ABSTRACT Aims To quantify the risk of cardiovascular disease (CVD) and all‐cause mortality associated with diabetic foot ulcer (DFU)‐related amputation using a large‐scale, nationally representative cohort. Materials and Methods This longitudinal study included individuals with diabetes who underwent standardized national health checkups between 2009 and 2012, with follow‐up data obtained from the Korean National Health Insurance Service claims database. CVD was defined as an incident myocardial infarction or stroke occurring after the index health checkup. Cox proportional hazards models were used to estimate the hazard ratios (HRs) for CVD and mortality in individuals with DFU‐related amputation compared with those with diabetes but without amputation. Results Among 1,229,689 individuals with diabetes, 1,486 (0.12%) had a DFU‐related amputation at baseline. The median follow‐up was 8.2 years in the non‐amputation group and 6.7 years in the DFU‐related amputation group. People with DFU‐related amputation had a significantly higher incidence rate of CVD compared with those without DFU‐related amputation (32.6 vs. 11.0 per 1000 person‐years) with a HR of 1.9 (95% CI 1.6–2.1). The HRs for myocardial infarction and stroke were 2.2 (95% CI 1.9–2.6) and 1.6 (95% CI 1.4–1.8), respectively. All‐cause mortality significantly increased in people with DFU‐related amputation compared with those without, with an HR of 2.1 (95% CI 1.9–2.3). Conclusions In this nationwide population‐based cohort, DFU‐related amputation was associated with nearly a twofold increased risk of cardiovascular events and mortality. These findings underscore the importance of comprehensive cardiovascular risk assessment and management in patients with diabetic foot complications.

BACKGROUND:Effective glycaemic control following cardiac surgery improves clinical outcomes, and continuous glucose monitoring (CGM) might be a valuable tool in achieving this objective. We investigated the effect of real-time CGM and telemonitoring on postoperative glycaemic control in people with type 2 diabetes (T2D) after coronary artery bypass grafting (CABG). METHODS:In this randomized clinical trial (RCT), adults with T2D undergoing CABG were assigned to either a test group utilizing real-time CGM (Dexcom G6) and telemetry for glycaemic control, or a control group with blinded CGM measures, relying on point-of-care measures. The primary outcome was the percentage of time in range (TIR) of blood glucose between 70 and 180 mg/dL (3.9-10.0 mmol/L), measured by CGM. RESULTS:Among 91 subjects, 48 were in the test group and 43 were in the control group. The least squares (LS) mean ± standard error of TIR was 60.3 ± 2.7%, 50.3 ± 2.9% in the test and control group, respectively. The test group had significantly higher TIR when adjusted with age, sex, body mass index, baseline fasting blood glucose and baseline glycated haemoglobin (LS mean difference, 10.0%; 95% confidence interval, 2.1-18.0; p = 0.014). The test group also had lower time above range and mean glucose levels, with no differences in time below range or hypoglycaemic events. CONCLUSIONS:In this RCT, real-time CGM and telemonitoring improved glycaemic control during postoperative period without increasing hypoglycaemia risk. Given the benefits of effective glycaemic control on perioperative outcomes, CGM may be helpful in managing T2D after CABG.

