Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Anti-Obesity Effects of GABA in C57BL/6J Mice with High-Fat Diet-Induced Obesity and 3T3-L1 Adipocytes.

Obesity is the excessive accumulation of body fat resulting from impairment in energy balance mechanisms. In this study, we aimed to investigate the mechanism whereby GABA (γ-aminobutyric acid) prevents high-fat diet-induced obesity, and whether it induces lipolysis and browning in white adipose tissue (WAT), using high-fat diet (HFD)-fed obese mice and 3T3-L1 adipocytes. We demonstrated that GABA substantially inhibits the body mass gain of mice by suppressing adipogenesis and lipogenesis. Consistent with this result, histological analysis of WAT demonstrated that GABA decreases adipocyte size. Moreover, we show that GABA administration decreases fasting blood glucose and improves serum lipid profiles and hepatic lipogenesis in HFD-fed obese mice. Furthermore, Western blot and immunofluorescence analyses showed that GABA activates protein kinase A (PKA) signaling pathways that increase lipolysis and promote uncoupling protein 1 (UCP1)-mediated WAT browning. Overall, these results suggest that GABA exerts an anti-obesity effect via the regulation of lipid metabolism.

Long-Term Nonoperative Management is Associated With Lower Mean 9-Year Follow-Up Survival Compared to Total Knee Arthroplasty in Knee Osteoarthritis Patients-Survival Analysis of a Nationwide South Korean Cohort.

BACKGROUND: Total knee arthroplasty (TKA) and medications are both considered as a treatment for knee osteoarthritis. However, the impact of the TKA on long-term survival remains controversial. This study aimed to compare 9-year follow-up survival between a TKA group with a nonoperative medication group. METHODS: From 2007 to 2009, knee osteoarthritis patients were divided into TKA (N = 2,228) and nonoperative medication (N = 76,430) groups, and followed for up to 9 years. The hazard ratio (HR) and subdistribution HR (SHR) were derived from Cox proportional hazards regressions and Fine and Gray analyses, respectively. RESULTS: The TKA group had a significantly lower adjusted mortality rate (adjusted HR , 0.78, 95% confidence interval [CI], 0.68-0.9) than the nonoperative medication group. Dose-response relationship between medication possession ratio and mortalities for overall (adjusted HR , 1.02; 95% CI, 1.01-1.04) and cardiovascular (CV) death (adjusted SHR, 1.03; 95% CI, 1.01-1.05) was also found. Also, there were significant interactions that indicate stronger protective survival effects of the TKA in several covariates: age >75 years (P = .04 for overall; P = .009 for CV), hypertension (P = .006 for overall), and ischemic heart disease (P = .009 for CV). CONCLUSIONS: This study suggests that TKA patients had better mean 9-year follow-up survival than the nonoperative medication group after adjusting for baseline differences. For overall death, including CV death, adjusted mortality rates were higher in the medication group and showed a dose-response relationship. Specifically, the protective effect of the TKA for overall or CV deaths was found to be higher for age >75, hypertension, or ischemic heart disease patients. LEVEL OF EVIDENCE: III.

Sex differences in the applicability of Western cardiovascular disease risk prediction equations in the Asian population.

AIMS: Cardiovascular diseases (CVDs) are the most common cause of death, but they can be effectively managed through appropriate prevention and treatment. An important aspect in preventing CVDs is assessing each individual's comprehensive risk profile, for which various risk engines have been developed. The important keys to CVD risk engines are high reliability and accuracy, which show differences in predictability depending on disease status or race. Framingham risk score (FRS) and the atherosclerotic cardiovascular disease risk equations (ASCVD) were applied to the Korean population to assess their suitability. METHODS: A retrospective cohort study was conducted using National Health Insurance Corporation sample cohort from 2003 to 2015. The enrolled participants over 30 years of age and without CVD followed-up for 10 years. We compared the prediction performance of FRS and ASCVD and calculated the relative importance of each covariate. RESULTS: The AUCs of FRS (men: 0.750; women: 0.748) were higher than those of ASCVD (men: 0.718; women: 0.727) for both sexes (Delong test P <0.01). Goodness of fits (GOF) were poor for all models (Chi-square P < 0.001), especially, underestimation of the risk was pronounced in women. When the men's coefficients were applied to women's data, AUC (0.748; Delong test P<0.01) and the GOF (chi-square P = 0.746) were notably improved in FRS. Hypertension was found to be the most influential variable for CVD, and this is one of the reasons why FRS, having the highest relative weight to blood pressure, showed better performance. CONCLUSION: When applying existing tools to Korean women, there was a noticeable underestimation. To accurately predict the risk of CVD, it was more appropriate to use FRS with men's coefficient in women. Moreover, hypertension was found to be a main risk factor for CVD.

