REVIEW published: 20 May 2021 doi: 10.3389/fcvm.2021.687585 Hydrophilic or Lipophilic Statins? Elisenda Climent 1,2 , David Benaiges 1,2,3 and Juan Pedro-Botet 1,2,3* 1 Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona, Campus Universitari Mar, Barcelona, Spain, 3 Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain 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 Edited by: with statin therapy may also be related to their solubility profile. Thus, the aim of the Ricardo Gómez-Huelgas, Regional University Hospital of present review was to collect clinical evidence on possible differences in cardiovascular Malaga, Spain outcomes among statins when their solubility profile is considered, and how this may Reviewed by: also be related to the occurrence of statin-related adverse effects. Ali Javaheri, Washington University School of Keywords: adverse effects, cardiovascular disease, hydrophilic, lipophilic, pleiotropic effects, statins Medicine in St. Louis, United States Daisy Sahoo, Medical College of Wisconsin, HYDROPHILICITY VS. LIPOPHILICITY United States *Correspondence: The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in water Juan Pedro-Botet or in lipid-containing media. In this respect, absorption is faster in lipophilic drugs, whereas the 86620@parcdesalutmar.cat 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: Specialty section: ionised or polar and non-ionised or non-polar. The ionised polar fraction is water-soluble whereas This article was submitted to the non-ionised is fat-soluble and is the only one that diffuses easily through cell membranes. Lipids in Cardiovascular Disease, The degree of molecule ionisation depends on three main factors: their acidic/basic nature, the a section of the journal dissociation constant of the molecule measured by pK and the pH of the medium where it is found. Frontiers in Cardiovascular Medicine However, the latter is the definite determinant of the drug’s availability to cross cell membranes and Received: 29 March 2021 act on diverse tissues. Moreover, the degree of digestive absorption and renal excretion of each drug Accepted: 28 April 2021 can be modified by changing the pH of the medium where it is found (1). Published: 20 May 2021 It must also be considered that hydrophilic substances can be excreted without undergoing Citation: any transformation. On the other hand, although the kidney can poorly filter ionised molecules Climent E, Benaiges D and Pedro-Botet J (2021) Hydrophilic or (lipophilic), these are mostly reabsorbed back into the tubule. For this reason, most lipophilic Lipophilic Statins? substances are metabolised to become more polar metabolites, which then become water-soluble. Front. Cardiovasc. Med. 8:687585. Thus, the hydro- or liposolubility of each drug is an aspect that should be carefully considered in doi: 10.3389/fcvm.2021.687585 clinical practise when deciding on the type of treatment, together with dose adjustment in patients Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? with renal failure. In that clinical scenario, lipophilic drugs Sufficient evidence of the possible beneficial or harmful effects should be avoided, although other clinical characteristics must related to statin solubility is lacking. It has been speculated that also be considered. 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 HYDROPHILIC VS. LIPOPHILIC STATINS a higher risk of adverse effects such as statin-associated muscle symptoms (SAMS). Since the introduction of lovastatin in 1987 as the first 3- The present comprehensive review aimed to describe the hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase clinical evidence available to date regarding the possible inhibitor approved for human therapy, statins have become the differences in cardiovascular outcomes among statins when most widely used lipid-lowering drugs with proven effect in their solubility profile is considered, and how this may also cardiovascular disease prevention in different clinical settings be related to statin-related adverse effects. We hope this (2–5). Statins have been classified in 3 categories based on review will aid better understanding of statins for physicians their potency and efficacy in lowering low-density lipoprotein and ultimately be useful for precise statin selection since, (LDL) cholesterol concentrations. First-generation statins though they share the same mechanism of action, different included lovastatin, pravastatin and fluvastatin, simvastatin and chemical and pharmacological characteristics may affect their atorvastatin belong to the second generation, and rosuvastatin therapeutic efficacy. and