Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study

Introduction

Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome (MetS), is common and accounts for 80% of cases of elevated liver function tests (LFTs). We assessed the long-term effects of multifactorial intervention on LFTs and their association with cardiovascular disease (CVD) events in patients with MetS without diabetes mellitus or CVD.

Material and methods

This prospective, randomized, open label study included 1,123 patients (aged 45-65 years). Patients received intensive lifestyle intervention and pharmacotherapy: atorvastatin in all patients (low density lipoprotein cholesterol [LDL-C] targets of<100 mg/dl [group A] or<130 mg/dl [group B]), inhibitors of the renin-angiotensin-aldosterone axis for hypertension, metformin for dysglycaemia and orlistat for obesity.

Results

Among participants, 326 had modestly elevated LFTs and ultrasonographic (US) evidence of NAFLD (165 patients in group A2 and 161 patients in group B2). The NAFLD resolved during the 42-month treatment period in 86% of patients in group A2 and in 74% of patients in group B2 (p<0.001). In both groups nearly 90% of patients attained lipid goals. Mean LDL-C and TG levels were higher in group B2 than in group A2 (p<0.001). There were no CVD events in group A2 whereas 5 non-fatal events occurred in group B2 (log-rank-p = 0.024). There were no major side-effects.

Conclusions

Attaining multiple treatment targets is safe and beneficial in primary prevention patients with MetS and NAFLD. Lipid levels and LFTs normalized, US findings associated with NAFLD resolved and no CVD events occurred in patients with LDL-C levels<100 mg/dl (group A2). Resolution of NAFLD might have contributed to the prevention of CVD events.     

Editorial: should chronic kidney disease be considered as a coronary heart disease equivalent?

Current evidence suggests that chronic kidney disease (CKD) is associated with an excess risk for cardiovascular disease (CVD) events. In patients with stage 3 CKD (estimated glomerular filtration rate-eGFR 30-59 ml/min/1.73 m2) lifestyle measures and appropriate drugs may reduce CVD risk and stabilize (or even reverse) renal function deterioration. Furthermore, CKD is included in recent international guidelines as a population at high CVD risk. The aim should be to effectively reduce CVD risk as well as progression of CKD.     

Non-alcoholic fatty liver disease in type 2 diabetes: pathogenesis and treatment options

Non-alcoholic fatty liver disease (NAFLD) is a common disorder and its prevalence is expected to increase due to the rising incidence of type 2 diabetes mellitus (T2DM) and obesity. NAFLD is associated with increased mortality rates and cardiovascular disease is the leading cause of death in these patients. The pathogenesis of NAFLD is not completely elucidated but insulin resistance and oxidative stress appear to play a major role. NAFLD is more prevalent and more severe in patients with T2DM. A multitude of pharmacological agents have been evaluated in NAFLD but most studies were small, short-term and yielded unsatisfactory results in terms of efficacy. Patients with T2DM and NAFLD appear to be even less responsive to the evaluated agents. Thus, the optimal management strategy for NAFLD remains unclear. On the other hand, preliminary data suggest that lifestyle intervention can reduce the incidence of NAFLD in overweight or obese patients with T2DM. Accordingly, prevention of obesity and T2DM is of paramount importance for the reduction of the prevalence of NAFLD and of its associated cardiovascular and liver-related complications.     

Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk?

Both elevated levels of uric acid and non-alcoholic fatty liver disease (NAFLD) have been associated with increased vascular risk. Furthermore, certain drugs (e.g. lipid and blood pressure lowering) that decrease)cardiovascular risk and improve/preserve renal function were shown to influence serum uric acid (SUA) levels and/or NAFLD. A link between hyperuricaemia and NAFLD has also been suggested. This review considers the associations between hyperuricaemia, NAFLD and vascular risk. We also discuss the effects of different drug treatments on SUA and NAFLD. As NAFLD is a very common condition, future work in this field is needed with regard to a more practical definitive diagnosis, evidence- based treatments and a better understanding of the possible links between NAFLD, elevated SUA levels, cardiovascular disease and chronic kidney disease. Whether treating hyperuricaemia and NAFLD will translate into a reduced risk of vascular events requires further investigation.     

Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease:an update

Non-alcoholic fatty liver disease(NAFLD) is considered to be an independent cardiovascular disease(CVD)risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis(NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease(CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness(AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis(mainly by simple non-invasive tests), CKD,and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above.     

Total serum insulin-like growth factor-1 and C-reactive protein in metabolic syndrome with or without diabetes

There are only a few data on the relationship of insulin-like growth factor-1 (IGF-1), implicated in glucose homeostasis, and C-reactive protein (CRP), a measure of subclinical systemic inflammation, in patients with the metabolic syndrome (MetS). The authors investigated, in a cross-sectional design, the correlation between total IGF-1 and CRP in 170 subjects. Among them 123 had the MetS (National Cholesterol Program ATP III definition) and 47 did not, and 136 had type 2 diabetes mellitus (DM) and 34 did not. Anthropometric variables, clinical characteristics, as well as laboratory measurements, including total IGF-1 and CRP, were recorded. CRP levels showed a significant negative correlation with total IGF-1 concentrations, both in the whole study population (r = -0.252, p = 0.001) and the MetS group (r = -0.203, p = 0.025), regardless of the presence of DM. This correlation remained significant after adjusting for age, gender, smoking status, and waist circumference (r = -0.18, p = 0.05). Both low IGF-1 and high CRP levels had an almost linear relationship with the number of MetS components (p = 0.029 and p = 0.020, respectively), suggesting a close relationship of both variables with the cardiovascular disease (CVD) risk involved. The correlation between high CRP and low total IGF-1 might indicate that an increase in CRP levels may well be a key factor for the reduction in IGF-1 concentrations. Both factors are related to an increase in risk for MetS and CVD and this finding might have clinical implications in preventing or treating MetS, DM, and CVD. Given the cross-sectional design of the study, this finding should be confirmed by larger prospective and, it is hoped, interventional studies.