Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan.

SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan. We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months. After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01-0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30-0.84, P = 0.009) compared to DPP4i. SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD.

Kawaguchi T ，Fujishima Y ，Wakasugi D ，Io F ，Sato Y ，Uchida S ，Kitajima Y ... -  《-》

Comparisons of the risks of new-onset prostate cancer in type 2 diabetes mellitus between SGLT2I and DPP4I users: a population-based cohort study.

Sodium-glucose cotransporter 2 inhibitors (SGLT2I) have been suggested to reduce new-onset cancer amongst type-2 diabetes mellitus (T2DM) patients. This study aims to compare the risks of prostate cancer between SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I) amongst T2DM patients. This was a retrospective population-based cohort study of prospectively recorded data on male patients with T2DM who were prescribed either SGLT2I or DPP4I between 1st January 2015 and 31st December 2020 from Hong Kong. The primary outcome was new-onset prostate cancer. The secondary outcomes included cancer-related mortality and all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbor search was performed and multivariable Cox regression was applied. A three-arm analysis including the glucagon-like peptide-1 receptor agonist (GLP1a) cohort was conducted. This study included 42129 male T2DM patients (median age: 61.0 years old [SD: 12.2]; SGLT2I: n = 17,120; DPP4I: n = 25,009). In the propensity score matched cohort, the number of prostate cancers was significantly lower in SGLT2I users (n = 60) than in DPP4I (n = 102). Over a follow-up duration of 5.61 years, SGLT2I was associated with lower prostate cancer risks (HR: 0.45; 95% CI: 0.30-0.70) than DPP4I after adjustments. The subgroup analyses showed that the interactions between SGLT2I and age, hypertension, heart failure, and GLP-1a were not statistically significant. The result remained consistent in the sensitivity analysis. The study demonstrated SGLT2I was associated with lower risks of new-onset prostate cancer after propensity score matching and adjustments compared to DPP4I amongst T2DM patients.

Chou OHI ，Lu L ，Chung CT ，Chan JSK ，Chan RNC ，Lee AYH ，Dee EC ，Ng K ，Pui HHH ，Lee S ，Cheung BMY ，Tse G ，Zhou J ... -  《-》

Effects of luseogliflozin on suspected MASLD in patients with diabetes: a pooled meta-analysis of phase III clinical trials.

Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, potentially exerts pleiotropic effects on the liver. However, the sufficient evidence is still lacking. We aimed to investigate the effects of luseogliflozin on hepatic steatosis, fibrosis, and cardiometabolic risk factors in diabetic patients by a pooled meta-analysis. In this pooled meta-analysis, we enrolled diabetic patients who participated in phase III clinical trials of luseogliflozin (luseogliflozin group n = 302, placebo group n = 191). The primary outcomes were changes in fatty liver index (FLI) and Hepamet fibrosis score (HFS) after 24 weeks. The secondary outcomes were changes in cardiometabolic risk factors after 24 weeks. Statistical analysis was performed using propensity scoring analysis by the inverse probability of treatment weighting method. Primary outcomes: Luseogliflozin significantly decreased FLI compared to placebo after 24 weeks (adjusted coefficient - 5.423, 95%CI - 8.760 to - 2.086, P = 0.0016). There was no significant difference in changes in HFS between the two groups. However, luseogliflozin significantly decreased HFS compared to placebo in diabetic patients with ALT > 30 U/L (adjusted coefficient - 0.039, 95%CI - 0.077 to - 0.001, P = 0.0438) and with FIB-4 index > 1.3 (adjusted coefficient - 0.0453, 95%CI - 0.075 to - 0.016, P = 0.0026). Secondary outcom8es: Luseogliflozin significantly decreased HbA1c level, HOMA-IR value, BMI, and uric acids level, and increased HDL cholesterol level compared to placebo. This pooled meta-analysis demonstrated that 24-week treatment with luseogliflozin improved hepatic steatosis and fibrosis indexes in diabetic patients, especially those with liver injury. Furthermore, luseogliflozin improved various cardiometabolic risk factors. Thus, luseogliflozin may be useful for improving MASLD in diabetic patients.

Kawaguchi T ，Murotani K ，Kajiyama H ，Obara H ，Yamaguchi H ，Toyofuku Y ，Kaneko F ，Seino Y ，Uchida S ... -  《-》

The moderating effect of dietary fiber intake on the association between sleep pattern and liver fibrosis in metabolic dysfunction-associated steatotic liver disease: a study from NHANES.