Disclosure: H. Son: None. S. Lee: None. J. Lee: None. M. Seong: None. H. Jung: None. Introduction & Objective: As genetic factors have a critical role in insulin secretion, sulfonylureas (SUs) offer potential for pharmacogenetic applications in type 2 diabetes (T2D). Previously, we reported whole exome sequencing (WES) analysis on SU-dependent T2D patients (ENDO 2024, abstract #7199), identifying 10 candidate genes with enriched functional variants in those with exceptional SU responsiveness. This pilot study explores whether any functional variants in these 10 genes predict glycemic responses to SUs in broader T2D population. Method: Participants were retrospectively enrolled from the Korea Biobank Network (IRB # H-2310-141-1479). Eligible participants were adults treated with SUs for more than 1 year. Individuals with conditions affecting drug prescription or glycemic control, such as systemic corticosteroid use or eGFR <45 mL/min, were excluded. Buffy coat samples underwent WES using the Agilent SureSelect V8 kit and Illumina NovaSeq 6000. Reads were aligned to hg19 with bwa-mem and processed per GATK guidelines, including variant calling with HaplotypeCaller. Variants were annotated using ANNOVAR. Changes in HbA1c levels following SU initiation and the proportion of participants achieving HbA1c levels < 7.0% were analyzed based on the number of candidate variants. Results: Forty participants were enrolled (the mean age 60 ± 9 years, male 75%, and the mean baseline HbA1c 8.5 ± 0.9%), and 33 (82.5%) carried at least one candidate variant. The median number of variants per individual was 2 (range: 0-4). Participants with two or more variants (n=21, high-variant group) exhibited a nominally greater reduction in HbA1c in 6 months compared to those with zero or one variant (n=19, low-variant group) (-1.74 vs. -1.46%-points, p=0.074). There was no significant baseline characteristics between the 2 groups. In logistic regression analysis for achieving an HbA1c below 7.0% at 1 year with clinical variables including age, sex, eGFR, and baseline HbA1c, -2 Log-Likelihood was 24.11. High-variant group achieved this goal in 81% and low-variant group in 68.4%. The inclusion of high-variant group as a variable in the logistic regression model slightly improved -2 Log-Likelihood to 23.18, with an odds ratio of 3.10 (p=0.175). Conclusion: This pilot study among Korean individuals with T2D provides preliminary evidence on the genetic determinants of SU efficacy, which were identified from SU-dependent patients. Expanding the cohort and developing a variant scoring system could lead to significant results, contributing to personalized treatment strategies for T2D. Funding: NRF (2022R1A2C2 004570), South Korea. Presentation: Monday, July 14, 2025

Background: Gestational diabetes mellitus (GDM) affects women with diverse pathological phenotypes, but little is known about the effects of this variation on perinatal outcomes. We explored the metabolic phenotypes of GDM and their impact on adverse pregnancy outcomes. Methods: Women diagnosed with gestational glucose intolerance or GDM were categorized into subgroups according to their pre-pregnancy body mass index (BMI) and the median values of the gestational Matsuda and Stumvoll indices. Logistic regression analysis was employed to assess the odds of adverse pregnancy outcomes, such as large-for-gestational age (LGA), small-for-gestational age, preterm birth, low Apgar score, and cesarean section. Results: A total of 309 women were included, with a median age of 31 years and a median BMI of 22.3 kg/m(2). Women with a higher pre-pregnancy BMI had a higher risk of LGA newborns (adjusted odds ratio [aOR] for pre-pregnancy BMI >= 25 kg/m(2) compared to 20-23 kg/m(2), 4.26; 95% confidence interval [CI], 1.99 to 9.12; P<0.001; P for trend=0.001), but the risk of other adverse pregnancy outcomes did not differ according to pre-pregnancy BMI. Women with insulin resistance had a higher risk of LGA (aOR, 1.88; 95% CI, 1.02 to 3.47; P=0.043) and cesarean section (aOR, 2.12; 95% CI, 1.29 to 3.50; P=0.003) than women in the insulin-sensitive group. In contrast, defective beta-cell function did not affect adverse pregnancy outcomes. Conclusion: Different metabolic phenotypes of GDM were associated with heterogeneous pregnancy outcomes. Women with obesity and those with insulin resistance are at greater risk of adverse outcomes and might need strict glycemic management during pregnancy.

