Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials

Recent randomized controlled trials (RCTs) tested the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors to specifically treat nonalcoholic fatty liver disease (NAFLD). We systematically searched three electronic databases (up to 31 October 2020) for identifying placebo-controlled or head-to-head RCTs that used SGLT-2 inhibitors for treatment of NAFLD. No published RCTs with paired liver biopsy data were available for the meta-analysis. Primary outcome measures were changes in serum liver enzyme levels and liver fat content on imaging techniques. Overall, we included a total of twelve RCTs testing the efficacy of dapagliflozin (n = six RCTs), empagliflozin (n = three RCTs), ipragliflozin (n = two RCTs) or canagliflozin (n = one RCT) to specifically treat NAFLD for a median period of 24 weeks with aggregate data on 850 middle-aged overweight or obese individuals with NAFLD (90% with type 2 diabetes). Compared to placebo/reference therapy, treatment with SGLT-2 inhibitors significantly decreased serum alanine aminotransferase (weighted mean differences (WMD): -10.0 IU/L, 95%CI -12.2 to -7.79 IU/L; I2 = 10.5%) and gamma-glutamyltransferase levels (WMD: -14.49 IU/L, 95%CI -19.35 to -9.63 IU/L, I2 = 38.7%), as well as the absolute percentage of liver fat content on magnetic resonance-based techniques (WMD: -2.05%, 95%CI -2.61 to -1.48%; I2 = 0%). In conclusion, SGLT-2 inhibitors seem to be a promising treatment option for NAFLD

Comparative effects of non-alcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease on risk of incident cardiovascular events: a meta-analysis of about 13 million individuals

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Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: -3.92%, 95% confidence intervals (CI) -6.27% to -1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52-6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation

Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies

Objective We performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers.Design We systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling.Results We included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.Conclusion This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.<br/

Long-term adverse effect of liver stiffness on Glycaemic Control in Type 2 Diabetic patients with nonalcoholic Fatty liver disease: A pilot study

Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07–20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD.<br/

Long-Term Adverse Effect of Liver Stiffness on Glycaemic Control in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study

Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07-20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD

Association between lower plasma adiponectin levels and higher liver stiffness in type 2 diabetic individuals with nonalcoholic fatty liver disease: an observational cross-sectional study

Purpose Little is known about the association between plasma adiponectin levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). We examined whether there is an association between lower plasma adiponectin levels and the presence/severity of NAFLD in people with T2DM. Methods We cross-sectionally recruited 79 men with non-insulin-treated T2DM and no known liver diseases, who had consecutively attended our diabetes outpatient service over a 6-month period and who underwent both ultrasonography and Fibroscan-measured liver stiffness (LSM). Nine single nucleotide polymorphisms (PNPLA3 rs738409 and other genetic variants) associated with NAFLD were investigated. Results Among the 79 participants included (mean age 67 +/- 10 years, BMI 27.7 +/- 4 kg/m(2)), 28 did not have NAFLD, 32 had steatosis alone, and 19 had NAFLD with coexisting significant fibrosis (LSM &gt;= 7.0 kPa by Fibroscan (R)). Compared to those without NAFLD, patients with hepatic steatosis alone and those with hepatic steatosis and coexisting significant fibrosis had lower high-molecular-weight adiponectin levels (5.5 [IQR 2.3-7.6] vs. 2.4 [1.8-3.7] vs. 1.6 [1.0-2.9] mu g/mL; p &lt; 0.001). After adjustment for age, body mass index, insulin resistance, and the PNPLA3 rs738409 variant, lower plasma adiponectin levels were found to be associated with increased odds of both steatosis alone (adjusted-odds ratio [OR] 2.44, 95% CI 1.04-5.56, p = 0.042) and NAFLD with coexisting significant fibrosis (adjusted-OR 3.84, 95% CI 1.23-10.0, p = 0.020). Similar findings were observed after adjustment for the other eight genotyped NAFLD-related polymorphisms. Conclusion Lower plasma adiponectin levels are closely associated with the presence and severity of NAFLD in men with T2DM, pointing to a role of adiponectin in NAFLD development and progression

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Supraventricular and Ventricular Tachyarrhythmias in Patients with Type 2 Diabetes

Background: Currently, it remains uncertain whether metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with increased risk of supraventricular and ventricular tachyarrhythmias in people with type 2 diabetes mellitus (T2DM). Methods: We retrospectively examined the data of 367 ambulatory patients with T2DM who underwent 24-hour Holter monitoring between 2015 and 2022 for clinical indications, and who did not have pre-existing permanent atrial fibrillation (AF), kidney failure or known liver diseases. Paroxysmal supraventricular tachycardia (PSVT), paroxysmal AF and episodes of ventricular tachyarrhythmias (i.e., presence of ventricular tachycardia, &gt;30 premature ventricular complexes per hour, or both) were recorded. The presence and severity of MAFLD was diagnosed by ultrasonography and fibrosis-4 (FIB-4) index. Results: Patients with T2DM who had MAFLD (n=238) had a significantly greater prevalence of PSVT (51.7% vs. 38.8%), paroxysmal AF (6.3% vs. 1.3%) and combined ventricular tachyarrhythmias (31.9% vs. 20.2%) compared to their counterparts without MAFLD (n=129). MAFLD was significantly associated with a greater than two-fold risk of having PSVT (adjusted-odds ratio [OR] 2.04, 95% confidence interval 1.04-4.00) or ventricular tachyarrhythmias (adjusted-OR 2.44, 95%CI 1.16-5.11), after adjusting for age, sex, smoking, diabetes-related factors, comorbidities, medication use and left ventricular ejection fraction on echocardiography. The risk of supraventricular and ventricular tachyarrhythmias was even greater amongst patients with MAFLD and FIB-4 ≥1.3. Conclusions: In ambulatory patients with T2DM, the presence and severity of fatty liver disease was strongly associated with an increased risk of supraventricular and ventricular arrhythmias on 24-hour Holter monitoring

Nonalcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals.

Objective Recent studies reported an association between non-alcoholic fatty liver disease (NAFLD) and increased risk of new-onset heart failure (HF). However, the magnitude of the risk and whether this risk changes with severity of liver disease remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of new-onset HF. Design We systematically searched Scopus, Web of Science and PubMed from database inception to March 2022 to identify eligible observational studies, in which NAFLD was diagnosed by serum biomarkers/scores, International Classification of Diseases (ICD) codes, imaging techniques or liver histology. The primary outcome was new-onset HF, as assessed mainly by ICD codes. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. Results We identified 11 longitudinal cohort studies with aggregate data on 11 242 231 middle-aged individuals from different countries and 97 716 cases of incident HF over a median of 10 years. NAFLD was associated with a moderately higher risk of new-onset HF (pooled random-effects hazard ratio 1.50, 95% CI 1.34 to 1.67, pI (2)=94.8%). This risk was independent of age, sex, ethnicity, adiposity measures, diabetes, hypertension and other common cardiovascular risk factors. Sensitivity analyses did not change these results. The funnel plot did not show any significant publication bias. Conclusion NAFLD is associated with a 1.5-fold higher long-term risk of new-onset HF, regardless of the presence of diabetes, hypertension and other common cardiovascular risk factors. However, the observational design of the studies does not allow for proving causality

Non-alcoholic fatty liver disease and risk of fatal and nonfatal cardiovascular events: an updated systematic review and meta-analysis

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