However, when the focus is on chronic ischaemic heart disease, the beneficial effects of LDL cholesterol reduction may be present to the same degree as the pleiotropic changes. In this respect, Deedwania et al. However, atorvastatin-treated patients had greater LDL cholesterol reductions than pravastatin-treated patients, a trend towards fewer MACE hazard ratio: 0. Hence, as previously mentioned, the probable superiority of lipophilic atorvastatin could once again be explained by its greater potency in lowering LDL cholesterol concentrations.
Finally, the possible pleiotropic effects that may account for all these observed results include decreased adenosine triphosphate ATP production with lipophilic statins and enhanced myocardial stunning after ischaemia and reperfusion 62 , with direct beneficial effects on cardiovascular outcomes. Moreover, it has been further observed that lipophilic simvastatin enhances myocardial stunning compared with controls and hydrophilic pravastatin However, both types of statins, apart from their lipid-lowering effect, increase nitric oxide production and release 63 , thus protecting the myocardium against ischaemia-reperfusion injury, and reduce infarct size 64 , Nevertheless, while some studies, particularly randomised controlled trials, detected superiority of hydrophilic statins regarding to secondary CHD prevention, others reported greater LDL cholesterol reductions with lipophilic statins, which could also account for the more favourable cardiovascular outcomes.
As for HF outcomes, we believe future randomised trials with longer follow-up are mandatory to confirm the possible superiority of one statin type over the other taking into account their solubility profile, and regardless of their intensity in lowering LDL cholesterol levels. The possible differences between statin types and the risk of atrial fibrillation related stroke has also been evaluated.
In this sense, a meta-analysis 66 including a total of 8 studies evaluated the clinical outcomes both for pre- and post-stroke statins.
They observed that post-stroke statin therapy reduced total mortality regardless of statin intensity. However, no differences were observed regarding statin treatment and a reduction in the risk of recurrent ischaemic stroke. As to pre-stroke statins, initiating lipid-lowering treatment before the event was associated with a lower risk of poor short-tem functional outcomes.
Another recent meta-analysis in atrial fibrillation patients conformed a reduction in all-cause and cardiovascular mortality rates Despite these favourable results, possible differences between statins about their solubility profile were not assessed; hence future studies are needed in this field to reach more solid conclusions that can be useful in clinical practise.
Although the different statin types have possible beneficial effects depending on their solubility profile, safety cannot be ignored. It has been argued that the benefits of lipophilic statins may transcend into diverse adverse reactions owing to their easy penetration into extrahepatic tissues.
However, solid evidence is still lacking in this field 17 , 28 , On the other hand, the hepatoselectivity of hydrophilic statins could also translate into specific organ damage, although their lower tissue absorption and lower dependence on the cytochrome P enzyme compared to lipophilic statins could explain a drop in the number of side effects in subjects treated with these types of statin Firstly, the prevalence of SAMS differs between statin classes.
Lipophilic statins such as simvastatin, atorvastatin, fluvastatin, pitavastatin and lovastatin, owing to their well-known ability to non-selectively diffuse into extrahepatic tissues, such as skeletal muscle, carry a higher risk of SAMS. In contrast, hydrophilic statins have less muscle penetration and therefore lower risk However, based on a recent observational cohort study, equipotent hydrophilic statins were not better tolerated compared to lipophilic statins It must also be considered that, beside the statin type, the risk of SAMS also depends on other factors such as the concomitant use of drugs metabolised by the same hepatic cytochrome P isoforms Other risk factors for SAMS to be consideret include family history of muscular symptoms with lipid-lowering therapy, untreated hypothyroidism, female sex, older age and low body mass index, among others Secondly, the presence of new-onset diabetes mellitus with statin therapy should also be mentioned.
This seems to be more frequent in patients with pre-existing risk factors, including metabolic syndrome traits 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; however, a relationship with statin solubility has not been described As for neurological disorders, it has been hypothesised that lipophilic statins could induce a higher risk given their increased ability to cross the blood-brain barrier 75 ; however, these findings have not been confirmed in further studies.
Furthermore, it should be noted that these effects may not be specific to statin type per se but rather result from changes in cholesterol concentrations. Finally, controversy persists regarding the effects of statins on renal function.
Except for hydrophilic pravastatin and rosuvastatin, the remaining statins are mainly metabolised by the liver and minimally cleared by the kidney. Mild transient proteinuria has previously been observed in some patients when receiving high-dose statin treatment; however, this has not been firmly associated with impaired renal function The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in lipid media or in water.
