Hydrophilic or Lipophilic Statins?
Journal: 2021/June - Frontiers in Cardiovascular Medicine
Abstract:
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.
Keywords: adverse effects; cardiovascular disease; hydrophilic; lipophilic; pleiotropic effects; statins.
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Hydrophilic or Lipophilic Statins?

Statins and Heart Failure

According to the 2016 European Society of Cardiology definition (10), heart failure (HF) is a complex disease caused by structural and/or functional cardiac abnormality, resulting in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Its management is challenging owing to the clinical heterogeneity of the disease, which leads to patients responding differently to evidence-based standard therapy. Furthermore, its prevalence has suffered an exponential increase in the last decade, rendering HF a serious public health issue (11).

The role of statin therapy in HF remains controversial, with conflicting findings from observational studies and clinical trials (12, 13). Next, we will analyse its impact in two different clinical settings: the prevention of HF and the treatment of established HF.

Statins and Incident HF

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 (14, 15) or more-intensive vs. less-intensive statin therapy (1619) found an HF incidence reduction in patients with stable 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 HF prevention.

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 (20). Although the mechanisms by which statins reduce non-fatal HF hospitalisations are not well-established, the lack of a significant effect on HF mortality may be attributed to a non-ischaemic cause of death in HF patients.

More recently, Imran et al. (21), evaluating nearly 8 million subjects in an observational cohort study, reported a reduction in HF in those treated with hydrophilic compared to lipophilic statins which seemed to be driven by high-dose rather than low-dose hydrophilic statins. This was the only large cohort study using health care data designed to compare the risk of incident HF between hydrophilic and lipophilic statins.

In summary, more evidence is needed to support the use of high-intensity hydrophilic statins in the context of incident HF prevention.

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, 23).

Beside small studies with atorvastatin (lipophilic) (2426) or other statins (27) suggesting a potential benefit of these therapies in HF patients, two randomised controlled trials with rosuvastatin (hydrophilic), GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca) (28) and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) (17) were specifically conducted in an HF population. No differences in major cardiac adverse events were registered when compared to placebo; however, a reduction in HF hospitalisation was observed in CORONA. Furthermore, in a pooled analysis of both trials, Feinstein et al. (29) found a small but significant risk reduction in myocardial infarction in ischaemic HF patients treated with the hydrophilic rosuvastatin.

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. (30), including 13 studies and 10,966 patients, reported a superiority of lipophilic statins regarding all-cause mortality [odds ratio (OR) 0.50; 95% confidence interval (CI): 0.11–0.89; p = 0.01], cardiovascular mortality (OR: 0.61; 95% CI: 0.25–0.97; p = 0.009) and hospitalisation for worsening HF (OR 0.52; 95% CI, 0.21–0.83; p = 0.0005); however, both statin types were comparable for cardiovascular hospitalisation (OR: 0.80; 95% CI: 0.31–1.28; p = 0.36). Similarly, other studies also showed a greater risk reduction in HF events, hospitalisation and mortality (cardiovascular and all-cause) with lipophilic vs. hydrophilic statins (20, 3134). It has been postulated that the greater exposure of lipophilic statins in extrahepatic tissues could account for a higher uptake by cardiac muscle (35).

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. (36) in another meta-analysis with 19 randomised controlled trials and ~6,200 patients obtained more favourable results with lipophilic statins in improving cardiac function and reducing inflammation, with a greater rise in left ventricular ejection fraction. Lipophilic statins were also superior to hydrophilic rosuvastatin and pravastatin regarding B-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α reductions during follow-up. Takagi et al. (37) found lipophilic atorvastatin to be superior to hydrophilic rosuvastatin in improving cardiac function, with superiority of the former in inflammation attenuation and endothelial dysfunction, refuting previous reports, which supported the superiority of rosuvastatin in hsCRP level reductions.

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 (38, 39). In this regard, previous evidence once again showed the superiority of lipophilic atorvastatin vs. hydrophilic rosuvastatin in sympathetic nerve activity reduction in patients with HF (40). In that face-to face trial (40), 5 mg of lipophilic atorvastatin was compared to 2.5 mg of hydrophilic rosuvastatin in patients with dilated cardiomyopathy. As to lipid profile outcome, total and LDL cholesterol reductions were similar between groups. However, the atorvastatin group presented an increased heart/mediastinum ratio (which is known marker of an increased noradrenaline uptake), improved left ventricular ejection fraction, and greater reduction in BNP levels. Hence, beyond improving lipid profile, these findings emphasise the role of statins on inflammation response (41). Moreover, preclinical evidence suggests that the pleiotropic effects of statins may improve survival rates in ischaemic and non-ischaemic HF subjects by regulating the autonomic nervous system through angiotensin II and nitric oxide modulation (42). However, preliminary human studies reported mixed results. Indeed, Horwich al. (43) found that short-term statin treatment failed to result in a significant reduction in autonomic nervous system activation in HF patients. In contrast, a large meta-analysis of 13 randomised trials reported that lipophilic statins significantly lowered all-cause mortality, hospitalisation for worsening HF and LDL cholesterol, regardless of age, baseline left ventricular ejection fraction and cause of HF (32).

