Background: We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus. Methods: We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months. Results: After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of β-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis. Conclusion Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.

OBJECTIVES: We explored whether the association between vitamin B2 and colorectal cancer (CRC) risk could be modified by the MTRR rs1801394 and MTR rs1805087 genetic polymorphisms and examined whether the interaction effects are sex-specific. METHODS: We performed a case-control study involving 1,420 CRC patients and 2,840 controls from the Korea National Cancer Center. Dietary vitamin B2 intake was assessed using a semiquantitative food frequency questionnaire, and the association with CRC was evaluated. Genotyping was performed using an Illumina MEGA-Expanded Array. For gene-nutrient interaction analysis, pre-matched (1,081 patients and 2,025 controls) and matched (1,081 patients and 1,081 controls) subsets were included. Unconditional and conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A higher intake of vitamin B2 was associated with a significantly lower CRC risk (OR, 0.65; 95% CI, 0.51 to 0.82; p<0.001). Carriers of at least 1 minor allele of MTRR rs1801394 showed a significantly higher CRC risk (OR, 1.43; 95% CI, 1.12 to 1.83). Males homozygous for the major allele (A) of MTRR rs1801394 and who had a higher intake of vitamin B2 had a significantly lower CRC risk (OR, 0.31; 95% CI, 0.18 to 0.54; p-interaction=0.02). In MTR rs1805087, males homozygous for the major allele (A) and who had a higher vitamin B2 intake had a significantly lower CRC risk (OR, 0.38; 95% CI, 0.25 to 0.60; p-interaction<0.001). CONCLUSIONS The MTRR rs1801394 and MTR rs1805087 genetic polymorphisms may modify the association between vitamin B2 and CRC risk, particularly in males. However, further studies are warranted to confirm these interaction results.

Background: The relationship between aspirin usage and the risk of colorectal cancer (CRC) among individuals with both hypertension (HTN) and diabetes mellitus (DM) remains unclear. This study aims to explore the impact of aspirin use on the site-specific CRC risk in patients with metabolic comorbidity. Methods: A case-control study was conducted among 1,331 CRC patients and 2,771 controls recruited from the Nation Cancer Center in Korea. Multinomial logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between aspirin use, metabolic disease status, and site-specific CRC risk. Results: Among the 4,102 participants, 1,191 individuals had neither HTN nor DM, 2,044 were diagnosed with HTN, 203 with DM, and 664 presented with HTN and DM comorbidity.An increasing number of HTN and DM was associated with an increased risk of overall CRC (HTN or DM: OR, 1.70; 95% CI, 1.39–2.07; HTN and DM: OR, 8.43; 95% CI, 6.37–11.16), while aspirin use was associated with a decreased risk of overall CRC (OR, 0.31; 95% CI, 0.21–0.46).These results remained consistent across anatomical sites. Among individuals with HTN and DM comorbidity, aspirin use notably associated with lower risk of overall CRC (OR, 0.39; 95% CI, 0.21–0.72), proximal colon (OR, 0.32; 95% CI, 0.13–0.71) and rectal cancer (OR, 0.27;95% CI, 0.08–0.97), but not distal colon cancer (OR, 0.58; 95% CI, 0.27–1.24). Conclusion This study showed that aspirin use is negatively associated with overall and sitespecific CRC, even among individuals with HTN and DM comorbidity.

Background: Long term quality of life is becoming increasingly crucial as survival following partial pancreatectomy rises. The purpose of this study was to investigate the difference in glucose dysregulation after pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). Methods: In this prospective observational study from 2015 to 2018, 224 patients who underwent partial pancreatectomy were selected: 152 (67.9%) received PD and 72 (32.1%) received DP. Comprehensive assessment for glucose regulation, including a 75 g oral glucose tolerance test was conducted preoperatively, and 1, 12, and 52 weeks after surgery. Patients were further monitored up to 3 years to investigate development of new-onset diabetes mellitus (NODM) in patients without diabetes mellitus (DM) at baseline or worsening of glucose regulation (≥1% increase in glycosylated hemoglobin [HbA1c]) in those with preexisting DM. Results: The disposition index, an integrated measure of β-cell function, decreased 1 week after surgery in both groups, but it increased more than baseline level in the PD group while its decreased level was maintained in the DP group, resulting in a between-group difference at the 1-year examination (P<0.001). During follow-up, the DP group showed higher incidence of NODM and worsening of glucose regulation than the PD group with hazard ratio (HR) 4.29 (95% confidence interval [CI], 1.49 to 12.3) and HR 2.15 (95% CI, 1.09 to 4.24), respectively, in the multivariate analysis including dynamic glycemic excursion profile. In the DP procedure, distal DP and spleen preservation were associated with better glucose regulation. DP had a stronger association with glucose dysregulation than PD. Conclusion Proactive surveillance of glucose dysregulation is advised, particularly for patients who receive DP.