The predominantly lipophilic statins can easily enter cells and interact with cell membranes, whereas hydrophilic statins present greater hepatoselectivity. Conflicting results have been observed on the superiority of hydrophilic or lipophilic statins regarding cardiovascular outcomes, including HF and CHD, both from primary and secondary prevention.
In this respect, the possible superiority of lipophilic statins seen in some studies could be explained by a greater LDL cholesterol reduction with this statin type, with the solubility profile playing a secondary role in the favourable cardiovascular outcomes observed. Finally, the non-selective diffusion of lipophilic statins into extrahepatic tissues could account for an increase in SAMS, albeit without differences between hydrophilic and lipophilic statins with respect to other adverse effects.
Thus, we believe future studies are essential in this field for the solubility profile of statins to be taken into account when deciding on the optimal lipid-lowering therapy for each patient in daily clinical practise. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. Goodman and Gilman's the Pharmacological Basis of Therapeutics. PubMed Abstract. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, participants in 14 randomised trials of statins. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from , participants in 26 randomised trials.
The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Egom EE, Hafeez H. Biochemistry of statins.
Adv Clin Chem. Atherosclerosis: conventional intake of cardiovascular drugs versus delivery using nanotechnology - a new chance for causative therapy? J Control Release. Polymers and nanoparticles for statin delivery: current use and future perspectives in cardiovascular disease. Pleiotropic effects of statin therapy.
Trends Mol Med. Eur Heart J. Heart failure: preventing disease and death worldwide. ESC Heart Fail. Statin therapy in heart failure. Is it time for a second look? Statins and heart failure. J Cardiol Ther. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. Google Scholar. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease.
J Card Fail. Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the treating to new targets TNT study. Rosuvastatin in older patients with systolic heart failure. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
Cholesterol and Recurrent Events Trial investigators. J Am Coll Cardiol. The effect of statin therapy on HF events: a collaborative meta-analysis of unpublished data from major randomized trials. Statin lipophilicity and the risk of incident heart failure. Statins and chronic heart failure: do we need a large-scale outcome trial? A statin in the treatment of heart failure? Eur J Heart Fail. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels.
Am J Cardiol. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. Statin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failure. Int J Cardiol. Statin therapy is associated with lower mortality among patients with severe heart failure.
Do statins reduce the risk of myocardial infarction in patients with heart failure? Lipophilic statin versus rosuvastatin hydrophilic treatment for heart failure: a meta-analysis and adjusted indirect comparison of randomised trials.
Cardiovasc Drugs Ther. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials. Heart Lung Circ. Effects of statin therapy on inflammatory markers in chronic heart failure: a meta-analysis of randomized controlled trials.
Arch Med Res. Effects of statin treatment on cardiac function in patients with chronic heart failure: a meta-analysis of randomized controlled trials. For example, when simvastatin is used alone, the incidence of myopathy is less than 0.
Fluvastatin is metabolized by CYP2C9 and is subject to potential interactions with agents such as amiodarone, gemfibrozil, fluconazole, metronidazole, and fluoxetine. However, in contrast to the relatively weak binding of simvastatin, atorvastatin, and lovastatin for CYP3A4, fluvastatin binds strongly to CYP2C9 and may inhibit the metabolism of the other agents that depend on this isoenzyme, such as warfarin.
Because rosuvastatin is relatively water-soluble, increased drug levels may result from severely diminished renal function. Interactions can occur with gemfibrozil an inhibitor of both isoenzymes, resulting in an approximate doubling of rosuvastatin exposure , 9 and theoretically with fluconazole, fluoxetine, fluvoxamine, and omeprazole as well. In addition, rosuvastatin drug levels are roughly twice as high in Japanese and Chinese people living in Asia than in Caucasian people living in Europe or North America.
Pravastatin is water soluble and does not depend on CYPmediated metabolism; it does, however, undergo acid hydrolysis and hepatic conjugation, and elimination occurs through renal and biliary excretion. In patients with diminished renal function, nonrenal mechanisms tend to increase in compensation, preventing accumulation and increased drug concentrations. To quantify the effects of pharmacokinetic interactions between CYP3A4-dependent statins and CYP3A4 inhibitors, simvastatin exposure, measured as area under the concentration- time curve, was increased 4- to fold when the statin was used in conjunction with known CYP3A4 inhibitors versus placebo Figure 2.
