Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common chronic liver diseases. Modern lifestyle, characterized by increasing rates of obesity and type 2 diabetes mellitus (T2DM), has led to a "pandemic" of NAFLD that imposes a personal health and socioeconomic burden. Apart from overnutrition and insulin resistance, various metabolic aberrations, gut microbiota and genetic predispositions are involved in the pathogenesis of the disease. The multifactorial nature of NAFLD's pathogenesis makes the development of pharmacological therapies for patients with this disease challenging. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are antidiabetic agents that reduce blood glucose mainly by increasing its renal excretion. As T2DM is one of the major contributors to NAFLD, SGLT-2i have emerged as promising agents for the management of NAFLD. In this review, we summarize the main animal studies on SGLT-2i in models of NAFLD.

Circulating Ferritin in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Objectives: To synthesize data on circulating ferritin between patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and non-NAFLD controls. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library. Thirty-one studies comprising data on 5631 individuals (2929 biopsy-proven NAFLD patients and 2702 controls) were included in the meta-analysis. Results: Higher circulating ferritin levels were observed in NAFLD patients than in controls [standardized mean difference (SMD) 1.14; 95% confidence interval (95% CI) 0.73-1.55], in patients with simple nonalcoholic fatty liver (NAFL) than in controls (SMD 0.57; 95% CI 0.34-0.80), in patients with nonalcoholic steatohepatitis (NASH) than in controls (SMD 0.95; 95% CI 0.69-1.22), and in NASH than in NAFL patients (SMD 0.62; 95% CI 0.25-0.99). There was moderate-to-high heterogeneity among studies in the above pairs of comparisons (I2 = 68-97%); no risk of publication bias was observed by Egger's test (P = 0.81, P = 0.72, P = 0.59, P = 0.42, respectively). The heterogeneity was reduced in the subgroup of biopsy-proven controls in all pairs of comparisons (I2 = 0-65%). The heterogeneity was also reduced after excluding studies with the Newcastle-Ottawa Scale (NOS) score <7 (n = 10) for the comparison of NAFLD patients vs. controls (I2 = 54%, P = 0.02). The meta-regression analysis revealed that the male ratio was positively associated with ferritin SMD in the comparison between NAFLD patients and controls and accounted for 32.7% (P = 0.002) of the heterogeneity in this pair of comparison. Conclusions: Circulating ferritin was higher in NAFLD (or NAFL or NASH) patients compared with controls. Higher levels of circulating ferritin were also associated with the severity of the disease, which, however, should be cautiously interpreted.PROSPERO registration ID: CRD42022354025.

Partial validation of a six-month high-fat diet and fructose-glucose drink combination as a mouse model of nonalcoholic fatty liver disease.

PURPOSE: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. METHODS: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. RESULTS: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. CONCLUSION: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period.

Circulating leptin in patients with nonalcoholic fatty liver disease-related liver fibrosis: a systematic review and a meta-analysis.

BACKGROUND AND AIM: Clinical data on the association between leptin levels and nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis are conflicting. This meta-analysis aimed to compare circulating leptin between NAFLD patients with versus without liver fibrosis or non-NAFLD controls. METHODS: A systematic search was conducted in PubMed, Scopus, and the Cochrane Library. Fifteen studies were included, reporting data from 964 individuals (422 NAFLD patients with fibrosis, 297 NAFLD patients without fibrosis, 245 no-NAFLD controls). RESULTS: Leptin standardized mean difference (SMD) was higher in NAFLD patients with fibrosis (F1-F4) than in controls (SMD: 2.27; 95% confidence interval [CI]: 0.81-3.73); however, this association did not remain robust after the exclusion of studies with morbidly obese individuals. No difference was observed in leptin SMD between NAFLD patients with fibrosis and those without fibrosis (F0), and NAFLD patients without fibrosis versus controls. Heterogeneity was high (I2: 66-98%) among studies. Meta-regression analysis revealed a positive association of leptin SMD with homeostasis model assessment-insulin resistance, when comparing NAFLD patients with fibrosis versus NAFLD patients without fibrosis (beta: 0.53; 95% CI: 0.04-1.03), and a negative association of leptin SMD with age, when comparing NAFLD patients with fibrosis versus controls (beta: -0.29; 95% CI: -0.53 to -0.05). CONCLUSION: Circulating leptin was higher in NAFLD patients with liver fibrosis than non-NAFLD controls, an association, however, attenuated after the exclusion of a study with morbidly obese individuals. Circulating leptin was not different between NAFLD patients with and without fibrosis, or NAFLD patients without fibrosis and controls.