Background: We investigated whether Lactobacillus plantarum strain LMT1-48, isolated from Korean fermented foods and newborn feces, is a suitable probiotic supplement to treat overweight subjects. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 100 volunteers with a body mass index of 25 to 30 kg/m2 were assigned randomly (1:1) to receive 2×1010 colony forming units of LMT1-48 or to a placebo treatment group. Body composition was measured by dual-energy X-ray absorptiometry, and abdominal visceral fat area (VFA) and subcutaneous fat area were measured by computed tomography scanning. Changes in body fat, VFA, anthropometric parameters, and biomarkers were compared between the two treatment groups (ClinicalTrials.gov number: NCT03759743). Results: After 12 weeks of treatment, the body weight decreased significantly from 76.6±9.4 to 75.7±9.2 kg in the LMT1-48 group but did not change in the placebo group (P=0.022 between groups). A similar pattern was found in abdominal VFA between the two groups (P=0.041). Serum insulin levels, the corresponding homeostasis model assessment of insulin resistance, and leptin levels decreased in the LMT1-48 group but increased in the placebo group (all P<0.05). Decrease in body weight and body mass index by treatment with LMT1-48 was correlated with increase in Lactobacillus levels significantly. LMT1-48 also increased Oscillibacter levels significantly, which were negatively correlated with triglyceride and alanine transaminase levels. Conclusion Administration of LMT1-48 decreased body weight, abdominal VFA, insulin resistance, and leptin levels in these subjects with overweight, suggesting its anti-obesogenic therapeutic potential.

BACKGROUND: With the globalization of drug development, multi-regional clinical trials (MRCTs) have emerged to facilitate rapid availability of medicines to patients worldwide. The present study aimed to has explored attitudes and perceptions towards adopting the Korean MRCT guideline. METHODS: An online survey, consisting of 16 questions, classified into two subjects, was administered to stakeholders in Korea. Most quantitative components were measured using the Likert scales. A content analysis of the qualitative components was carried out to identify the keywords in open-ended responses. RESULTS: A total of 94 survey responses were analyzed: 51 participants from pharmaceutical companies, 11 from clinical research organizations, and 21 from clinical trial centers. The content of the guideline was rated as appropriate for clarity, acceptability, and applicability (96.8, 96.8, and 93.6%, respectively). The local environmental impact of the systemic/political, academic/technical, and industrial/economical aspects of the guideline was rated as appropriate at 95.7, 97.9, and 91.5%, respectively. The suggested adoption period was 1~2 years (40, 42.6%). The concept and individuals' domestic circumstances were the key problems affecting the clarity, applicability, and local environmental impact of the guideline. CONCLUSION The Korean MRCT guideline was well-developed. Their overall impact on the local environmental impact of MRCTs in Korea was expected to be beneficial, but methods are needed to minimize the negative impacts. The findings of this study can inform the priorities for the future adoption of the guideline in Korea.