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 in vitro (44). Similarly, it has been speculated that lipophilic statins might inhibit CoQ10 biosynthesis, leading to disturbances in cardiac energy metabolism (45). A previous study showed that switching from lipophilic simvastatin to the hydrophilic pravastatin led to an increase in plasma adiponectinaemia with no change in LDL cholesterol concentrations (46).

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. (47) suggested that the impact of lipophilic atorvastatin was greater than that of hydrophilic rosuvastatin in HF patients with regards to the improvement in left ventricular ejection fraction and soluble suppression of tumorigenicity reduction, a novel fibrosis marker.

Finally, we believe the results of a post-hoc analysis of the CORONA trial are worth mentioning (48). Plasma galectin 3 (a mediator of fibrogenesis) levels were evaluated in subjects with established systolic HF included in the CORONA trial that were randomised to 10 mg or rosuvastatin daily or placebo. It was observed that among patients with below the median plasma concentrations of galectin 3 (≤19 ng/ml), those receiving rousvastatin treatment presented a lower primary event rate (defined as cardiovascular death, myocardial infarction or stroke), lower mortality rate and lower rate of all-cause mortality or HF hospitalisation. However, these benefits were not observed in patients with higher galectin 3 levels. Thus, these results may highlight the hypothetical role of galectin 3 to identify subjects with HF or chronic left ventricular systolic dysfuncion that might benefit of statins treatment, although further studies are required.

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.

Statins and Incident HF

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 (14, 15) or more-intensive vs. less-intensive statin therapy (1619) found an HF incidence reduction in patients with stable 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 HF prevention.

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 (20). Although the mechanisms by which statins reduce non-fatal HF hospitalisations are not well-established, the lack of a significant effect on HF mortality may be attributed to a non-ischaemic cause of death in HF patients.

More recently, Imran et al. (21), evaluating nearly 8 million subjects in an observational cohort study, reported a reduction in HF in those treated with hydrophilic compared to lipophilic statins which seemed to be driven by high-dose rather than low-dose hydrophilic statins. This was the only large cohort study using health care data designed to compare the risk of incident HF between hydrophilic and lipophilic statins.

In summary, more evidence is needed to support the use of high-intensity hydrophilic statins in the context of incident HF prevention.

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, 23).

Beside small studies with atorvastatin (lipophilic) (2426) or other statins (27) suggesting a potential benefit of these therapies in HF patients, two randomised controlled trials with rosuvastatin (hydrophilic), GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca) (28) and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) (17) were specifically conducted in an HF population. No differences in major cardiac adverse events were registered when compared to placebo; however, a reduction in HF hospitalisation was observed in CORONA. Furthermore, in a pooled analysis of both trials, Feinstein et al. (29) found a small but significant risk reduction in myocardial infarction in ischaemic HF patients treated with the hydrophilic rosuvastatin.

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. (30), including 13 studies and 10,966 patients, reported a superiority of lipophilic statins regarding all-cause mortality [odds ratio (OR) 0.50; 95% confidence interval (CI): 0.11–0.89; p = 0.01], cardiovascular mortality (OR: 0.61; 95% CI: 0.25–0.97; p = 0.009) and hospitalisation for worsening HF (OR 0.52; 95% CI, 0.21–0.83; p = 0.0005); however, both statin types were comparable for cardiovascular hospitalisation (OR: 0.80; 95% CI: 0.31–1.28; p = 0.36). Similarly, other studies also showed a greater risk reduction in HF events, hospitalisation and mortality (cardiovascular and all-cause) with lipophilic vs. hydrophilic statins (20, 3134). It has been postulated that the greater exposure of lipophilic statins in extrahepatic tissues could account for a higher uptake by cardiac muscle (35).

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. (36) in another meta-analysis with 19 randomised controlled trials and ~6,200 patients obtained more favourable results with lipophilic statins in improving cardiac function and reducing inflammation, with a greater rise in left ventricular ejection fraction. Lipophilic statins were also superior to hydrophilic rosuvastatin and pravastatin regarding B-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α reductions during follow-up. Takagi et al. (37) found lipophilic atorvastatin to be superior to hydrophilic rosuvastatin in improving cardiac function, with superiority of the former in inflammation attenuation and endothelial dysfunction, refuting previous reports, which supported the superiority of rosuvastatin in hsCRP level reductions.

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 (38, 39). In this regard, previous evidence once again showed the superiority of lipophilic atorvastatin vs. hydrophilic rosuvastatin in sympathetic nerve activity reduction in patients with HF (40). In that face-to face trial (40), 5 mg of lipophilic atorvastatin was compared to 2.5 mg of hydrophilic rosuvastatin in patients with dilated cardiomyopathy. As to lipid profile outcome, total and LDL cholesterol reductions were similar between groups. However, the atorvastatin group presented an increased heart/mediastinum ratio (which is known marker of an increased noradrenaline uptake), improved left ventricular ejection fraction, and greater reduction in BNP levels. Hence, beyond improving lipid profile, these findings emphasise the role of statins on inflammation response (41). Moreover, preclinical evidence suggests that the pleiotropic effects of statins may improve survival rates in ischaemic and non-ischaemic HF subjects by regulating the autonomic nervous system through angiotensin II and nitric oxide modulation (42). However, preliminary human studies reported mixed results. Indeed, Horwich al. (43) found that short-term statin treatment failed to result in a significant reduction in autonomic nervous system activation in HF patients. In contrast, a large meta-analysis of 13 randomised trials reported that lipophilic statins significantly lowered all-cause mortality, hospitalisation for worsening HF and LDL cholesterol, regardless of age, baseline left ventricular ejection fraction and cause of HF (32).

