Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Once-weekly insulins: a promising approach to reduce the treatment burden in people with diabetes.

Despite the availability of new classes of glucose-lowering drugs that improve glycaemic levels and minimise long-term complications, at least 20-25% of people with type 2 diabetes require insulin therapy. Moreover, a substantial proportion of these individuals do not achieve adequate metabolic control following insulin initiation. This is due to several factors: therapeutic inertia, fear of hypoglycaemia and/or weight gain, poor communication, complexity of insulin titration, and the number of injections needed, with the associated reduced adherence to insulin therapy. Once-weekly insulins provide a unique opportunity to simplify basal insulin therapy and to allow good glycaemic control with a low risk of hypoglycaemia. Several approaches to developing a stable and effective once-weekly insulin have been proposed, but, to date, insulin icodec and basal insulin Fc (insulin efsitora alfa) are the only two formulations for which clinical studies have been reported. The results of Phase I and II studies emphasise both efficacy (in term of glucose levels) and potential risks and adverse events. Phase III studies involving insulin icodec are reassuring regarding the risk of hypoglycaemia compared with daily basal insulin analogues. Despite some concerns raised in ongoing clinical trials, the available data suggest that weekly insulins may also be an option for individuals with type 1 diabetes, especially when adherence is suboptimal. For the first time there is an opportunity to make an important breakthrough in basal insulin therapy, particularly in people with type 2 diabetes, and to improve not only the quality of life of people with diabetes, but also the practice of diabetologists.

Impact of MASLD and MetALD on clinical outcomes: A meta-analysis of preliminary evidence.

A recent Delphi consensus proposed a new definition for metabolic dysfunction associated steatotic liver disease (MASLD) and introduced a disease entity called MetALD, a condition in which steatotic liver disease (SLD), metabolic dysfunction and moderate alcohol intake coexist. Given the limited available data on the prognostic implications of these disease entities, we performed a systematic review and meta-analysis of available cohort studies to evaluate the association of MASLD and MetALD with hard clinical outcomes. We included 5 studies for a total of 9 824 047 participants. Compared with participants without SLD, increased rates of all-cause mortality and incident cardiovascular disease were present for both MASLD and MetALD. Moreover, MetALD was also associated with significantly higher risks of cancer-related mortality (n = 2 studies, random-effects HR 2.10, 95% CI 1.35-3.28) and cardiovascular mortality (n = 3 studies, random-effects HR 1.17, 95% CI 1.12-1.22). Although preliminary, available evidence indicates a more unfavourable prognosis for patients with MetALD compared with those with MASLD.

Time trends in liver-related mortality in people with and without diabetes: Results from a population based study.

CONTEXT: Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk changed in recent years. OBJECTIVE: The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population. METHODS: Data were retrieved from the healthcare utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost ten million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related and non-viral non-alcohol related (NVNA). RESULTS: Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1,000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The Standardized Mortality Ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer. CONCLUSION: While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes comprised the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period.

Adherence to GLP1-RA and SGLT2-I affects clinical outcomes and costs in patients with type 2 diabetes.

AIMS: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system. RESULTS: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA. CONCLUSIONS: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting.

NAIF: A novel artificial intelligence-based tool for accurate diagnosis of stage F3/F4 liver fibrosis in the general adult population, validated with three external datasets.

OBJECTIVE: The purpose of this study was to determine the effectiveness of a new AI-based tool called NAIF (NAFLD-AI-Fibrosis) in identifying individuals from the general population with advanced liver fibrosis (stage F3/F4). We compared NAIF's performance to two existing risk score calculators, aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (Fib4). METHODS: To set up the algorithm for diagnosing severe liver fibrosis (defined as Fibroscan® values E ≥ 9.7 KPa), we used 19 blood biochemistry parameters and two demographic parameters in a group of 5,962 individuals from the NHANES population (2017-2020 pre-pandemic, public database). We then assessed the algorithm's performance by comparing its accuracy, precision, sensitivity, specificity, and F1 score values to those of APRI and Fib4 scoring systems. RESULTS: In a kept-out sub dataset of the NHANES population, NAIF achieved a predictive precision of 72 %, a sensitivity of 61 %, and a specificity of 77 % in correctly identifying adults (aged 18-79 years) with severe liver fibrosis. Additionally, NAIF performed well when tested with two external datasets of Italian patients with a Fibroscan® score E ≥ 9.7 kPa, and with an external dataset of patients with diagnosis of severe liver fibrosis through biopsy. CONCLUSIONS: The results of our study suggest that NAIF, using routinely available parameters, outperforms in sensitivity existing scoring methods (Fib4 and APRI) in diagnosing severe liver fibrosis, even when tested with external validation datasets. NAIF uses routinely available parameters, making it a promising tool for identifying individuals with advanced liver fibrosis from the general population. Word count abstract: 236.

