Which statins are hydrophilic

Information on long-term outcomes including all-cause death, recurrent MI re-MI and admission for HF was collected by visiting the research outpatient clinic or by verbal or written contact with the patient or family members. According to the propensity score, patients were selected using a 5-to-1 digit-matching technique using the nearest-neighbor method. Cox regression analysis was performed to assess whether treatment with either statin was associated with a lower risk of these events.

Propensity score was incorporated as a variable into the models before matching. Subgroup analysis was performed in patients after propensity score matching to clarify an interaction between statin treatment and subgroup category for long-term outcome, if statistical significance for the outcomes was observed in the overall patients. From a large database of the OACIS registry, we identified 1, patients who fulfilled the inclusion criteria of the present study.

Of these, pravastatin and rosuvastatin, which are categorized as hydrophilic statins, were prescribed to and patients, respectively, while simvastatin, atorvastatin, pitavastatin and fluvastatin, which are categorized as lipophilic statins, were prescribed to , , and 74 patients, respectively. Before propensity score matching, compared with the lipophilic statin group, hydrophilic statin group patients were more likely to be older and more likely to have lower cholesterol on admission.

There was also no significant difference in EF measured on echocardiography before discharge or in medication at discharge, except for antiplatelets, which were significantly lower in the hydrophilic statin group than in lipophilic statin group.

The lower risk with hydrophilic statins compared with lipophilic statins for admission for HF appeared to be consistent across the subgroups. Cumulative incidence of A all-cause death, B recurrent myocardial infarction re-MI , C admission for heart failure HF , and D a composite of these major adverse cardiac events; MACE in diabetic patients with acute myocardial infarction stratified according to statin use at discharge, before propensity score matching.

Model 2, adjusted for propensity score. Abbreviations as in Tables 1,3. Cumulative incidence of A all-cause death, B recurrent myocardial infarction re-MI , C admission for heart failure HF , and D a composite of these major adverse cardiac events; MACE , in diabetic patients with acute myocardial infarction stratified by statin use at discharge, after propensity score matching.

Abbreviations as in Table 3. Subgroup analysis after propensity score matching of admission for heart failure HF stratified according to the prescription of hydrophilic and lipophilic statins at discharge. We examined whether hydrophilic statin use was associated with better long-term outcomes than lipophilic statin use in 1, diabetic patients with AMI who were discharged alive using the OACIS registry database. We found that 1 the risk of HF admission was significantly lower in patients taking hydrophilic statins than in those with lipophilic statins both before and after propensity score matching, although there was no significant difference in the risk of all-cause death, non-fatal re-MI or MACE between the 2 types of statin; and 2 there was no heterogeneity between statins and various subgroups for HF admission, with all subgroups showing a lower risk with hydrophilic statins than with lipophilic statins after propensity score matching.

Inconsistent results for clinical outcomes between hydrophilic and lipophilic statins have been reported. A meta-analysis by Bonsu et al involving 10, HF patients found that lipophilic statins were associated with lower risk of all-cause mortality OR, 0. The present findings are partially consistent with previous studies that found no significant difference between the 2 types of statins in the risk of all-cause death 6 , 7 or re-MI. Although all-cause death was similar between the 2 studies, re-MI and admission for HF were higher in the current study than in the ALPS-AMI study, possibly due to the present study having a longer follow-up period and the more severe conditions related to DM.

Although we cannot determine the mechanism of this association of hydrophilic statins with lower risk of admission for HF than lipophilic statins, several possibilities may be considered.

Demyanets et al reported that lipophilic but not hydrophilic statins induce a pro-apoptotic state in human adult cardiac myocytes in vitro. Also, it has been speculated that lipophilic statins might potentially be harmful, likely through the inhibition of CoQ10 biosynthesis, leading to disturbances in cardiac energy metabolism.

Sugiyama et al reported that pravastatin improved glucose metabolism associated with an increase in adiponectin, 21 which is known to have anti-atherogenic properties in patients with CAD, 22 and to protect against the development of systolic dysfunction after AMI through its ability to suppress cardiac hypertrophy and interstitial fibrosis, and also to protect against myocyte and capillary loss, as seen in an experimental model in mice.

Randomized controlled trials RCT are needed to confirm these observations. Although we cannot determine why these factors were extracted, one possibility is simply that it is a chance observation, on the basis that few physicians might consider the differences in drug actions between hydrophilic and lipophilic statins based on these factors.

Several limitations of this study warrant mention. First, it was conducted under an observational rather than randomized design, leading to the possibility of bias in the receipt of statin type. To minimize this potential bias, we first analyzed the whole population, then performed propensity score matching analysis.

We obtained similar results with robustness between the whole and propensity score-matched groups, suggesting that any such bias might be minimal. Nonetheless, the clinical question of whether hydrophilic statin use reduces risk for long-term outcomes in DM patients with AMI needs to be evaluated in RCT, because there still exists potential bias even after propensity score matching in the current observational study.

Second, we did not have information on drug dosage at discharge, discontinuation or adverse event rates of the drugs, or laboratory data during the follow-up period, including those for LDL-C, BNP, or C-reactive protein, which would help clarify the mechanisms underlying the observations. Compared with lipophilic statins, hydrophilic statin use was associated with lower risk of admission for HF in diabetic patients with AMI.

Confirmation of these results in an RCT is warranted. Yasuhiko S. Yasushi S. The other authors declare no conflicts of interest. National Center for Biotechnology Information , U. Journal List Circ Rep v.

Circ Rep. Published online Mar Author information Article notes Copyright and License information Disclaimer. Six hundred and fifty-four patients were randomly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg pravastatin or an intensive lipid-lowering regimen with 80 mg atorvastatin. Moving forward, it must be acknowledged that the previously mentioned studies focused mainly on acute coronary syndrome. Here, the possible beneficial effects of one statin type or the other hydrophilic vs.

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. Keywords: adverse effects; cardiovascular disease; hydrophilic; lipophilic; pleiotropic effects; statins. Abstract Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media.

Publication types Review.