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 in vitro (44). Similarly, it has been speculated that lipophilic statins might inhibit CoQ10 biosynthesis, leading to disturbances in cardiac energy metabolism (45). A previous study showed that switching from lipophilic simvastatin to the hydrophilic pravastatin led to an increase in plasma adiponectinaemia with no change in LDL cholesterol concentrations (46).

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. (47) suggested that the impact of lipophilic atorvastatin was greater than that of hydrophilic rosuvastatin in HF patients with regards to the improvement in left ventricular ejection fraction and soluble suppression of tumorigenicity reduction, a novel fibrosis marker.

Finally, we believe the results of a post-hoc analysis of the CORONA trial are worth mentioning (48). Plasma galectin 3 (a mediator of fibrogenesis) levels were evaluated in subjects with established systolic HF included in the CORONA trial that were randomised to 10 mg or rosuvastatin daily or placebo. It was observed that among patients with below the median plasma concentrations of galectin 3 (≤19 ng/ml), those receiving rousvastatin treatment presented a lower primary event rate (defined as cardiovascular death, myocardial infarction or stroke), lower mortality rate and lower rate of all-cause mortality or HF hospitalisation. However, these benefits were not observed in patients with higher galectin 3 levels. Thus, these results may highlight the hypothetical role of galectin 3 to identify subjects with HF or chronic left ventricular systolic dysfuncion that might benefit of statins treatment, although further studies are required.

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.

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, 50).

Primary CHD Prevention

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 (4). Furthermore, a 2013 Cochrane analysis corroborated these findings with a 14% reduction (OR: 0.86, 95% CI: 0.79–0.94) in all-cause mortality and 25% (RR: 0.75, 95% CI: 0.70–0.81) in cardiovascular events (51).

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 (4) included some studies that compared various statin types; however, the differences observed in cardiovascular outcomes were attributed to statin potency (intensive vs. less intensive), and no mention was made of the solubility profile resulting in more favourable outcomes.

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) (5259).

Table 2

Trials comparing hydrophilic and lipophilic statins and coronary artery disease.

Study (reference)Study designFollow-up (months)Trial comparisonPrimary endpointsMain results
PROVE IT-TIMI 22 (52)RCT, double-blind24Pravastatin 40 mg vs. atorvastatin 80 mgMACEMACE 26.3% after pravastatin and 22.4% after atorvastatin; p = 0.005
REVERSAL (53)RCT, double-blind18Atorvastatin 80 mg vs. pravastatin 40 mgPercentage change in total atheroma volumeSignificantly lower progression rate of atheroma volume in atorvastatin group (p = 0.02). Coronary 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, double-blind12Atorvastatin 80 mg vs. pravastatin 40 mgTotal duration of ischaemia on 48 h holter- monitorAbsolute change from baseline in total duration of ischaemia at month 12 significantly reduced in both 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 (55)RCT, double-blind24Lipophilic (atorvastatin, simvastatin, pitavastatin, fluvastatin) vs. hydrophilic (pravastatin)CV death, non-fatal MI, recurrent acute myocardial ischaemiaAlthough LDL cholesterol was reduced more potently in the lipophilic group (−34 vs. −19%; p = 0.0069), ACS tended to occur less frequently (3.6 vs. 9.9%; p = 0.0530) and the incidence of new Q-wave in ECG was significantly lower (75 vs. 89%; p = 0.0056) in the hydrophilic group.
CENTAURUS (56)RCT, double-blind parallel group trial3Atorvastatin 80 mg vs. rosuvastatin 20 mgPercentage change in ApoB/ApoA-1 ratioRosuvastatin 20 mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (−44.4 vs. −42.9%, p = 0.02), but not at 3 months (both −44.4%, p = 0.87).
LUNAR (57)RCT, open-label, parallel group trial3Atorvastatin 80 mg vs. rosuvastatin 20–40 mgChange in LDL cholesterolRosuvastatin 40 mg efficacy in lowering LDL cholesterol levels was significantly greater vs. atorvastatin 80 mg (46.8 vs. 42.7% decrease, p = 0.02). Comparable 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, double-blind12Atorvastatin 80 mg vs. rosuvastatin 40 mg vs. controls on chronic statin therapy without reloadingIncidence of peri- procedural MI, MACE12 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; p = 0.003 and 25.0 vs. 6.1; p = 0.001).
At 30-day, 6- and 12-month follow-up, the incidence of 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 -label, blinded-endpoint24Atorvastatin 10–20 mg vs. pravastatin 10–20 mgAll-cause death, CV death, MI, stroke, revascularisation, hospitalisationPrimary 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; p = 0.299), whereas greater reductions in 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.

Back in 2004, the PROVE IT-TIMI 22 trial (52) compared a standard therapy of 40 mg pravastatin daily with an intensive therapy of 80 mg atorvastatin daily, observing that an intensive lipid-lowering statin strategy provided greater protection against death or major adverse cardiovascular events (MACE) than a standard regimen. Similarly to the results from observational studies, the greater LDL cholesterol reduction with lipophilic atorvastatin compared to hydrophilic pravastatin could probably account for the more favourable cardiovascular results observed in subjects receiving the former, although whether the solubility profile of each statin could also play a role in these observed differences could also be speculated.

