Stefano Ciardullo

Background and Objective: The role of circulating fatty acids (FA) as well as the association between their composition and metabolic dysfunction‐associated steatotic liver disease (MASLD) is not known. Here, we evaluate the association between specific FA subtypes and both MASLD and liver fibrosis in a general population setting. Methods: In this cross‐sectional study, serum levels of FAs were measured after an overnight fast in a representative sample of the general US population. Concentrations of total FA were assessed using capillary gas chromatography coupled with negative‐ion mass spectrometry. They were divided into saturated (palmitic, stearic and butyric acid), monounsaturated (palmitoleic and oleic acid), ω‐6 polyunsaturated (ω‐6 PUFA: linoleic and arachidonic acid) and ω‐3 PUFA (alpha‐linolenic, docosanoic [DHA] and eicosapentaenoic [EPA] acid). Explorative end points were: insulin resistance, liver steatosis and fibrosis estimated using the Homeostatic Model of Insulin Resistance (HOMA‐IR), a fatty liver index (FLI) score ≥ 60 and a Fibrosis 4 (FIB‐4) score ≥ 1.3, respectively. Logistic regression analyses were performed to assess their associations with different FAs after adjustment for confounders. Results: A total of 2440 people were included in the study. Concentrations of all considered FAs increased progressively across HOMA‐IR quartiles. A similar trend was identified when the population was segregated according to FLI. In logistic regression analyses adjusted for age, sex, body mass index and race‐ethnicity, when evaluated as a percentage of all circulating FAs, linoleic acid, arachidonic acid and DHA were inversely associated with insulin resistance and liver steatosis. Finally, only alpha‐linolenic acid was associated with a lower risk of liver fibrosis (OR: 0.48, 95% CI 0.25–0.93, p = 0.031). Conclusions: This study provides initial epidemiologic evidence in humans that ω‐3 PUFA in particular are associated with a lower risk of liver steatosis and alpha‐linolenic acid in particular was also protective against fibrosis, supporting data in animal models. Moreover, their circulating levels might be manipulated using nutritional strategies in clinical studies.

Background/Objectives: Insulin resistance is a key factor in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD), but accurately measuring it in patients with type 2 diabetes (T2D) remains challenging. This study examines the relationship between a recently proposed insulin resistance index and the presence of liver steatosis and fibrosis in individuals with T2D. Methods: This cross-sectional study utilized data from the 2017–2020 National Health and Nutrition Examination Survey. Patients with T2D who did not have chronic viral hepatitis or significant alcohol intake were included. The insulin sensitivity (IS) index was calculated using a formula incorporating body mass index, urine albumin-to-creatinine ratio, triglycerides, and gamma-glutamyl transferase. Liver stiffness and steatosis were assessed through transient elastography. MASLD was defined as a controlled attenuation parameter (CAP) of ≥274 decibels/meter (dB/m), while significant liver fibrosis was defined as a liver stiffness measurement (LSM) of ≥8 kPa. Multivariable logistic regression models, adjusted for potential confounders, were used to evaluate the association between IS and these liver outcomes. Results: A total of 1084 patients with T2D were analyzed. The prevalence of MASLD and significant liver fibrosis was 74.1% (95% CI 68.7–78.9) and 25.4% (95% CI 21.2–30.2), respectively. After adjusting for age, sex, waist circumference, and race/ethnicity, lower IS scores (indicating higher insulin resistance) were independently associated with increased odds of both MASLD (quartile 1 vs. quartile 4: OR 2.66, 95% CI 1.23–5.71) and significant liver fibrosis (quartile 1 vs. quartile 4: OR 3.30, 95% CI 1.45–7.51). These findings remained consistent across subgroups stratified by age, sex, and obesity status. Conclusions: This novel IS model, derived from commonly available clinical and biochemical markers, is independently associated with liver steatosis and fibrosis. Its application may help identify patients with more advanced MASLD, facilitating early intervention and risk stratification.

Background: Metabolic and bariatric surgery improves most obesity-related comorbidities. Here, we evaluate the effect of different metabolic and bariatric surgery interventions on the use of medications to treat chronic conditions. Materials and Methods: This was an observational population-based cohort study performed in Lombardy, Italy. Healthcare utilization databases were used to identify all residents who underwent a metabolic and bariatric surgery procedure between 2010 and 2020 with available follow-up data for at least three years after surgery. We included patients undergoing laparoscopic sleeve gastrectomy (LSG), gastric bypass (GB), laparoscopic adjustable gastric banding (LAGB), and biliopancreatic diversion (BPD). Results: During the period 2010 to 2020, 19,450 patients (22.5% males, 13.5% with diabetes) underwent a metabolic and bariatric surgery procedure. LSG was the most commonly performed procedure (65%), followed by LAGB (19%), GB (15%), and BPD (1%). There was a significant reduction in the use of glucose-lowering and antihypertensive drugs after the procedure in all groups. Compared to LSG, the reduction in the use of glucose-lowering drugs was greater following GB (reduction at 3 years: 59 vs 65%, p-interaction < 0.001) and lower following LAGB (59 vs 25%, p-interaction < 0.001). There was a significant reduction in lipid-lowering drug use following LSG and GB (3-year reduction: 21 and 50%, p-interaction < 0.001), and in psychiatric drug use following LSG, GB, and LAGB (with no difference between groups). In all groups, proton pump inhibitor use increased during the first 6 months, followed by a decrease from 1 year afterward. Conclusion: The present study including a large number of patients undergoing metabolic and bariatric surgery procedures shows robust reductions in the use of glucose, blood pressure and lipid-lowering drugs at 3 years follow-up, suggesting benefits of surgery on both quality of life and healthcare costs.