AbstractDiagnosing post‐gastrectomy hypoglycemia is challenging, often relying on medical history with documented low plasma glucose levels. Here, we present three cases of patients who presented a high probability of post‐gastrectomy hypoglycemia diagnosed and managed successfully using “theragnostic” continuous glucose monitoring and alpha‐glucosidase inhibitors. In the first week, patients maintained their current lifestyle without medical intervention; in the second week, voglibose 0.2 mg before meals was prescribed. Continuous glucose monitoring data from the first week confirmed the diagnosis with multiple hypoglycemic events after postprandial peaks, whereas data from the second week showed reduced hypoglycemic events and lower glycemic variability, demonstrating voglibose's therapeutic effect. This report highlights the effective management of post‐gastrectomy hypoglycemia using voglibose and theragnostic continuous glucose monitoring, showing its potential benefits and safety for similar cases.

Background Identifying risk factors for postpartum type 2 diabetes in women with gestational diabetes mellitus (GDM) is crucial for effective interventions. We examined whether changes in insulin sensitivity after delivery affects the risk of type 2 diabetes in women with GDM. Methods This prospective cohort study included 347 women with GDM or gestational impaired glucose tolerance, who attended the follow-up visits at 2 months postpartum and annually thereafter. Changes in insulin sensitivity were calculated using the Matsuda index at GDM diagnosis and at 2 months postpartum (ΔMatsuda index). After excluding women with pregestational diabetes or those followed up only once, we analyzed the risk of postpartum type 2 diabetes based on the ΔMatsuda index tertiles. Results The incidence of type 2 diabetes at the two-month postpartum visit decreased with increasing ΔMatsuda index tertiles (16.4%, 9.5%, and 1.8%, P=0.001). During a 4.1-year follow-up, 26 out of 230 women who attended more than two follow-up visits (11.3%) developed type 2 diabetes. Compared to the lowest tertile, subjects in the highest ΔMatsuda index tertile showed a significantly reduced risk of type 2 diabetes (hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.93; P=0.036) after adjusting for confounders. Conclusion Improvement in insulin sensitivity after delivery is associated with a reduced risk of postpartum type 2 diabetes in women with GDM. Postpartum changes in insulin sensitivity could be a useful prediction for future type 2 diabetes development in women with GDM.

Diabetic foot ulcer (DFU) and subsequent amputation represents significant health burden associated with diabetes. It is widely recognized that individuals with diabetic end stage kidney disease (ESKD) and proliferative diabetic retinopathy (PDR) face an elevated risk of limb amputation, but vice versa remains unclear. This study aimed to investigate the incidence rate and quantify the risk of ESKD and PDR in people who experienced DFU amputation. Using the database from National Health Insurance Service in South Korea, we included people with diabetes who received national health screening from 2009 to 2012. DFU amputation was defined using International Classification of Diseases 10th revision codes (ICD-10). Incident cases of ESKD or PDR were defined as diagnoses occurring at least one year following DFU amputation, as determined by the ICD-10 codes. Cox proportional hazard regression analysis was used to estimate the risk of incident ESKD or PDR after DFU amputation adjusting for covariates. Among 1,447,438 individuals enrolled, 1,512 (0.10%) had received DFU amputation at baseline. The incidence rate (IR) of ESKD was significantly higher in people who received DFU amputation compared to those who did not (14.8 vs 1.6 per 1,000 person-years), and adjusted hazard ratio (HR) was 2.46 (95% CI 2.08-2.91). Similar result was observed for PDR; IR was 24.7 vs 6.5 per 1,000 person-years and adjusted HR was 2.08 (95% CI 1.82-2.38). When we performed subgroup analysis based on major vs minor amputation, subjects who received major amputations had higher risk for ESKD (HR 3.13, 95% CI 2.39-4.11) and PDR (HR 2.39, 95% CI 1.87-3.07) compared with subjects who received minor amputations (ESKD: HR 2.17, 95% CI 1.75-2.69; PDR: HR 1.97, 95% CI 1.68-2.31). In summary, using a national health information database, we found that people who received DFU amputation have significantly increased risk of microvascular complications of ESKD or PDR. Disclosure N. Song: None. B. Kim: None. J. Jang: None. H. Yang: None. H. Son: None. H. Jung: Research Support; Novo Nordisk. Y. Cho: None. K. Park: None. K. Han: None. S. Kwak: Employee; SNUH Venture.

