Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study.

AIMS: Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). METHODS: We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524-842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262 uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. CONCLUSIONS: The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.

Association between different modalities of insulin administration and metabolic dysfunction-associated fatty liver disease in adults with type 1 diabetes mellitus.

AIM: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively). RESULTS: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7%  vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7%  vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14-0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders. CONCLUSION: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age.

Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14.

AIM: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. MATERIALS AND METHODS: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ß-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. RESULTS: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ß=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ß=-0.31) and worst ß-cell function (p=0.023; ß=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. CONCLUSIONS: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Associations between higher plasma ferritin and hepcidin levels with liver stiffness in patients with type 2 diabetes: An exploratory study.

BACKGROUND: Currently, there is no information about the association between circulating levels of ferritin and hepcidin and liver fibrosis in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). METHODS: We enrolled 153 patients with T2DM with no known liver diseases, who consecutively attended our diabetes outpatient service and who underwent liver ultrasonography and liver stiffness measurement (LSM) by vibration-controlled transient elastography (Fibroscan® for the non-invasive assessment of liver fibrosis). Plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively. RESULTS: After stratification of patients by LSM tertiles [1st tertile median LSM: 3.6 (interquartile range: 3.3-4.0) kPa, 2nd tertile: 5.3 (4.9-5.9) kPa and 3rd tertile: 7.9 (6.7-9.4) kPa], we found that plasma ferritin and hepcidin concentrations increased across LSM tertiles [median ferritin: 68.7 (interquartile range: 25.1-147) vs. 85.8 (48.3-139) vs. 111 (59.3-203) µg/L, p = 0.021; median hepcidin: 2.5 (1.1-5.2) vs. 4.4 (2.5-7.3) vs. 4.1 (1.9-6.8) nmol/L, p = 0.032]. After adjustment for age, sex, diabetes duration, waist circumference, haemoglobin A1c, HOMA-insulin resistance score, triglycerides, haemoglobin, presence of hepatic steatosis on ultrasonography and patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genetic variant, higher plasma ferritin levels were associated with greater LSM values (adjusted-odds ratio 2.10, 95% confidence interval 1.23-3.57, p = 0.005). Higher plasma hepcidin levels were also associated with greater LSM values (adjusted-odds ratio 1.90, 95% confidence interval 1.15-3.13, p = 0.013). CONCLUSIONS: Higher levels of plasma ferritin and hepcidin were associated with greater NAFLD-related liver fibrosis (assessed by LSM) in patients with T2DM, even after adjustment for established cardiometabolic risk factors, diabetes-related variables and other potential confounders.

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis.

BACKGROUND AND AIMS: Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). METHODS AND RESULTS: We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: -6.55; 95% CI -11.0 to -2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. CONCLUSIONS: This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.

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, >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, alcohol intake, 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 MAFLD was strongly associated with an increased risk of supraventricular and ventricular arrhythmias on 24-hour Holter monitoring.

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 Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized ß coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized ß coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized ß coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized ß coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.

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/m2), 28 did not have NAFLD, 32 had steatosis alone, and 19 had NAFLD with coexisting significant fibrosis (LSM ≥ 7.0 kPa by Fibroscan®). 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] µg/mL; p < 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.

Non-alcoholic 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, p<0.0001; I 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.

Association between higher serum uric acid levels and plasma N-terminal pro-B-type natriuretic peptide concentrations in patients with coronary artery disease and without overt heart failure.

BACKGROUND: The association between serum uric acid (SUA) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in patients with coronary artery disease (CAD) is unclear. METHODS: We retrospectively studied 171 patients with suspected or established CAD and without overt heart failure who were consecutively admitted to our Division of Cardiology from February to August 2016. Plasma NT-proBNP concentrations were measured using a chemiluminescent immunoassay method. A conventional echocardiography and coronary angiogram were also performed in all patients. RESULTS: Patients in the 3rd SUA tertile had higher median plasma NT-proBNP concentrations compared with those belonging to 2nd or 1st SUA tertile, respectively (443 [IQR: 222-1381] vs. 224 [99-487] vs. 162 [68-307] pg/mL; p < 0.001). After adjustment for age, sex, body mass index, hypertension, diabetes, chronic kidney disease, prior ischemic heart disease, prior heart failure, medication use, and left ventricular ejection fraction (LVEF), patients belonging to the 3rd SUA tertile had an increased risk of higher plasma NT-proBNP concentrations (adjusted-standardized beta coefficient: 0.310, p < 0.001). Almost identical results were found when patients treated with allopurinol (n = 14), or those with prior HF (n = 8) were excluded from the analyses. CONCLUSIONS: These results show that increased SUA levels are strongly associated with higher plasma NT-proBNP concentrations in patients with suspected or established CAD and without overt heart failure, independent of established cardiovascular risk factors, LVEF, medication use and other potential confounders.

Growing up with type 1 diabetes mellitus: Data from the Verona Diabetes Transition Project.

AIM: Transition from paediatric to adult care is a critical step in life of emerging adults with type 1 diabetes. We assessed, according to indicators established by panel of experts, clinical, socio-demographic and psychosocial factors in young adults with type 1 diabetes throughout structured transition to investigate the associations, if any, with HbA1c value at time of transition. METHODS: The "Verona Diabetes Transition Project" started in January 2009: a structured transition program, shared between paediatric and adult clinic, was organised with a multi-disciplinary team. All young adults underwent a semi-structured interview by a psychologist, before transition. Minimum age for transition was 18 years. RESULTS: 222 (M/F = 113/109) young adults moved to adult care from January 2009 to March 2020. The mean time between the last paediatric visit and the first adult visit ranged from 13.6 ± 6.1 months at the beginning of the project to 3.6 ± 11.5 months over the following years. At first adult clinic attendance, women showed higher HbA1c values (70 ± 11 mmol/mol vs. 65 ± 7 mmol/mol or 8.57% ± 1.51% vs. 8.14% ± 0.98%, p = 0.01), higher frequency of disorders of eating behaviours (15.6% vs. 0%, p < 0.001) and poor diabetes acceptance (23.9% vs. 9.7%, p < 0.001) than men. Mediation analyses showed a significant mediating role of glucose control 2 years before transition in the relationship between poor diabetes acceptance and glucose control at transition. CONCLUSIONS: This study demonstrated a delay reduction in establishing care with an adult provider and suggested the potential role of low diabetes acceptance on glycemic control at transition. Further studies are needed to confirm and expand these data.

Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.

OBJECTIVE: Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD. DESIGN: We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. RESULTS: 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I2 =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias. CONCLUSION: This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.

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.

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

BACKGROUND: Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events. METHODS: We systematically searched PubMed, Scopus, and Web of Science from database inception to July 1, 2021, to identify eligible observational studies examining the risk of incident CVD events amongst adult (age ≥18 years) individuals with and without NAFLD and in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, non-fatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf. FINDINGS: We identified 36 longitudinal studies with aggregate data on 5 802 226 middle-aged individuals (mean age 53 years [SD 7]) and 99 668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6·5 years (IQR 5·0-10·2). NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1·45, 95% CI 1·31-1·61; I2=86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2·50, 95% CI 1·68-3·72; I2=73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results. INTERPRETATION: NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality. FUNDING: None.

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.

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.