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Landmark study
Importance of targeting obesity to reduce residual cardiovascular risk
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New potential for non-alcoholic fatty liver disease?
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MSDA Kyoto 2014
A highlight of R3i activities
MSDA Kyoto 2014
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The National Lipid Association (NLA)
The National Lipid Association (NLA) is a nonprofit, multidisciplinary medical society focused on enhancing the practice of lipid management in clinical medicine.
EDITORIAL
20 June 2014
Addressing the epidemic of non-alcoholic fatty liver disease
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans
An Editorial from the R3i Trustees

Non-alcoholic fatty liver disease (NAFLD) is the most common acquired non-communicable liver disease in the Western world and its incidence is increasing rapidly, in line with of the global obesity epidemic.
Moreover, the escalation of obesity and metabolic syndrome in the emerging economies, such as the Latin America region, means that NAFLD is also becoming more prevalent here. Increasing obesity among children and adolescents is a key driver of the increase in NAFLD in this population.
R3i Goes Global:
Latin America launch at SOCESP March 22, 2014
Over 6,000 cardiologists attended the Sociedade de Cardiologia do Estado de Sao Paulo Congress (SOCESP), a clear indication of the tsunami of cardiometabolic disease facing this region.
sao-paolo SOCESP 2014

‘Latin America poses a real challenge, due to escalating rates of obesity, diabetes and cardiometabolic disease. Integration of Latin America within the R3i provides an important opportunity to target the high residual cardiovascular and microvascular risk in this region.‘

- Prof. Jean-Charles Fruchart, President, R3i Foundation

R3i Goes Global
Key interviews from SOCESP 2014
RECENT PUBLICATIONS
• **STOP-PRESS: FIRST trial fails primary endpoint**
In the recently reported FIRST trial, the combination of fenofibric acid plus atorvastatin did not further decrease progression of atherosclerosis, compared with atorvastatin alone, in high-risk patients with mixed dyslipidaemia. The rationale for the FIRST trial has been previously reported on the R3i website. Briefly, this multicentre, double-blind, placebo-controlled study included patients with mixed dyslipidaemia (fasting triglycerides =150 mg/dL or 1.7 mmol/L; high-density lipoprotein cholesterol =45 mg/dL or 1.2 mmol/L [men] or =55 mg/dL or 1.4 mmol/L [women]; low-density lipoprotein cholesterol =100 mg/dL or 2.6 mmol/L once and averaging =105 mg/dL or 2.7 mmol/L) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg) were randomised to fenofibric acid 135 mg/day or placebo. The primary end point, the rate of change from baseline to week 104 of the mean posterior-wall carotid intima-media thickness, measured by ultrasound, was similar in each group (-0.006 mm/y with fenofibric acid plus atorvastatin versus 0.000 mm/y with atorvastatin alone; p=0.22). The study will be discussed in a future Landmark Trial analysis.
Effects of fenofibric acid on carotid intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: randomized, placebo-controlled study (FIRST).
Davidson MH, Rosenson RS, Maki KC et al.
