Breakthrough in the Treatment of Metabolic Associated Steatotic Liver Disease: Is it all over?

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease - MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to continue ongoing trials? How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? How to define cost-effective strategies that might prevent the generation of unacceptable differences within the population, given the high costs of novel drugs and the extremely high numbers of candidates to treatment? Only a close surveillance of drug use in the real world, generated by insurance databases and national healthcare system registries, might provide adequate answers to these compelling questions.

Effectiveness of the flash glucose monitoring system in preventing severe hypoglycemic episodes and in improving glucose metrics and quality of life in subjects with type 1 diabetes at high risk of acute diabetes complications.

AIMS: To assess the effectiveness of the intermittent-scanned continuous glucose monitoring (isCGM) system in preventing severe hypoglycemic episodes and in improving glucose parameters and quality of life. METHODS: Four hundred T1D individuals were enrolled in a prospective real-word study with an intermittently scanned continuous glucose monitoring device during the 12-months follow-up. The primary endpoint was the incidence of severe hypoglycemic events. RESULTS: 82% of subjects were naïve to the use of the device (group A) and 18% were already wearing the system (group B). The cumulative incidence of severe hypoglycemia (SH) at 12 months was 12.06 per 100 person-year (95% CI: 8.35-16.85) in group A and 10.14 (95% CI: 4.08-20.90) in group B without inter-group differences. In group A there was a significant decrease in SH at 12 months compared to 3 months period (p = 0.005). Time in glucose range significantly increased in both groups accompanied with a significant decrease in glucose variability. HbA1c showed a progressive significant time-dependent decrease in group A. The use of the device significantly improved the perceived quality of life. CONCLUSION: This study confirmed the effectiveness of the isCGM in reducing hypoglycemic risk without glucose deterioration, with potential benefits on adverse outcomes in T1D individuals. TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT04060732.

Metformin and the Liver: Unlocking the Full Therapeutic Potential.

Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.

Anxiety and depression in metabolic-associated steatotic liver disease: relation with socio-demographic features and liver disease severity.

PURPOSE: We aimed to evaluate the prevalence of anxiety and depression traits in Italian patients with metabolic dysfunction-associated steatotic liver disease (MASLD), and the possible relation with the severity of liver disease. METHODS: Demographic, anthropometric, clinical and laboratory parameters were collected in patients referred to a metabolic unit for a comprehensive evaluation of possible liver disease. Hepatic steatosis and fibrosis were evaluated by surrogate biomarkers. Imaging (controlled attenuation parameter-CAP and vibration-controlled transient elastography-VCTE). Beck depression inventory (BDI) and state-trait anxiety inventory-Y (STAI-Y) were used to define depressive/anxiety states; calorie intake and lifestyle were self-assessed by questionnaires. RESULTS: The whole sample comprised 286 patients (61.9% females; mean age 52.0 years; BMI, 34.6 kg/m2); 223 fulfilled MASLD criteria. BDI and trait anxiety scores were lower in the MASLD cohort, and the prevalence of both moderate/severe depression and severe trait anxiety was reduced compared with non-MASLD cases, despite VCTE-diagnosed fibrosis F3-F4 present in over 15% of cases. However, after correction for demographic and anthropometric confounders, MASLD was not associated with a lower risk of moderate/severe depression or severe anxiety trait (odds ratio, 0.34; 95% confidence interval, 0.12-1.01 and 0.79, 0.27-2.34). Additional adjustment for the severity of fibrosis did not change the results. No differences in state anxiety were observed. CONCLUSION: The risk of anxiety and depression in MASLD is not different from that generated by diabetes and obesity per se. MASLD patients do not perceive liver disease as a specific source of psychological distress, possibly as a consequence of the unawareness of progressive liver disease.

Association between Albumin Alterations and Renal Function in Patients with Type 2 Diabetes Mellitus.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin concentrations could complement the diagnosis of DKD. To this end, one hundred and seventeen T2DM patients without (n = 42) and with (n = 75) DKD (DKD I-III upon KDIGO classification) were evaluated; the total albumin concentration (tHA) was quantified by a bromocresol green assay, while structural alterations were profiled via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). The concentrations of native albumin (eHA, effective albumin) and reduced albumin (rHA) were subsequently assessed. The HRMS analyses revealed a reduced relative amount of native albumin in DKD patients along with an increased abundance of altered forms, especially those bearing oxidative modifications. Accordingly, both eHA and rHA values varied during the stages of progressive renal failure, and these alterations were dose-dependently correlated with renal dysfunction. A ROC curve analysis revealed a significantly greater sensitivity and specificity of eHA and rHA than of tHA for diagnosing DKD. Importantly, according to the multivariate logistic regression analysis, the eHA was identified as an independent predictor of DKD.

