Structured diabetes self-management education improves glycemic control, but implementation in primary care remains inconsistent, and evidence for nationwide digitally integrated care models is limited. This study evaluated the effectiveness of a nationwide mobile-app and care coordinator–assisted Chronic Disease Management Program in Primary care clinic (CDMPP) in patients with type 2 diabetes mellitus (T2DM). This open-label, multicenter, community-based clinical trial enrolled 568 participants. Participants in Intervention group 1 (n=147) received an individualized mobile-app–assisted CDMPP that included multidisciplinary education, remote monitoring, and periodic evaluation of care plans. Intervention group 2 (n=141) received the same care as group 1, with additional remote lifestyle counseling by care coordinators based on physician communication. The control group (n=280) received standard clinical care. Outcomes were assessed at 6 months. The primary outcome was change in HbA1c. Secondary outcomes included achievement of target HbA1c, blood pressure, lipid levels, and changes in lifestyle behaviors, depression, and quality of life. The intervention 1 significantly reduced HbA1c levels by 0·32% (95% confidence interval (CI), –0·52 to –0·11; P=0·001) compared with the control group. Intervention group 2 achieved an additional HbA1c reduction of 0·29% (95% CI, –0·53 to –0·05; P=0·014) relative to intervention group 1. The intervention significantly increased the proportion of participants who engaged in regular exercise, improved their dietary habits, and did not adversely affect their psychological well-being. A systematic, individualized, mobile app–assisted CDMPP can effectively improve glycemic control in patients with T2DM. Additional lifestyle counseling delivered by care coordinators provides further glycemic benefit. These findings support an implementable model for enhancing chronic disease care in primary care settings. Clinical Research Information Service (CRIS), Republic of Korea KCT0008396

BACKGROUND:Despite the increasing use of continuous glucose monitoring (CGM) systems, limited data exist on their perceived benefits and challenges among patients and healthcare providers. This study explored CGM-related experiences in South Korea. METHODS:An anonymous online survey was conducted between January and December 2021 at four university hospitals. Respondents included patients with diabetes mellitus (DM), physicians, and DM education nurses. The survey assessed the use of CGM, its benefits, and barriers. Most devices were first-generation CGMs: FreeStyle Libre 1 (Abbott Diabetes Care), Dexcom G6 (Dexcom Inc.), and Medtronic Guardian 3 (Medtronic MiniMed). RESULTS:Among 1,010 patients (33.4% with type 1 DM [T1DM], 63.6% with type 2 DM [T2DM], and 3.1% others; mean age, 51.4±14.6 years), 92.7% found CGM helpful. Although 59.6% reported discomfort, 81.9% intended to continue using CGM, indicating that perceived benefits outweighed barriers. The key advantages were glucose monitoring without finger pricks (T1DM, 57.9%; T2DM, 56.2%) and maintenance of target glucose levels. Discomfort was related to discomfort during activities (53.8%), skin problems (45.0%), and pain (43.0%). Healthcare provider recommendations were associated with reduced discomfort (adjusted odds ratio, 0.36; 95% confidence interval, 0.21-0.60). Physicians (n=29) cited high costs as the main barrier (T1DM, 58.9%; T2DM, 64.8%); only 51.9% and 14.5% prescribed CGM for T1DM and T2DM, respectively. Insulin adjustment and glucose control were the main reasons for prescription, while cost (89.3%) and limited consultation time (67.9%) were barriers. DM educators (n=9) reported heavy workloads, with training and follow-up times averaging 31.7±7.5 minutes and 21.7±9.7 minutes, respectively; 77.8% of DM educators identified frequent patient inquiries as their greatest burden. CONCLUSION:CGM provides significant clinical benefits but is limited by discomfort, costs, and educational burden. Sustained adoption requires device improvements, insurance support, and workforce expansion.