• Da Qing Diabetes Prevention Study: importance of sustained lifestyle intervention
Findings from the landmark Da Qing Diabetes Prevention Study show that sustained lifestyle intervention can reduce cardiovascular and all-cause mortality and diabetes in Chinese people with impaired glucose tolerance. This study included 577 adults with impaired glucose tolerance who were enrolled by 33 clinics in Da Qing, China in 1986. Subjects were randomised (1:1:1:1) to a control group (n=138) or lifestyle intervention groups (diet, exercise, or both, n=439). The intervention lasted for 6 years and patients were followed-up after 23 years. The primary outcomes were all-cause mortality, cardiovascular disease mortality and diabetes incidence; 542 (94%) subjects had complete data for mortality. Over the 23-year follow-up period, 174 participants died (121 in the intervention groups versus 53 in the control group). Compared with the control group, the cumulative incidence of cardiovascular disease mortality and all-cause mortality was lower in the intervention group (11.9% versus 19.6%, hazard ratio 0.59, 95% CI 0.36–0.96; p=0.033 for cardiovascular mortality and 28.1% versus 38.4%, hazard ratio 0.71, 95% CI 0.51–0.99; p=0.049 for all-cause mortality). There was significantly greater effect in women than men; lifestyle intervention was associated with 72% reduction in cardiovascular mortality in women (versus 9% in men), and 54% reduction in all-cause mortality (versus 3% in men). These differences may relate to higher smoking rates in men. The incidence of diabetes was also significantly lower in the intervention group (72.6% versus 89.9%, hazard ratio 0.55, 95% CI 0.40–0.76; p=0.001); this effect was similar in both men and women. These findings based on hard outcomes data provide further justification for the importance of sustained lifestyle intervention to control the consequences of impaired glucose tolerance and diabetes, and have important implications for public health policy about diabetes prevention.
Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study.
Li G, Zhang P, Wang J et al.
• Intestinal insulin signalling, atherogenic dyslipidaemia and metabolic syndrome
This study investigated the role of intestinal triglyceride-rich lipoprotein overproduction in atherogenic dyslipidaemia in obese subjects. Duodenal samples from 20 obese subjects undergoing bariatric surgery were matched for age, sex, and body mass index irrespective of insulin sensitivity (homeostasis model assessment of insulin resistance). Intestinal insulin signalling was defective in insulin-resistant subjects, as shown by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, possibly as a result of high oxidative stress and inflammation. In addition, the study showed an increase in de novo lipogenesis and apolipoprotein B-48 biogenesis coincident with triglyceride-rich lipoprotein overproduction in insulin-resistant subjects. These subjects also showed high expression levels of liver and intestinal fatty acid-binding proteins and microsomal transfer protein. The authors concluded that dysregulation of intestinal insulin signalling, possibly induced by oxidative stress and inflammation, may represent a key mechanism which contributes to atherogenic dyslipidaemia in patients with metabolic syndrome.
Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.
Veilleux A, Grenier E, Marceau P, Carpentier AC, Richard D, Levy E.
• Will lipidomics offer new possibilities as biomarkers of metabolic syndrome susceptibility?
Findings from the San Antonio Family Heart Study (SAFHS) highlight the additive value of the plasma lipidomic profile in metabolic syndrome. This study used a novel statistical approach to quantify the value of the plasma lipidome in explaining metabolic syndrome variability in Mexican American families recruited in the SAFHS, involving two steps: principal components analysis of the high resolution plasma lipidomics data, and construction of a subject-subject lipidomic similarity matrix. The analysis was based on data for 1,206 subjects (from 42 families, mean age 40 years, 60% female), with a high prevalence of type 2 diabetes (~15%), central obesity (~48%) and elevated triglycerides (~41%). The plasma lipidome contributed to 22% variability in insulin sensitivity (HOMA-IR) and 16% – 22% variability in glucose, insulin and waist circumference independent of obesity and measures of lipidaemic status. These findings argue for consideration of the biological pathways involved in lipid/lipoprotein metabolism, in addition to specific lipid/lipoprotein classes, and highlight a potential role for evaluating differences in the plasma lipidome as biomarkers for increased susceptibility to the metabolic syndrome. Indeed, a recent study has shown that the lipidomic approach has allowed for identification of distinct ceramide molecular species strongly associated with fatal outcome of coronary artery disease patients independently of traditional risk factors.1
1. Tarasov K, Ekroos K, Suoniemi M et al. Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J Clin Endocrinol Metab 2014;99:E45-E52.
Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families.
Kulkarni H, Meikle PJ, Mamtani M et al.
• Periodontal disease: a novel cardiovascular risk factor?
