In contrast, liver cells were not affected, with the IGF-1/Akt signaling maintained.55 Other in vitro studies have revealed that lactone forms of statins are more potent than their acid counterparts because of their increased passive transport across muscle membranes where they lead to decreased mitochondrial ATP production via direct effects on production machinery. A recent cohort analysis of pregnant women found that statin exposure during the first trimester was associated with an increased risk of fetal ventricular septal defect, and there was a higher incidence of congenital cardiac abnormalities in pregnancies exposed to statin therapy.128 Of further potential clinical importance is a recent animal study, which revealed significant adverse effects of atorvastatin, but not pravastatin, on cardiac muscle integrity, which effected cardiac mitochondrial structure and function, as well as cardiac cytoarchitecture.129, Common and rare genetic variants may contribute to statin toxicity via mutations in genes that encode proteins regulating statin pharmacokinetics (drug receptors, transporters, and metabolizing enzymes) and pharmacodynamics (muscle enzymes).23 These can include polymorphisms or mutations in genes encoding the CYP450 (cytochrome P450) enzymes, coenzyme Q, myophosphorylase, glycine amidinotransferase, UDP glucuronosyltransferase, palmitoyltransferase 2, myoadenylate deaminase, ATP-binding cassette sub-family B, multidrug resistance protein 1, and multidrug resistance–associated protein 2 efflux transporters.15,19,23,41,65 Genetic differences in the activity of CYP450 enzymes can affect statin interactions with other drugs, whereas genetic differences in membrane transporters can alter first pass hepatic uptake and thus residual circulating concentrations and peripheral tissue exposure.81 In addition, mouse studies have revealed that statin therapy may also alter gene expression, including hepatic genes related to lipid and glucose homeostasis, such as Pparα, Trib3, and Slc2a2, which may also contribute to their adverse side effects.130, The importance of the HMG-CoA pathway–mediated effects can also be inferred from Mendelian randomization studies. organization. Inhibitors of HMG-CoA reductase reduce receptor-mediated endocytosis in human kidney proximal tubular cells. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Understanding Patient Adherence and Concerns with STatins and MedicatION Discussions With Physicians (ACTION): a survey on the patient perspective of dialogue with healthcare providers regarding statin therapy. Gut microbiome associates with lipid-lowering effect of Rosuvastatin in vivo. But what are the facts? Vitamin d levels and lipid response to atorvastatin. There is now overwhelming evidence to support reducing LDL-c (low-density lipoprotein cholesterol) to reduce atherosclerotic cardiovascular disease (CVD).3 Statins are the most widely prescribed and evidence-based lipid-lowering drug in the world for lowering LDL-c and reducing cardiovascular morbidity and mortality, both in primary and secondary prevention.4 Recent statistics demonstrate increasing statin use in adults aged ≥40 years5 and in patients with elevated atherosclerotic CVD risk.6 Meta-analysis highlights the benefits of LDL-c reduction, with every 1 mmol/L (38.7 mg/dL) reduction associated with a significant 22% relative risk reduction in major vascular and coronary events.7 This is supported by the Cholesterol Treatment Trialists Collaboration. Another case is that of Mike Hope. NLA Task Force on Statin Safety–2014 update. And doctors are dependent on drugs. One of Merck’s Patents actually states, "Since CoQ10 ... is of benefit in congestive heart failure patients, the combination with HMG-CoA reductase inhibitors (statin drugs) should be of value in such patients who also have the added risk of high cholesterol." The American Heart Association is qualified 501(c)(3) tax-exempt Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry. But the second most common side effect is rarely discussed in the literature, and not listed in the package insert of any of the commonly prescribed statin drugs; it is known as Transient Global Amnesia (TGA), a sudden and temporary loss of memory. These can alter muscle cell membrane stability, fluidity, as well as protein signaling and activity; impact mitochondrial function; and reduce membrane cholesterol content.5 Alterations to statin uptake or metabolism can also result in increased exposure of skeletal muscle to statins, which can lead to altered mitochondrial function, calcium signaling, and cell cycle pathways.45 Given the wide variation in the presentation of SAMS and the inconsistent evidence with respect to treatment of the condition, however, it is likely that >1 pathological mechanism contributes (Figure 2).5,46 More detailed description of these proposed mechanisms is discussed below. The SNP results in an increase in the plasma concentration because of increased bioavailability as a result of decreased intestinal efflux.15 More recently, the rs717620 (-24C>T) SNP in the ABCC2 gene, which encodes a transmembrane transporter, has been shown to alter response to simvastatin and atorvastatin. The major reason for discontinuation of statin therapy is statin-associated muscle symptoms (SAMSs),2 which are the most well-documented side effect of statins, although there appears to be no unifying mechanism. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. The last thing any human should do is to artificially restrict their natural ability to manufacture cholesterol in the liver as needed - you do so at your peril! Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Effects of vitamin D supplementation on adherence to and persistence with long-term statin therapy: secondary analysis from the randomized, double-blind, placebo-controlled ViDA study. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Fact: Elevated cholesterol is a so called 'disease' invented in the 1980's (how come our ancestors didn't know about it?) However, an increasing number of mainstream and alternative health-care professionals believe that simple dietary changes are a far safer and more effective option in reducing oxidised LDL (low density lipoproteins) and VLDL (very low density lipoproteins) rather than potentially harmful drugs ... Quote: Prof Simon Capewell, an expert in clinical epidemiology at Liverpool University said: "The recent statin recommendations are deeply worrying, effectively condemning all middle-aged adults to lifelong medications of questionable value". http://www.bbc.co.uk/news/health-27784711. Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers. From the School of Public Health, Curtin University, Perth, Western Australia, Australia (N.C.W. Trial designs for statin muscle intolerance. Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS). Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. If hepatotoxicity symptoms are present, liver transaminases, total bilirubin, and alkaline phosphatase are recommended. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Local Info In the BBC Report (above) you may be shocked to learn that NICE (The National Institute For Health and Care Excellence) - a UK Government Agency riddled with experts receiving 'kick-backs' from drug companies - continues to peddle misleading and flawed opinion relating to the 'safe' use of Statins. It has been observed for both hydrophilic and lipophilic statins and appears to occur more frequently in older patients and those on high-dose statin therapy.21 Mechanistically, the incidence of new-onset type 2 diabetes mellitus is not known but may be related to both on-target and off-target action, including effects on body weight, body mass index, adipocyte differentiation, blood glucose homeostasis via gluconeogenesis and the insulin signaling cascade, changes in circulating free fatty acids or hormones such as adiponectin and leptin, as well as impaired β-cell function.16,23,80,81, In the pancreas, insulin secretion is initiated by an increase in intracellular calcium controlled by voltage-gated calcium channels, with changes in these channels significantly affecting glucose homeostasis.16 In vitro studies have shown that simvastatin inhibited glucose-induced calcium signaling in rat pancreatic islet β-cells via direct blockage of L-type calcium channels, although this was not seen with pravastatin, suggesting that effects are related to lipophilicity.82 In addition, reductions in endogenous pancreatic cholesterol levels have also been proposed to contribute to impaired calcium channel function, either through incorrect sorting of membrane-bound lipid raft proteins or changes in the conformation of channel subunits.83 A recent in vitro study has also suggested that mitochondria isolated from rat pancreas and treated with statins had reduced complex II activity that was accompanied by oxidative stress, mitochondrial swelling, and reduced membrane potential.84, Within adipose tissue and skeletal muscle, glucose uptake is facilitated by the GLUT4 (glucose transporter 4), which is initiated by insulin-receptor tyrosine kinase phosphorylation, facilitating recruitment of GLUT4 from intracellular storage to the plasma membrane.16 In vitro studies have shown an attenuation of adipocyte maturation and a decrease in GLUT4 expression in both differentiating and mature adipocytes with atorvastatin treatment because of inhibition in the formation of isoprenoids.