Unexplored Roles of Erythrocytes in Atherothrombotic Stroke.

Stroke constitutes the second highest cause of morbidity and mortality worldwide while also impacting the world economy, triggering substantial financial burden in national health systems. High levels of blood glucose, homocysteine, and cholesterol are causative factors for atherothrombosis. These molecules induce erythrocyte dysfunction, which can culminate in atherosclerosis, thrombosis, thrombus stabilization, and post-stroke hypoxia. Glucose, toxic lipids, and homocysteine result in erythrocyte oxidative stress. This leads to phosphatidylserine exposure, promoting phagocytosis. Phagocytosis by endothelial cells, intraplaque macrophages, and vascular smooth muscle cells contribute to the expansion of the atherosclerotic plaque. In addition, oxidative stress-induced erythrocytes and endothelial cell arginase upregulation limit the pool for nitric oxide synthesis, leading to endothelial activation. Increased arginase activity may also lead to the formation of polyamines, which limit the deformability of red blood cells, hence facilitating erythrophagocytosis. Erythrocytes can also participate in the activation of platelets through the release of ADP and ATP and the activation of death receptors and pro-thrombin. Damaged erythrocytes can also associate with neutrophil extracellular traps and subsequently activate T lymphocytes. In addition, reduced levels of CD47 protein in the surface of red blood cells can also lead to erythrophagocytosis and a reduced association with fibrinogen. In the ischemic tissue, impaired erythrocyte 2,3 biphosphoglycerate, because of obesity or aging, can also favor hypoxic brain inflammation, while the release of damage molecules can lead to further erythrocyte dysfunction and death.

Combination Therapies for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a "magic bullet" to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.

Circulating adiponectin in patients with nonalcoholic fatty liver disease-related liver fibrosis: A systematic review and a meta-analysis.

BACKGROUND AND AIM: There are conflicting data on adiponectin concentrations in nonalcoholic fatty liver disease (NAFLD). The main aim was to compare circulating total adiponectin concentrations in NAFLD patients with versus without liver fibrosis. METHODS: A systematic search was performed in PubMed, Scopus, and Cochrane Library. Twenty-two studies comprising 1753 biopsy-proven NAFLD individuals (1290 with and 463 without fibrosis) were included in the meta-analysis. RESULTS: There was no difference in adiponectin concentration between NAFLD patients with versus without fibrosis (standardized mean difference [SMD]: -0.15; 95% confidence interval [95% CI]: -0.35 to 0.05). Heterogeneity was moderate among studies (Ι2 : 60%, P < 0.001); no risk of publication bias was observed (Egger's test; P = 0.37). The sensitivity analysis, performed after the exclusion of studies with (i) children/adolescents and morbidly obese patients (n = 3) and (ii) adiponectin measurement with other methods than enzyme-linked immunosorbent assay (ELISA) (n = 9), revealed significantly lower adiponectin concentrations in NAFLD patients with fibrosis (i) SMD: -0.23, 95% CI: -0.41 to -0.04; (ii) SMD: -0.30, 95% CI: -0.55 to -0.04, respectively). Meta-regression analysis revealed no significant association of adiponectin SMD with age, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, homeostasis model assessment insulin resistance and the proportion of men. CONCLUSIONS: Overall, patients with NAFLD and fibrosis had similar adiponectin concentrations with patients with NAFLD without fibrosis. However, adiponectin concentration was lower in NAFLD patients with fibrosis than those without fibrosis within the adult patients without morbid obesity and in studies in which adiponectin was measured with the same method (ELISA).

Sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is considered the most prevalent chronic hepatic disease, as it has been estimated that one of four individuals in the general population has been affected by NAFLD. The evolution of the referred entity, which includes nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, may have crucial and even fatal consequences, leading to cirrhosis and hepatocellular carcinoma. Although NAFLD has also been linked with cardiovascular and renal diseases, and all-cause mortality increment, pharmacological therapy is as yet an unfulfilled demand. Since NAFLD is closely associated with type 2 diabetes mellitus (T2DM), a variety of anti-diabetic drugs have been investigated for their effectiveness towards NAFLD. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) improve blood glucose levels through increasing renal glucose excretion and they are recommended as one of standard therapeutic categories for T2DM patients. Based on preclinical animal studies, SGLT-2i have shown a beneficial effect on NAFLD, inducing histologically proven amelioration of hepatic steatosis, inflammation and fibrosis. Promising data have been also derived by clinical trials, which have indicated a potentially beneficial effect of SGLT-2i on NAFLD, at least in terms of liver function tests and imaging. Thus, it is not strange that there are many ongoing trials on the effect of various SGLT-2i in NAFLD. In conclusion, current evidence concerning the effect of SGLT-2i on NAFLD is encouraging; however, data from ongoing clinical trials with histological endpoints are awaited.

