Edited by: Ricardo Gómez-Huelgas, Regional University Hospital of Malaga, Spain
Reviewed by: Ali Javaheri, Washington University School of Medicine in St. Louis, United States; Daisy Sahoo, Medical College of Wisconsin, United States
This article was submitted to Lipids in Cardiovascular Disease, a section of the journal Frontiers in Cardiovascular Medicine
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Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media. The predominantly lipophilic statins (simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin) can easily enter cells, whereas hydrophilic statins (rosuvastatin and pravastatin) present greater hepatoselectivity. Although the beneficial role of statins in primary and secondary cardiovascular prevention has been unequivocally confirmed, the possible superiority of one statin or other regarding their solubility profile is still not well-established. In this respect, although some previously published observational studies and clinical trials observed a superiority of lipophilic statins in cardiovascular outcomes, these results could also be explained by a greater low-density lipoprotein cholesterol reduction with this statin type. On the other hand, previous studies reported conflicting results as to the possible superiority of one statin type over the other regarding heart failure outcomes. Furthermore, adverse events with statin therapy may also be related to their solubility profile. Thus, the aim of the present review was to collect clinical evidence on possible differences in cardiovascular outcomes among statins when their solubility profile is considered, and how this may also be related to the occurrence of statin-related adverse effects.
The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in water or in lipid-containing media. In this respect, absorption is faster in lipophilic drugs, whereas the ease for renal excretion is greater in hydrophilic medications.
As most drugs are weak acids or bases, in an aqueous solution they can be present in two phases: ionised or polar and non-ionised or non-polar. The ionised polar fraction is water-soluble whereas the non-ionised is fat-soluble and is the only one that diffuses easily through cell membranes. The degree of molecule ionisation depends on three main factors: their acidic/basic nature, the dissociation constant of the molecule measured by pK and the pH of the medium where it is found. However, the latter is the definite determinant of the drug's availability to cross cell membranes and act on diverse tissues. Moreover, the degree of digestive absorption and renal excretion of each drug can be modified by changing the pH of the medium where it is found (
It must also be considered that hydrophilic substances can be excreted without undergoing any transformation. On the other hand, although the kidney can poorly filter ionised molecules (lipophilic), these are mostly reabsorbed back into the tubule. For this reason, most lipophilic substances are metabolised to become more polar metabolites, which then become water-soluble.
Thus, the hydro- or liposolubility of each drug is an aspect that should be carefully considered in clinical practise when deciding on the type of treatment, together with dose adjustment in patients with renal failure. In that clinical scenario, lipophilic drugs should be avoided, although other clinical characteristics must also be considered.
Since the introduction of lovastatin in 1987 as the first 3-hydroxy-3-methyl-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 (
Structurally, statins have three main parts as detailed in
Chemical structure of hydrophilic and lipophilic statins.
Main characteristics of the different statins available in clinical practise.
Dose range (mg/daily) | 10–80 | 20–80 | 1–4 | 5–40 | 10–80 | 5–40 | 20–80 |
Bioavailability (%) | <5 | 6 | >60 | <5 | 12 | 20 | 17 |
Active metabolites | Yes | No | No | Yes | Yes | Yes (minimal) | No |
Protein binding (%) | >95 | 98 | 96 | 95 | ≥90 | 89 | 50 |
Half-life (hours) | 2 | 4.7 | 12 | 1–2 | 14 | 19 | 1–2 |
Faecal excretion (%) | 83 | 90 | 75 | 58 | 90 | 90 | 71 |
Renal excretion (%) | 10 | <6 | 2 | 13 | <2 | 10 | 20 |
Liver metabolisation | CYP450 3A4 | CYP450 2C9 (minor) | CYP450 2C9 | CYP450 3A4 | CYP450 3A4 | CYP450 2C9 and 2C19 | Sulphation |
Solubility | Lipophilic | Lipophilic | Lipophilic | Lipophilic | Lipophilic | Hydrophilic | Hydrophilic |
Sufficient evidence of the possible beneficial or harmful effects related to statin solubility is lacking. It has been speculated that the ability of lipophilic statins to reach extrahepatic tissues could account for the more favourable cardiovascular outcomes in subjects receiving this type of lipid-lowering drug, although with a higher risk of adverse effects such as statin-associated muscle symptoms (SAMS).
The present comprehensive review aimed to describe the clinical evidence available to date regarding the possible differences in cardiovascular outcomes among statins when their solubility profile is considered, and how this may also be related to statin-related adverse effects. We hope this review will aid better understanding of statins for physicians and ultimately be useful for precise statin selection since, though they share the same mechanism of action, different chemical and pharmacological characteristics may affect their therapeutic efficacy.
Statins inhibit cholesterol synthesis, thereby enhancing LDL clearance from the circulation. Since mevalonic acid is the precursor of numerous metabolites, HMG-CoA reductase inhibition potentially results in pleiotropic effects that may affect several tissue functions and modulate specific signal transduction pathways (
Cholesterol biosynthetic pathway.
Atheroprotective effects of statins. NO, nitric oxide; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
One of the factors to be considered when evaluating outcomes of lipid-lowering treatment with statins is their solubility. Therefore, the role of both hydrophilic and lipophilic statins regarding beneficial pleiotropic effects and thus a possible improvement in cardiovascular primary or secondary prevention needs to be analysed further.
According to the 2016 European Society of Cardiology definition (
The role of statin therapy in HF remains controversial, with conflicting findings from observational studies and clinical trials (
Some trials (including both hydrophilic and lipohilic statins) on cardiovascular prevention reported interesting findings in the HF field. In this respect, those which compared statin vs. placebo (
A large-scale meta-analysis of randomised primary and secondary cardiovascular prevention clinical trials with statins showed a modest reduction (10%) in first non-fatal HF hospitalisation with statin therapy, with no effect on HF death. However, no differences were found in risk reduction between patients who presented an incident myocardial infarction or not. Only 10–15% of non-fatal HF hospitalisations were preceded by a documented within-trial non-fatal myocardial infarction (
More recently, Imran et al. (
In summary, more evidence is needed to support the use of high-intensity hydrophilic statins in the context of incident HF prevention.