Kim et al. (60) found a higher composite of MACE in the hydrophilic statin group at 1 and 6 months (1 month: 10.0 vs. 4.4%; p = 0.001; 6 months: 19.9 vs. 14.2%; p = 0.022), whereas no significant difference in MACE was observed at 1 year of follow-up (21.5 vs. 17.9%; p = 0.172). Both statin arms showed similar efficacy in the lipid profile and the use of a hydrophilic statin did not predict 1-year MACE, all-cause death, acute myocardial infarction or re-percutaneous coronary intervention.

To shed light on this matter, further trials such as that reported by Sakamoto et al. (55) in 2007 directly compared the lipophilics atorvastatin, fluvastatin, pitavastatin and simvastatin to hydrophilic pravastatin. Although LDL cholesterol was reduced more potently in the lipophilic than the hydrophilic groups (−34 vs. −19%; p = 0.0069), acute coronary syndromes tended to occur less frequently (3.6 vs. 9.9%; p = 0.0530) and the incidence of new a Q-wave appearance on electrocardiogram was significantly lower (75 vs. 89%; p = 0.0056) with hydrophilic pravastatin than with lipophilic statins. The CENTAURUS trial (56) also obtained more favourable results with hydrophilic statins, with rosuvastatin 20 mg being more effective than lipophilic atorvastatin 80 mg in reducing the apoB/apoA-1 ratio at 1 month (−44.4 vs. −42.9%, p = 0.02), although these results were not further confirmed with a longer follow-up. Finally, Izawa et al. (59) obtained more favourable results with hydrophilic pravastatin (MACE 30.4% after pravastatin vs. 31.4% in the atorvastatin group), although greater reductions in total and LDL cholesterol were achieved in the atorvastatin group (p < 0.001 for each).

On the other hand, the findings of Bytyçi et al. (61) between hydrophilic and lipophilic statins were comparable in terms of risk reduction for MACE (RR: 0.969; 95% CI: 0.835–1.125; p = 0.682), myocardial ischaemia (RR: 0.880; 95% CI: 0.731–1.058; p = 0.174), cardiovascular death (RR: 0.757; 95% CI: 0.486–1.180; p = 0.219) and all-cause mortality (RR: 0.797; 95% CI: 0.590–1.075; p = 0.137). However, the cardiovascular hospitalisation rate was lower (RR: 0.789; 95% CI: 0.643–0.969; p = 0.024) and alanine aminotransferase (ALT) elevation higher (RR: 2.689; 95% CI: 1.841–3.954; p < 0.001) in lipophilic- than in hydrophilic-treated patients.

With regard to coronary atherosclerosis progression/regression studies, the REVERSAL trial (53) assessed the effect of different statin regimens designed to produce intensive or moderate lipid lowering of the coronary artery atheroma burden and progression. 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. They observed that the percentage change in atheroma volume revealed a significantly lower progression rate in the lipophilic atorvastatin group compared with the hydrophilic pravastatin group (p = 0.02). However, as in the CTT meta-analysis (4), this could probably be explained by the fact that the LDL cholesterol reduction was greater in the atorvastatin than the pravastatin groups (p < 0.001), and hence the solubility profile of each statin and the possible superiority of lipophilic statins could play a secondary role in the observed differences.

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. (54) evaluated 893 outpatients with chronic stable ischaemic heart disease randomised to atorvastatin 80 mg (lipophilic) or pravastatin 40 mg (hydrophilic) and followed for 12 months. The primary efficacy parameter (absolute change from baseline in total ischaemia duration at month 12) was significantly reduced in both groups at months 3 and 12 (p < 0.001 for each treatment group) with no significant difference between treatment groups. However, atorvastatin-treated patients had greater LDL cholesterol reductions than pravastatin-treated patients, a 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). 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 (45). 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, 65).

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.

Primary CHD Prevention

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 (4). Furthermore, a 2013 Cochrane analysis corroborated these findings with a 14% reduction (OR: 0.86, 95% CI: 0.79–0.94) in all-cause mortality and 25% (RR: 0.75, 95% CI: 0.70–0.81) in cardiovascular events (51).

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 (4) included some studies that compared various statin types; however, the differences observed in cardiovascular outcomes were attributed to statin potency (intensive vs. less intensive), and no mention was made of the solubility profile resulting in more favourable outcomes.

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) (5259).

Table 2

Trials comparing hydrophilic and lipophilic statins and coronary artery disease.