Background: We explored the utility of a small multi-gene DNA panel for assessing molecular profiles of thyroid nodules and influencing clinical decisions by comparing outcomes between tested and untested nodules.Methods: Between April 2022 and May 2023, we prospectively performed fine-needle aspiration (FNA) with gene testing via DNA panel of 11 genes (BRAF, RAS [NRAS, HRAS, KRAS], EZH1, DICER1, EIF1AX, PTEN, TP53, PIK3CA, TERT promoter) in 278 consecutive nodules (panel group). Propensity score-matching (1:1) was performed with 475 nodules that consecutively underwent FNA without gene testing between January 2021 and December 2021 (control group).Results: In the panel group, positive call rate for mutations was 41.7% (BRAF 16.2%, RAS 12.6%, others 11.5%, double mutation 1.4%) for all nodules, and 40.0% (BRAF 4.3%, RAS 19.1%, others 15.7%, double mutation 0.9%) for indeterminate nodules. Benign call rate was 69.8% for all nodules, and 75.7% for indeterminate nodules. In four nodules, additional TP53 (in addition to BRAF or EZH1) or PIK3CA (in addition to BRAF or TERT) mutations were co-detected. Sensitivity, specificity, positive predictive value, and negative predictive value were 80.0%, 53.3%, 88.1%, 38.1% for all nodules, and 78.6%, 45.5%, 64.7%, 62.5% for indeterminate nodules, respectively. Panel group exhibited lower surgical resection rates than the control group for all nodules (27.0% vs. 52.5%, P<0.001), and indeterminate nodules (23.5% vs. 68.2%, P<0.001). Malignancy risk was significantly different between the panel and control groups (81.5% vs. 63.9%, P=0.008) for all nodules.Conclusion: Our panel aids in managing thyroid nodules by providing information on malignancy risk based on mutations, potentially reducing unnecessary surgery in benign nodules or patients with less aggressive malignancies.

Introduction & Objective: Effective glycemic control following cardiac surgery improves overall clinical outcomes, and continuous glucose monitoring (CGM) is a valuable tool in achieving this objective. We investigated the effect of CGM on postoperative glycemic control in patients with diabetes after coronary artery bypass grafting (CABG). Method: In this randomized clinical trial involving adults with type 2 diabetes undergoing CABG, all participants utilized real-time CGM (Dexcom G6) after scheduled CABG, and received a basal bolus insulin regimen. The subjects were randomly assigned to either a test group utilizing CGM for glycemic control, or a control group with blinded CGM measures, relying on point-of-care measures. The primary outcome was the percentage of time in range (TIR) of blood glucose between 70-180 mg/dL, as measured by CGM. Results: Of total 96 subjects, 49 were in the test group and 47 in the control group. CGM was applied for 5.9 ± 2.0 days. Participants had a mean age of 68.9 ± 9.3 years, and baseline glycated hemoglobin was 7.2 ± 0.9 %. The least squares (LS) mean ± standard error of TIR was 58.9 ± 2.7%, 50.2 ± 2.8% in the test and control group, respectively. TIR was significantly higher in the test group than in the control group when adjusted with age, sex, body mass index, and baseline glycated hemoglobin (LS mean difference, 8.3%; 95% confidence interval, 0.4-16.3; p=0.041). Time above range and mean glucose levels were also significantly lower in the test group than in the control group. No differences in time below range, coefficient of variation, and hypoglycemic event rate were observed between the two groups. Conclusion: In this randomized clinical trial, Dexcom G6 CGM has enhanced glycemic control without increasing the risk of hypoglycemia. Given the benefits of effective glycemic control on perioperative outcomes, CGM may be helpful in managing type 2 diabetes after CABG. Disclosure H. Son: None. S. Sohn: None. H. Kim: None. H. Choe: None. H. Lee: None. H. Jung: Research Support; Novo Nordisk. Y. Cho: None. K. Park: None. H. Hwang: None. S. Kwak: Employee; SNUH Venture.