Analyses from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, suggest that tooth loss and gingivitis may be potential risk markers for cardiovascular disease. The STABILITY trial investigated the potential of darapladib, a selective oral inhibitor of lipoprotein-associated phospholipase A2, for prevention of major cardiovascular events in 15,828 patients with stable coronary heart disease. At baseline, all subjects had a physical examination and blood testing, and completed a lifestyle questionnaire, which included information on dental health. Specifically, the questionnaire collected data on the remaining number of teeth (none, 1–14, 15–20, 21–25, or 26–32 (all)) and frequency of gum bleeding (never/rarely, sometimes, often or always). There was a high overall prevalence of tooth loss; 16% of subjects reported having no teeth, and 41% reported having fewer than 15 remaining teeth. Furthermore, 26% of subjects reported gum bleeding when brushing teeth. Analyses showed that increasing prevalence of tooth loss was significantly associated with higher fasting glucose levels, low-density lipoprotein (LDL) cholesterol levels, systolic blood pressure and waist circumference. Similarly, a higher prevalence of gum bleeding was significantly associated with higher LDL cholesterol levels and systolic blood pressure. In conclusion, the authors suggest that dental health may be a marker of cardiovascular disease risk, although acknowledging that demographic, genetic and socioeconomic disparities may be confounding factors to this association.
Periodontal disease in patients with chronic coronary heart disease: Prevalence and association with cardiovascular risk factors.
Vedin O, Hagstrom E, Gallup D et al.
• High prevalence of atherogenic dyslipidaemia in Turkey: a public health issue
An increased prevalence of low plasma concentration of high-density lipoprotein cholesterol (HDL-C) in Turkey is already well recognised. This report highlights the high prevalence of atherogenic dyslipidaemia, especially among the 46-to-65-year-old age group. The study included 4,309 people (aged 20 to 83 years) from both urban and rural regions according to a stratified sampling method. Overall, 36.2% had high low-density lipoprotein cholesterol (LDL-C), 41.5% had low HDL-C, and 35.7% had elevated triglycerides; at least one lipid abnormality was identified in the majority of subjects (79% of men and 80% of women). Moreover, the presence of these lipid abnormalities increased with age, and was highest in the 46-to-65-year-old age group. These findings highlight an unmet need for increased awareness of the high prevalence of dyslipidaemia, including elevated triglycerides and low HDL-C, in this population.
Prevalence of dyslipidemia and associated risk factors in Turkish adults.
Bayram F, Kocer D, Gundogan K et al.
• Overprescription of statins: need to target all risk factors to impact CVD
Based on a North European population (=55 years), statin therapy would be recommended for almost all male patients and two-thirds of female patients according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of cholesterol. These estimations exceed predictions for the 2011 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines. Predictions were based on 4,854 subjects in the Rotterdam Study (mean age 65.5 years, 55% women); at baseline, 14% of male and 13% of female subjects were on a statin. For the 2013 ACC/AHA guidelines, there was a shift in the proportion of the study cohort from ‘treatment considered’ to ‘treatment recommended’ categorisations; for men, the relative percentages were 96.4% versus 3.3%, and for women, 65.8% and 14.2%. In contrast, for the 2011 ESC/EAS guidelines, treatment was recommended for 66.1% of men (versus considered in 31.6%) and 39.1% of women (versus considered in 51.4%), based on 10-year risk estimations. Thus, by lowering the cut-off for treatment, the 2013 ACC/AHA guidelines have substantially overestimated the proportion of individuals at high levels of actual cardiovascular disease risk. As well as highlighting the potential risk of statin overprescription, these findings also implicate the need for education and intervention aimed at prevention of risk factor aggregation so as to reduce future cardiovascular disease rates.
Comparison of application of the ACC/AHA Guidelines, Adult Treatment Panel III Guidelines, and European Society of Cardiology Guidelines for Cardiovascular Disease Prevention in a European cohort.
Kavousi M, Leening MJG, Nanchen D et al.