Study (reference)Study designFollow-up (months)Trial comparisonPrimary endpointsMain results
PROVE IT-TIMI 22 (52)RCT, double-blind24Pravastatin 40 mg vs. atorvastatin 80 mgMACEMACE 26.3% after pravastatin and 22.4% after atorvastatin; p = 0.005
REVERSAL (53)RCT, double-blind18Atorvastatin 80 mg vs. pravastatin 40 mgPercentage change in total atheroma volumeSignificantly lower progression rate of atheroma volume in atorvastatin group (p = 0.02). Coronary 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, double-blind12Atorvastatin 80 mg vs. pravastatin 40 mgTotal duration of ischaemia on 48 h holter- monitorAbsolute change from baseline in total duration of ischaemia at month 12 significantly reduced in both 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 (55)RCT, double-blind24Lipophilic (atorvastatin, simvastatin, pitavastatin, fluvastatin) vs. hydrophilic (pravastatin)CV death, non-fatal MI, recurrent acute myocardial ischaemiaAlthough LDL cholesterol was reduced more potently in the lipophilic group (−34 vs. −19%; p = 0.0069), ACS tended to occur less frequently (3.6 vs. 9.9%; p = 0.0530) and the incidence of new Q-wave in ECG was significantly lower (75 vs. 89%; p = 0.0056) in the hydrophilic group.
CENTAURUS (56)RCT, double-blind parallel group trial3Atorvastatin 80 mg vs. rosuvastatin 20 mgPercentage change in ApoB/ApoA-1 ratioRosuvastatin 20 mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (−44.4 vs. −42.9%, p = 0.02), but not at 3 months (both −44.4%, p = 0.87).
LUNAR (57)RCT, open-label, parallel group trial3Atorvastatin 80 mg vs. rosuvastatin 20–40 mgChange in LDL cholesterolRosuvastatin 40 mg efficacy in lowering LDL cholesterol levels was significantly greater vs. atorvastatin 80 mg (46.8 vs. 42.7% decrease, p = 0.02). Comparable 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, double-blind12Atorvastatin 80 mg vs. rosuvastatin 40 mg vs. controls on chronic statin therapy without reloadingIncidence of peri- procedural MI, MACE12 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; p = 0.003 and 25.0 vs. 6.1; p = 0.001).
At 30-day, 6- and 12-month follow-up, the incidence of 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 -label, blinded-endpoint24Atorvastatin 10–20 mg vs. pravastatin 10–20 mgAll-cause death, CV death, MI, stroke, revascularisation, hospitalisationPrimary 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; p = 0.299), whereas greater reductions in 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.

Back in 2004, the PROVE IT-TIMI 22 trial (52) compared a standard therapy of 40 mg pravastatin daily with an intensive therapy of 80 mg atorvastatin daily, observing that an intensive lipid-lowering statin strategy provided greater protection against death or major adverse cardiovascular events (MACE) than a standard regimen. Similarly to the results from observational studies, the greater LDL cholesterol reduction with lipophilic atorvastatin compared to hydrophilic pravastatin could probably account for the more favourable cardiovascular results observed in subjects receiving the former, although whether the solubility profile of each statin could also play a role in these observed differences could also be speculated.

Kim et al. (60) found a higher composite of MACE in the hydrophilic statin group at 1 and 6 months (1 month: 10.0 vs. 4.4%; p = 0.001; 6 months: 19.9 vs. 14.2%; p = 0.022), whereas no significant difference in MACE was observed at 1 year of follow-up (21.5 vs. 17.9%; p = 0.172). Both statin arms showed similar efficacy in the lipid profile and the use of a hydrophilic statin did not predict 1-year MACE, all-cause death, acute myocardial infarction or re-percutaneous coronary intervention.

To shed light on this matter, further trials such as that reported by Sakamoto et al. (55) in 2007 directly compared the lipophilics atorvastatin, fluvastatin, pitavastatin and simvastatin to hydrophilic pravastatin. Although LDL cholesterol was reduced more potently in the lipophilic than the hydrophilic groups (−34 vs. −19%; p = 0.0069), acute coronary syndromes tended to occur less frequently (3.6 vs. 9.9%; p = 0.0530) and the incidence of new a Q-wave appearance on electrocardiogram was significantly lower (75 vs. 89%; p = 0.0056) with hydrophilic pravastatin than with lipophilic statins. The CENTAURUS trial (56) also obtained more favourable results with hydrophilic statins, with rosuvastatin 20 mg being more effective than lipophilic atorvastatin 80 mg in reducing the apoB/apoA-1 ratio at 1 month (−44.4 vs. −42.9%, p = 0.02), although these results were not further confirmed with a longer follow-up. Finally, Izawa et al. (59) obtained more favourable results with hydrophilic pravastatin (MACE 30.4% after pravastatin vs. 31.4% in the atorvastatin group), although greater reductions in total and LDL cholesterol were achieved in the atorvastatin group (p < 0.001 for each).

On the other hand, the findings of Bytyçi et al. (61) between hydrophilic and lipophilic statins were comparable in terms of risk reduction for MACE (RR: 0.969; 95% CI: 0.835–1.125; p = 0.682), myocardial ischaemia (RR: 0.880; 95% CI: 0.731–1.058; p = 0.174), cardiovascular death (RR: 0.757; 95% CI: 0.486–1.180; p = 0.219) and all-cause mortality (RR: 0.797; 95% CI: 0.590–1.075; p = 0.137). However, the cardiovascular hospitalisation rate was lower (RR: 0.789; 95% CI: 0.643–0.969; p = 0.024) and alanine aminotransferase (ALT) elevation higher (RR: 2.689; 95% CI: 1.841–3.954; p < 0.001) in lipophilic- than in hydrophilic-treated patients.

With regard to coronary atherosclerosis progression/regression studies, the REVERSAL trial (53) assessed the effect of different statin regimens designed to produce intensive or moderate lipid lowering of the coronary artery atheroma burden and progression. 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. They observed that the percentage change in atheroma volume revealed a significantly lower progression rate in the lipophilic atorvastatin group compared with the hydrophilic pravastatin group (p = 0.02). However, as in the CTT meta-analysis (4), this could probably be explained by the fact that the LDL cholesterol reduction was greater in the atorvastatin than the pravastatin groups (p < 0.001), and hence the solubility profile of each statin and the possible superiority of lipophilic statins could play a secondary role in the observed differences.