Background/Objectives: Recent studies have highlighted the Triglyceride–Glucose Index (TYG) as a significant risk factor for mortality and co-morbidities in various populations, including those with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. However, its prognostic role in obese individuals remains less clear. Methods: Utilizing data from an obese cohort of 1359 subjects and from the 1999–2004 cycles of the National Health and Nutrition Examination Survey (NHANES) with 15,267 subjects, this study investigates the prognostic value of TYG and blood glucose in relation to age and sex and other factors such as metabolic syndrome, Charlson Comorbidity Index, T2DM and glucose tolerance, in predicting mortality among obese subjects. Over a median follow-up of about 13 years, 11.3% of the obese cohort and 20.6% of the NHANES cohort died. Our findings indicate that while TYG and blood glucose are significantly related to mortality, they offer only modest improvements over models incorporating age, sex, and other risk factors that showed a prognostic power of 76.1% and 86.0% in the respective cohorts. Conclusions: These results suggest that while TYG holds potential as a prognostic biomarker, its utility beyond established risk factors requires further validation in clinical settings.

Background and aim: We assessed the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) and significant liver fibrosis in adults with type 1 diabetes mellitus (T1DM) and the association of MASLD with insulin sensitivity and continuous glucose monitoring metrics. Methods: We consecutively enrolled 198 adults with T1DM undergoing vibration‐controlled transient elastography with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). All participants had a continuous glucose monitoring (CGM) device. Insulin sensitivity was evaluated by estimated glucose disposal rate (eGDR). MASLD was defined as CAP ≥ 248 db/m and the presence of at least one cardiometabolic risk factor. Significant liver fibrosis was defined as LSM ≥ 7 kPa. Results: Patients had a mean age of 56 years, mean BMI of 26.0 ± 5.9 kg/m ² , and mean eGDR of 7.1 ± 2.3 mg/kg/min. 73 (37%) patients had MASLD (using a CAP threshold of 274 dB/m), 16 (8.1%) of whom had significant liver fibrosis. MASLD was associated with a significantly lower eGDR (beta coefficient = −0.367, 95% confidence interval −0.472 to −0.261; p < 0.001). This association remained significant, even after adjustment for age, sex, body mass index, plasma triglycerides, diabetes duration, daily insulin dose, time above the range of glucose levels, LSM and chronic kidney disease. No association was observed between MASLD and CGM‐derived metrics. These results were not different when we used a CAP threshold of 274 dB/m for diagnosing MASLD. Conclusion: In T1DM, MASLD was inversely associated with eGDR and biomarkers of insulin resistance but not with CGM‐derived metrics.

Aims To compare medication persistence and efficacy of oral and subcutaneous semaglutide, in a real-world setting. Materials and methods This is a single-center, retrospective observational cohort study. Patients with type 2 diabetes mellitus (T2DM) starting treatment with either formulation of semaglutide between January 1 2019 and July 31 2023 and with at least one follow-up visit were included. The primary endpoint was the difference in the proportion of patients that continued treatment after 6, 12 and 18 months. Main secondary endpoints were change in HbA1c and body weight. Results We included 242 patients on oral (n = 121) and subcutaneous (n = 121) semaglutide. At baseline, patients in the oral semaglutide group were significantly older (mean age: 67 ± 11 vs. 63 ± 11 years, p = 0.002) and had a lower body mass index (BMI: 30.5 ± 5.6 vs. 33.9 ± 7.1 kg/m², p < 0.001). The proportion of patients persistent to treatment was significantly lower in the oral group at 6 (85.3% vs. 94.8%; p < 0.001), 12 (72.3% vs. 92.4%, p < 0.001) and 18 (46.0% vs. 83.8%; p < 0.001) months. Most common reasons for discontinuation were gastro-intestinal side effects. When adjusted for age and BMI, body weight and HbA1c reduction were not significantly different between the two formulations, as the proportion of patients achieving the composite outcome of weight loss ≥ 5% and HbA1c < 7.0%. Conclusions The present real-world study suggests that persistence is significantly lower when semaglutide is administered as a once-daily tablet compared with a weekly injection, while there are no differences in efficacy between the two formulations.

Natriuretic peptides (NPs) are polypeptide hormones involved in the homeostasis of the cardiovascular system. They are produced by cardiomyocytes and regulate circulating blood volume and sodium concentration. Clinically, measurements of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are recommended by international guidelines as evidence is accumulating on their usefulness. They have a high negative predictive value, and in the setting of low NPs, a diagnosis of heart failure (HF) can be safely excluded in both emergency (BNP < 100 pg/mL, NT-proBNP < 300 pg/mL) and outpatient settings (BNP < 35 pg/mL and NT-proBNP < 125 pg/mL). Moreover, the 2023 consensus from the European Society of Cardiology suggests threshold values for inclusion diagnosis. These values are also associated with increased risks of major cardiovascular events, cardiovascular mortality, and all-cause mortality whether measured in inpatient or outpatient settings. Among patients without known HF, but at high risk of developing it (e.g., in the setting of diabetes mellitus, hypertension, or atherosclerotic cardiovascular disease), NPs may be useful in stratifying cardiovascular risk, optimizing therapy, and reducing the risk of developing overt HF. In the diabetes setting, risk stratification with the use of these peptides can guide the physician to a more informed and appropriate therapeutic choice as recommended by guidelines. Notably, NP levels should be carefully interpreted in light of certain conditions that may affect their reliability, such as chronic kidney disease and obesity, as well as demographic variables, including age and sex. In conclusion, NPs are useful in the diagnosis and prognosis of HF, but they also offer advantages in the primary prevention setting.