BACKGRUOUND:In this study, we aimed to validate the potential of miR-374 in ameliorating hyperglycemia by regulating peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression in pancreatic islets and liver. METHODS:To identify miRNAs targeting PGC-1α, we performed miRNA chip analysis in rat islets under hyperglycemic and euglycemic conditions. Luciferase reporter assay was performed to identify miR binding sites in the 3'-untranslated region (3' UTR) of PGC-1α. In db/db mice, miRNA-encapsulated adenoviruses were administered and intraperitoneal glucose tolerance test and glucose stimulated insulin secretion tests were performed. For enhanced delivery to β-cells, we developed exendin-4 (Ex-4) coated cationic lipoparticles (CCLs) encapsulating miRNAs. The therapeutic potential of Ex-4-CCL-miRNA was further evaluated in insulin-producing cells derived from induced pluripotent stem cells. RESULTS:By analyzing miRNA expression in primary rat islets exposed under hyperglycemic environment, we identified miR-374 as a potential target. In vitro experiments confirmed that miR-374 significantly suppressed PGC-1α expression in β-cells and hepatocytes by binding to its 3'-UTR. In vivo experiments using adenovirus-mediated miR-374 (Ad-miR-374) delivering directly to the pancreas and liver of db/db mice demonstrated improved glycemic control, enhanced insulin secretion, and downregulated hepatic gluconeogenesis-related genes (G6Pase, Pepck, PC). To enhance the clinical applicability of miR-374, we developed Ex-4-CCLs. Ex-4-CCL-miR-374 successfully alleviated hyperglycemia, restored pancreatic islet function, and decreased gluconeogenesis gene expression in db/db mice. Furthermore, Ex-4-CCL-miR-374 improved insulin secretory function in glucotoxicity-exposed human induced pluripotent stem cell-derived insulin producing cells. CONCLUSION:Based on these findings, we propose that Ex-4-CCL-miR-374 as a promising therapeutic approach to reverse β-cell dysfunction and improve hepatic insulin resistance in type 2 diabetes mellitus.

Abstract Background Suicide is a significant yet preventable public health issue. Body mass index (BMI) is a readily measurable indicator associated with various health outcomes. However, the relationship between BMI and suicidal death risk is complex and warrants further investigation, particularly within contemporary, non-Western contexts with consideration of potential confounders. The purpose of this study was to investigate the relationship between BMI and the risk of suicidal death. Methods This study was nationwide, retrospective, observational study based on Korean National Health Insurance Service database. We analyzed 4,045,081 participants who were aged > 19 years and underwent national health surveillance in 2009. The participants were categorized according to their BMI (underweight: < 18.5 kg/m², normal weight: 18.5–23 kg/m², overweight: 23–25 kg/m², class I obesity: 25–30 kg/m², and class II obesity: > 30 kg/m²). The primary outcome was the death events caused by suicide which was defined by International Classification of Disorders (ICD-10) codes (X60–X84) and death records documented by the Korea National Statistical Office. Multivariate Cox proportional hazard regression analysis was performed to estimate the risk of suicidal death with respect to BMI categories after adjusting for potential confounders (age, sex, income, diabetes, hypertension, dyslipidemia, smoking, drinking, exercise, self-abuse, waist circumference, schizophrenia, bipolar disorder, eating disorder, cancer, anxiety, and substance use disorder). Results Underweight individuals had an increased risk (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.31–1.57) while overweight (HR 0.79, 95% CI 0.76–0.83), class I (HR 0.76, 95% CI 0.71–0.80) and class II obesity (HR 0.71, 95% CI 0.63–0.81) were associated with decreased risks of suicidal deaths compared to those of the normal weight individuals (BMI 18.5–23). This trend was consistent regardless of the presence of major depressive disorder (MDD) or the type of living arrangements of the participants. Conclusions Suicidal death risk was inversely correlated with BMI categories, independent of MDD or living arrangements. Our data suggests the importance of physiological factors associated with body mass in understanding suicidal death risk. Furthermore, these data provide valuable insights to where the public health resources should be invested to reduce suicidal death rates.

AIMS:This study aimed to evaluate the efficacy and safety of triple therapy with lobeglitazone 0.5 mg as an add-on treatment compared with placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and empagliflozin. MATERIALS AND METHODS:In this Phase 3, multicentre, double-blind, randomised trial, patients with T2DM who had an insufficient response to metformin (≥1000 mg/day) and empagliflozin 10 mg/day (Study 1) or 25 mg/day (Study 2) were randomised to receive either lobeglitazone 0.5 mg/day, or placebo once daily for 24 weeks. Participants then entered an open-label extension phase for an additional 28 weeks, bringing the total treatment duration to 52 weeks. The primary endpoint was the change from baseline in glycated haemoglobin (HbA1c) at 24 weeks. RESULTS:At 24 weeks, the mean change in HbA1c was significantly greater with lobeglitazone than with placebo, regardless of the background empagliflozin dose (-0.71%; 95% confidence interval, -0.88 to -0.55; p < 0.001 in Study 1 and -0.62%; -0.79 to -0.45; p < 0.001 in Study 2). A higher proportion of patients achieved HbA1c levels <7% with lobeglitazone compared to placebo (48.7% vs. 13.4% in Study 1, and 44.4% vs. 13.0% in Study 2; p < 0.001). Although the incidence of adverse events was numerically different between groups, no statistically significant differences were observed, indicating a generally comparable profile for the triple combination therapy with metformin, empagliflozin, and lobeglitazone. CONCLUSIONS:Lobeglitazone as an add-on to empagliflozin and metformin significantly improved glycaemic control in patients with T2DM inadequately controlled on metformin and empagliflozin dual therapy. The treatment was well tolerated, with a low incidence of adverse events.