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. (54) evaluated 893 outpatients with chronic stable ischaemic heart disease randomised to atorvastatin 80 mg (lipophilic) or pravastatin 40 mg (hydrophilic) and followed for 12 months. The primary efficacy parameter (absolute change from baseline in total ischaemia duration at month 12) was significantly reduced in both groups at months 3 and 12 (p < 0.001 for each treatment group) with no significant difference between treatment groups. However, atorvastatin-treated patients had greater LDL cholesterol reductions than pravastatin-treated patients, a 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). 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 (45). 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, 65).

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.

Statins and Atrial Fibrillation-Related Stroke

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 (67). 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.

Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona, Spain
Department of Medicine, Universitat Autònoma de Barcelona, Campus Universitari Mar, Barcelona, Spain
Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
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
*Correspondence: Juan Pedro-Botet tac.ramtulasedcrap@02668
This article was submitted to Lipids in Cardiovascular Disease, a section of the journal Frontiers in Cardiovascular Medicine
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
Received 2021 Mar 29; Accepted 2021 Apr 28.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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. 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.

Keywords: adverse effects, cardiovascular disease, hydrophilic, lipophilic, pleiotropic effects, statins
Abstract

Acknowledgments

The authors thank Miss Christine O'Hara for review of the English version of the manuscript.