Development of a New Model of Insulin Sensitivity in Patients With Type 2 Diabetes and Association With Mortality.

CONTEXT: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies. OBJECTIVE: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality. METHODS: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015. RESULTS: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality. CONCLUSION: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication.

Liver fibrosis, NT-ProBNP and mortality in patients with MASLD: A population-based cohort study.

BACKGROUND & AIM: Liver fibrosis is the strongest predictor of liver-related mortality in many chronic liver diseases. NT-ProBNP is independently associated with cardiovascular mortality in general population settings. Here, we evaluate the relative contribution of non-invasively identified liver fibrosis and NT-ProBNP on all-cause and cardiovascular mortality in patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD). METHODS AND RESULTS: Serum NT-ProBNP levels were measured in 4229 patients with MASLD from the general population without a known history of heart failure that participated in the 1999-2004 cycles of the National Health and Nutrition Examination Survey. Presence of liver fibrosis was estimated using the Fibrosis-4 index (FIB-4). We applied Cox proportional hazard models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP and FIB-4 levels and all-cause and cardiovascular mortality through December 2019. Mortality was lower for participants with normal levels of both biomarkers, intermediate if a single biomarker was elevated and highest when both were above the chosen threshold. In the multivariable-adjusted models, both elevated FIB-4 (≥2.67) and elevated NT-ProBNP levels (≥125 pg/ml) were independently associated with higher risks of all-cause mortality (HR 2.2, 95 % CI 1.5-3.2 and HR 1.6, 95 % CI 1.4-2.0, respectively) and cardiovascular mortality (HR 2.1, 95 % CI 1.2-3.7 and HR 2.1, 95 % CI 1.5-2.9, respectively). The associations remained consistent in subgroup analyses based on sex, obesity and age. CONCLUSIONS: Both FIB-4 and NT-ProBNP are independently associated with higher mortality in patients with MASLD. Their combined use might prove useful to risk-stratify patients in clinical practice.

Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes: Screening, Diagnosis, and Treatment.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~70% of patients with type 2 diabetes (T2D), with ~20% showing signs of advanced liver fibrosis. Patients with T2D are at an increased risk of developing cirrhosis, liver failure, and hepatocellular carcinoma and their liver-related mortality is doubled compared with non-diabetic individuals. Nonetheless, the condition is frequently overlooked and disease awareness is limited both among patients and among physicians. Given recent epidemiological evidence, clinical practice guidelines recommend screening for NAFLD/MASLD and advanced liver fibrosis in patients with T2D. While many drugs are currently being tested for the treatment of NAFLD/MASLD, none of them have yet received formal approval from regulatory agencies. However, several classes of antidiabetic drugs (namely pioglitazone, sodium-glucose transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and multi-agonists) have shown favorable effects in terms of liver enzymes, liver fat content and, in some occasions, on histologic features such as inflammation and fibrosis. Therefore, diabetologists have the opportunity to actively treat NAFLD/MASLD, with a concrete possibility of changing the natural history of the disease. In the present narrative review, we summarize evidence and clinical recommendations for NAFLD/MAFLD screening in the setting of T2D, as well as on the effect of currently available glucose-lowering drugs on hepatic endpoints.

Liver stiffness is associated with all-cause mortality in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Several studies reported an association between liver stiffness measurement (LSM) obtained through vibration-controlled transient elastography (VCTE) and all-cause mortality in patients with nonalcoholic fatty liver disease (NAFLD). The objective of this systematic review and meta-analysis was to summarize available evidence on the nature and magnitude of this association. METHODS: We systematically searched PubMed-MEDLINE and Scopus up to April 2023 for observational cohort studies in which LSM was measured with VCTE in patients with NAFLD or in general population settings, with a follow-up ≥1 year and with available data on all-cause mortality. Measures of association from individual studies were meta-analysed using random effects models. Of the 517 titles initially scrutinized, we included seven studies with data on 18 771 participants (47.1% male) and a mean follow-up of 3.6 years. We included effect estimates obtained in the models with the highest degree of adjustment for potential confounders available in each study. RESULTS: When analysed as a categorical variable based on specific LSM cut-offs, liver fibrosis was associated with an increased risk of all-cause death (HR 2.10, 95% CI 1.56-2.83; test for overall effect z = 4.919, p < 0.001). Results were consistent when LSM was considered as a continuous variable (HR for 1 kPa increase: 1.03, 95% CI 1.01-1.05; test for overall effect z = 3.341, p = 0.001). There was borderline significant heterogeneity among the studies (I2 = 50.2% and I2 = 66.7% in the two analyses, respectively). No significant publication bias was detected by funnel plot analysis and Egger's and Begg's tests. CONCLUSION: The present meta-analysis indicates that LSM, as a proxy of liver fibrosis, is independently and directly associated with a higher mortality risk in patients with NAFLD.

