The prevalence and severity of metabolic dysfunction–associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with... Show moreThe prevalence and severity of metabolic dysfunction–associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach. Show less
BackgroundThe estimated global prevalence and burden of non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), is increasing. Yet, NAFLD remains... Show moreBackgroundThe estimated global prevalence and burden of non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), is increasing. Yet, NAFLD remains largely underdiagnosed. In addition to hepatic morbidity and mortality, NAFLD is associated with increased cardiovascular complications, warranting a multidisciplinary approach. Despite its rapidly increasing prevalence, knowledge of NAFLD among healthcare workers is limited, especially with specialists outside the field of hepatology and gastroenterology. ObjectivesTo investigate knowledge, practice and opinions/attitudes of healthcare workers towards diagnosis and management of NAFLD/NASH. MethodsThe survey was designed in collaboration with a multidisciplinary scientific committee established especially for this study. The survey was disseminated to healthcare workers from seven different disciplines through four collaborating societies, social media and at a cardiology-themed conference from February to June 2022. Median and interquartile range were mentioned for numeric responses and proportions for categorical responses or responses on a Likert scale. Likert scale responses were treated as ordinal data and analysed with the appropriate tests. ResultsThe full dataset included 613 respondents from 88 different countries (including 488 physicians). 64% of the surveyed physicians underestimated the prevalence of NAFLD. General practitioners and cardiologists underestimated the prevalence most often (74% and 77%, respectively). Compared to the other disciplines, cardiologists were least familiar with the symptoms and diagnostic criteria and felt least confident in diagnosing and managing NAFLD. Overall, 65% of physicians reported regularly using evidence-based guidelines for managing NAFLD, yet 72% reported challenges in providing lifestyle recommendations. A lack of awareness was the most common reported reason for the lack of screening for NAFLD (68% respectively). ConclusionsDespite the growing burden of NAFLD, there is a significant gap in awareness, knowledge, and management among physicians treating patients with cardiometabolic comorbidities, particularly cardiologists. Hepatologists and gastroenterologists could play a role in educating their fellow physicians. Show less
Background: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether... Show moreBackground: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-alpha/gamma agonists improve non-invasive tests of liver steatosis and fibrosis. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-alpha/gamma agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). Results: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. Conclusion: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-alpha/gamma agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment. Show less
The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients,... Show moreThe prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality-in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma-it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood- and imaging-based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity. Show less
Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The... Show moreObjectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids. Design: A placebo-controlled randomized, proof-of-concept study. Methods: Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test. Results: Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change. Conclusion: Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin-glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia. Show less
Hart, J.W.H. 't; Leeman, M.; Mourik, B.C.; Pouw, N.; Biter, L.U.; Apers, J.A.; ... ; Dunkelgruen, M. 2021
Background: In metabolic-bariatric fast-track surgery, patients are scheduled for discharge on postoperative day 1. The neutrophil-to-lymphocyte ratio (NLR) could be an inexpensive and rapid way to... Show moreBackground: In metabolic-bariatric fast-track surgery, patients are scheduled for discharge on postoperative day 1. The neutrophil-to-lymphocyte ratio (NLR) could be an inexpensive and rapid way to identify patients at risk of early complications. This study aimed to determine the predictive value of the NLR on early complications.Methods: Prospective data were collected of all patients undergoing primary metabolic surgery in a single center, between April 2018 and April 2019. The association between NLR, leukocyte count, hemoglobin, and C-reactive protein (CRP) was compared with early complications.Results: In total, 829 patients underwent primary metabolic surgery: 336 (40.5%) Roux-en-Y gastric bypass, 410 (49.5%) sleeve gastrectomy, and 83 (10.0%) one anastomosis gastric bypass. Major complications occurred in 34 (4.1%) patients, who had significantly higher levels of postoperative NLR (p < 0.001), delta-NLR (p < 0.001), leukocyte count (p < 0.001), and CRP (p = 0.008). The ideal cutoff points to predict complications after metabolic surgery were 6.73 for postoperative NLR (sensitivity 74% and specificity 70%) and 4.68 for delta-NLR (sensitivity 77% and specificity 75%).Conclusion: Postoperative NLR and delta-NLR were independently associated with early major complications after metabolic surgery. These markers may be useful to help identify patients who are at risk for complications, and can aid in the decision making for safe postoperative discharge on day 1 or early intervention. Show less
Aim Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a... Show moreAim Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. Material and Methods Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. Results Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. Conclusions In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants. Show less
Zijlstra, L.E.; Jukema, J.W.; Mooijaart, S.P.; Vries, M.A. de; Stott, D.J.; Cabezas, M.C.; Trompet, S. 2018
Objective-To compare the effects of rosiglitazone (8 mg/d, n = 19) and metformin (2 g/d, n = 18) on postprandial lipemia in patients with HIV-lipodystrophy. Methods and Results-Lipodystrophy in HIV... Show moreObjective-To compare the effects of rosiglitazone (8 mg/d, n = 19) and metformin (2 g/d, n = 18) on postprandial lipemia in patients with HIV-lipodystrophy. Methods and Results-Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat-loading tests at baseline and after treatment. Rosiglitazone (-34%) and metformin (-37%) reduced homeostasis model assessment similarly (P < 0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (P < 0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (P < 0.01) compared with baseline. Metformin did not change any of the postprandial measurements. Conclusion-Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population. (Arterioscler Thromb Vasc Biol. 2011;31:228-233.) Show less