Acknowledgments

References

  • 1. Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Chabner BA, Knollman BC, editors. Goodman and Gilman's the Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; (2011) p. 17–39. [PubMed]
  • 2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. . Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. (2005) 366:1267–78. 10.1016/S0140-6736(05)67394-1 [] [[PubMed]
  • 3. Cholesterol Treatment Trialists' (CTT) CollaborationBaigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. . Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. (2010) 376:1670–81. 10.1016/S0140-6736(10)61350-5 ] [[Google Scholar]
  • 4. Cholesterol Treatment Trialists' (CTT) CollaboratorsMihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. . 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. Lancet. (2012) 380:581–90. 10.1016/S0140-6736(12)60367-5 ] [[Google Scholar]
  • 5. 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. Lancet. (2019) 393:407–15. 10.1016/S0140-6736(18)31942-1 ] [
  • 6. Egom EE, Hafeez H. Biochemistry of statins. Adv Clin Chem. (2016) 73:127–68. 10.1016/bs.acc.2015.10.005 [] [[PubMed]
  • 7. Groner J, Goepferich A, Breunig M. Atherosclerosis: conventional intake of cardiovascular drugs versus delivery using nanotechnology - a new chance for causative therapy?J Control Release. (2021) 333:536–59. 10.1016/j.jconrel.2021.03.034 [] [[PubMed]
  • 8. Nenna A, Nappi F, Larobina D, Verghi E, Chello M, Ambrosio L. Polymers and nanoparticles for statin delivery: current use and future perspectives in cardiovascular disease. Polymers. (2021) 13:711. 10.3390/polym13050711 ] [
  • 9. Wang C-Y, Liu P-Y, Liao JK. Pleiotropic effects of statin therapy. Trends Mol Med. (2008) 14:37–44. 10.1016/j.molmed.2007.11.004 ] [
  • 10. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. . 2016 ESC Guidelines for the diagnosis treatment of acute chronic heart failure: The Task Force for the diagnosis treatment of acute chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. (2016) 37:2129–200. 10.1093/eurheartj/ehw128 [] [[PubMed]
  • 11. Ponikowski P, Anker SD, AlHabib KF, Cowie MR, Force TL, Hu S, et al. . Heart failure: preventing disease and death worldwide. ESC Heart Fail. (2014) 1:4–25. 10.1002/ehf2.12005 [] [[PubMed]
  • 12. Javaheri A, Rader DJ, Javaheri S. Statin therapy in heart failure. Is it time for a second look?Hypertension. (2014) 63:909–10. 10.1161/HYPERTENSIONAHA.113.02703 [] [[PubMed]
  • 13. Chillarón JJ, Benaiges D, Climent E, Flores-Le Roux JA, Pedro-Botet J. Statins and heart failure. J Cardiol Ther. (2015) 2:405–9. 10.17554/j.issn.2309-6861.2015.02.86 [[PubMed]
  • 14. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group . Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. (1998) 339:1349–57. [[PubMed]
  • 15. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. (1997) 3:249–54. 10.1016/S1071-9164(97)90022-1 [] [[PubMed]
  • 16. Khush KK, Waters DD, Bittner V, Deedwania PC, Kastelein JJ, Lewis SJ, et al. . Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the treating to new targets (TNT) study. Circulation. (2007) 115:576–83. 10.1161/CIRCULATIONAHA.106.625574 [] [[PubMed]
  • 17. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, et al. . Rosuvastatin in older patients with systolic heart failure. N Engl J Med. (2007) 357:2248–61. 10.1056/NEJMoa0706201 [] [[PubMed]
  • 18. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. . The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. (1996) 335:1001–9. 10.1056/NEJM199610033351401 [] [[PubMed]
  • 19. Scirica BM, Morrow DA, Cannon CP, Ray KK, Sabatine MS, Jarolim P, et al. . Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol. (2006) 47:2326–31. 10.1016/j.jacc.2006.03.034 [] [[PubMed]
  • 20. Preiss D, Campbell RT, Murray HM, Ford I, Packard CJ, Sattar N, et al. . The effect of statin therapy on HF events: a collaborative meta-analysis of unpublished data from major randomized trials. Eur Heart J. (2015) 36:1536–46. 10.1093/eurheartj/ehv072 ] [
  • 21. Imran T, Wong A, Schneeweiss S, Desai RJ. Statin lipophilicity and the risk of incident heart failure. Cardiology. (2020) 145:375–83. 10.1159/000506003 [] [[PubMed]
  • 22. Krum H, McMurray JJ. Statins and chronic heart failure: do we need a large-scale outcome trial?J Am Coll Cardiol. (2002) 39:1567–73. 10.1016/S0735-1097(02)01827-2 [] [[PubMed]
  • 23. Kjekshus J, Dunselman P, Blideskog M, Eskilson C, Hjalmarson Å, McMurray JV, et al. . A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Eur J Heart Fail. (2005) 7:1059–69. 10.1016/j.ejheart.2005.09.005 [] [[PubMed]
  • 24. Wojnicz R, Wilczek K, Nowalany-Kozielska E, Szyguła-Jurkiewicz B, Nowak J, Poloński L, et al. . Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol. (2006) 97:899–904. 10.1016/j.amjcard.2005.09.142 [] [[PubMed]
  • 25. Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Schlegel TT, et al. . Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure. J Card Fail. (2008) 14:140–4. 10.1016/j.cardfail.2007.10.013 [] [[PubMed]
  • 26. Xie RQ, Cui W, Liu F, Yang C, Pei WN, Lu JC. Statin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failure. Int J Cardiol. (2010) 140:255–7. 10.1016/j.ijcard.2008.11.030 [] [[PubMed]
  • 27. Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure. Am J Cardiol. (2004) 93:1124–9. 10.1016/j.amjcard.2004.01.039 [] [[PubMed]
  • 28. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. . Effect of rosuvastatin in patients with chronic HF (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. (2008) 372:1231–9. 10.1016/S0140-6736(08)61240-4 [] [[PubMed]
  • 29. Feinstein MJ, Jhund P, Kang J, Ning H, Maggioni A, Wikstrand J, et al. . Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual-level reanalysis of CORONA and GISSI-HF. Eur J Heart Fail. (2015) 17:434–41. 10.1002/ejhf.247 [] [[PubMed]
  • 30. Bonsu KO, Reidpath DD, Kadirvelu A. Lipophilic statin versus rosuvastatin (hydrophilic) treatment for heart failure: a meta-analysis and adjusted indirect comparison of randomised trials. Cardiovasc Drugs Ther. (2016) 30:177–88. 10.1007/s10557-015-6636-z [] [[PubMed]
  • 31. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, Abbate A, Vrtovec B, Khan BV, et al. . Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. (2009) 104:1708–16. 10.1016/j.amjcard.2009.07.055 [] [[PubMed]
