patients (n = 116) in a randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT, clinicaltrials.gov Identifier: NCT02289963) was performed. Patients with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized to alirocumab (75 mg every 2 weeks; with dose increased to 150 mg at Week 12 if LDL-C ≥ 70 mg/dL at Week 8) or placebo for 24 weeks. The primary efficacy endpoint was the percent change in LDL-C from baseline to Week 24. Safety was assessed for a total of 32 weeks. RESULTS: At Week 24, the percent change in calculated LDL-C in the alirocumab group (n = 57) was -51%, whereas that in the placebo group (n = 59) was 2.5%. Alirocumab significantly improved other lipid parameters, including non-high-density lipoprotein cholesterol, apolipoprotein B and A1, lipoprotein (a), high-density lipoprotein cholesterol, and total cholesterol. A significantly higher proportion of patients in the alirocumab group reached an LDL-C target below 70 mg/dL than those in the placebo group (81.3% vs 15.4%). The incidence of treatment-emergent adverse events was comparable between both groups. CONCLUSION: Alirocumab treatment provided a favorable effect on LDL-C levels and other lipid parameters, and was generally well-tolerated in patients from Taiwan. The results of current analysis were consistent with the overall ODYSSEY phase 3 program.

O-GlcNAcylation disrupts STRA6-retinol signals in kidneys of diabetes.

BACKGROUND: O-GlcNAcylation is an important mechanism of diabetic complication. Retinoid homeostasis regulates cell-physiological functions through STRA6-retinol signaling. Therefore, we investigated whether O-GlcNAcylation disrupted STRA6-retinol signals in diabetes. METHODS: Immunoprecipitation and proximity ligation assay were used to investigate O-GlcNAcylation of STRA6-retinol signals in kidneys of db/db and ob/ob mice. Western blot and immunohistochemistry were done for STRA6/CRBP1/LRAT/RALDH1/RARs pathway, GFAT, OGT, TGFß1 and collagen 1 level. HPLC and ELISA for retinol, retinal, and retinoic acid concentrations were performed in vivo and vitro. RBP4 binding with STRA6 was measured in vitro. To verify whether O-GlcNAcylation disrupted STRA6-retinol signals, treatment of TMG and OSMI-1, transfection of OGA and OGT, and OGT siRNA were performed in HK-2 cells. RESULTS: STRA6 and RALDH1 were highly O-GlcNAc-modified in glomeruli and tubules of db/db and ob/ob mice. RBP4, p-Try, p-JAK2, and p-STAT5 on STRA6 immunoprecipitate were reduced. Cellular retinol signals (CRBP1, LRAT, ADH, retinol, retinal, RA, RARα, RARγ and RXRα) remarkably decreased in kidneys of db/db, ob/ob mice and HG-cultured cells. TMG and OGT transfection induced O-GlcNAcylation of STRA6 and RALDH1, repressed RBP4-bound STRA6, and retinol signals in NG-cultured cells. OSMI-1, OGA transfection, and OGT silence reversed O-GlcNAc-modification of STRA6 and RALDH1, and rescued the decrease of retinol signals, and reversed the increase of TGFß1 and collagen 1 in HG-treated cells. CONCLUSIONS: O-GlcNAcylation significantly modified STRA6 and RALDH1, suppressed RBP4 binding activity, and disrupted retinol signals in the kidney of diabetes. GENERAL SIGNIFICANCE: This study first indicates that STRA6-retinol signals were directly disrupted by O-GlcNAcylation in diabetic kidney.

Successful management of type IV hypersensitivity reactions to human insulin analogue with injecting mixtures of biphasic insulin aspart and dexamethasone.

Although hypersensitivity reaction to insulin was supposed to be less-frequent with current insulin analogue, case reports with different types of allergic reactions to insulin analogue were still reported. The most common form is type I hypersensitivity reaction with IgE-mediated. Besides, type III (IgG and IgM-mediated) and type IV (T-cell mediated delayed reaction) hypersensitivity reactions were also reported. Here we presented a long-standing type 2 diabetes with insulin requirements with hypersensitivity reactions to insulin actrapid, insulin aspart, insulin glargine, insulin detemir, and biphasic insulin aspart 30. Insulin desensitization was performed as initial management but failed as skin biopsy with immunohistochemical staining proved type IV hypersensitivity reaction. We continued with the next treatment approach using subcutaneous injection with the mixture of biphasic insulin aspart 30 and dexamethasone to alleviate allergy, and the result was successful with steroid-free biphasic insulin aspart 30 injection eight months later. Besides, the treatment effect had lasted after ten years even with switched type of insulin analogue from biphasic insulin aspart 30 to insulin glargine and insulin aspart. The case report demonstrated a good example of how clinicians deal with the rare but important questions of hypersensitivity reactions to insulin analogue.