Diabetic Foot Ulcer (DFU), a critical complication of diabetes, impacts about 8% of individuals with diabetes and leads to a 20% risk of lower extremity amputation. People with DFU amputation are widely recognized to have an increased risk of cardiovascular disease (CVD) and mortality. However, previous studies have been limited by their small scale and cross-sectional design. The aim of this study was to quantify the risk of CVD and related mortality following DFU amputation, utilizing a large-scale prospective database.We included over 1.2 million individuals with diabetes who participated in nationwide health checkups from 2009 to 2012, with clams data linked through the Korean National Health Insurance Service. Incident CVD was defined as myocardial infarction (MI), stroke and cardiovascular mortality that occurred at least one year after a DFU amputation. Cox proportional hazard model was used to assess the risk of CVD in people with DFU amputation compared to those with diabetes but not amputated. Among 1,229,689 individuals with diabetes, 1,487 (0.12%) had a DFU amputation at baseline. Individuals with DFU tended to be older, predominantly male, and more often belong to the lower income 10%. During a median follow-up of 7.2 years (interquartile range 3.08), people with DFU amputation had a significantly higher incidence rate of CVD compared to those without DFU amputation (32.6 vs 11.0 per 1,000 person-years) with a hazard ratio (HR) of 1.8 (95% CI 1.6-2.1). Specifically, the HRs for MI and stroke were 2.2 (95% CI 1.9-2.6) and 1.6 (95% CI 1.4-1.8). Furthermore, CVD mortality significantly increased in people with DFU amputation compared to those without, with an HR of 2.11. (95% CI 1.9-2.3).Using a comprehensive nationwide health information database, we found that individuals with DFU amputation had up to a two-fold higher risk of CVD and associated mortality compared to those with diabetes but without DFU. Disclosure H. Yang: None. B. Kim: None. J. Jang: None. H. Son: None. H. Jung: Research Support; Novo Nordisk. Y. Cho: None. K. Park: None. K. Han: None. S. Kwak: Employee; SNUH Venture. Funding Funds of National Health Insurance Service and Korean Diabetes Association (2023-285)

Background: We aimed to assess how the ageing-related changes in body composition contribute to the prevalence and incidence of diabetes using artificial intelligence (AI)-based analysis of abdominal computed tomography (CT) images. Methods: In this retrospective cohort study, we identified 15330 subjects age ≥18 years with abdominal CT scans at baseline, who underwent medical checkup at Seoul National University Hospital Healthcare System Gangnam Center from January 1, 2011 to September 30, 2012. Of these, 11693 subjects with available follow-up data were included in the longitudinal analysis. The volume of each body segment involved in abdominal CT images was measured by using an AI-based image analysis software. Findings: The ratio of visceral fat to subcutaneous fat (VF/SF ratio) increased with ageing. The optimal cutoffs of VF/SF ratio to predict the prevalence of diabetes were 1.2 and 0.5 in men and women, respectively. A VF/SF ratio over the cutoff was associated with a higher prevalence of diabetes (age and BMI adjusted OR 2.1, [95% CI 1.8-2.4] in men; 3.1, [2.4-3.9] in women). The same cutoffs of VF/SF ratio were used to predict incident diabetes in ten years of follow-up. Subjects with normal glucose tolerance at baseline who had higher VF/SF ratio had increased risk of progression to prediabetes or diabetes (age and BMI adjusted HR 1.2, [95% CI 1.1-1.4] in men; 1.4, [1.2-1.6] in women). Subjects with prediabetes at baseline who had higher VF/SF ratio also more frequently progressed to diabetes (age and BMI adjusted HR 1.4, [95% CI 1.2-1.6] in men; 1.8, [1.5-2.3] in women). Interpretation: VF/SF ratio in the abdomen change with ageing and are associated with the prevalence and future incidence of diabetes. AI-based analysis of abdominal CT images may help easily obtain body composition data to clinically assess the risk of incident diabetes. Disclosure Y.Kim: None. H.Son: None. J.Yoon: None. H.Choe: None. T.Oh: None. Y.Cho: Consultant; LG Chem. Funding Ministry of Health & Welfare, Republic of Korea