A novel model for predicting diabetes remission after bariatric surgery based on the measurement of C-peptide and creatinine in serum: A pilot study.

BACKGROUND AND AIMS: Bariatric surgery is effective for treating type 2 diabetes (T2D) in patients with obesity, although a significant proportion of these patients do not achieve diabetes remission after the surgery even after significant weight loss and metabolic improvement. C-peptide is a valuable marker of beta cell function and insulin secretion, but renal function must be considered when interpreting measurements in patients with T2D. The study aims to investigate the association of serum levels of C-peptide adjusted for creatinine with diabetes remission and glycemic target achievement after bariatric surgery in patients with obesity and T2D. METHODS AND RESULTS: Prospective data from a cohort of 84 patients with obesity and T2D submitted to Roux-en-Y gastric bypass (RYGB) were collected at baseline and at least a 6-month follow up. A multivariate binomial regression model showed that Ln(C-peptide/creatinine) and age were significantly associated with 6-month T2D remission. The area under the curve for the receiver operating characteristic analysis (AUROC) to predict remission was 0.87, and more accurate than the AUROC based on C-peptide levels alone (0.75). The same model was also able to predict achieving an HbA1c target of 7 % (53 mmol/mol) (AUROC 0.96). CONCLUSION: In conclusion, Ln(C-peptide/creatinine) ratio could be a useful tool in predicting T2D remission and target achievement after RYGB surgery, providing a more accurate reflection of beta cell function in bariatric patients.

Long-term follow-up of web-based and group-based behavioural intervention in NAFLD in a real world clinical setting.

BACKGROUND: The long-term results of web-based behavioural intervention in non-alcoholic fatty liver disease (NAFLD) have not been described in patients followed in specialised centres. AIMS: To analyse the long-term effectiveness of web education compared with the results achieved by a group-based behavioural intervention in the same years 2012-2014. METHODS: We followed 679 patients with NAFLD (web-based, n = 290; group-based, n = 389) for 5 years. Weight loss ≥10% was the primary outcome; secondary outcomes were attrition, changes in liver enzymes and in biomarkers of steatosis (Fatty liver Index) and fibrosis (Fibrosis-4 index). RESULTS: The cohorts differed in age, education, working status and presence of diabetes. Attrition was higher in the web-based cohort (hazard ratio: 1.53; 95% CI: 1.24-1.88), but not different after adjustment for confounders. Among patients in active follow-up, 50% lost ≥5% of initial body weight and 19% lost ≥10%, without difference between cohorts. Alanine aminotransferase levels fell to within the normal range in 51% and 45% of web- and group-based cohorts, respectively. Fatty Liver Index declined progressively and, by year 5, it ruled out steatosis in 4.8%, whereas 24.9% were in the indeterminate range. Fibrosis-4 index increased in both cohorts, driven by age, but the prevalence of cases ruling-in advanced fibrosis remained very low (around 1%). Improvements in the class of both surrogate biomarkers were associated with ≥5% weight loss. CONCLUSIONS: Although burdened by attrition, web-based behavioural intervention is feasible and effective in NAFLD, expanding the cohort involved in behavioural programs and reducing the risk of progressive disease.

Risk of binge eating disorder in patients with metabolic dysfunction-associated steatotic liver disease.

PURPOSE: Very few data exist on the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and eating disorders. The study aimed to evaluate the presence of binge eating disorder (BED), in MASLD subjects. METHODS: Demographic, clinical investigation, anthropometric measurements and laboratory were collected in 129 patients with MASLD (34.1% males; age, 53.7 years; BMI, 34.4 kg/m2) addressed by general practitioners to a hospital-based unit of metabolic disorders. The risk of binge eating was tested by the binge eating scale (BES); values in the range 17-26 were considered "possible" BED, values > 26 were considered "probable" BED. Hepatic steatosis and fibrosis were tested by surrogate biomarkers and imaging (transient elastography). Calorie intake and lifestyle were self-assessed by questionnaires. RESULTS: Possible BED was present in 17.8% of cases, probable BED in another 7.6%, and were neither associated with gender, obesity class, diabetes, features of metabolic syndrome, nor with presence and severity of hepatic steatosis and fibrosis. Also steatosis grade by CAP and fibrosis stage by liver stiffness did not correlate with BES. However, an association was present between the daily caloric intake and "possible" BED (odds ratio, 1.14; 95% confidence interval, 1.05-1.24; "probable" BED, 1.21; 1.07-1.37), after adjustment for confounders. CONCLUSION: Binge eating, as scored by BES, is present in a significant proportion of MASLD cases screened for metabolic disorders in a specialized center. It may impact behavioral treatment, reducing the chance of weight loss without systematic psychological support. LEVEL OF EVIDENCE: Level III, cohort analytic study.