pitavastatin to the third. Structurally, statins have three main parts as detailed in Figure 1: the analogue of HMG-CoA, a complex ring STATIN SOLUBILITY AND structure which binds the statin molecule to the HMG-CoA CARDIOVASCULAR OUTCOMES reductase enzyme and, finally, a side chain ring structure that determines structure solubility. They reduce LDL cholesterol Statins inhibit cholesterol synthesis, thereby enhancing LDL levels by inhibiting the rate-limiting enzyme for cholesterol clearance from the circulation. Since mevalonic acid is the biosynthesis, HMG-CoA reductase. This is a membrane- precursor of numerous metabolites, HMG-CoA reductase associated protein located in the endoplasmic reticulum, inhibition potentially results in pleiotropic effects that may affect and the interaction of statins with membranes is likely to several tissue functions and modulate specific signal transduction influence their ability to inhibit this enzyme. Statins differ pathways (Figure 2). These effects include anti-inflammatory markedly in their solubility owing to the presence/absence of and antioxidant activities, improvement in endothelial function, polar moieties on the largely hydrophobic backbones. These increased bioavailability of nitric oxide and delay in the structural variations result in a differential distribution within progression of atherosclerotic plaques (9) (Figure 3). All these the phospholipid bilayer of the cell membranes. According to vasculoprotective effects may account for a greater magnitude their solubility, statins can be categorised as hydrophilic and of and earlier time to cardiovascular benefit than apparently lipophilic. The predominantly lipophilic statins (simvastatin, explained by changes in LDL cholesterol levels alone. However, fluvastatin, lovastatin, pitavastatin, and atorvastatin) can easily leaving aside in vitro and experimental studies, it is not possible pass more deeply into the membranes where they interact from available clinical evidence to isolate the potential benefits with the surrounding acyl chains. By contrast, hydrophilic of pleiotropic effects of statins from those conferred by LDL agents (pravastatin and, to a lesser degree, rosuvastatin) remain cholesterol reduction. associated with the polar surface of the membrane and require One of the factors to be considered when evaluating outcomes protein transporters to enter the cell to inhibit the HMG- of lipid-lowering treatment with statins is their solubility. CoA reductase enzyme (6). The distinct solubility and location Therefore, the role of both hydrophilic and lipophilic statins are also likely to be key factors involved in the metabolic regarding beneficial pleiotropic effects and thus a possible differences among statins. Lipophilic statins can enter cells by improvement in cardiovascular primary or secondary prevention passive diffusion and therefore become widely distributed in needs to be analysed further. different tissues. However, the liver-specific, carrier-mediated mechanisms required for hydrophilic statin uptake could Statins and Heart Failure potentially reduce their ability to exert non-LDL effects at According to the 2016 European Society of Cardiology definition extrahepatic sites. Furthermore, the elimination of statins is also (10), heart failure (HF) is a complex disease caused by structural affected by solubility since lipophilic statins are metabolised by and/or functional cardiac abnormality, resulting in reduced membrane-bound cytochrome P450 (CYP) enzymes, whereas cardiac output and/or elevated intracardiac pressures at rest or hydrophilic statins are mostly eliminated without modification. during stress. Its management is challenging owing to the clinical The main characteristics of each statin type, including dose heterogeneity of the disease, which leads to patients responding range, bioavailabilty, liver metabolisation and other relevant differently to evidence-based standard therapy. Furthermore, its aspects are further detailed in Table 1. As an attempt to improve prevalence has suffered an exponential increase in the last decade, statin bioavailability and effectiveness, a wide variety of polymer- rendering HF a serious public health issue (11). and nanoparticle-based approaches for statin delivery have The role of statin therapy in HF remains controversial, with been described (7, 8). conflicting findings from observational studies and clinical trials Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? FIGURE 1 | Chemical structure of hydrophilic and lipophilic statins. TABLE 1 | Main characteristics of the different statins available in clinical