Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials

BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea

BACKGROUND: We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia. RESULTS: The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. −0.9±6.0 kg, P=0.011). CONCLUSION: The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.

Effects of Incretin-Based Therapies on Diabetic Microvascular Complications

The morbidity and mortality associated with diabetic complications impose a huge socioeconomic burden worldwide. Therefore, the ultimate goal of managing diabetes mellitus (DM) is to lower the risk of macrovascular complications and highly morbid microvascular complications such as diabetic nephropathy (DN) and diabetic retinopathy (DR). Potential benefits of incretin-based therapies such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on the diabetic macrovascular complications have been recently suggested, owing to their pleiotropic effects on multiple organ systems. However, studies primarily investigating the role of these therapies in diabetic microvascular complications are rare. Nevertheless, preclinical and limited clinical data suggest the potential protective effect of incretin-based agents against DN and DR via their anti-inflammatory, antioxidative, and antiapoptotic properties. Evidence also suggests that these incretin-dependent and independent beneficial effects are not necessarily associated with the glucose-lowering properties of GLP-1 RAs and DPP-4 inhibitors. Hence, in this review, we revisit the preclinical and clinical evidence of incretin-based therapy for DR and DN, the two most common, morbid complications in individuals with DM. In addition, the review discusses a few recent studies raising concerns of aggravating DR with the use of incretin-based therapies.

Role of NO/VASP Signaling Pathway against Obesity-Related Inflammation and Insulin Resistance

Obesity has quickly become a worldwide pandemic, causing major adverse health outcomes such as dyslipidemia, type 2 diabetes mellitus, cardiovascular disease and cancers. Obesity-induced insulin resistance is the key for developing these metabolic disorders, and investigation to understand the molecular mechanisms involved has been vibrant for the past few decades. Of these, low-grade chronic inflammation is suggested as a critical concept in the development of obesity-induced insulin resistance, and the anti-inflammatory effect of nitric oxide (NO) signaling has been reported to be linked to improvement of insulin resistance in multiple organs involved in glucose metabolism. Recently, a body of evidence suggested that vasodilatory-stimulated phosphoprotein (VASP), a downstream mediator of NO signaling plays a crucial role in the anti-inflammatory effect and improvement of peripheral insulin resistance. These preclinical studies suggest that NO/VASP signaling could be an ideal therapeutic target in the treatment of obesity-related metabolic dysfunction. In this review, we introduce studies that investigated the protective role of NO/VASP signaling against obesity-related inflammation and insulin resistance in various tissues.

Mechanism of Hypoglycemia-Associated Cardiovascular Diseases / 임상당뇨병

Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes mellitus. However, the benefit of intensive glycemic control in reducing CVD is unclear. In large clinical trials, intensive glycemic control was associated with increased incidence of hypoglycemia and all-cause mortality. Although it is uncertain whether hypoglycemia is a direct cause of CVD, a marker of vulnerability, or both, numerous studies have reported that hypoglycemia is associated with increased cardiovascular events such as cardiac arrhythmia and ischemia. The potential mechanisms of hypoglycemia-associated CVD include sympathoadrenal activation, repolarization abnormality, cardiac autonomic neuropathy, increased thrombogenesis, inflammatory reaction, and endothelial dysfunction. In this article, we review the evidence of an association of hypoglycemia with CVD in patients with diabetes and discuss the possible mechanisms through which hypoglycemia might result in adverse cardiovascular outcomes.

Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes.

A Case of IgG4-Related Lung Disease Mimicking Non-Specific Interstitial Pneumonia / 대한내과학회지

Immunoglobulin (Ig) G4-related disease is a recently described systemic inflammatory disease characterized by high serum IgG4 concentrations and sclerosing inflammation of numerous IgG4-positive plasma cells that responds favorably to steroid treatment. Although initial description of this disorder focused on its pancreatic presentation, it has become apparent that it is a systemic disease. In this report, we describe a case of IgG4-related lung disease presenting as non-specific interstitial pneumonia in a 78-year-old male with interstitial lung disease. Pathological examination through video-assisted thoracic surgery showed a non-specific interstitial pneumonia pattern and numerous (> 50/high-power field) infiltrating IgG4-positive plasma cells. Laboratory tests also revealed a high serum IgG4 concentration. Prednisolone therapy was initiated and his symptoms and reticular opacity improved after two months of treatment.

