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Abstract
There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein
cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class
of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread
use, discontinuation and nonadherence remains a major gap in both the primary and
secondary prevention of atherosclerotic cardiovascular disease. The major reason for
statin discontinuation is because of the development of statin-associated muscle symptoms,
but a range of other statin-induced side effects also exist. Although the mechanisms
behind these side effects have not been fully elucidated, there is an urgent need
to identify those at increased risk of developing side effects as well as provide
alternative treatment strategies. In this article, we review the mechanisms and clinical
importance of statin toxicity and focus on the evaluation and management of statin-associated
muscle symptoms.
The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to "healthy adherer" behavioral attributes more so than to pharmacological benefits. To explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI). Population-based, observational, longitudinal study of 31 455 elderly AMI survivors between 1999 and 2003 in Ontario. All patients filled a prescription for statins, beta-blockers, or calcium channel blockers, with the latter drug considered a control given the absence of clinical trial-proven survival benefits. Patient adherence was subdivided a priori into 3 categories--high (proportion of days covered, > or =80%), intermediate (proportion of days covered, 40%-79%), and low (proportion of days covered, <40%)--and compared with long-term mortality (median of 2.4 years of follow-up) using multivariable survival models (and propensity analyses) adjusted for sociodemographic factors, illness severity, comorbidities, and concomitant use of evidence-based therapies. Among statin users, compared with their high-adherence counterparts, the risk of mortality was greatest for low adherers (deaths in 261/1071 (24%) vs 2310/14,345 (16%); adjusted hazard ratio, 1.25; 95% confidence interval, 1.09-1.42; P = .001) and was intermediary for intermediate adherers (deaths in 472/2407 (20%); adjusted hazard ratio, 1.12; 95% confidence interval, 1.01-1.25; P = .03). A similar but less pronounced dose-response-type adherence-mortality association was observed for beta-blockers. Mortality was not associated with adherence to calcium channel blockers. Moreover, sensitivity analyses demonstrated no relationships between drug adherence and cancer-related admissions, outcomes for which biological plausibility do not exist. The long-term survival advantages associated with improved drug adherence after AMI appear to be class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not merely reflect an epiphenomenon of "healthy adherer" behavioral attributes.
Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway. Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.
The gut microbiome, which hosts up to 1000 bacterial species that encode about 5 million genes, perform many of the functions required for host physiology and survival. Consequently, it is also known as "our forgotten organ". The recent development of next-generation sequencing technologies has greatly improved metagenomic research. In particular, it has increased our knowledge about the microbiome and its mutually beneficial relationships with the human host. Microbial colonization begins immediately at birth. Although influenced by a variety of stimuli, namely, diet, physical activity, travel, illness, hormonal cycles and therapies, the microbiome is practically stable in healthy adults. This suggests that the microbiome plays a role in the maintenance of a healthy state in adulthood. Quantitative and qualitative alterations in the composition of the gut microbiome could lead to pathological dysbiosis, and have been related to an increasing number of intestinal and extra-intestinal diseases. With the increase in knowledge about gut microbiome functions, it is becoming increasingly more possible to develop novel diagnostic, prognostic and, most important, therapeutic strategies based on microbiome manipulation.
[1
]From the School of Public Health, Curtin University, Perth, Western Australia, Australia
(N.C.W.)
[2
]School of Medicine, University of Western Australia, Perth, Australia (N.C.W., G.F.W.)
[3
]Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Western Australia,
Australia (G.F.W.)
[4
]Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University
of Colorado School of Medicine, Anschutz Medical Campus, Aurora (R.H.E.).
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