practise. Lovastatin Fluvastatin Pitavastatin Simvastatin Atorvastatin Rosuvastatin Pravastatin 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 (12, 13). Next, we will analyse its impact in two different (14, 15) or more-intensive vs. less-intensive statin therapy (16– clinical settings: the prevention of HF and the treatment of 19) found an HF incidence reduction in patients with stable established HF. coronary heart disease or a history of acute coronary syndrome without previous HF. Thus, efficacy in myocardial ischaemic event reduction could be involved in their benefit in incident Statins and Incident HF HF prevention. Some trials (including both hydrophilic and lipohilic statins) on A large-scale meta-analysis of randomised primary and cardiovascular prevention reported interesting findings in the HF secondary cardiovascular prevention clinical trials with statins field. In this respect, those which compared statin vs. placebo showed a modest reduction (10%) in first non-fatal HF Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? FIGURE 2 | Cholesterol biosynthetic pathway. FIGURE 3 | Atheroprotective effects of statins. NO, nitric oxide; LDL, low-density lipoprotein; HDL, high-density lipoprotein. hospitalisation with statin therapy, with no effect on HF death. low-dose hydrophilic statins. This was the only large cohort study However, no differences were found in risk reduction between using health care data designed to compare the risk of incident patients who presented an incident myocardial infarction or not. HF between hydrophilic and lipophilic statins. Only 10–15% of non-fatal HF hospitalisations were preceded by In summary, more evidence is needed to support the use a documented within-trial non-fatal myocardial infarction (20). of high-intensity hydrophilic statins in the context of incident Although the mechanisms by which statins reduce non-fatal HF HF prevention. hospitalisations are not well-established, the lack of a significant effect on HF mortality may be attributed to a non-ischaemic Statins in the Treatment of Established HF cause of death in HF patients. Data from the major lipid-lowering trials on the effects of statin More recently, Imran et al. (21), evaluating nearly 8 million therapy on prevalent HF are scant since the majority excluded subjects in an observational cohort study, reported a reduction patients with this syndrome (22, 23). in HF in those treated with hydrophilic compared to lipophilic Beside small studies with atorvastatin (lipophilic) (24–26) statins which seemed to be driven by high-dose rather than or other statins (27) suggesting a potential benefit of these Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? therapies in HF patients, two randomised controlled trials ejection fraction, and greater reduction in BNP levels. Hence, with rosuvastatin (hydrophilic), GISSI (Gruppo Italiano per lo beyond improving lipid profile, these findings emphasise the role Studio della Sopravvivenza nell’Insufficienza cardiaca) (28) and of statins on inflammation response (41). Moreover, preclinical CORONA (Controlled Rosuvastatin Multinational Trial in Heart evidence suggests that the pleiotropic effects of statins may Failure) (17) were specifically conducted in an HF population. No improve survival rates in ischaemic and non-ischaemic HF differences in major cardiac adverse events were registered when subjects by regulating the autonomic nervous system through compared to placebo; however, a reduction in HF hospitalisation angiotensin II and nitric oxide modulation (42). However, was observed in CORONA. Furthermore, in a pooled analysis preliminary human studies reported mixed results. Indeed, of both trials, Feinstein et al. (29) found a small but significant Horwich al. (43) found that short-term statin treatment failed risk reduction in myocardial infarction in ischaemic HF patients to result in a significant reduction in autonomic nervous system treated with the hydrophilic rosuvastatin. activation in HF patients. In contrast, a large meta-analysis of Data on comparative effects between lipophilic and 13 randomised trials reported that lipophilic statins significantly hydrophilic statin exposure for HF-related outcomes are lowered all-cause mortality, hospitalisation for worsening HF limited. Using an indirect comparison approach, the meta- and LDL cholesterol, regardless of age, baseline left ventricular analysis of Bonsu et al. (30), including 13 studies and 10,966 ejection fraction and cause of HF (32). patients, reported a superiority of lipophilic statins regarding all- Other studies evaluated possible explanations for more cause mortality [odds ratio (OR) 0.50; 95% confidence interval favourable results with hydrophilic statins. In this respect, some (CI): 0.11–0.89; p = 0.01], cardiovascular mortality (OR: 0.61; studies reported that fat-soluble statins induced a pro-apoptotic 95% CI: 0.25–0.97; p = 0.009) and hospitalisation for worsening state in human adult cardiac myocytes in vitro (44). Similarly, HF (OR 0.52; 95% CI, 0.21–0.83; p = 0.0005); however, both it has been speculated that lipophilic statins might inhibit statin types were comparable for cardiovascular hospitalisation CoQ10 biosynthesis, leading to disturbances in cardiac energy (OR: 0.80; 95% CI: 0.31–1.28; p = 0.36). Similarly, other studies metabolism (45). A previous study showed that switching from also showed a greater risk reduction in HF events, hospitalisation lipophilic simvastatin to the hydrophilic pravastatin led to an and mortality (cardiovascular and all-cause) with lipophilic vs. increase in plasma adiponectinaemia with no change in LDL hydrophilic statins (20, 31–34). It has been postulated that the cholesterol concentrations (46). greater exposure of lipophilic statins in extrahepatic tissues could A recent study comparing the effects of atorvastatin vs. account for a higher uptake by cardiac muscle (35). rosuvastatin on left ventricular function, inflammatory and The supposed superiority of lipophilic statins has also fibrosis biomarkers in patients with chronic HF, published by El been observed when cardiac function and anti-inflammatory Said et al. (47) suggested that the impact of lipophilic atorvastatin effects were evaluated in patients with established HF. In this was greater than that of hydrophilic rosuvastatin in HF patients respect, Bonsu et al. (36) in another meta-analysis with 19 with regards to the improvement in left ventricular ejection randomised controlled trials and ∼6,200 patients obtained more fraction and soluble suppression of tumorigenicity reduction, a favourable results with lipophilic statins in improving cardiac novel fibrosis marker. function and reducing inflammation, with a greater rise in Finally, we believe the results of a post-hoc analysis of the left ventricular ejection fraction. Lipophilic statins were also CORONA trial are worth mentioning (48). Plasma galectin 3 superior to hydrophilic rosuvastatin and pravastatin regarding (a mediator of fibrogenesis) levels were evaluated in subjects B-type natriuretic peptide (BNP), high sensitivity C-reactive with established systolic HF included in the CORONA trial that protein (hsCRP), interleukin 6 and tumour necrosis factor α were randomised to 10 mg or rosuvastatin daily or placebo. reductions during follow-up. Takagi et al. (37) found lipophilic It was observed that among patients with below the median atorvastatin to be superior to hydrophilic rosuvastatin in plasma concentrations of galectin 3 (≤19 ng/ml), those receiving improving cardiac function, with superiority of the former in rousvastatin treatment presented a lower primary event rate inflammation attenuation and endothelial dysfunction, refuting (defined as cardiovascular death, myocardial infarction or previous reports, which supported the superiority of rosuvastatin stroke), lower mortality rate and lower rate of all-cause mortality in hsCRP level reductions. or HF hospitalisation. However, these benefits were not observed Mortality in patients with HF has also been associated in patients with higher galectin 3 levels. Thus, these results may with cardiac sympathetic nerve activity, which in turn is highlight the hypothetical role of galectin 3 to identify subjects one of the most important prognostic factors (38, 39). with HF or chronic left ventricular systolic dysfuncion that might In this regard, previous evidence once again showed the benefit of statins treatment, although further studies are required. superiority of lipophilic atorvastatin vs. hydrophilic rosuvastatin Thus, to date, the rationale for proving the superiority of in sympathetic nerve activity reduction in patients with one statin type over the other remains unclear. Although some HF (40). In that face-to face trial (40), 5 mg of lipophilic studies have described possible pathophysiological mechanisms atorvastatin was compared to 2.5 mg of hydrophilic rosuvastatin that could favour hydrophilic or lipophilic statins regarding HF in patients with dilated cardiomyopathy. As to lipid profile outcomes, these have not been further confirmed. Future trials outcome, total and LDL cholesterol reductions were similar with larger sample size and longer follow-up are essential to between groups. However, the atorvastatin group presented