Background: Detecting the risk of postpartum diabetes in women with gestational diabetes mellitus (GDM) is essential for proper intervention. We investigated whether changes in insulin sensitivity after delivery affect the risk of diabetes in Korean women with GDM. Method: In a prospective cohort including women with GDM, we included those who attended the postpartum visit at 2 months and yearly thereafter. The change in insulin sensitivity was defined as ∆Matsuda index, the difference between the initial postpartum visit and during pregnancy. We analyzed the risk of diabetes according to tertiles of ∆Matsuda index. Results: During 3.4 years of follow-up, 60 out of 347 subjects (17.3%) developed diabetes. The incidence of diabetes decreased as the tertile of ∆Matsuda index increased (26.7%, 17.2%, and 7.8%, P = 0.001). Subjects in the second and third tertile of ∆Matsuda index showed lower risk of diabetes compared to the subjects in the first tertile (HR, 0.45; 95% CI, 0.24-0.82; HR, 0.18; 95% CI, 0.07-0.48) after adjusting for age, family history of diabetes, gravida, lactation, fasting glucose, and postpartum BMI. Conclusion: Amelioration of insulin resistance lowers the risk of diabetes in Korean women with GDM. Although the assessment of insulin sensitivity is not standardized, changes in insulin sensitivity may be a useful predictor for diabetes in women with GDM. Disclosure H.Son: None. J.Moon: None. N.H.Cho: None. H.Jang: None.

Background: We aimed to assess how the ageing-related changes in body composition contribute to the prevalence and incidence of diabetes using artificial intelligence (AI)-based analysis of abdominal computed tomography (CT) images. Methods: In this retrospective cohort study, we identified 15330 subjects age ≥18 years with abdominal CT scans at baseline, who underwent medical checkup at Seoul National University Hospital Healthcare System Gangnam Center from January 1, 2011 to September 30, 2012. Of these, 11693 subjects with available follow-up data were included in the longitudinal analysis. The volume of each body segment involved in abdominal CT images was measured by using an AI-based image analysis software. Findings: The ratio of visceral fat to subcutaneous fat (VF/SF ratio) increased with ageing. The optimal cutoffs of VF/SF ratio to predict the prevalence of diabetes were 1.2 and 0.5 in men and women, respectively. A VF/SF ratio over the cutoff was associated with a higher prevalence of diabetes (age and BMI adjusted OR 2.1, [95% CI 1.8-2.4] in men; 3.1, [2.4-3.9] in women). The same cutoffs of VF/SF ratio were used to predict incident diabetes in ten years of follow-up. Subjects with normal glucose tolerance at baseline who had higher VF/SF ratio had increased risk of progression to prediabetes or diabetes (age and BMI adjusted HR 1.2, [95% CI 1.1-1.4] in men; 1.4, [1.2-1.6] in women). Subjects with prediabetes at baseline who had higher VF/SF ratio also more frequently progressed to diabetes (age and BMI adjusted HR 1.4, [95% CI 1.2-1.6] in men; 1.8, [1.5-2.3] in women). Interpretation: VF/SF ratio in the abdomen change with ageing and are associated with the prevalence and future incidence of diabetes. AI-based analysis of abdominal CT images may help easily obtain body composition data to clinically assess the risk of incident diabetes. Disclosure Y.Kim: None. H.Son: None. J.Yoon: None. H.Choe: None. T.Oh: None. Y.Cho: Consultant; LG Chem. Funding Ministry of Health & Welfare, Republic of Korea