AIMS:To evaluate the efficacy and safety of adding lobeglitazone to a triple therapy regimen in Korean patients with type 2 diabetes whose blood glucose levels were inadequately controlled despite dual therapy with metformin and sitagliptin. MATERIALS AND METHODS:This randomised, double-blind, placebo-controlled, phase 3 study involved 231 Korean patients with type 2 diabetes whose HbA1c levels ranged from 7.0% to 10.0% despite treatment with metformin (≥1000 mg/day) and sitagliptin (100 mg/day). Participants received lobeglitazone (0.5 mg/day) or placebo for 24 weeks, followed by a 28-week open-label phase in which all patients received lobeglitazone. The primary endpoint was the change in glycated haemoglobin (HbA1c) at 24 weeks; secondary endpoints included changes in fasting plasma glucose (FPG), homeostatic model assessment for insulin resistance (HOMA-IR), HOMA for β-cell function (HOMA-β), quantitative insulin-sensitivity check index (QUICKI) and lipid profile. Safety assessments were also conducted. RESULTS:At week 24, lobeglitazone treatment demonstrated a significantly greater reduction in HbA1c compared with placebo (-1.00% ± 0.09% vs. 0.02% ± 0.09%), with a between-group difference in the adjusted mean change [-1.03%; p < 0.0001]. Additionally, lobeglitazone significantly reduced FPG compared with placebo at week 24 and improved HOMA-IR, HOMA-β and QUICKI. Lipid parameters were also improved by lobeglitazone administration. Adverse events were similar in both treatment arms. CONCLUSIONS:The addition of lobeglitazone in patients with type 2 diabetes inadequately controlled with metformin and sitagliptin is a beneficial therapeutic option, not only providing effective glycaemic control but also improving insulin function such as sensitivity and enhancing certain lipid parameters.

BACKGROUND:Moyamoya vasculopathy (MMV) is a rare cerebrovascular disease of unclear cause. In this study, we aimed to determine whether metabolic syndrome (MetS) is associated with the development of MMV and subsequent stroke risk in young adults. METHODS:Using a nationwide database, we retrospectively analyzed the data of 6 891 400 Korean adults aged 20 to 40 years who underwent health screening between 2009 and 2012. Participants were monitored until December 31, 2021, to identify patients newly diagnosed with MMV. We further examined the risk of ischemic and hemorrhagic stroke in patients newly diagnosed with MMV without prior stroke. Hazard ratios (HR) were calculated using multivariable Cox regression models adjusted for relevant confounders. RESULTS:Over a median follow-up of 9.65 years, 1754 individuals developed MMV. These participants exhibited significantly poorer baseline metabolic profiles, including a higher body mass index and a higher prevalence of diabetes, hypertension, and dyslipidemia (all P < 0.0001). Metabolic syndrome was associated with a significantly increased risk of MMV development (adjusted HR, 2.94 [95% CI, 2.60-3.33]). The association between metabolic derangements and MMV risk was stronger in women. Among newly diagnosed patients with MMV, metabolic syndrome was associated with an increased risk of subsequent stroke (adjusted HR, 2.05 [95% CI, 1.25-3.37]), primarily ischemic stroke. CONCLUSIONS:Metabolic syndrome could substantially increase the risk of MMV development and subsequent stroke events in young adults. These findings emphasize the importance of managing metabolic health to prevent MMV and related neurological outcomes.