Basal insulin therapy: Unmet medical needs in Asia and the new insulin glargine in diabetes treatment.

Diabetes remains a global epidemic and a tremendous health challenge, especially in the Asian population. Dramatic increases in the prevalence of diabetes across different countries or areas in Asia have been reported in recent epidemiological studies. Although clinical guidelines have strengthened appropriate antihyperglycemic medications and lifestyle modifications for optimal diabetes management, inadequate glycemic control still occurs in many patients with an increased risk of developing microvascular and macrovascular complications. Insulin administration is the main therapy for diabetes in response to the inability to secrete insulin, and is recommended in current guidelines to treat patients with type 2 diabetes after failure of oral antidiabetic drugs. Clinical studies have shown that long-acting insulin analogs improve basal glycemic control with reduced risk of hypoglycemia. In the present review, we discuss previous challenges with basal insulin therapy in Asia, the pharmacological development of insulin analogs to overcome the unmet medical needs and recent clinical studies of the new ultra-long-acting insulin analog, insulin glargine U300. Furthermore, relevant findings of current real-world evidence are also included for the comparison of the efficacy and safety of different insulin formulations. Based on the accumulating evidence showing a low incidence of hypoglycemia and technical benefits of dose titration, treatment with glargine U300 can be a promising strategy for Asian diabetes patients to achieve glycemic targets with favorable safety.

ASSOCIATIONS BETWEEN TRIGLYCERIDE/HIGH-DENSITY LIPOPROTEIN CHOLESTEROL RATIO AND MICRO- AND MACROANGIOPATHIES IN TYPE 2 DIABETES MELLITUS.

OBJECTIVE: The triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio has been reported to be a marker of insulin resistance. The aim of this study was to investigate associations between the TG/HDL-C ratio and micro- and macroangiopathies in patients with type 2 diabetes mellitus (DM). METHODS: A total of 1,981 (851 male and 1,130 female) patients with type 2 DM were enrolled from our outpatient clinic. These patients were stratified into 4 groups according to TG/HDL-C ratio quartiles. RESULTS: There were significant trends for stepwise increases in albuminuria ≥30 mg/g ( P<.001), coronary artery disease (CAD, P = .040), cerebrovascular disease (CVA, P = .002) and ankle-brachial index (ABI) <0.9 ( P = .001) corresponding to TG/HDL-C ratio quartiles, but not diabetic retinopathy ( P = .105). Furthermore, quartile 4 of the TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and ABI <0.9 after multivariate analysis compared to quartile 1. CONCLUSION: A high TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and peripheral artery occlusive disease (PAOD) in patients with DM, which translated into an increased risk of cardiovascular disease. ABBREVIATIONS: ABI = ankle-brachial index; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; CVA = cerebrovascular disease; DM = diabetes mellitus, DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; OR = odds ratio; PAOD = peripheral artery occlusive disease; TGs = triglycerides.

Association Between Metabolic Syndrome and Microvascular and Macrovascular Disease in Type 2 Diabetic Mellitus.

BACKGROUND: The prevalence of metabolic syndrome (MetS) in patients with type 2 diabetes mellitus is high. The aim of this study was to investigate the association between MetS and micro- and macrovascular disease in patients with diabetes and the associated risk factors. METHODS: The study enrolled 1,986 (854 men and 1,132 women) patients with type 2 diabetes mellitus from outpatient clinics. MetS was defined according to the Adult Treatment Panel III for Asians. RESULTS: Of the enrolled patients, 1,363 had MetS and 623 did not. The patients with MetS had significantly higher rates of albuminuria (40.8% vs. 21.8%, P < 0.001), retinopathy (37.9% vs. 28.6%, P < 0.001), coronary artery disease (19.4% vs. 11.6%, P < 0.001), cerebrovascular disease (5.8% vs. 3.2%, P = 0.014), and an ankle-brachial index < 0.9 or ≥ 1.3 (6.1% vs. 3.0%, P = 0.015). Moreover, there were significant trends for stepwise increases in albuminuria, retinopathy, coronary artery disease, cerebrovascular disease and peripheral artery disease corresponding to the number of MetS components (all P for trend < 0.05). Risk factors including MetS, old age, sex, wide pulse pressure, increased hemoglobin A1c, dyslipidemia and decline renal function were associated with micro- and macrovascular disease. CONCLUSIONS: MetS and the number of its components were significantly associated with micro- and macrovascular disease in the study patients with diabetes and this resulted in a higher risk of cardiovascular disease. Screening programs to allow for early detection and interventions should be established to lower the risk of cardiovascular disease.

Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease.

BACKGROUND: Impaired renal function can lead to the accumulation of metformin, and elevated concentrations of metformin have been associated with lactic acidosis. The aim of this study was to evaluate the effect of continuous metformin treatment in patients with type 2 diabetes mellitus (DM) and moderate chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) 30-0 ml/min/1.73 m2) on renal function. METHODS: A total of the 616 patients were enrolled from the research database of Kaohsiung Medical University Hospital from January 1 to 2009 and December 31, 2013. The patients were divided into two groups: those who continued metformin treatment (continuation group; n = 484), and those who discontinued metformin treatment for at least 100 days (interruption group; n = 132). RESULTS: The slope of eGFR in the metformin interruption group was statistically lower than that in the metformin continuation group (0.75 ± 0.76 vs. -1.32 ± 0.24 mL/min/1.73 m2/year, p = 0.0007). After adjusting for baseline covariates in the multivariate linear regression analysis, the continuation of metformin (unstandardized coefficient ß, -2.072; 95% confidence interval, -3.268- -0.876) was a risk factor for the patients with DM and moderate CKD. CONCLUSIONS: Metformin may have an adverse effect on renal function in patients with type 2 DM and moderate CKD.

Abnormally Low or High Ankle-Brachial Index Is Associated With the Development of Diabetic Retinopathy in Type 2 Diabetes Mellitus.

Although some studies have reported an association between peripheral artery disease (PAD) and diabetic retinopathy (DR) in patients with diabetes, whether or not a causal relationship exists is unknown. The aim of this study was to investigate whether PAD, as indicated by an abnormally low or high ankle-brachial index (ABI), is associated with the development of DR in patients with type 2 diabetes mellitus (DM) without DR. We enrolled 414 (221 men and 193 women) patients with type 2 DM who underwent ABI measurements at our outpatient clinic. PAD was defined as an abnormally low (<0.9) or high (≥1.3) ABI in either leg, and DR was defined as being non-proliferative or proliferative. Of the enrolled patients, 69 (16.7%) had an ABI <0.9 or ≥1.3. The median follow-up period was 23 (15-40) months, during which 74 (17.9%) patients developed DR. In multivariate analysis, an ABI <0.9 or ≥1.3 was independently associated with the development of DR (vs. ABI ≥0.9 to <1.3; hazard ratio, 2.186; 95% confidence interval, 1.261 to 3.789; p = 0.005). An abnormal ABI was associated with the development of DR in our patients with type 2 DM without DR.

A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT).

BACKGROUND: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, has been shown to provide significant reductions in low-density lipoprotein cholesterol (LDL-C). Data about its efficacy and safety in patients from South Korea and Taiwan are limited. OBJECTIVE: ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan. METHODS: Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were randomized (1:1) to alirocumab (75 mg every 2 weeks, with dose increase to 150 mg every 2 weeks at week 12 if LDL-C ≥70 mg/dL at week 8) or placebo for 24 weeks. The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24. Safety was assessed throughout. RESULTS: At week 24, alirocumab changed LDL-C levels by -57.1% (placebo: +6.3%). In the alirocumab group, 9 patients (9.5%) received dose increase at week 12. At week 24, 85.8% of patients in the alirocumab group reached LDL-C <70 mg/dL (placebo: 14.2%; P ≤ .0001 vs placebo). Alirocumab significantly improved non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total cholesterol, lipoprotein (a), and HDL-C vs placebo (P ≤ .05). Two consecutive calculated LDL-C values <25 mg/dL were recorded in 27.8% of alirocumab-treated patients. Overall, 58.8% (alirocumab) and 61.8% (placebo) of patients experienced treatment-emergent adverse events; 2.1% and 1.0% discontinued treatment due to treatment-emergent adverse events, respectively. CONCLUSION: Alirocumab significantly improved LDL-C, apolipoprotein B, non-HDL-C, lipoprotein (a), HDL-C, and total cholesterol in Asian patients. Alirocumab was generally well tolerated. These findings are consistent with ODYSSEY findings to date.