Objective: Polygenic risk score (PRS) for type 2 diabetes (T2D) has been reported to be associated with beta cell function, but whether it is also associated with the longitudinal change of beta cell function is largely unknown. We aimed to evaluate the association of PRS and the trajectory of beta cell function in a community based prospective cohort. Method: We analyzed 6,323 participants without T2D at baseline from Ansan-Ansung cohort with 75-g 2-hour oral glucose tolerance tests taken biennially for 14 years. Disposition index (DI), derived from insulinogenic index at 60 minutes and Matsuda index, was used as a marker for beta cell function. PRS was calculated using 1.2 million variants from trans-ancestry T2D genome-wide association study using Bayesian regression (PRS-CSx). Participants were stratified into low (1st quintile), intermediate (2nd to 4th quintiles) and high genetic risk (5th quintile). Lifestyle was categorized as unfavorable, intermediate and favorable lifestyle according to Life’s Essential 8. Linear mixed model was applied. Result: During a median follow-up of 13 years, 379 (30.6%), 875 (23.0%) and 171 (13.4%) participants developed T2D in high, intermediate and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 33% lower DI at baseline (53 [95% CI 50, 56] vs 79 [74, 84]; P = 7.9×10-15), and a 1.7-fold faster rate of decline in log2(DI) per year (-0.035 [-0.028, -0.042] vs -0.020 [-0.013, -0.027]; P = 0.0026). Notably, we found significant interaction between the rate of decline in DI and T2D PRS (P = 8.5×10-5). Healthy lifestyle was associated with decreased rate of decline in DI across all genetic risk group. Conclusion: Having a high genetic risk for T2D was associated with not only a lower DI at baseline, but also a faster rate of decline in DI. Genetic information could be used to identify those at risk for rapid decline of beta cell function and emphasize lifestyle modification. Disclosure H.Lee: None. J.Choi: None. H.Son: None. K.Park: None. N.H.Cho: None. S.Kwak: None. Funding Ministry of Health & Welfare, Republic of Korea

AIMS:To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. MATERIALS AND METHODS:This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. RESULTS:The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. CONCLUSIONS:GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.

BACKGROUND:The relationship between diet and risk genotypes in nonalcoholic steatohepatitis (NASH) development and fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. OBJECTIVE:We aimed to investigate the effects of diet on NASH development and fibrosis progression in patients with NAFLD stratified by the PNPLA3 genotype. METHODS:We performed a prospective study in a cohort of patients with biopsy-confirmed NAFLD. Histologic deterioration was obtained using serial transient elastography at every 1 or 2 y. The primary outcome was fibrosis progression, and the secondary outcome was development of high-risk NASH, defined as FibroScan-aspartate aminotransferase score ≥0.67 during the follow-up of patients with nonalcoholic fatty liver at the baseline. Dietary intake was evaluated using a semiquantitative food frequency questionnaire. RESULTS:The primary outcome was observed in 42 (29.0%) of the 145 patients during a median follow-up of 49 mo; neither the total energy intake nor each macronutrient intake significantly affected the primary outcome occurrence. Conversely, the total energy intake (HR per 1-SD: 3.03; 95% CI: 1.31, 7.01) and the PNPLA3 rs738409 genotype [HR per 1 risk allele (G): 2.06; 95% CI: 1.11, 3.83)] were independent risk factors for high-risk NASH. The significant interaction between the total energy intake and PNPLA3 genotype was noted in developing high-risk NASH (P = 0.044). As the number of PNPLA3 risk alleles decreased, the effect of the total energy intake on high-risk NASH increased; the HR per 1-SD increment in total energy intake was 1.52 (95% CI: 0.42, 5.42), 3.54 (95% CI: 1.23, 10.18), and 8.27 (95% CI: 1.20, 57.23) for the GG, CG, and CC genotypes, respectively. CONCLUSIONS:The total energy intake adversely affected the development of high-risk NASH in patients with biopsy-confirmed NAFLD. The effect was more prominent in patients without the PNPLA3 risk allele, highlighting the importance of personalized dietary interventions in NAFLD treatment.