PURPOSE: Neutrophils are considered key effector cells in the pathogenic mechanisms of airway inflammation in asthma. This study assessed the activation status of neutrophils in adult asthmatics, and the therapeutic potential of FTY720, a synthetic sphingosine-1-phosphate analog, on activated neutrophils using an in vitro stimulation model. METHODS: We isolated peripheral blood neutrophils (PBNs) from 59 asthmatic patients (including 20 aspirin-exacerbated respiratory disease [AERD] and 39 aspirin-tolerant asthma [ATA] groups). PBNs were stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or lipopolysaccharide (LPS) and their activation status was determined based on reactive oxygen species (ROS) production, cell surface expression of CD11b, interleukin (IL)-8 and matrix metallopeptidase (MMP)-9 release. PBNs were primed with FTY720 to evaluate its anti-inflammatory action. RESULTS: In vitro PBN stimulation with fMLP or LPS induced a significant increase in ROS/CD11b/IL-8/MMP-9 levels (P < 0.05 for all). In asthmatics, fMLP-induced ROS level was significantly correlated with values of forced expiratory volume in 1 second/forced vital capacity (r = −0.278; P = 0.036), maximal mid-expiratory flow (r = −0.309; P = 0.019) and PC20 methacholine (r = −0.302; P = 0.029). In addition, ROS levels were significantly higher in patients with AERD and in those with severe asthma than in those with ATA or non-severe asthma (P < 0.05 for all). FTY720 treatment could suppress ROS/CD11b levels, and LPS-induced IL-8 and MMP-9 levels (P < 0.05 for all). Responders to FTY720 treatment had significantly higher neutrophil counts in sputum (P = 0.004). CONCLUSIONS: Our findings suggest a useful in vitro PBN stimulation model for evaluating the neutrophil functional status and the therapeutic potentials of neutrophil-targeting candidates in asthmatics.
Adult ; Asthma ; Fingolimod Hydrochloride ; Forced Expiratory Volume ; Humans ; In Vitro Techniques ; Inflammation ; Interleukin-8 ; Interleukins ; Methacholine Chloride ; N-Formylmethionine Leucyl-Phenylalanine ; Neutrophil Activation ; Neutrophils ; Phenotype ; Reactive Oxygen Species ; Sputum ; Vital Capacity

BACKGROUND: Although a growing number of guidelines and clinical researches are available for immunosuppressive treatment of post-transplantation, there is no clinical practice guideline for the care of kidney transplant recipients in Korea. Selection of a researchable question is the most important step in conducting qualified guideline development. Thus, we aimed to formulate key questions for Korean guideline to aid clinical decision-making for immunosuppressive treatment. METHODS: Based on previous published guidelines review, a first survey was constructed with 29 questions in the range of immunosuppressive treatments. The experts were asked to rate the clinical importance of the question using a 5-point Likert scale. The questions reached 60% or more from the first survey and additional new questions were included in the second survey. In analyzing the responses to items rated on the 9-point scale, consensus agreement on each question was defined as 75% or more of experts rating 7 to 9. RESULTS: In the first survey, 50 experts were included. Among the 29 questions, 27 were derived to get 60% or more importance and 3 new questions were additionally identified. Through the second survey, 9 questions were selected that experts reached consensus on 75% and over of the options. Finally, we developed key questions using PICO (patient, intervention, comparison, and outcome) methodology. CONCLUSION: The experts reached a high level of consensus on many of key questions in the survey. Final key questions provide direction for developing clinical practice guideline in the immunosuppressive treatment of transplantation.
Clinical Decision-Making ; Consensus ; Kidney Transplantation ; Kidney ; Korea ; Transplant Recipients

OBJECTIVE: Multi-regional clinical trials have been widely used for accelerating global drug development by multinational pharmaceutical companies. In this study, we aimed to review and analyze the international trends in regulations and guidelines on multi-regional clinical trials by regulatory authorities and international organizations, such as International Conference on Harmonisation, for referring to policies, including development of domestic guidelines for multi-regional clinical trials. METHODS: The policies, regulations, and guidelines published by the US Food and Drug Administration, European Medicines Agency, Pharmaceuticals and Medical Devices Agency (Japan), and China Food and Drug Administration were searched, and the International Conference on Harmonisation E17 draft guideline was reviewed. RESULTS: The regulatory authorities in developed countries have developed and implemented regulations and guidelines on multi-regional clinical trials to promote simultaneous global drug development and evaluate the regional differences in drug safety and efficacy. International Conference on Harmonisation developed the draft guideline for planning/designing of multi-regional clinical trials in 2016, which recommends the general principles for strategy-related issues and design of multi-regional clinical trials, and for protocol-related issues, such as consideration of regional variability, subject selection, dose selection, endpoints, comparators, overall sample size, allocation to regions, collecting information on efficacy and safety, and statistical analysis. CONCLUSION: It is important to understand the international regulatory requirements for designing and planning of multi-regional clinical trials for global drug development. Moreover, it is necessary to prepare multi-regional clinical trial guidelines in accordance with the Korean regulation for clinical trials and drug administration.
China ; Developed Countries ; Sample Size ; Social Control, Formal* ; United States Food and Drug Administration