Non‐alcoholic fatty liver disease (NAFLD) is associated with visceral obesity, insulin resistance, type 2 diabetes (T2D) and has been often considered as the hepatic expression of the metabolic ...syndrome (MetS). Epidemiological studies highlight a bidirectional relationship of NAFLD with T2D in which NAFLD increases the risk of incident T2D and T2D increases the risk of severe non‐alcoholic steatohepatitis (NASH) and liver fibrosis. Regarding the molecular determinants of NAFLD, we specifically focused in this review on adipocyte dysfunction as a key molecular link between visceral adipose tissue, MetS and NAFLD. Notably, the subcutaneous white adipose tissue expandability appears a critical adaptive buffering mechanism to prevent lipotoxicity and its related metabolic complications, such as NAFLD and T2D. There is a clinical challenge to consider therapeutic strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis. Strategies that promote significant and sustained weight loss (~10% of total body weight) such as metabolic and bariatric surgery or incretin‐based therapies (GLP‐1 receptor agonists or dual GLP‐1/GIP or GLP‐1/glucagon receptor co‐agonists) are among the most efficient ones. In addition, insulin sensitizers such as PPARγ (pioglitazone) and pan‐PPARs agonists (lanifibranor) have shown some beneficial effects on both NASH and liver fibrosis. Since NASH is a complex and multifactorial disease, it is conceivable that targeting different pathways, not only insulin resistance but also inflammation and fibrotic processes, is required to achieve NASH resolution.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Institut Pasteur de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 545, and Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de ...Médecine, Lille; INSERM, U 915, Université de Nantes, Faculté de Médecine, and Clinique d'Endocrinologie, Institut du Thorax, Nantes, France; and Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR -deficient ( FXR –/– ) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR –/– mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
To compare the efficacy and safety of liraglutide versus lixisenatide as add-on to metformin in patients with type 2 diabetes not achieving adequate glycemic control on metformin alone.
In this ...26-week, randomized, parallel-group, open-label trial, 404 patients were randomized 1:1 to liraglutide 1.8 mg or lixisenatide 20 µg as add-on to metformin. Liraglutide was administered once daily at any time of the day. Lixisenatide was administered once daily within 1 h prior to the morning or evening meal.
At week 26, liraglutide reduced HbA1c (primary end point) more than lixisenatide (estimated treatment difference -0.62% 95% CI -0.8; -0.4; P < 0.0001), with more patients reaching HbA1c <7% (53 mmol/mol) and ≤6.5% (48 mmol/mol) versus lixisenatide (74.2% and 54.6% for liraglutide vs. 45.5% and 26.2% for lixisenatide; P < 0.0001 for both). Liraglutide reduced fasting plasma glucose more than lixisenatide (estimated treatment difference -1.15 mmol/L 95% CI -1.5; -0.8; P < 0.0001). Liraglutide provided greater reduction in mean 9-point self-measured plasma glucose (P < 0.0001). However, postprandial glucose increments were smaller with lixisenatide for the meal directly after injection compared with liraglutide (P < 0.05), with no differences between treatments across all meals. Both drugs promoted similar body weight decrease (-4.3 kg for liraglutide, -3.7 kg for lixisenatide; P = 0.23). The most common adverse events in both groups were gastrointestinal disorders. Greater increases in pulse, lipase, and amylase were observed with liraglutide. Hypoglycemic episodes were rare and similar between the two treatments.
At the dose levels studied, liraglutide was more effective than lixisenatide as add-on to metformin in improving glycemic control. Body weight reductions were similar. Both treatments were well tolerated, with low risk of hypoglycemia and similar gastrointestinal adverse event profiles.
Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological ...treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator‐activated receptor alpha/delta (PPAR‐α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet WD‐fed human apolipoprotein E2 hApoE2 transgenic mice, methionine‐ and choline‐deficient diet‐fed db/db mice, and CCl4‐induced fibrosis in rats). GFT505 demonstrated liver‐protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin‐1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR‐α‐independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock‐in/PPAR‐α knockout mice. In these mice, GFT505 also prevented WD‐induced liver steatosis and inflammation, indicating a contribution of PPAR‐α‐independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma‐glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR‐α/δ agonist, GFT505, is a promising liver‐targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR‐α‐dependent and ‐independent mechanisms. (Hepatology 2013; 58:1941–1952)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature ...cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18–80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction 95% CI 53·4–65·1, monthly dose: 61·3% reduction 53·6–69·0; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction 95% CI 54·5–65·8 and 65·6% reduction 59·8–71·3; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients 9% vs five 5% in the placebo group) and muscle-related adverse events (ten patients 5% vs 1 1%). Interpretation In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. Funding Amgen Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest ...that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca
handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart.
Objective: Familial hypercholesterolemia (FH) is associated with a high risk of premature atherosclerotic cardiovascular disease (ASCVD). However, this risk is highly heterogeneous and current risk ...prediction algorithms for FH suffer from limitations. The primary objective of this study was to develop a score predicting incident ASCVD events over 10 years in a large multinational FH cohort. The secondary objective was to investigate the prediction of major adverse cardiovascular events and cardiovascular mortality using this score. Approach and Results: We prospectively followed 3881 patients with adult heterozygous FH with no prior history of ASCVD (32 361 person-years of follow-up) from 5 registries in Europe and North America. The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75, which was superior to the SAFEHEART-RE (Spanish Familial Hypercholesterolemia Cohort; 0.69). Subjects with an elevated FH-Risk-Score had decreases in 10-year ASCVD-free survival, 10-year major adverse cardiovascular event-free survival, and 30-year survival for CV mortality compared with the low-risk group, with hazard ratios of 5.52 (3.94–7.73), 4.64 (2.66–8.11), and 10.73 (2.51–45.79), respectively. The FH-Risk-Score showed a similar performance in subjects with and without an FH-causing mutation. Conclusions: The FH-Risk-Score is a stronger predictor of future ASCVD than the SAFEHEART-RE and was developed in FH subjects with no prior cardiovascular event. Furthermore, the FH-Risk-Score is the first score to predict CV death and could offer personalized cardiovascular risk assessment and treatment for patients with FH. Future studies are required to validate the FH-Risk-Score in different ethnic groups.
Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and ...glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic
(seipin knockout SKO) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice.
FFludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the
-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the
-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.
Abstract
Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in ...secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy.
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