As previously stated, the active acid forms of the statins undergo hepatic glucuronidation, and the fibrates block glucuronide. It is now known that gemfibrozil is a more potent glucuronide blocker than fenofibrate. Fenofibrate, in contrast, has no effect on statin concentrations. The interactions between statins and warfarin are complex. Warfarin goes through several different CYP pathways, any of which might serve as a source of interactions with statins. However, whereas most of the interactions previously described result in inhibited statin metabolism, interactions with warfarin tend to work in the opposite direction and inhibit warfarin metabolism.
The clinical result is an increase in the international normalized ratio INR , a standardized measure of prothrombin time. The CYP3A4-dependent statins simvastatin, lovastatin, and atorvastatin all have the potential to raise the INR in patients taking warfarin; the effect is variable, and monitoring INR is important to determine whether the warfarin dosage must be adjusted. Patients most often start receiving statin therapy for the purpose of lowering concentrations of LDL cholesterol; other goals in improving the lipid profile include elevating high-density lipoprotein HDL cholesterol and lowering triglycerides.
Subsequent clinical decisions are made if any of these goals are not met by the initially chosen regimen. Other agents that may be added to the statin regimen are fenofibrate although it is relatively weak in terms of reducing LDL cholesterol , ezetimibe a cholesterol absorption inhibitor , and bile acid sequestrants.
If the HDL cholesterol remains low or triglycerides remain high, fibrates or niacin may be added, but again at the cost of an increased risk of toxicity. Another option for reducing triglyceride levels is the addition of fish oils omega-3 fatty acids to the regimen.
An additional safety concern when drugs are added to a statin regimen is that the likelihood of interactions rises sharply with polypharmacy.
When more than 2 drugs are taken, the theoretical number of possible interactions is computed as N! Interactions are not always serious or clinically apparent, but it is obvious that as more drugs compete for common CYP pathways, the risk of a clinically-relevant interaction increases. For patients taking multiple medications, it is especially important to select agents that are least likely to incur an additional risk of interaction; for patients who require the addition of lipid-lowering pharmacotherapy to a drug regimen that is already complex, the preferred agents would be the statins that are least dependent on the CYP system in general and on CYP3A4 in particular.
IMS Health. Available at: www. Accessed October 26, Statin-associated myopathy with normal creatine kinase levels. Jacobson TA. Combination lipid-lowering therapy with statins: safety issues in the postcerivastatin era. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. The interaction of diltiazem with lovastatin and pravastatin.
Effect of itraconazole on the pharmacokinetics of atorvastatin. Andrus MR. Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. Grundy SM. Alternative approaches to cholesterol-lowering therapy. Institute for Value-Based Medicine.
Finally, controversy persists regarding the effects of statins on renal function. Except for hydrophilic pravastatin and rosuvastatin, the remaining statins are mainly metabolised by the liver and minimally cleared by the kidney. Mild transient proteinuria has previously been observed in some patients when receiving high-dose statin treatment; however, this has not been firmly associated with impaired renal function The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in lipid media or in water.
The predominantly lipophilic statins can easily enter cells and interact with cell membranes, whereas hydrophilic statins present greater hepatoselectivity. Conflicting results have been observed on the superiority of hydrophilic or lipophilic statins regarding cardiovascular outcomes, including HF and CHD, both from primary and secondary prevention. In this respect, the possible superiority of lipophilic statins seen in some studies could be explained by a greater LDL cholesterol reduction with this statin type, with the solubility profile playing a secondary role in the favourable cardiovascular outcomes observed.
Finally, the non-selective diffusion of lipophilic statins into extrahepatic tissues could account for an increase in SAMS, albeit without differences between hydrophilic and lipophilic statins with respect to other adverse effects.
Thus, we believe future studies are essential in this field for the solubility profile of statins to be taken into account when deciding on the optimal lipid-lowering therapy for each patient in daily clinical practise. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Journal List Front Cardiovasc Med v. Front Cardiovasc Med. Published online May Author information Article notes Copyright and License information Disclaimer. This article was submitted to Lipids in Cardiovascular Disease, a section of the journal Frontiers in Cardiovascular Medicine. Received Mar 29; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Abstract Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media.
Keywords: adverse effects, cardiovascular disease, hydrophilic, lipophilic, pleiotropic effects, statins. Hydrophilicity vs. Lipophilicity The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in water or in lipid-containing media.