Insulin resistance and metabolic flexibility as drivers of liver and cardiac disease in T2DM.

Metabolic flexibility refers to the ability of tissues to adapt their use of energy sources according to substrate availability and energy demands. This review aims to disentangle the emerging mechanisms through which altered metabolic flexibility and insulin resistance promote NAFLD and heart disease progression. Insulin resistance and metabolic inflexibility are central drivers of hepatic and cardiac diseases in individuals with type 2 diabetes. Both play a critical role in the complex interaction between glucose and lipid metabolism. Disruption of metabolic flexibility results in hyperglycemia and abnormal lipid metabolism, leading to increased accumulation of fat in the liver, contributing to the development and progression of NAFLD. Similarly, insulin resistance affects cardiac glucose metabolism, leading to altered utilization of energy substrates and impaired cardiac function, and influence cardiac lipid metabolism, further exacerbating the progression of heart failure. Regular physical activity promotes metabolic flexibility by increasing energy expenditure and enabling efficient switching between different energy substrates. On the contrary, weight loss achieved through calorie restriction ameliorates insulin sensitivity without improving flexibility. Strategies that mimic the effects of physical exercise, such as pharmacological interventions or targeted lifestyle modifications, show promise in effectively treating both diabetes and NAFLD, finally reducing the risk of advanced liver disease.

[A&F: obstacles to implementing interventions in the health system.] / A&F: gli ostacoli nell'implementare interventi nel sistema sanitario.

Understanding how well a clinician or health care team is performing provides an essential foundation for improvement. If done well, Audit and Feedback (A&F) provides data in non-judgemental, motivating insights and leads to changes in clinical processes that benefit patients. This article will explore obstacles to optimizing the potential positive effects of A&F to improve patient care and outcomes by examining three interrelated steps in the process: the audit; the feedback; and the action. The audit requires data that will be perceived as both valid and actionable. Acquiring and using such data properly often requires partnerships. Feedback recipients need to know how to turn data into action. The A&F, therefore, should include components that direct the recipient toward feasible next steps to undertake the change that will lead to improvement. The proposed actions may be individual (learning new diagnostic or therapeutic strategies, trying a more patient-centered approach, etc.) or organizational (more proactive approaches often including the involvement of additional team members). The ability to turn feedback into action will depend on the culture of the recipient-group, and its level of experience with these change processes. Feedback facilitation or coaching may be useful for some groups or certain kinds of desired changes in practice. Inadequate leadership and support for health professionals, as they try to respond to A&F, is also often a barrier. Finally, with the final focus on the challenges of the individual Work Packages (WP) within the Easy-Net network program, the article focuses on what were the facilitating and hindering factors, the obstacles encountered, and the resistance to change overcome, useful considerations in support of the increasingly widespread implementation of A&F activities in our Healthcare System in the future.

Looking ahead to potential incretin combination therapies for nonalcoholic steatohepatitis in patients with diabetes.

INTRODUCTION: There are no drugs approved by regulatory agencies for the treatment of nonalcoholic fatty liver disease (NAFLD); incretin combination therapies are being developed for treatment of type 2 diabetes and research has moved to test their usefulness in NAFLD. AREAS COVERED: We reviewed the literature on the effectiveness of dual and triple peptides combining receptor agonists of the glucagon-like peptide 1, the glucose-dependent insulinotropic peptide, and glucagon to treat NAFLD and its associated metabolic diseases, and/or the cardiovascular risk intimately connected with the cluster of the metabolic syndrome. Other combination peptides involved the glucagon-like peptide 2 receptor, the fibroblast growth factor 21, the cholecystokinin receptor 2, and the amylin receptor. EXPERT OPINION: Both dual and triple agonists are promising, based on animal, pharmacokinetic and proof-of concept studies, showing effectiveness both in the presence and the absence of diabetes on a few validated surrogate NAFLD biomarkers, but the majority of studies are still in progress. Considering the long natural history of NAFLD, final proof of their efficacy on primary clinical liver outcomes might be also derived from the analysis of large databases of National Healthcare Systems or Insurance companies, when used in diabetes for improving glycemic control, after careful propensity-score matching.