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 (
Beside small studies with atorvastatin (lipophilic) (
Data on comparative effects between lipophilic and hydrophilic statin exposure for HF-related outcomes are limited. Using an indirect comparison approach, the meta-analysis of Bonsu et al. (
The supposed superiority of lipophilic statins has also been observed when cardiac function and anti-inflammatory effects were evaluated in patients with established HF. In this respect, Bonsu et al. (
Mortality in patients with HF has also been associated with cardiac sympathetic nerve activity, which in turn is one of the most important prognostic factors (
Other studies evaluated possible explanations for more favourable results with hydrophilic statins. In this respect, some studies reported that fat-soluble statins induced a pro-apoptotic state in human adult cardiac myocytes
A recent study comparing the effects of atorvastatin vs. rosuvastatin on left ventricular function, inflammatory and fibrosis biomarkers in patients with chronic HF, published by El Said et al. (
Finally, we believe the results of a
Thus, to date, the rationale for proving the superiority of one statin type over the other remains unclear. Although some studies have described possible pathophysiological mechanisms that could favour hydrophilic or lipophilic statins regarding HF outcomes, these have not been further confirmed. Future trials with larger sample size and longer follow-up are essential to ascertain whether real differences exist among statins owing to their solubility profile, and hence play a role when the optimal lipid-lowering therapy is decided upon for each patient in clinical practise. Meanwhile, statin use as HF therapy is not recommended.
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 (
The valuable role of statins in primary CHD prevention has been unequivocally confirmed in previous reports. Data from the Cholesterol Treatment Trialists' (CTT) Collaborators of statin treatment in people at low cardiovascular risk demonstrated a 9% reduction [relative risk (RR): 0.91, 95% CI: 0.85–0.97] in all-cause mortality and 25% (RR: 0.75, 95% CI: 0.70–0.80) in major vascular events per 1.0 mmol/L reduction in LDL cholesterol, even among low-risk patients (
Whether the solubility profile of each statin type could account for this favourable cardiovascular benefit remains open to debate. In this respect, the previously mentioned CTT meta-analysis (
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 (
Trials comparing hydrophilic and lipophilic statins and coronary artery disease.
PROVE IT-TIMI 22 ( |
RCT, double-blind | 24 | Pravastatin 40 mg vs. atorvastatin 80 mg | MACE | MACE 26.3% after pravastatin and 22.4% after atorvastatin; |
REVERSAL ( |
RCT, double-blind | 18 | Atorvastatin 80 mg vs. pravastatin 40 mg | Percentage change in total atheroma volume | Significantly lower progression rate of atheroma volume in atorvastatin group ( |
SAGE ( |
RCT, double-blind | 12 | Atorvastatin 80 mg vs. pravastatin 40 mg | Total duration of ischaemia on 48 h holter- monitor | Absolute change from baseline in total duration of ischaemia at month 12 significantly reduced in both groups ( |
MUSASHI-AMI ( |
RCT, double-blind | 24 | Lipophilic (atorvastatin, simvastatin, pitavastatin, fluvastatin) vs. hydrophilic (pravastatin) | CV death, non-fatal MI, recurrent acute myocardial ischaemia | Although LDL cholesterol was reduced more potently in the lipophilic group (−34 vs. −19%; |
CENTAURUS ( |
RCT, double-blind parallel group trial | 3 | Atorvastatin 80 mg vs. rosuvastatin 20 mg | Percentage change in ApoB/ApoA-1 ratio | Rosuvastatin 20 mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (−44.4 vs. −42.9%, |
LUNAR ( |
RCT, open-label, parallel group trial | 3 | Atorvastatin 80 mg vs. rosuvastatin 20–40 mg | Change in LDL cholesterol | Rosuvastatin 40 mg efficacy in lowering LDL cholesterol levels was significantly greater vs. atorvastatin 80 mg (46.8 vs. 42.7% decrease, |
The ROMA II ( |
RCT, double-blind | 12 | Atorvastatin 80 mg vs. rosuvastatin 40 mg vs. controls on chronic statin therapy without reloading | Incidence of peri- procedural MI, MACE | 12 and 24-h post-PCI CK-MB elevation >3 × occurred more frequently in control than in the rosuvastatin and atorvastatin groups (at 24-h: 25.0 vs. 7.1; |
ALPS-AMI ( |
RCT, open -label, blinded-endpoint | 24 | Atorvastatin 10–20 mg vs. pravastatin 10–20 mg | All-cause death, CV death, MI, stroke, revascularisation, hospitalisation | Primary endpoint occurred in 77 (30.4%) and in 80 patients (31.4%) in the pravastatin and atorvastatin groups, respectively (hazard ratio, 1.181; 95% CI: 0.862–1.619; |
Back in 2004, the PROVE IT-TIMI 22 trial (
Kim et al. (
To shed light on this matter, further trials such as that reported by Sakamoto et al. (
On the other hand, the findings of Bytyçi et al. (
With regard to coronary atherosclerosis progression/regression studies, the REVERSAL trial (
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. lipophilic) may probably depend more on their pleiotropic effects since the impact of lipid-lowering therapy in LDL cholesterol reduction has not yet been attained. 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. (
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 (
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 (
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 (
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 (
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 (
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 (
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.
The first version of the manuscript was written by EC, and revised and approved by DB and JP-B. 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.
The authors thank Miss Christine O'Hara for review of the English version of the manuscript.