Exploring the landscape of steatotic liver disease in the general US population.

BACKGROUND AND OBJECTIVE: The aim of the present study is to explore the epidemiologic impact of the definition of steatotic liver disease (SLD) proposed by a multi-society (American Association for the Study of the Liver-the European Association for the Study of Liver Diseases-Asociación Latinoamericana para el Estudio del Hígado) Delphi consensus statement. METHODS: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey who were evaluated by vibration-controlled transient elastography. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter and liver stiffness measurement using cut-offs of 274 dB/m and 8.0 kPa, respectively. Recently proposed criteria for metabolic dysfunction-associated steatotic liver disease (MASLD), MetALD (MASLD + significant alcohol consumption), MASLD-Viral hepatitis and cryptogenic SLD were applied. RESULTS: SLD was present in 42.1% (95% CI: 40.3-43.9) of the 3173 included participants. Among patients with SLD, 99.4% met the metabolic dysfunction definition. Moreover, 89.4%, 7.7%, 2.4%, 0.4% and 0.1% were defined as MASLD, MetALD, MASLD-Viral, alcoholic liver disease (ALD) (significant alcohol consumption without metabolic dysfunction) and cryptogenic, respectively. No patients without metabolic dysfunction had significant liver fibrosis, which was present in 15.2%, 9.5% and 19.5% of patients with MASLD, MetALD and MASLD-viral, respectively. Approximately, 90% of the overall adult US population could be diagnosed with metabolic dysfunction according to the consensus criteria. A high degree of concordance was found between MASLD and the previously proposed metabolic dysfunction-associated fatty liver disease definition. CONCLUSIONS: Metabolic dysfunction is present in almost all patients with SLD in the United States. The new change in diagnostic criteria did not significantly impact disease prevalence.

Differential Association of Sex Hormones with Metabolic Parameters and Body Composition in Men and Women from the United States.

Sex hormones impact body composition. Data on the specific impact of each hormone on different body depots in men and women are scarce. The aim of this study is to evaluate the association between testosterone, estradiol and body fat distribution in the general population. This is a population-based cross-sectional study based on data from the 2013-2016 cycles of the National Health and Nutrition Examination Survey. Dual energy X-ray absorptiometry (DXA) and liquid chromatography tandem mass spectrometry were performed on participants aged 18-59 years to evaluate body composition and sex hormone levels, respectively. Weighted multivariable linear regression analyses were performed to evaluate the association between these parameters after adjustment for potential confounders. A total of 6655 participants (3309 males and 3346 females) was included in the analysis. Men with lower testosterone levels were older, had a higher body mass index (BMI) and had a generally unfavorable metabolic profile, while no specific trends were found in women. Among men, testosterone was positively associated with lean body mass and was negatively associated with fat mass and the android/gynoid (A/G) ratio, while an opposite trend was found for estradiol. Among women, testosterone did not impact body composition, while estradiol levels were positively associated with lean mass and were negatively associated with fat mass. Our results support the notion that the impact of different sex hormones on specific fat depots varies substantially between men and women.

Noninvasive identification of probable fibrotic nonalcoholic steatohepatitis across the spectrum of glucose tolerance in the United States.