In East Asians, type 2 diabetes mellitus (T2DM) is primarily characterized by significant defects in insulin secretion and comparatively low insulin resistance. Recently, the prevalence of T2DM has rapidly increased in East Asian countries, including Korea, occurring concurrently with rising obesity rates. This trend has led to an increase in the average body mass index among East Asian T2DM patients, highlighting the influence of insulin resistance in the development of T2DM within this group. Currently, the incidence of T2DM in Korea is declining, which may indicate potential adaptive changes in insulin secretory capacity. This review focuses on the changing epidemiology of T2DM in East Asia, with a particular emphasis on the characteristics of peak functional β-cell mass.

Type 1 diabetes mellitus is characterized by absolute insulin deficiency, which requires life‐long insulin replacement. Exogenous multiple‐daily insulin injections are most commonly prescribed for patients with type 1 diabetes mellitus. However, exogenous insulin supply often fails to cope with real‐time changing life‐log variables, such as activity, diet and stress, which results in recurrent hypo‐ and hyperglycemia in patients with type 1 diabetes mellitus. Islet transplantation is an ideal method to treat patients with type 1 diabetes mellitus, as it can restore the endogenous capacity of glucose‐stimulated insulin secretion. However, due to donor scarcity and technical barriers, only a limited number of islet transplantations have been carried out in Asia, including South Korea. Since 2013, our center has carried out two allogenic islet transplantations, with one case leading to near total insulin independence after one‐to‐one islet transplantation. Although the other patient failed to restore endogenous insulin production, there was a remarkable improvement in hypoglycemia. We speculate that islet transplantation remains an important and ideal treatment option for patients with type 1 diabetes mellitus who suffer from recurrent severe hypoglycemia.

One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

AIM:To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS:After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS:Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS:Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

