Mechanistically, statin toxicity is thought to arise because of HMG-CoA reductase inhibition effects, direct cellular and subcellular effects, or a combination of both.5 Other possible causes include genetic factors, drug-drug interactions, vitamin D status, and other metabolic or immune effects (Figure 1).21 Regardless of the mechanistic pathway, the end result is a change in drug bioavailability and activity, which can lead to nonadherence and intolerance.32 Adverse side effects have generally been shown to be class, dose, time, age, sex, and comorbidity dependent; however, considerable variability exists. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. Antioxidant-rich foods, like colorful fruits and vegetables. The role of mitochondria in statin-induced myopathy. Predictors of nonadherence to statins: a systematic review and meta-analysis. It appears to have no effect on atorvastatin or pitavastatin. The effects of 2 weeks of statin treatment on mitochondrial respiratory capacity in middle-aged males: the LIFESTAT study. This must include an accurate clinical assessment, listening to patient concerns, reviewing past adverse events and possible contributing factors, providing evidence-based counseling about the potential for adverse events as well as the cardiovascular benefits of statin therapy, and shared decision making with the patient when reintroducing therapy.18,33 Treatment and management algorithms have been developed to aid both diagnosis and management of SAMS in a bid to standardize nomenclature and phenotypes, as well as the type of data that should be collected from each patient.37 Development was based on 2012 Therapeutic Guidelines: Cardiovascular and 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidemias, with input from experts (Figure 3).23,29,36, Figure 3. Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: a meta-analysis. Simvastatin and lovastatin are administered as an inactive lactone form that is converted to the active form in the body. Why do the Media report negative news about statins? Unfortunately, one of those famous principles -, A significant number of patients who take statin drugs are completely unaware of the dangerous side effects they can cause. Statin myotoxicity: a review of genetic susceptibility factors. Increased cytosolic calcium can also increase calcium and phospholipid-dependent PKC (protein kinase C) activity, which promotes the closing of the chloride-1 channel, resulting in membrane hyperexcitability.47, In addition, muscle mitochondrial integrity is maintained by multiple signaling pathways, including the IGF-1/Akt pathways. Adverse effects: Like all medicines, statins can cause adverse side effects. Finally an answer comes to him. He returned to using Lipitor and within a short time experienced another memory lapse episode that lasted more than 12 hours. Prognosis after statin discontinuation is generally favorable, with liver-related fatalities only having been observed in patients treated with atorvastatin and simvastatin.115 Three prospective studies have shown that most patients (87%) with statin-induced hepatotoxicity were symptomatic with hepatocellular rather than cholestatic or mixed liver injury. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. The role of nutraceuticals in statin intolerant patients. ), Correspondence to Gerald F. Watts, DSc, MD, PhD, School of Medicine, University of Western Australia, GPO Box X2213, Perth WA 6847, Australia, Email, Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Western Australia, Australia (G.F.W. Dallas, TX 75231 However, Merck chose not to exercise these Patents, nor to help educate doctors and patients on the potential dangers of ingesting statins without CoQ10. Extreme-risk category: High prevalence among stable coronary patients and an emerging widening treatment gap in achieving LDL-cholesterol less than 55 mg/dL. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. The highly conserved mevalonate pathway is an important metabolic pathway, which plays a key role in many cellular processes via the synthesis of sterol and nonsterol isoprenoids (Figure 1). This was accompanied by upregulation of LDL receptor and SREBP2 (sterol regulatory element-binding protein 2) mRNA expression, suggestive of adaptations to sterol regulation. Intolerance to statins: mechanisms and management. 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 fundamental problem is that MD’s give patients the idea they get a free pass to eat unhealthy foods and live a toxic lifestyle, just take your statins! sex hormone production, hair growth, sleep, or proper brain and nervous system function.). There is speculation that insufficient vitamin D status may complicate and confound the adverse effects of statins, possibly because of a preferential shunting of the CYP3A4 enzyme toward hydroxylation of vitamin D, reducing the enzyme’s availability for statin metabolism and thus increasing circulating statin levels.32,137,138 Conversely, high vitamin D status may also cause enhanced CYP450 activity, increasing statin metabolism and reducing drug bioavailability.138, Although the exact interaction between vitamin D and statins is unclear, vitamin D status does appear to play a role in the lipid-lowering response to statins, with vitamin D–deficient patients having no response to low (10–20 mg) or high-dose (40–80 mg) atorvastatin.139 Interestingly, supplementation with vitamin D was shown to enhance the effects of atorvastatin, which is unexpected given both are metabolized by CYP3A4.138 Biopsies of skeletal muscle in adults with vitamin D deficiency show type II muscle fiber atrophy with enlarged interfibrillar spaces and infiltration of fat, fibrosis, and glycogen granules.140 Retrospective, cross-sectional, and meta-analysis reveal an association between low vitamin D levels and myalgia in patients on statin therapy,141–143 although normalization of serum vitamin D levels has been shown to facilitate successful statin rechallenge in ≈88% of patients previously intolerant because of SAMS.144 A recent secondary analysis trial has shown that monthly vitamin D supplementation results in improved adherence to statin medication in older adults on long-term statin therapy.145, The microbiome plays an important role in our physiology, immune system development, digestion, and overall health.146 While extremely dynamic, the microbiota composition and structure can be influenced by a number of factors including medication. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): revision for clinical use, content validation, and inter-rater reliability. GATM polymorphism associated with the risk for statin-induced myopathy does not replicate in case-control analysis of 715 dyslipidemic individuals. Although liver function panels are recommended before commencement of statin therapy and at initial follow-up, further monitoring is only recommended if concerns emerge. AKT indicates protein kinase B; Ca+2, calcium; CYP, cytochrome P450; IGF-1, insulin-like growth factor 1; LPL, lipoprotein lipase; PI3K, phosphoinositide 3-kinase; and UGTs, UDP glucuronosyltransferases. By continuing to browse this site you are agreeing to our use of cookies. In vitro studies suggest differing effects on these signaling cascades in response to different statins, with simvastatin and atorvastatin cytotoxic at lower doses (10 μmol/L) compared with rosuvastatin cytotoxicity at higher doses (50 μmol/L).53, The upstream effects of statins on the HMG-CoA–mediated pathway relate to an increase in fatty acid synthesis. In hypercholesterolemic statin-treated patients, a significant association was observed between myalgia and 2 SNPs (rs2276307 and rs1935349) in the genes HTR3B and HTR7, which encode serotonin receptors. In patients with a previous ischemic stroke, however, although statins reduced the risk of a recurrent ischemic stroke, they did nonsignificantly increase the risk of intracerebral hemorrhage. Although there is still insufficient evidence about their long-term safety and effectiveness, these nutraceuticals may offer alternative treatment options in the management of statin intolerance.194. 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Intolerance: the ODYSSEY alternative randomized trial symptoms, aggression, hostility, and effects on muscle. Cycle, nerve growth factor signaling, and management of statin intolerance: a Collaborative meta-analysis data!