Serum Ceruloplasmin Level as a Predictor for the Progression of Diabetic Nephropathy in Korean Men with Type 2 Diabetes Mellitus

BACKGROUND: Oxidative stress is known to be associated with progression of diabetic kidney disease. Ceruloplasmin acts as a pro-oxidant under conditions of severe oxidative stress. Thus, we conducted a longitudinal observational study to evaluate whether the serum ceruloplasmin level is a predictive biomarker for progression of diabetic nephropathy. METHODS: A total of 643 Korean men with type 2 diabetes mellitus were enrolled. Serum ceruloplasmin was measured using a nephelometric method. Progression of diabetic nephropathy was defined as transition in albuminuria class (i.e., normoalbuminuria to microalbuminuria, microalbuminuria to macroalbuminuria, or normoalbuminuria to macroalbuminuria) and/or a greater than 2-fold increase of serum creatinine at follow-up compared with the baseline value. RESULTS: During the follow-up period (median, 2.7 years; range, 0.3 to 4.4 years), 49 of 643 patients (7.6%) showed the progression of diabetic nephropathy and three patients (0.5%) developed end-stage renal disease. Baseline ceruloplasmin levels were higher in the progressors than in the nonprogressors (262.6+/-40.9 mg/L vs. 233.3+/-37.8 mg/L, P<0.001). Kaplan-Meier analysis showed a significantly higher incidence of nephropathy progression according to ceruloplasmin tertile (log-rank test, P<0.001). The hazard ratio (HR) for progression of diabetic nephropathy was significantly higher in the highest ceruloplasmin tertile category compared with the lowest ceruloplasmin tertile category, even after adjusting for confounding variables (HR, 3.32; 95% confidence interval, 1.28 to 8.61; P=0.003). CONCLUSION: Baseline serum ceruloplasmin is an independent predictive factor for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus.

Multiple Myeloma in a Patient with Acromegaly

Acromegaly is a slowly progressing condition resulting from excess growth hormone (GH), generally caused by a GH-secreting pituitary adenoma. Cancer is the third most common cause of mortality in patients with acromegaly, and insulin-like growth factor 1 (IGF-1) is known to influence tumor formation by increasing cell proliferation and inhibiting apoptosis. Multiple myeloma (MM) is a plasma cell neoplasm, and previous studies have suggested the possible role of IGF-1 in its development of MM. However, no cases of acromegaly accompanied with MM have been reported in Asia to date. We here report the case of a 58-year-old woman with acromegaly accompanied with MM who presented with longstanding acromegalic manifestations resulting from a GH-secreting pituitary adenoma and also exhibited anemia, a reversed albumin/globulin ratio, and plasmacytosis on bone marrow examination. Because IGF-1 has been suggested to play an important role in the development and progression of MM, the patient promptly underwent surgical removal of the pituitary adenoma via a transsphenoidal approach. Since there is currently no consensus on therapeutic guidelines and suggested prognosis for MM with acromegaly, long-term follow-up of such cases is needed.

Association of Plasma Homocysteine Level and Arterial Stiffness in Subjects with Type 2 Diabetes Mellitus

OBJECTIVE: Plasma homocysteine (Hcy) is considered to be a marker of endothelial dysfunction and a predictor of cardiovascular disease (CVD). Arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV) is not only a marker of vascular damage but a significant predictor of CVD. Previous studies about the effect of high plasma Hcy levels on arterial stiffness have yielded inconsistent results. We therefore assessed the association between Hcy and baPWV in a relatively large number of subjects with type 2 diabetes mellitus (DM). METHODS: We retrospectively assessed plasma Hcy concentration and arterial stiffness in 1,477 Korean type 2 diabetic patients. Participants were also evaluated for plasma glucose, hemoglobin A1c (HbA1c), duration of DM, microvascular complications, lipid profile, and high sensitivity C-reactive protein (hsCRP). Arterial stiffness was measured noninvasively by baPWV. RESULTS: Correlation analysis indicated a significant positive association between serum Hcy levels and baPWV (r=0.245, p<0.001). In a multiple linear regression analysis, the association between serum Hcy levels and baPWV was independent of traditional cardiovascular risk factors (standardized beta=3.8, p=0.01). CONCLUSION: The results support the hypothesis that plasma Hcy levels are associated with arterial stiffness in patients with type 2 DM. Prospective studies are warranted to determine whether lowering serum Hcy level could reduce arterial stiffness and cardiovascular morbidity in type 2 DM.

Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice

We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) gamma-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.

Characteristics of Cognitive Faculties in Elderly Depressive Patientscomplaining of Memory Decline and Patients with Amnestic Mild Cognitive Impairment

OBJECTIVES: Elderly depression is often misdiagnosed as a dementing illness such as Alzheimer's disease (AD). Moreover, depressive symptoms often are presented in the early phase of AD. It is difficult to distinguish the difference between mild cognitive impairment (MCI) and depression. The purpose of this study is to explore neuropsychological characteristics of patients with amnestic MCI (aMCI) and depression. We hypothesized that there would be the difference in the cognitive function of those groups and this made clearer the nature of a depression and aMCI. METHODS: A community dwelling older people aged over 60 years were enrolled for the study. We compared 24 patients with aMCI, 23 with depression complaining subjective memory decline, and 26 normal elderly. Demographic and neuropsychological data were gathered and assessed by trained psychologist. RESULTS: Patients with aMCI and depression had significant differences separately from normal controls in particular cognitive function. Patients with aMCI showed more cognitive declines in learning than normal older people. Patients with depression had less performance in attention and executive function than normal controls. CONCLUSION: To understand the clinical difference and underlying pathophysiology of aMCI and depression, the precise criteria of aMCI gathering more homogeneous group of depression in severity and onset time will be needed.