Epidemiology, Pathogenesis, Diagnosis and Emerging Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated rising prevalence, in concert with the epidemics of obesity and type 2 diabetes. The pathogenesis of NAFLD is not fully elucidated. Besides weight gain and insulin resistance, many other factors seem to contribute, including adipokines, gut microbiota and genetic predisposition. The disease starts as hepatic steatosis, which may proceed to nonalcoholic steatohepatitis (NASH); if fibrosis is added, the risk of cirrhosis and/or hepatocellular carcinoma is augmented. Liver biopsy is considered the gold standard for the diagnosis and staging of NAFLD; the early use of reliable and easily applied diagnostic tools, such as noninvasive biomarkers, is needed to identify patients at different-preferably early-stages of disease however. Whilst lifestyle modification is the first step to manage NAFLD, there is poor compliance, leading to the need of drug therapy. Accordingly, a variety of medications is under investigation. Given the multifaceted pathophysiology of NAFLD, probably, a combination of approaches in an individualized basis may be a more appropriate management. This review summarizes evidence on the epidemiology, pathogenesis, diagnosis and treatment of NAFLD.

Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). There is currently no approved treatment for NAFLD. The main aim was the evaluation of the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) vs. dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment on noninvasive indices of hepatic steatosis and fibrosis in patients with T2DM. METHODS: In this retrospective study, three noninvasive indices of hepatic steatosis [HSI, NAFLD ridge score, and triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio] and five of fibrosis (APRI, FIB-4, NAFLD fibrosis score, BAAT and BARD) were calculated before and after (6-18 months) the addition of a DPP-4i (n = 152) or a GLP-1 RA (n = 37) in patients with T2DM. RESULTS: Regarding steatosis indices, NAFLD ridge score was significantly decreased in the GLP-1 RA group (baseline: 0.90 ± 0.34, follow-up: 0.67 ± 0.24; p = 0.001), but not in the DPP-4i group (p = 0.25); the difference for group∗time interaction was significant (p = 0.02). HSI showed a trend between groups, being significantly different at baseline and follow-up (p < 0.001) with no significant difference in group∗time interaction. Indices of fibrosis were not essentially changed within or between groups. CONCLUSIONS: NAFLD ridge score was significantly decreased after the addition of GLP-1 RA in patients with T2DM. This study warrants further prospective clinical trials.

Prevalence and geographic variation of abdominal obesity in 7- and 9-year-old children in Greece; World Health Organization Childhood Obesity Surveillance Initiative 2010.

BACKGROUND: In children, abdominal obesity is a better predictor of the presence of cardiovascular risk factors than body mass index (BMI)-defined obesity. We aimed to evaluate the prevalence of abdominal obesity in the Greek pediatric population and to assess the impact of residence on the prevalence of both BMI-defined and abdominal obesity. METHODS: In the context of the Childhood Obesity Surveillance Initiative of the World Health Organization (WHO) Regional Office for Europe, a national representative sample of 7.0-7.9 and 9.0-9.9-year-old children was evaluated (n = 2,531 and 2,700, respectively). Overweight and obesity according to BMI were estimated using both the WHO and International Obesity Task Force cut-off points. Abdominal obesity was defined as waist circumference/height ratio >0.5. RESULTS: The prevalence of abdominal obesity did not differ between 7-year-old boys and girls (25.2 and 25.3%, respectively; p = NS). Among 9-year-old children, abdominal obesity was more prevalent in boys than in girls (33.2 and 28.2%, respectively; p = 0.005). Among normal weight and overweight children, the prevalence of abdominal obesity was 1.6-6.8 and 21.8-49.1%, respectively. The prevalence of abdominal and BMI-defined obesity did not differ between children living in the mainland, in Crete and in other islands except in 7-year-old girls, where the prevalence of BMI-defined obesity was highest in those living in Crete, intermediate in those living in other islands and lowest in those living in the mainland. In 9-year-old boys and in 7- and 9-year-old girls, the prevalence of abdominal obesity was highest in children living in Athens and lowest in children living in Thessaloniki, whereas children living in other cities and in villages showed intermediate rates. The prevalence of abdominal obesity in 7-year-old boys and the prevalence of BMI-defined obesity did not differ between children living in cities and villages. CONCLUSIONS: The prevalence of pediatric abdominal obesity in Greece is among the highest worldwide. Boys and children living in the capital are at higher risk for becoming obese. Given that abdominal obesity is more prevalent than BMI-defined obesity and appears to be more sensitive in identifying cardiovascular risk, measurement of waist circumference might have to be incorporated in the screening for childhood obesity.