Development of Prediction Model Using Machine-Learning Algorithms for Nonsteroidal Anti-inflammatory Drug-Induced Gastric Ulcer in Osteoarthritis Patients: Retrospective Cohort Study of a Nationwide South Korean Cohort.

Background: Nonsteroidal anti-inflammatory drugs (NSAID) are currently among the most prescribed medications worldwide to relieve pain and reduce inflammation, especially in patients suffering osteoarthritis (OA). However, NSAIDs are known to have adverse effects on the gastrointestinal system. If a gastric ulcer occurs, planned OA treatment needs to be changed, incurring additional treatment costs and causing discomfort for both patients and clinicians. Therefore, it is necessary to create a gastric ulcer prediction model that can reflect the detailed health status of each individual and to use it when making treatment plans. Methods: Using sample cohort data from 2008 to 2013 from the National Health Insurance Service in South Korea, we developed a prediction model for NSAID-induced gastric ulcers using machine-learning algorithms and investigated new risk factors associated with medication and comorbidities. Results: The population of the study consisted of 30,808 patients with OA who were treated with NSAIDs between 2008 and 2013. After a 2-year follow-up, these patients were divided into two groups: without gastric ulcer (n=29,579) and with gastric ulcer (n=1,229). Five machine-learning algorithms were used to develop the prediction model, and a gradient boosting machine (GBM) was selected as the model with the best performance (area under the curve, 0.896; 95% confidence interval, 0.883-0.909). The GBM identified 5 medications (loxoprofen, aceclofenac, talniflumate, meloxicam, and dexibuprofen) and 2 comorbidities (acute upper respiratory tract infection [AURI] and gastroesophageal reflux disease) as important features. AURI did not have a dose-response relationship, so it could not be interpreted as a significant risk factor even though it was initially detected as an important feature and improved the prediction performance. Conclusions: We obtained a prediction model for NSAID-induced gastric ulcers using the GBM method. Since personal prescription period and the severity of comorbidities were considered numerically, individual patients' risk could be well reflected. The prediction model showed high performance and interpretability, so it is meaningful to both clinicians and NSAID users.

Development of In Vitro Embryo Production System Using Collagen Matrix Gel Attached with Vascular Endothelial Growth Factor Derived from Interleukin-1 Beta-Treated Porcine Endometrial Tissue.

The aim of this study was to establish an embryo culture system using collagen gel attached with vascular endothelial growth factor (VEGF) derived from interleukin-1 beta (IL-1ß)-treated endometrial tissues from pigs. Endometria were separated from the porcine uterus at the follicular phase of the estrous cycle and were cultured with IL-1ß. The collagen gels coincubated with IL-1ß-treated endometria (C, without endometrial tissue; CE, with endometrial tissue; and CEI, IL-1ß-treated endometrial tissue) were used for embryo culture. We found that, compared with the comparable figures in the control group, prostaglandin synthase-2 (PTGS-2) mRNA was increased in IL-1ß-treated endometrial tissue (p < 0.05). The VEGF protein was not observed in collagen gel coincubated without endometrial tissue (C); however, it was detected in collagen gels coincubated with endometrial tissue (CE and CEI). The embryo cleavage rates and blastocyst formation did not differ among the treatment groups. The proportion of blastocysts did not differ among the groups. However, the number of blastocyst cells was significantly (p < 0.05) higher in the CEI group than in the other groups. These results clarify the effects of the intrauterine environment on preimplantation embryos and may be useful in research on the effects of extracellular matrix- and cytokine-treated endometrial tissue on embryo development.