Hydrophilic vs. Lipophilic Statins Since the introduction of lovastatin in as the first 3-hydroxymethyl-glutaryl-coenzyme A HMG-CoA reductase inhibitor approved for human therapy, statins have become the most widely used lipid-lowering drugs with proven effect in cardiovascular disease prevention in different clinical settings 2 — 5.
Open in a separate window. Figure 1. Table 1 Main characteristics of the different statins available in clinical practise.
Statin Solubility and Cardiovascular Outcomes Statins inhibit cholesterol synthesis, thereby enhancing LDL clearance from the circulation.
Figure 2. Figure 3. Statins and Incident HF Some trials including both hydrophilic and lipohilic statins on cardiovascular prevention reported interesting findings in the HF field. Statins in the Treatment of Established HF Data from the major lipid-lowering trials on the effects of statin therapy on prevalent HF are scant since the majority excluded patients with this syndrome 22 , Statins and Coronary Heart Disease As in HF outcomes, previous studies have also yielded conflicting results concerning the possible benefits of different statin types owing to their solubility in primary of CHD prevention and in established cardiovascular disease 49 , Secondary CHD Prevention The possible differences between hydrophilic and lipophilic statins have mainly been evaluated regarding secondary cardiovascular prevention in patients with acute coronary syndrome and stable CHD Table 2 52 — Table 2 Trials comparing hydrophilic and lipophilic statins and coronary artery disease.
Coronary atherosclerosis progression in pravastatin group 2. Comparable results for rosuvastatin 20 and atorvastatin 80 mg. Increase in HDL cholesterol was significantly greater with rosuvastatin 40 At day, 6- and month follow-up, the incidence of MACE was higher in the control group than in the rosuvastatin or atorvastatin groups at month: Statins and Atrial Fibrillation-Related Stroke The possible differences between statin types and the risk of atrial fibrillation related stroke has also been evaluated.
Statin Solubility and Adverse Effects Although the different statin types have possible beneficial effects depending on their solubility profile, safety cannot be ignored.
Conclusions The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in lipid media or in water.
Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References 1. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. Goodman and Gilman's the Pharmacological Basis of Therapeutics. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, participants in 14 randomised trials of statins.
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from , participants in 26 randomised trials. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Egom EE, Hafeez H. Biochemistry of statins. Adv Clin Chem. Atherosclerosis: conventional intake of cardiovascular drugs versus delivery using nanotechnology - a new chance for causative therapy? J Control Release. Polymers and nanoparticles for statin delivery: current use and future perspectives in cardiovascular disease.
Pleiotropic effects of statin therapy. Trends Mol Med. Eur Heart J. Heart failure: preventing disease and death worldwide. ESC Heart Fail. Statin therapy in heart failure. Is it time for a second look? Statins and heart failure. J Cardiol Ther. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
N Engl J Med. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the treating to new targets TNT study. Rosuvastatin in older patients with systolic heart failure. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
Cholesterol and Recurrent Events Trial investigators. J Am Coll Cardiol. The effect of statin therapy on HF events: a collaborative meta-analysis of unpublished data from major randomized trials. Statin lipophilicity and the risk of incident heart failure.
Statins and chronic heart failure: do we need a large-scale outcome trial? A statin in the treatment of heart failure? Eur J Heart Fail. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol. Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure.
Statin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failure. Int J Cardiol. Statin therapy is associated with lower mortality among patients with severe heart failure.
Do statins reduce the risk of myocardial infarction in patients with heart failure? Lipophilic statin versus rosuvastatin hydrophilic treatment for heart failure: a meta-analysis and adjusted indirect comparison of randomised trials. Cardiovasc Drugs Ther. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials.
Heart Lung Circ. Effects of statin therapy on inflammatory markers in chronic heart failure: a meta-analysis of randomized controlled trials.
Arch Med Res. Effects of statin treatment on cardiac function in patients with chronic heart failure: a meta-analysis of randomized controlled trials.
Clin Cardiol. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. Effects of statin treatment on inflammation and cardiac function in heart failure: an adjusted indirect comparison meta-analysis of randomized trials.
Cardiovasc Ther. Takagi H, Umemoto T. Atorvastatin, not rosuvastatin, improves cardiac function in heart failure: a meta-analysis of randomized trials. Prognostic value of myocardial I metaiodobenzylguanidine MIBG parameters in patients with heart failure: a systematic review.
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