Since the seminal success of Edmonton protocol in 2000, pancreatic islet transplantation has been very actively pursued worldwide1. This breakthrough has provided considerable encouragement to patients affected with type 1 diabetes, particularly those experiencing severe hypoglycemia and poor glycemic control, as well as healthcare professionals dedicated to their treatment. As of the latest report, over 1,300 patients have undergone pancreatic islet transplantation2. Notably, several recent studies have presented long-term follow-up results extending beyond 10 or even 20 years2. Despite these advancements, the field faces a significant challenge stemming from the diverse criteria employed across studies for assessing graft survival and transplantation success. This challenge is exacerbated by disparate transplantation protocols and confinement of studies to specific countries or institutions, hindering a comprehensive assessment of transplantation responses and the identification of prognostic factors. To integrate and compile data from islet transplantation, the Collaborative Islet Transplant Registry (CITR) was established in 2001, with participation from more than 39 centers across over 10 countries to date2. Over the past two decades, this expansive registry has played a crucial role in aggregating islet transplantation data, significantly advancing our understanding of this therapeutic approach. This year, the CITR has reported three pivotal studies based on the accumulation and long-term analysis of this extensive dataset (Table 1)2-4. Primary outcome Secondary outcome High predictability of C-peptide for primary outcome The higher the C-peptide level, the greater the likelihood of achieving each outcome Cut-off value of C-peptide for optimal graft function: ≥1.0 ng/mL Outperformance of the mixed-meal tolerance test-stimulated C-peptide-to-glucose ratio in predictive ability for all primary outcomes except absence of SHEs, compared with both fasting and stimulated C-peptide First, Bernhard Hering and colleagues4 provided important clinical insights into transplantation protocols and post-transplant management by proposing a common set of four favorable factors. This study involved an extensive and thorough exploration, encompassing various affecting factors such as recipient/donor characteristics, islet graft properties, and immunosuppression methods. Four factors were identified with the highest predictive power, including recipient age of 35years or older, total infused islets of 325,000 islet equivalents or more, induction of immunosuppression with T cell depletion and/or tumor necrosis factor-alpha (TNF-α) inhibition, and maintenance with both the mechanistic target of rapamycin (mTOR) and a calcineurin inhibitor with the highest predictive power. Importantly, with the exception of age, these factors are modifiable and amenable to intervention. Secondly, David Baidal et al.3 observed a robust correlation between clinical outcomes and concurrent measurements of fasting and stimulated C-peptide levels, along with the C-peptide-to-glucose ratio. This finding implies that retention of C-peptide function should be regarded as another potential goal of islet transplantation. Lastly, in The Lancet Diabetes & Endocrinology, Mikaël Chetboun et al.2 reported the primary graft function (PGF; islet graft function after islet the last islet infusion) and 5 year outcome results. They utilized the BETA-2 score (derived from fasting C-peptide, fasting plasma glucose, HbA1c, and insulin dose expressed as continuous variables), based on 28 days after last islet transplantation, as an indicator to predict the 5 year success rate of islet transplantation2. This is significant as it introduces an indicator for predicting the success rate of transplantation, which, until now, either did not exist or was challenging to apply in practice due to diverse standards in various studies. Notably, the correlation analysis between PGF and long-term outcome considered all possible confounding factors, enhancing the reliability and verification power of the study, given its multi-center nature involving more than 1,000 transplants. It is important to note that the PGF was evaluated at 28 days after the last islet infusion. As the authors have already mentioned2, this timeframe is considered appropriate, taking into account graft engraftment and vascularization. Additionally, it could allow sufficient time for stabilizing glucose homeostasis after transplantation. Previous studies have measured the BETA-2 score at 3 months or continuously after islet transplantation to analyze its relationship with transplantation outcomes5. However, given the rapid decline in graft function during the first month after transplantation and a gradual decrement thereafter5, the 1-month time point suggested in this study appears to be appropriate for evaluating graft function to predict clinical outcomes. Lastly, they are unveiling a prediction model based on the results of this study (accessible on http://pgf.diabinnov.com/), providing crucial information for predicting the prognosis after islet transplantation, determining the need for additional islet transplantation, and offering valuable guidance to healthcare professionals and patients before and after islet transplantation. It is imperative to emphasize that the BETA-2 score at 28 days after transplantation is derived from the composite outcomes of various donor and recipient factors, encompassing islet number and function, immune responses, metabolic factors, and even unknown or poorly measured elements. Therefore, considering a multivariate analysis incorporating PGF in the model, it is necessary to reevaluate their conclusion that the number of islet infusions and the transplanted islet mass had no significant impact on major clinical outcomes. While the BETA-2 score can serve as a useful indicator for assessing graft function and predicting long-term outcomes, successful islet transplantation still requires meticulous preparation and vigilant post-transplant management, addressing factors ranging from islet number, mass, and function to post-transplant immunosuppressants1, 3. Chetboun et al.2 applied the Igls 2.0 criteria (revised from the original version), which distinguishes clinical outcomes based on glucose regulation from beta cell graft function using C-peptide and insulin requirement. Consequently, they excluded insulin dependence from the category of unsuccessful islet transplantation but considered fasting C-peptide as low as 0.2 ng/mL as a favorable outcome. This aspect warrants careful attention when interpreting their findings. As noted in another CITR report this year, the retention of C-peptide is closely tied to outcomes such as metabolic restoration, loss of severe hypoglycemic events (defined as hypoglycemia associated with loss of consciousness or requiring third-party assistance for recovery), and achieving insulin independence3. Despite the use of more lenient criteria for defining unsuccessful islet transplantation, the 5 year transplant success rate in this integrated registry remains below 30%. If more stringent parameters, such as insulin independence or a significant reduction in insulin requirement as suggested in the initial Igls criteria (a consensus definition for outcomes of beta cell replacement therapy in the treatment of diabetes from the international pancreas and islet transplantation association (IPITA)/European pancreas and islet transplantation (EPITA), consisting of four factors: HbA1c, severe hypoglycemia, insulin requirement, and C-peptide), and a higher C-peptide level (at least 0.3 ng/mL or more) are employed, the success rate could be anticipated to be even lower. This underscores that, despite significant progress in pancreatic islet transplantation, there is still considerable more room for improvement in achieving successful islet transplantation in the future. Over the past two decades, remarkable advancements have transpired in islet transplantation. The outcomes delineated by the CITR, spanning this period and involving more than 30 centers, provide valuable insights that could significantly contribute to the broader adoption of islet transplantation. We are now able to systematically address common favorable factors associated with successful transplantation outcomes, and there is a growing recognition that maintaining C-peptide levels after transplantation may be another critical goal for successful outcomes. Furthermore, it is now pertinent to deliberate the utilization of the BETA-2 score, measured at 28 days after islet transplantation, as a pivotal tool for guiding re-transplantation decisions in patients. Prospective clinical trials are warranted to explore the BETA-2 score threshold at 28 days, guiding re-transplantation decisions, assessing the target goal of graft function, and validating these findings across diverse ethnic groups including Asian populations. In addition to benefiting from this extensive registry data, the development of modalities capable of assessing islet function before transplantation, such as islets-on-chip, along with the advancement of innovative immunomodulatory approaches, may pave the way for more successful islet transplantation in the future. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1C1C1013016) to E.Y.L.; by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (grant number: HI13C0954) and Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ01345301) Rural Development Administration, Republic of Korea to K.H.Y. Editorial services were provided by Caron Modeas, Evolved Editing, LLC. Kun-Ho Yoon is an Editorial Board member of Journal of Diabetes Investigation and a co-author of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication.

BackgroundGuidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. MethodsThe Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. ResultsAfter 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were –1.38%±0.08%, –1.03%±0.08%, and –0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. ConclusionEarly combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Background This study examines integrating physical and mental healthcare for disadvantaged persons with type 2 diabetes mellitus and mild-to-moderate depression in the community, using a mobile application within a public-private-academic partnership. Methods The Korean Diabetes Association has developed a mobile application combining behavioral activation for psychological well-being and diabetes self-management, with conventional medical therapy. Participants were randomly assigned to receive the application with usual care or only usual care. Primary outcomes measured changes in psychological status and diabetes self-management through questionnaires at week 12 from the baseline. Secondary outcomes assessed glycemic and lipid control, with psychological assessments at week 16. Results Thirty-nine of 73 participants completed the study (20 and 19 in the intervention and control groups, respectively) and were included in the analysis. At week 12, the intervention group showed significant reductions in depression severity and perceived stress compared to the control group. Additionally, they reported increased perceived social support and demonstrated improved diabetes self-care behavior. These positive effects persisted through week 16, with the added benefit of reduced anxiety. While fasting glucose levels in the intervention group tended to improve, no other significant differences were observed in laboratory assessments between the groups. Conclusion This study provides compelling evidence for the potential efficacy of a mobile application that integrates physical and mental health components to address depressive symptoms and enhance diabetes self-management in disadvantaged individuals with type 2 diabetes mellitus and depression. Further research involving larger and more diverse populations is warranted to validate these findings and solidify their implications.

Background: This study evaluated the effects of a mobile diabetes management program called “iCareD” (College of Medicine, The Catholic University of Korea) which was integrated into the hospital’s electronic medical records system to minimize the workload of the healthcare team in the real clinical practice setting.Methods: In this retrospective observational study, we recruited 308 patients. We categorized these patients based on their compliance regarding their use of the iCareD program at home; compliance was determined through self-monitored blood glucose inputs and message subscription rates. We analyzed changes in the ABC (hemoglobin A1c, blood pressure, and low-density lipoprotein cholesterol) levels from the baseline to 12 months thereafter, based on the patients’ iCareD usage patterns.Results: The patients comprised 92 (30%) non-users, 170 (55%) poor-compliance users, and 46 (15%) good-compliance users; the ABC target achievement rate showed prominent changes in good-compliance groups from baseline to 12 months (10.9% vs. 23.9%, P<0.05), whereas no significant changes were observed for poor-compliance users and non-users (13.5% vs. 18.8%, P=0.106; 20.7% vs. 14.1%, P=0.201; respectively).Conclusion: Implementing the iCareD can improve the ABC levels of patients with diabetes with minimal efforts of the healthcare team in real clinical settings. However, the improvement of patients’ compliance concerning the use of the system without the vigorous intervention of the healthcare team needs to be solved in the future.

Background: This study investigates the impact of fluctuating lipid levels on endothelial dysfunction. Methods: Human aortic and umbilical vein endothelial cells were cultured under varying palmitic acid (PA) concentrations: 0, 50, and 100 mu M, and in a variability group alternating between 0 and 100 mu M PA every 8 hours for 48 hours. In the lipid variability group, cells were exposed to 100 mu M PA during the final 8 hours before analysis. We assessed inflammation using real-time polymerase chain reaction, Western blot, and cytokine enzyme -linked immunosorbent assay (ELISA); reactive oxygen species (ROS) levels with dichlorofluorescin diacetate assay; mitochondrial function through oxygen consumption rates via XF24 flux analyzer; and endothelial cell functionality via wound healing and cell adhesion assays. Cell viability was evaluated using the MTT assay. Results: Variable PA levels significantly upregulated inflammatory genes and adhesion molecules (Il6, Mcp1, Icam, Vcam, E-selectin, iNos) at both transcriptomic and protein levels in human endothelial cells. Oscillating lipid levels reduced basal respiration, adenosine triphosphate synthesis, and maximal respiration, indicating mitochondrial dysfunction. This lipid variability also elevated ROS levels, contributing to a chronic inflammatory state. Functionally, these changes impaired cell migration and increased monocyte adhesion, and induced endothelial apoptosis, evidenced by reduced cell viability, increased BAX, and decreased BCL2 expression. Conclusion: Lipid variability induce endothelial dysfunction by elevating inflammation and oxidative stress, providing mechanistic insights into how lipid variability increases cardiovascular risk.