AIM: Identifying patients with fibrotic nonalcoholic steatohepatitis (NASH) is crucial in order to refer them to specialist care as fibrotic NASH represents one of the major inclusion criteria for clinical trials. The aim of this study is to report the prevalence of fibrotic NASH in the general US population across the spectrum of glucose tolerance and evaluate the performance of the recently proposed Fibrotic NASH Index (FNI). METHODS: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey. Participants with available data to calculate FNI (which is based on AST, HbA1c and HDL-cholesterol) and with a reliable vibration controlled transient elastography examination were included. We excluded participants with chronic viral hepatitis, significant alcohol consumption or other forms of liver disease. Probable fibrotic NASH was defined as a Fibroscan-AST (FAST) score ≥ 0.35. RESULTS: We included a total of 6268 participants. The overall prevalence of probable fibrotic NASH was 5.9 % (95 % CI 5.2-6.7) and it increased progressively from participants with normal glucose tolerance (3.7 %, 95 % CI 2-9-4.7) to those with diabetes (14.7 %, 95 % CI 12.1-17.8). The performance of FNI for probable fibrotic NASH was satisfactory in the overall population (area under the receiver operating characteristic curve (AUROC): 0.93, 95 % CI 0.92-0.94) and it maintained a good accuracy also in participants with diabetes (n = 1113, AUROC 0.89, 95 % CI 0.86-0.92). In all groups it outperformed Fibrosis-4. CONCLUSIONS: FNI is an easy and reliable test to screen for NASH and its performance is maintained in patients with diabetes, a condition that was shown to negatively influence the performance of several non-invasive scores.

Serum neurofilament light chain levels are associated with all-cause mortality in the general US population.

INTRODUCTION: Serum neurofilament light chain (sNfL) levels are biomarkers of neuro-axonal injury in multiple neurological diseases. Little is known on their potential role as prognostic markers in people without known neurological conditions. OBJECTIVE: The aim of this study is to evaluate the association between sNfL levels and all-cause mortality in a general population setting. METHODS: sNfL levels were measured in 2071 people aged 25-75 years from the general US population that participated in the 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES). Cognitive function was evaluated in a subset of participants aged 60-75 years using the Consortium to Establish a Registry for Alzheimer's Disease-Word Learning test, the Animal Fluency test and the Digit Symbol Substitution test. We applied Cox proportional hazard models adjusted for several potential confounders to evaluate the association between sNfL and all-cause mortality through December 2019 by linking NHANES data with data from the National Death Index. RESULTS: In a cross-sectional analysis, higher sNfL levels were associated with worse performance in all three cognitive function tests. Over a median follow-up of 6.1 years, 85 participants died. In a multivariable model adjusted for age, sex, race-ethnicity, diabetes, chronic kidney disease, harmful alcohol consumption, cigarette smoke and prevalent cardiovascular disease, higher sNfL levels were significantly and positively associated with all-cause mortality (HR per unit increase in log-transformed sNfL: 2.46, 95% CI 1.77-3.43, p < 0.001). Results were robust when analyses were stratified according to age, sex, body mass index and kidney function. CONCLUSION: We found a positive association between sNfL levels and mortality in the general US population. Further studies are needed to understand the biological mechanisms underlying this association.

Adherence to antidiabetic drug therapy and reduction of fatal events in elderly frail patients.

BACKGROUND: To evaluate the protective effect of oral antidiabetic drugs in a large cohort of elderly patients with type 2 diabetes differing for age, clinical status, and life expectancy, including patients with multiple comorbidities and short survival. METHODS: A nested case-control study was carried out by including the cohort of 188,983 patients from Lombardy (Italy), aged ≥ 65 years, who received ≥ 3 consecutive prescriptions of antidiabetic agents (mostly metformin and other older conventional agents) during 2012. Cases were the 49,201 patients who died for any cause during follow-up (up to 2018). A control was randomly selected for each case. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drug prescriptions. Conditional logistic regression was used to model the risk of outcome associated with adherence to antidiabetic drugs. The analysis was stratified according to four categories of the clinical status (good, intermediate, poor, and very poor) differing for life expectancy. RESULTS: There was a steep increase in comorbidities and a marked reduction of the 6-year survival from the very good to the very poor (or frail) clinical category. Progressive increase in adherence to treatment was associated with a progressive decrease in the risk of all-cause mortality in all clinical categories and at all ages (65-74, 75-84 and ≥ 85 years) except for the frail patient subgroup aged ≥ 85 years. The mortality reduction from lowest to highest adherence level showed a tendency to be lower in frail patients compared to the other categories. Similar although less consistent results were obtained for cardiovascular mortality. CONCLUSIONS: In elderly diabetic patients, increased adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the patients' clinical status and age, with the exception of very old patients (age ≥ 85 years) in the very poor or frail clinical category. However, in the frail patient category the benefit of treatment appears to be less than in patients in good clinical conditions.