an ascertain whether real differences exist among statins owing increased heart/mediastinum ratio (which is known marker of to their solubility profile, and hence play a role when the an increased noradrenaline uptake), improved left ventricular optimal lipid-lowering therapy is decided upon for each patient Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? in clinical practise. Meanwhile, statin use as HF therapy is lipophilics atorvastatin, fluvastatin, pitavastatin and simvastatin not recommended. to hydrophilic pravastatin. Although LDL cholesterol was reduced more potently in the lipophilic than the hydrophilic Statins and Coronary Heart Disease groups (−34 vs. −19%; p = 0.0069), acute coronary syndromes As in HF outcomes, previous studies have also yielded conflicting tended to occur less frequently (3.6 vs. 9.9%; p = 0.0530) and results concerning the possible benefits of different statin types the incidence of new a Q-wave appearance on electrocardiogram owing to their solubility in primary of CHD prevention and in was significantly lower (75 vs. 89%; p = 0.0056) with hydrophilic established cardiovascular disease (49, 50). pravastatin than with lipophilic statins. The CENTAURUS trial (56) also obtained more favourable results with hydrophilic Primary CHD Prevention statins, with rosuvastatin 20 mg being more effective than The valuable role of statins in primary CHD prevention has lipophilic atorvastatin 80 mg in reducing the apoB/apoA-1 ratio been unequivocally confirmed in previous reports. Data from the at 1 month (−44.4 vs. −42.9%, p = 0.02), although these Cholesterol Treatment Trialists’ (CTT) Collaborators of statin results were not further confirmed with a longer follow-up. treatment in people at low cardiovascular risk demonstrated a Finally, Izawa et al. (59) obtained more favourable results with 9% reduction [relative risk (RR): 0.91, 95% CI: 0.85–0.97] in all- hydrophilic pravastatin (MACE 30.4% after pravastatin vs. 31.4% cause mortality and 25% (RR: 0.75, 95% CI: 0.70–0.80) in major in the atorvastatin group), although greater reductions in total vascular events per 1.0 mmol/L reduction in LDL cholesterol, and LDL cholesterol were achieved in the atorvastatin group (p even among low-risk patients (4). Furthermore, a 2013 Cochrane < 0.001 for each). analysis corroborated these findings with a 14% reduction (OR: On the other hand, the findings of Bytyçi et al. (61) between 0.86, 95% CI: 0.79–0.94) in all-cause mortality and 25% (RR: 0.75, hydrophilic and lipophilic statins were comparable in terms of 95% CI: 0.70–0.81) in cardiovascular events (51). risk reduction for MACE (RR: 0.969; 95% CI: 0.835–1.125; p = Whether the solubility profile of each statin type could 0.682), myocardial ischaemia (RR: 0.880; 95% CI: 0.731–1.058; p account for this favourable cardiovascular benefit remains open = 0.174), cardiovascular death (RR: 0.757; 95% CI: 0.486–1.180; to debate. In this respect, the previously mentioned CTT p = 0.219) and all-cause mortality (RR: 0.797; 95% CI: 0.590– meta-analysis (4) included some studies that compared various 1.075; p = 0.137). However, the cardiovascular hospitalisation statin types; however, the differences observed in cardiovascular rate was lower (RR: 0.789; 95% CI: 0.643–0.969; p = 0.024) and outcomes were attributed to statin potency (intensive vs. less alanine aminotransferase (ALT) elevation higher (RR: 2.689; 95% intensive), and no mention was made of the solubility profile CI: 1.841–3.954; p < 0.001) in lipophilic- than in hydrophilic- resulting in more favourable outcomes. treated patients. With regard to coronary atherosclerosis Secondary CHD Prevention progression/regression studies, the REVERSAL trial (53) The possible differences between hydrophilic and lipophilic assessed the effect of different statin regimens designed to statins have mainly been evaluated regarding secondary produce intensive or moderate lipid lowering of the coronary cardiovascular prevention in patients with acute coronary artery atheroma burden and progression. Six hundred and syndrome and stable CHD (Table 2) (52–59). fifty-four patients were randomly assigned to receive a moderate Back in 2004, the PROVE IT-TIMI 22 trial (52) compared lipid-lowering regimen consisting of 40 mg pravastatin or a standard therapy of 40 mg pravastatin daily with an intensive an intensive lipid-lowering regimen with 80 mg atorvastatin. therapy of 80 mg atorvastatin daily, observing that an intensive They observed that the percentage change in atheroma volume lipid-lowering statin strategy provided greater protection against revealed a significantly lower progression