Arterial stiffness and peripheral arterial disease in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with increased cardiovascular risk. We aimed to evaluate arterial stiffness and the ankle brachial index (ABI), two markers of subclinical cardiovascular disease, in SLE. We studied 55 patients with SLE (12.7% males, age 53.3 ± 15.3 years) and 61 age- and gender-matched controls. Arterial stiffness was evaluated by measuring pulse wave velocity (PWV), augmentation index (AIx) and central systolic, diastolic, pulse and mean blood pressure (BP). Peripheral arterial disease was defined as ABI ≤ 0.90. Regarding markers of arterial stiffness, patients with SLE had lower PWV and AIx than controls (p < 0.01 and p < 0.05, respectively). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, PWV and AIx did not differ between the two groups. Central systolic, diastolic, pulse and mean BP also did not differ between the two groups. In patients with SLE, PWV correlated independently with systolic BP (B = 0.05, p < 0.001) and waist/hip ratio (B = 6.72, p < 0.05). Regarding ABI, the lowest ABI was lower in patients with SLE than in controls (p < 0.005). However, after adjusting for differences in cardiovascular risk factors between patients with SLE and controls, the lowest ABI did not differ between the two groups. The prevalence of PAD also did not differ between patients with SLE and controls (10.0 and 5.4%, respectively; p = NS). Markers of arterial stiffness and the ABI do not appear to differ between patients with SLE and age- and gender-matched controls. However, given the small sample size, larger studies are needed to clarify whether SLE promotes arterial stiffness and PAD.

Prevalence, etiology and management of non-alcoholic fatty liver disease in patients with polycystic ovary syndrome.

Obesity and insulin resistance (IR) are frequently present in patients with polycystic ovary syndrome (PCOS). Both disorders also play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Accordingly, NAFLD is frequently present in patients with PCOS. In the present review, we summarize the findings of the major studies that assessed the prevalence of NAFLD in patients with PCOS. The factors driving the increased frequency of NAFLD in patients with PCOS are also analyzed. Finally, we discuss the management options of NAFLD in patients with PCOS. In addition to IR, elevated androgen levels and inflammation also appear to play a role in the development and progression of NAFLD in patients with PCOS. Lifestyle changes should represent the cornerstone of management of NAFLD. On the other hand, pharmacotherapy appears to have limited efficacy and questionable safety. Moreover, there are very limited data with the various agents used for the management of NAFLD specifically in patients with PCOS. Accordingly, well-designed studies are clearly needed to evaluate the role of pharmacotherapy in the management of NAFLD in PCOS.

Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and its prevalence is increasing driven by the pandemic of obesity and type 2 diabetes mellitus. NAFLD can progress to cirrhosis and is associated with increased risk for cardiovascular disease and hepatocellular cancer. Diet and exercise are limited by suboptimal long-term adherence in patients with NAFLD. On the other hand, current pharmacological treatment of NAFLD has limited efficacy and unfavorable safety profile. In this context, obeticholic acid (OCA), a selective agonist of the farnesoid X receptors, might represent a useful option in these patients. Preclinical studies suggest that OCA improves hepatic steatosis, inflammation and fibrosis. A proof-of-concept study and the randomized, placebo-controlled Farnesoid X Receptor Ligand Obeticholic Acid in non-alcoholic steatohepatitis Treatment (FLINT) trial also showed improvements in liver histology in patients with NAFLD who received OCA. Weight loss and reduction in blood pressure were also observed. However, the effects of OCA on insulin resistance are conflicting and the lipid profile is adversely affected by this agent. In addition, pruritus is frequently observed during treatment with OCA and might lead to treatment discontinuation. However, given the limitations of existing treatments for NAFLD, OCA might represent a useful therapeutic option in selected patients with NAFLD.