Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent evidence on non-traditional ...determinants of cardiometabolic health has advanced our understanding of lifestyle–disease interactions. Chronic exposure to environmental stressors like poor diet quality, sedentarism, ambient air pollution and noise, sleep deprivation and psychosocial stress affect numerous traditional and non-traditional intermediary pathways related to ASCVD. These include body composition, cardiorespiratory fitness, muscle strength and functionality and the intestinal microbiome, which are increasingly recognized as major determinants of cardiovascular health. Evidence points to partially overlapping mechanisms, including effects on inflammatory and nutrient sensing pathways, endocrine signalling, autonomic function and autophagy. Of particular relevance is the potential of low-risk lifestyle factors to impact on plaque vulnerability through altered adipose tissue and skeletal muscle phenotype and secretome. Collectively, low-risk lifestyle factors cause a set of phenotypic adaptations shifting tissue cross-talk from a proinflammatory milieu conducive for high-risk atherosclerosis to an anti-atherogenic milieu. The ketone body ß-hydroxybutyrate, through inhibition of the NLRP-3 inflammasome, is likely to be an intermediary for many of these observed benefits. Adhering to low-risk lifestyle factors adds to the prognostic value of optimal risk factor management, and benefit occurs even when the impact on conventional risk markers is discouragingly minimal or not present. The aims of this review are (a) to discuss novel lifestyle risk factors and their underlying biochemical principles and (b) to provide new perspectives on potentially more feasible recommendations to improve long-term adherence to low-risk lifestyle factors.
Abstract
Aims
Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide ...targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease.
Methods and results
A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200–500 mg/dL (2.26–5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6–12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222–329) mg/dL 2.96 (2.51–3.71) mmol/L. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site.
Conclusion
Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease.
Trial registration number
NCT03385239.
Structured Graphical Abstract
Structured Graphical Abstract
Potential clinical indications for olezarsen. Triglyceride levels represent a continuum of risk with levels 1.7–5.6 mmol/L (150–500 mg/dL) representing primarily cardiovascular disease risk (cardiovascular disease prevention), levels between 5.6 and 10.0 mmol/L (500–885 mg/dL) representing both cardiovascular disease and pancreatitis risk and >10.0 mmol/L primarily pancreatitis risk in patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome (represented by milky plasma). Treatment with olezarsen with the planned Phase 3 doses of 50 and 80 mg subcutaneously monthly would be expected to substantially reduce triglyceride levels in the entire continuum of hypertriglyceridaemia.
Abstract Objective There is a growing body of literature examining the clustering of health risk behaviours, but little consensus about which risk factors can be expected to cluster for which sub ...groups of people. This systematic review aimed to examine the international literature on the clustering of smoking, poor nutrition, excess alcohol and physical inactivity (SNAP) health behaviours among adults, including associated socio-demographic variables. Method A literature search was conducted in May 2014. Studies examining at least two SNAP risk factors, and using a cluster or factor analysis technique, or comparing observed to expected prevalence of risk factor combinations, were included. Results Fifty-six relevant studies were identified. A majority of studies (81%) reported a ‘healthy’ cluster characterised by the absence of any SNAP risk factors. More than half of the studies reported a clustering of alcohol with smoking, and half reported clustering of all four SNAP risk factors. The methodological quality of included studies was generally weak to moderate. Males and those with greater social disadvantage showed riskier patterns of behaviours; younger age was less clearly associated with riskier behaviours. Conclusion Clustering patterns reported here reinforce the need for health promotion interventions to target multiple behaviours, and for such efforts to be specifically designed and accessible for males and those who are socially disadvantaged.
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