rate in the lipophilic death or major adverse cardiovascular events (MACE) than a atorvastatin group compared with the hydrophilic pravastatin standard regimen. Similarly to the results from observational group (p = 0.02). However, as in the CTT meta-analysis (4), this studies, the greater LDL cholesterol reduction with lipophilic could probably be explained by the fact that the LDL cholesterol atorvastatin compared to hydrophilic pravastatin could probably reduction was greater in the atorvastatin than the pravastatin account for the more favourable cardiovascular results observed groups (p < 0.001), and hence the solubility profile of each statin in subjects receiving the former, although whether the solubility and the possible superiority of lipophilic statins could play a profile of each statin could also play a role in these observed secondary role in the observed differences. differences could also be speculated. Moving forward, it must be acknowledged that the previously Kim et al. (60) found a higher composite of MACE in the mentioned studies focused mainly on acute coronary syndrome. hydrophilic statin group at 1 and 6 months (1 month: 10.0 vs. Here, the possible beneficial effects of one statin type or 4.4%; p = 0.001; 6 months: 19.9 vs. 14.2%; p = 0.022), whereas no the other (hydrophilic vs. lipophilic) may probably depend significant difference in MACE was observed at 1 year of follow- more on their pleiotropic effects since the impact of lipid- up (21.5 vs. 17.9%; p = 0.172). Both statin arms showed similar lowering therapy in LDL cholesterol reduction has not yet been efficacy in the lipid profile and the use of a hydrophilic statin attained. However, when the focus is on chronic ischaemic did not predict 1-year MACE, all-cause death, acute myocardial heart disease, the beneficial effects of LDL cholesterol reduction infarction or re-percutaneous coronary intervention. may be present to the same degree as the pleiotropic To shed light on this matter, further trials such as that changes. In this respect, Deedwania et al. (54) evaluated reported by Sakamoto et al. (55) in 2007 directly compared the 893 outpatients with chronic stable ischaemic heart disease Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? TABLE 2 | Trials comparing hydrophilic and lipophilic statins and coronary artery disease. Study (reference) Study Follow-up Trial comparison Primary Main results design (months) endpoints PROVE IT-TIMI 22 RCT, 24 Pravastatin 40 mg MACE MACE 26.3% after pravastatin and 22.4% after (52) double-blind vs. atorvastatin atorvastatin; p = 0.005 80 mg REVERSAL (53) RCT, 18 Atorvastatin 80 mg Percentage Significantly lower progression rate of atheroma volume double-blind vs. pravastatin change in total in atorvastatin group (p = 0.02). Coronary 40 mg atheroma volume atherosclerosis progression in pravastatin group (2.7%; 95% CI, 0.2–4.7%; p = 0.001) compared with baseline. No progression in atorvastatin arm (−0.4%; CI −2.4 to 1.5%; p = 0.98) compared with baseline. SAGE (54) RCT, 12 Atorvastatin 80 mg Total duration of Absolute change from baseline in total duration of double-blind vs. pravastatin ischaemia on 48 h ischaemia at month 12 significantly reduced in both 40 mg holter- monitor groups (p < 0.001 for each treatment group) with no significant difference between treatment groups. Atorvastatin greater LDL cholesterol reductions than pravastatin, trend towards fewer MACE (hazard ratio, 0.71; 95% CI, 0.46–1.09; p = 0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% CI, 0.13–0.83; p = 0.014). MUSASHI-AMI RCT, 24 Lipophilic CV death, Although LDL cholesterol was reduced more potently in (55) double-blind (atorvastatin, non-fatal MI, the lipophilic group (−34 vs. −19%; p = 0.0069), ACS simvastatin, recurrent acute tended to occur less frequently (3.6 vs. 9.9%; p = pitavastatin, myocardial 0.0530) and the incidence of new Q-wave in ECG was fluvastatin) vs. ischaemia significantly lower (75 vs. 89%; p = 0.0056) in the hydrophilic hydrophilic group. (pravastatin) CENTAURUS (56) RCT, 3 Atorvastatin 80 mg Percentage Rosuvastatin 20 mg was more effective than atorvastatin double-blind vs. rosuvastatin change in 80 mg in decreasing apoB/apoA-1 ratio at 1 month parallel group 20 mg ApoB/ApoA-1 (−44.4 vs. −42.9%, p = 0.02), but not at 3 months trial ratio (both −44.4%, p = 0.87). LUNAR (57) RCT, 3 Atorvastatin 80 mg Change in LDL Rosuvastatin 40 mg efficacy in lowering LDL cholesterol open-label, vs. rosuvastatin cholesterol levels was significantly greater vs. atorvastatin 80 mg parallel group 20–40 mg (46.8 vs. 42.7% decrease, p = 0.02). Comparable trial results for rosuvastatin 