Background This study investigates the long-term efficacy and safety of evogliptin add-on therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM) previously received dapagliflozin and metformin (DAPA/MET) combination. Methods In this multicenter randomized placebo-controlled phase 3 trial, patients with glycosylated hemoglobin (HbA1c) levels 7.0% to 10.5% (n=283) previously used DAPA 10 mg plus MET (≥1,000 mg) were randomly assigned to the evogliptin 5 mg once daily or placebo group (1:1). The primary endpoint was the difference in the HbA1c level from baseline at week 24, and exploratory endpoints included the efficacy and safety of evogliptin over 52 weeks (trial registration: ClinicalTrials.gov NCT04170998). Results Evogliptin add-on to DAPA/MET therapy was superior in HbA1c reduction compared to placebo at weeks 24 and 52 (least square [LS] mean difference, –0.65% and –0.55%; 95% confidence interval [CI], –0.79 to –0.51 and –0.71 to –0.39; P<0.0001). The proportion of patients achieving HbA1c <7% was higher in the triple combination group at week 52 (32.14% vs. 8.51% in placebo; odds ratio, 5.62; P<0.0001). Evogliptin significantly reduced the fasting glucose levels and mean daily glucose levels with improvement in homeostatic model assessment of β-cell function (LS mean difference, 9.04; 95% CI, 1.86 to 16.21; P=0.0138). Adverse events were similar between the groups, and no serious adverse drug reactions were reported in the evogliptin group. Conclusion Long-term triple combination with evogliptin added to DAPA/MET showed superior HbA1c reduction and glycemic control compared to placebo at 52 weeks and was well tolerated.

Background: Moyamoya syndrome (MMS) is a rare and chronic vascular disorder of unknown etiology. This study aimed to investigate the correlation between MMS development and metabolic syndrome (MetS) or obesity in young adults. Methods: This study was a nationwide, retrospective, observational study based on the Korean National Health Insurance Service database. A total of 6,891,400 participants aged 20–40 years who underwent national health surveillance from 2009 to 2012 were enrolled. Hazard ratios (HR) for MMS development were estimated based on body mass index (BMI) or MetS components, and subgroup analysis was performed based on sex. Potential confounders, including age, sex, income, smoking status, drinking, and regular exercise, were adjusted for using Cox regression analysis.Findings: During the study period, 1,754 participants developed MMS. Participants who developed MMS had a higher baseline BMI, were more prone to be smokers, female, and have diabetes, hypertension, and dyslipidemia compared with those who did not develop MMS (p<.0001). Importantly, MetS (HR 2.94, 95% confidence interval [CI], 2.60-3.33) and obesity (25 ≤ BMI <30 kg/m2 HR 1.70 [95% CI, 1.50-1.93], BMI ≥30 kg/m2 HR 2.55 [95% CI, 2.13-3.04]) were correlated with a greater risk of MMS. In obese individuals, the presence of MetS significantly elevated the odds of MMS (HR 1.79 [95% CI, 1.58-2.03]) to HR 3.74 [95% CI, 3.25-4.30]). The detrimental effect of metabolic derangements on the risk of MMS was consistently greater in females.Interpretation: MetS and obesity are important risk factors for MMS development in young adults.Funding: This study was not awarded any grants from public, private, or nonprofit funding agencies.Declaration of Interest: All authors declare no conflicts of interest. Ethical Approval: The institutional review board (IRB) of the Catholic University of Korea approved the study (no. KC23ZISI0012). The claimed data were provided to the researchers from the Korean National Health Insurance Corporation after de-identification; hence, the IRB waived the informed consent requirement.

Background Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin. Methods In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500). Results Adjusted mean change of HbA1c at week 24 was –0.80% with enavogliflozin and –0.75% with dapagliflozin (difference, –0.04%; 95% confidence interval, –0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was –32.53 and –29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (–1.85 vs. –1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (–3.77 kg vs. –3.58 kg) and blood pressure (systolic/diastolic, –5.93/–5.41 mm Hg vs. –6.57/–4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated. Conclusion Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.