The effect of concentration and application time of hydrogen peroxide on the microtensile bond strength of resin restorations to the dentin at different depths / 대한치과보존학회지

The purpose of this study was to examine the effect of hydrogen peroxide at different application time and concentrations on the microtensile bond strength of resin restorations to the deep and the pulp chamber dentin. A conventional endodontic access cavity was prepared in each tooth, and then the teeth were randomly divided into 1 control group and 4 experimental groups as follows: Group 1, non treated; Group 2, with 20% Hydrogen peroxide(H2O2); Group 3, with 10% H2O2; Group 4, with 5% H2O2; Group 5, with 2.5% H2O2; the teeth of all groups except group 1 were treated for 20, 10, and 5min. The treated teeth were filled using a Superbond C&B (Sun medical Co., Shiga, Japan). Thereafter, the specimens were stored in distilled water at 37degrees C for 24-hours and then sectioned into the deep and the chamber dentin. The microtensile bond strength values of each group were analyzed by 3-way ANOVA and Tukey post hoc test(p 0.05). The higher H2O2 concentration, the more opened dentinal tubules under a scanning electron microscope(SEM) examination.

The Reliability and Validity of the Korean Version of Family Questionnaire: A Questionnaire Measuring Expressed Emotion / 신경정신의학

OBJECTIVES: The present study was designed to assess the reliability and validity of Korean version of Family Questionnaire (FQ-K), a brief questionnaire measuring expressed emotion (EE). METHODS: A sample of 84 first-order relatives of schizophrenics completed the FQ-K and the data were analyzed for internal consistency and factor structure. Additionally non-random subset of participants (n=34) refilled FQ-K after two weeks for testretest reliability and naturalistic follow-up data of 36 were obtained for any re-hospitalization events to assess predictive validity. RESULTS: Internal consistency of FQ-K was good (Cronbach's alpha=.819) and principal component factor analysis revealed the two-factor structure (criticism and emotional overinvolvement) identical to previously reported for the FQ. The FQ-K also showed reasonable test-retest reliability and excellent predictive validity was indicated in that outcome of re-hospitalization was superior for low expressed emotion patients at six-month naturalistic follow-up. CONCLUSION: The Korean version of FQ proved to be a reliable and valid instrument measuring expressed emotion in relatives of Korean patients with schizophrenia.

Comparison of canal shaping methods with GT(TM) rotary file and condensation methods / 대한치과보존학회지

The purpose of this study was to compare the shaping time of two shaping methods and the leakage of three different obturation techniques. Ninty three canaled human molar teeth were used, which were randomly divided into two groups of forty teeth each and ten control teeth. After working length determination, the one group was prepared crown-down technique using rotary root canal instruments of GT rotary files .12/20, .10/20, .08/20 and .06/20 taper(Maillefer Instrument SA. Switzerland). The other group was instrumented with Gates Glidden burs(#1, #2, and #3) to coronal preparation and GT rotary files .08/20 and .06/20 taper to apical preparation. Shaping time was measured. After root canals were instrumented, they were divided to three subgroups and obturated as follows: Subgroup 1, obturated with single cone method : Subgroup 2, obturated with lateral condensation : Subgroup 3, obturated with continuous wave technique. Three subgroups were obturated using non-standardized gutta-percha cone(Diadent, Korea, .06 or .08 taper) and AH-26(Dentsply DeTrey, Germany) as a root canal cement. Ten unobturated teeth served as positive and negative controls. After immersion in 2% methylene blue solution for 1 month, the teeth were washed during 24h. The teeth were demineralized in 10% nitric acid and dehydrated by immersion in 80, 90 and 100% ethyl alcohol. The teeth were finally cleared and stored in 100% methylsalicylate, and apical dye penetration was evaluated under stereomicroscope (Leica M420, LC, U.S.A) at x8.75 magnification. Liner measurement of dye penetration was assessed with the use of digitalized image analysing system (analySIS, GmbH, Germany). The data were analysed statistically using independent T-test and Two-way ANOVA and Tukey test. The result were as follows: 1. In canal prepared with GT(TM)rotary file, shaphing time taked more than the group of using Gates Glidden drill to coronal preparation without statistical significance (p>0.05). 2. The group of single cone obturation using canal preparation of GT(TM) rotary files showed significantly more apical leakage than those of lateral condensation and continuous wave technique regardless of shaping method (p0.05). 5. The group of single cone obturation using canal preparation of GT(TM) rotary files and Gates Glidden drill showed more apical leakage than the group of lateral condensation using same shaping method without statistical significance (p>0.05).