20 and atorvastatin 80 mg. Increase in HDL cholesterol was significantly greater with rosuvastatin 40 (11.9%, p < 0.001) and 20 mg (9.7%, p < 0.01) than with atorvastatin 80 mg (5.6%). The ROMA II (58) RCT, 12 Atorvastatin 80 mg Incidence of peri- 12 and 24-h post-PCI CK-MB elevation >3× occurred double-blind vs. rosuvastatin procedural MI, more frequently in control than in the rosuvastatin and 40 mg vs. controls MACE atorvastatin groups (at 24-h: 25.0 vs. 7.1; p = 0.003 and on chronic statin 25.0 vs. 6.1; p = 0.001). therapy without At 30-day, 6- and 12-month follow-up, the incidence of reloading MACE was higher in the control group than in the rosuvastatin or atorvastatin groups (at 12-month: 41.0 vs. 11.4 vs. 12.0%; p = 0.001). ALPS-AMI (59) RCT, open 24 Atorvastatin All-cause death, Primary endpoint occurred in 77 (30.4%) and in 80 -label, 10–20 mg vs. CV death, MI, patients (31.4%) in the pravastatin and atorvastatin blinded- pravastatin stroke, groups, respectively (hazard ratio, 1.181; 95% CI: endpoint 10–20 mg revascularisation, 0.862–1.619; p = 0.299), whereas greater reductions in hospitalisation total and LDL cholesterol were achieved in the atorvastatin group (p < 0.001 for each). ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; ECG, electrocardiogram; MACE, major adverse cardiovascular event; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomised controlled trial. randomised to atorvastatin 80 mg (lipophilic) or pravastatin treatment groups. However, atorvastatin-treated patients had 40 mg (hydrophilic) and followed for 12 months. The primary greater LDL cholesterol reductions than pravastatin-treated efficacy parameter (absolute change from baseline in total patients, a trend towards fewer MACE (hazard ratio: 0.71; 95% ischaemia duration at month 12) was significantly reduced CI: 0.46, 1.09; p = 0.114) and a significantly greater reduction in both groups at months 3 and 12 (p < 0.001 for in all-cause death (hazard ratio: 0.33; 95% CI: 0.13, 0.83; p = each treatment group) with no significant difference between 0.014). Hence, as previously mentioned, the probable superiority Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? of lipophilic atorvastatin could once again be explained by its absorption and lower dependence on the cytochrome P450 greater potency in lowering LDL cholesterol concentrations. enzyme compared to lipophilic statins could explain a drop in Finally, the possible pleiotropic effects that may account the number of side effects in subjects treated with these types for all these observed results include decreased adenosine of statin (69). triphosphate (ATP) production with lipophilic statins and Firstly, the prevalence of SAMS differs between statin classes. enhanced myocardial stunning after ischaemia and reperfusion Lipophilic statins such as simvastatin, atorvastatin, fluvastatin, (62), with direct beneficial effects on cardiovascular outcomes. pitavastatin and lovastatin, owing to their well-known ability Moreover, it has been further observed that lipophilic to non-selectively diffuse into extrahepatic tissues, such as simvastatin enhances myocardial stunning compared with skeletal muscle, carry a higher risk of SAMS. In contrast, controls and hydrophilic pravastatin (45). However, both hydrophilic statins have less muscle penetration and therefore types of statins, apart from their lipid-lowering effect, increase lower risk (70). However, based on a recent observational cohort nitric oxide production and release (63), thus protecting the study, equipotent hydrophilic statins were not better tolerated myocardium against ischaemia-reperfusion injury, and reduce compared to lipophilic statins (71). It must also be considered infarct size (64, 65). that, beside the statin type, the risk of SAMS also depends on Nevertheless, while some studies, particularly randomised other factors such as the concomitant use of drugs metabolised controlled trials, detected superiority of hydrophilic statins by the same hepatic cytochrome P450 isoforms (72). Other regarding to secondary CHD prevention, others reported greater risk factors for SAMS to be consideret include family history LDL cholesterol reductions with lipophilic statins, which could of muscular symptoms with lipid-lowering therapy, untreated also account for the more favourable cardiovascular outcomes. As hypothyroidism, female sex, older age and low body mass index, for HF outcomes, we believe future randomised trials with longer among others (73). follow-up are mandatory to confirm the possible superiority Secondly, the presence of new-onset diabetes mellitus with of one statin type