Lifestyle Intervention in NAFLD: Long-Term Diabetes Incidence in Subjects Treated by Web- and Group-Based Programs.

BACKGROUND: Behavioral programs are needed for prevention and treatment of NAFLD and the effectiveness of a web-based intervention (WBI) is similar to a standard group-based intervention (GBI) on liver disease biomarkers. OBJECTIVE: We aimed to test the long-term effectiveness of both programs on diabetes incidence, a common outcome in NAFLD progression. METHODS: 546 NAFLD individuals (212 WBI, 334 GBI) were followed up to 60 months with regular 6- to 12-month hospital visits. The two cohorts differed in several socio-demographic and clinical data. In the course of the years, the average BMI similarly decreased in both cohorts, by 5% or more in 24.4% and by 10% or more in 16.5% of cases available at follow-up. After excluding 183 cases with diabetes at entry, diabetes was newly diagnosed in 48 cases during follow-up (31 (16.6% of cases without diabetes at entry) in the GBI cohort vs. 17 (9.7%) in WBI; p = 0.073). Time to diabetes was similar in the two cohorts (mean, 31 ± 18 months since enrollment). At multivariable regression analysis, incident diabetes was significantly associated with prediabetes (odds ratio (OR) 4.40; 95% confidence interval (CI) 1.97-9.81; p < 0.001), percent weight change (OR 0.57; 95% CI 0.41-0.79; p < 0.001) and higher education (OR 0.49; 95% CI 0.27-0.86; p = 0.014), with no effect of other baseline socio-demographic, behavioral and clinical data, and of the type of intervention. The importance of weight change on incident diabetes were confirmed in a sensitivity analysis limited to individuals who completed the follow-up. CONCLUSION: In individuals with NAFLD, WBI is as effective as GBI on the pending long-term risk of diabetes, via similar results on weight change.

Improved glycaemic control in patients with type 2 diabetes has a beneficial impact on NAFLD, independent of change in BMI or glucose lowering agent.

BACKGROUND AND AIM: The current focus of the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) is lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with type 2 diabetes (T2D) and obesity. In patients with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. METHODS AND RESULTS: In a retrospective analysis of data from 637 people with T2D, we examined the longitudinal impact of optimizing glycaemic control with DPP-IV inhibitors, GLP-1RAs and SGLT2 inhibitors on Fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Multiple linear regression analysis demonstrated a significant correlation between the change in glycated haemoglobin and change in FLI after adjustment for change in BMI, age, sex, and drug class (R = 0.467, p = 0.031). The greatest reduction in FLI was observed in patients with the largest reduction in glycated haemoglobin (p < 0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. CONCLUSIONS: Improvements in glucose control that are independent of weight loss are associated with improvement in NAFLD and should form an integral part of the management patients with co-existent NAFLD and T2D.

Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort. METHODS: We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC. RESULTS: MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006). CONCLUSIONS: The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Promoting weight loss and psychological well-being in patients with obesity: A sequential combination of behavioural lifestyle intervention and well-being therapy.

Behavioural lifestyle interventions focused on diet and physical activity are a cornerstone for the treatment of obesity. However, their effects vary substantially across individuals in terms of magnitude and durability. Personalized approaches that target psychological well-being may be promising to facilitate healthy behaviours and sustained weight loss. This preliminary study aimed to explore whether the sequential combination of behavioural lifestyle intervention (BLI) and well-being therapy (WBT) may result in more favourable outcomes than BLI alone in promoting weight loss (primary outcome) and improving psychological well-being, distress, dietary behaviours and physical activity (secondary outcomes). A total of 83 patients with obesity were randomly assigned to BLI/WBT (N = 38) or BLI group (N = 45). The BLI group received a 12-week behavioural weight loss programme, whereas the BLI/WBT group received the same programme followed by an additional 4-week WBT, adapted for group interventions. Data were collected at pretreatment (baseline, T1), at the end of BLI/WBT (T2), at 6-month (T3) and 12-month (T4) follow-ups. There was a significant weight loss in both treatment groups at T2, T3 and T4. The BLI/WBT group showed greater improvements in depressive symptoms at T3 and T4, in autonomy at T2, in personal growth at T4 and in global well-being at T4 compared with BLI group. WBT yielded no additional effect on weight loss. However, the secondary outcomes indicate that WBT may have enduring effects that reduce vulnerability to psychological distress in patients with obesity. In order to confirm these preliminary findings and explore whether a more intensive and individualized WBT can foster sustained weight loss, future studies are needed.