Insufficient nocturnal sleep was associated with a higher risk of fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary fiber intake may improve the stimulate the secretion of sleep cytokines, inhibit the inflammatory pathway, contribute to regulating sleep disorders and alleviate liver fibrosis. The associations of dietary fiber intake, sleep patterns, with liver fibrosis remain unclear. The study aimed to explore the associations between dietary fiber, sleep, and liver fibrosis, as well as the moderating effect of dietary fiber intake between sleep patterns and liver fibrosis in MASLD patients. Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2017 to 2020, a cross-sectional study included participants with MASLD was performed to assess the relationship between sleep patterns, dietary fiber intake, and liver fibrosis. Weighted univariate and multivariate logistic regression models were used to examine the linear connection between sleep pattern, dietary fiber intake, and liver fibrosis. Restricted cubic spline (RCS) method was also performed to describe the nonlinear relationship. A two-part linear regression model was also used to estimate threshold effects. The moderating effect of dietary fiber intake was further investigated in different subgroups. All results were presented as odds ratios (ORs) and 95% confidence intervals (CIs). Totally, 1343 MASLD patients were included for final analysis. Among them, 207 (15.41%) have liver fibrosis. Dietary fiber intake did not correlate significantly with sleep pattern in patients with MASLD (Spearman's r = -0.028, P = 0.1678). Poor sleep pattern was related to higher odds of liver fibrosis (OR = 3.23, 95%CI: 1.05-9.90), while dietary fiber intake ≥ 15 gm/day was associated with lower liver fibrosis risk (OR = 0.51, 95%CI: 0.32-0.83). On the association between sleep pattern and liver fibrosis stratified by dietary fiber intake revealed that poor sleep patterns (OR = 15.13, 95%CI: 4.40-52.01) remained associated with increased liver fibrosis risk among individuals with dietary fiber intake < 15 gm/day. No connection was observed between poor sleep patterns and liver fibrosis in MASLD patients with higher dietary fiber intake, with moderate dietary fiber supplementation beneficial in mitigating poor sleep patterns associated with liver fibrosis. The similar findings were also found in patients aged < 50 years old, ≥ 50 years old, females, those with and without CVD groups, hypertension, and dyslipidemia. Particularly, dietary fiber intake also moderates the relationship between sleep patterns and liver fibrosis in the F4 stage (OR = 13.26, 95%CI: 4.08-43.11). Dietary fiber intake affects the relationship between sleep patterns and liver fibrosis in MASLD patients.

Jia G ，Jia M ，Li C 《BMC GASTROENTEROLOGY》

Albuminuria-based stratification of end-stage kidney disease progression and mortality with sodium-glucose cotransporter 2 inhibitors (SGLT2i): A retrospective cohort study in type 2 diabetes and chronic kidney disease.

Clinical trials have shown the kidney-protective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, their real-world impact, particularly across varying levels of albuminuria, remains less well understood. This study aimed to evaluate the association of SGLT2i, compared with other oral glucose-lowering drugs, with end-stage kidney disease (ESKD) progression in patients with type 2 diabetes and chronic kidney disease (CKD) stratified by urine albumin-to-creatinine ratio (UACR) levels. Using data from a national database spanning from 2016 to 2021, the study included patients with type 2 diabetes and CKD with estimated glomerular filtration rates (eGFRs) below 60 mL/min/1.73 m2 and who started on SGLT2i or other oral glucose-lowering drugs. Patients were stratified into groups by UACR ≥300 mg/g and <300 mg/g. Propensity score matching was used to minimize confounding, and progression to ESKD was evaluated using competing risks and Cox proportional-hazards models. All-cause mortality was also analyzed. Following propensity score matching, 18,514 patients in the severely increased albuminuria group (UACR ≥300 mg/g) were tracked, with 2.6% progressing to ESKD over 3 years. In contrast, only 0.3% of the 26,946 patients with UACR <300 mg/g progressed to ESKD. SGLT2i use was associated with a 30% reduction in risk of ESKD progression, compared with the use of other oral glucose-lowering drugs, in the severely increased albuminuria group (hazard ratio[HR]: 0.70, 95% confidence interval [CI]: 0.61-0.80). In the lower albuminuria group, no significant association was evident, though there was a nonsignificant trend toward protection over time. A consistent reduction in mortality risk was observed across all albuminuria levels. SGLT2i are associated with a reduction in the progression to ESKD among patients with severely increased albuminuria, with less pronounced effects observed in those with lower albuminuria levels, suggesting variability in renal outcomes based on albuminuria severity. The consistent survival benefit across all albuminuria levels supports the potential utility of SGLT2i in diabetes and CKD treatment strategies, emphasizing the need for more targeted research.

Chang TJ ，Lee YC ，Wu LC ，Chang CH ... -  《-》