over the other taking into account their statin therapy should also be mentioned. This seems to be more solubility profile, and regardless of their intensity in lowering frequent in patients with pre-existing risk factors, including LDL cholesterol levels. metabolic syndrome traits (74). It has been observed for both hydrophilic and lipophilic statins and appears to occur more Statins and Atrial Fibrillation-Related frequently in older patients and those on high-dose statin Stroke therapy; however, a relationship with statin solubility has not The possible differences between statin types and the risk been described (70). of atrial fibrillation related stroke has also been evaluated. As for neurological disorders, it has been hypothesised In this sense, a meta-analysis (66) including a total of 8 that lipophilic statins could induce a higher risk given their studies evaluated the clinical outcomes both for pre- and post- increased ability to cross the blood-brain barrier (75); however, stroke statins. They observed that post-stroke statin therapy these findings have not been confirmed in further studies. reduced total mortality regardless of statin intensity. However, Furthermore, it should be noted that these effects may not be no differences were observed regarding statin treatment and specific to statin type per se but rather result from changes in a reduction in the risk of recurrent ischaemic stroke. As to cholesterol concentrations. pre-stroke statins, initiating lipid-lowering treatment before the Finally, controversy persists regarding the effects of statins event was associated with a lower risk of poor short-tem on renal function. Except for hydrophilic pravastatin and functional outcomes. Another recent meta-analysis in atrial rosuvastatin, the remaining statins are mainly metabolised fibrillation patients conformed a reduction in all-cause and by the liver and minimally cleared by the kidney. Mild cardiovascular mortality rates (67). Despite these favourable transient proteinuria has previously been observed in results, possible differences between statins about their solubility some patients when receiving high-dose statin treatment; profile were not assessed; hence future studies are needed in however, this has not been firmly associated with impaired this field to reach more solid conclusions that can be useful in renal function (76). clinical practise. CONCLUSIONS STATIN SOLUBILITY AND ADVERSE EFFECTS The classification of drugs as hydrophilic or lipophilic depends on their ability to dissolve in lipid media or in water. The Although the different statin types have possible beneficial predominantly lipophilic statins can easily enter cells and effects depending on their solubility profile, safety cannot be interact with cell membranes, whereas hydrophilic statins present ignored. It has been argued that the benefits of lipophilic greater hepatoselectivity. statins may transcend into diverse adverse reactions owing to Conflicting results have been observed on the superiority their easy penetration into extrahepatic tissues. However, solid of hydrophilic or lipophilic statins regarding cardiovascular evidence is still lacking in this field (17, 28, 68). On the other outcomes, including HF and CHD, both from primary and hand, the hepatoselectivity of hydrophilic statins could also secondary prevention. In this respect, the possible superiority translate into specific organ damage, although their lower tissue of lipophilic statins seen in some studies could be explained by Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 May 2021 | Volume 8 | Article 687585 Climent et al. Hydrophilic or Lipohilic? a greater LDL cholesterol reduction with this statin type, with AUTHOR CONTRIBUTIONS the solubility profile playing a secondary role in the favourable cardiovascular outcomes observed. The first version of the manuscript was written by EC, and revised Finally, the non-selective diffusion of lipophilic statins into and approved by DB and JP-B. All authors contributed to the extrahepatic tissues could account for an increase in SAMS, albeit article and approved the submitted version. without differences between hydrophilic and lipophilic statins with respect to other adverse effects. Thus, we believe future ACKNOWLEDGMENTS studies are essential in this field for the solubility profile of statins to be taken into account when deciding on the optimal The authors thank Miss Christine O’Hara for review of the lipid-lowering therapy for each patient in daily clinical practise. English version of the manuscript. REFERENCES levels. 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