  • 32. Liu G, Zheng XX, Xu YL, Lu J, Hui RT, Huang XH. Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials. Heart Lung Circ. (2014) 23:970–7. 10.1016/j.hlc.2014.05.005 [] [[PubMed]
  • 33. Zhang L, Zhang S, Jiang H, Sun A, Wang Y, Zou Y, et al. . Effects of statin therapy on inflammatory markers in chronic heart failure: a meta-analysis of randomized controlled trials. Arch Med Res. (2010) 41:464–71. 10.1016/j.arcmed.2010.08.009 [] [[PubMed]
  • 34. Zhang L, Zhang S, Jiang H, Sun A, Zou Y, Ge J. Effects of statin treatment on cardiac function in patients with chronic heart failure: a meta-analysis of randomized controlled trials. Clin Cardiol. (2011) 34:117–23. 10.1002/clc.20821 ] [
  • 35. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. (2005) 19:117–25. 10.1111/j.1472-8206.2004.00299.x [] [[PubMed]
  • 36. Bonsu KO, Reidpath DD, Kadirvelu A. Effects of statin treatment on inflammation and cardiac function in heart failure: an adjusted indirect comparison meta-analysis of randomized trials. Cardiovasc Ther. (2015) 33:338–46. 10.1111/1755-5922.12150 [] [[PubMed]
  • 37. Takagi H, Umemoto T. Atorvastatin, not rosuvastatin, improves cardiac function in heart failure: a meta-analysis of randomized trials. Int J Cardiol. (2012) 155:296–9. 10.1016/j.ijcard.2011.11.079 [] [[PubMed]
  • 38. Verberne HJBL, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. (2008) 29:1147–59. 10.1093/eurheartj/ehn113 [] [[PubMed]
  • 39. Nishiyama KTT, Tsutamoto T, Yamaji M, Kawahara C, Yamamoto T, Fujii M, et al. . Dose-dependent prognostic effect of carvedilol in patients with chronic heart failure: special reference to transcardiac gradient of norepinephrine. Circ J. (2009) 73:2270–5. 10.1253/circj.CJ-09-0456 [] [[PubMed]
  • 40. Tsutamoto T, Sakai H, Ibe K, Yamaji M, Kawahara C, Nakae I, et al. . Effect of atorvastatin vs. rosuvastatin on cardiac sympathetic nerve activity in non-diabetic patients with dilated cardiomyopathy. Circ J. (2011) 75:2160–6. 10.1253/circj.CJ-11-0222 [] [[PubMed]
  • 41. Millar PJ, Floras JS. Statins and the autonomic nervous system. Clin Sci. (2014) 126:401–15. 10.1042/CS20130332 [] [[PubMed]
  • 42. Horwich TB, Middlekauff HR. Potential autonomic nervous system effects of statins in heart failure. Heart Fail Clin. (2008) 4:163–70. 10.1016/j.hfc.2008.01.004 ] [
  • 43. Horwich TB, Middlekauff HR, Maclellan WR, Fonarow GC. Statins do not significantly affect muscle sympathetic nerve activity in humans with nonischemic heart failure: a double-blind placebo-controlled trial. J Card Fail. (2011) 17:879–86. 10.1016/j.cardfail.2011.07.008 ] [
  • 44. Demyanets S, Kaun C, Pfaffenberger S, Hohensinner PJ, Rega G, Pammer J, et al. . Hydroxymethylglutaryl-coenzyme A reductase inhibitors induce apoptosis in human cardiac myocytes in vitro. Biochem Pharmacol. (2006) 71:1324–30. 10.1016/j.bcp.2006.01.016 [] [[PubMed]
  • 45. Ichihara K, Satoh K. Disparity between angiographic regression and clinical event rates with hydrophobic statins. Lancet. (2002) 359:2195–8. 10.1016/S0140-6736(02)09098-0 [] [[PubMed]
  • 46. Kai T, Arima S, Taniyama Y, Nakabou M, Kanamasa K. Comparison of the effect of lipophilic and hydrophilic statins on serum adiponectin levels in patients with mild hypertension and dyslipidemia: Kinki Adiponectin Interventional (KAI) Study. Clin Exp Hypertens. (2008) 30:530–40. 10.1080/10641960802251925 [] [[PubMed]
  • 47. El Said NO, El Wakeel LM, Khorshid H, Darweesh EAG, Ahmed MA. Impact of lipophilic vs hydrophilic statins on the clinical outcome and biomarkers of remodelling in heart failure patients: a prospective comparative randomized study. Br J Clin Pharmacol. (2020). 10.1111/bcp.14695. [Epub ahead of print]. [] [[PubMed]
  • 48. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, et al. . Galectin-3 predicts response to statin therapy in the controlled rosuvastatin multinational trial in heart failure (CORONA). Eur Heart J. (2012) 33:2290–6. 10.1093/eurheartj/ehs077 [] [[PubMed]
  • 49. Chitose T, Sugiyama S, Sakamoto K, Shimomura H, Yamashita T, Hokamaki J, et al. . Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction – a pilot study. Atherosclerosis. (2014) 237:251–8. 10.1016/j.atherosclerosis.2014.08.053 [] [[PubMed]
  • 50. Khurana S, Gupta S, Bhalla H, Nandwani S, Gupta V. Comparison of anti-inflammatory effect of atorvastatin with rosuvastatin in patients of acute coronary syndrome. J Pharmacol Pharmacother. (2015) 6:130–5. 10.4103/0976-500X.162011 ] [
  • 51. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. . Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. (2013) 2013:CD004816. 10.1002/14651858.CD009217.pub2 ] [
  • 52. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. . Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. (2004) 350:1495–504. 10.1056/NEJMoa040583 [] [[PubMed]
  • 53. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. . Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. (2004) 291:1071–80. 10.1001/jama.291.9.1071 [] [[PubMed]
  • 54. Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D, et al. . Effects of intensive versus moderate lipidlowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation. (2007) 115:700–7. 10.1161/CIRCULATIONAHA.106.654756 [] [[PubMed]
  • 55. Sakamoto T, Kojima S, Ogawa H, Shimomura H, Kimura K, Ogata Y, et al. . Usefulness of hydrophilic vs lipophilic statins after acute myocardial infarction: subanalysis of MUSASHI-AMI. Circ J. (2007) 71:1348–53. 10.1253/circj.71.1348 [] [[PubMed]
  • 56. Lablanche JM, Leone A, Merkely B, Morais J, Alonso J, Santini M, et al. . Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing apolipoprotein B/apolipoprotein A-1 ratio in patients with acute coronary syndrome: results of the CENTAURUS study. Arch Cardiovasc Dis. (2010) 103:160–9. 10.1016/j.acvd.2010.01.005 [] [[PubMed]
  • 57. Pitt B, Loscalzo J, Monyak J, Miller E, Raichlen J. Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). Am J Cardiol. (2012) 109:1239–46. 10.1016/j.amjcard.2011.12.015 [] [[PubMed]
  • 58. Sardella G, Lucisano L, Mancone M, Conti G, Calcagno S, Stio RE, et al. . Comparison of high reloading rosuvastatin and atorvastatin pretreatment in patients undergoing elective PCI to reduce the incidence of myocardial periprocedural necrosis. The ROMA II trial. Int J Cardiol. (2013) 168:3715–20. 10.1016/j.ijcard.2013.06.017 [] [[PubMed]
  • 59. Izawa A, Kashima Y, Miura T, Ebisawa S, Kitabayashi H, Yamamoto H, et al. . Assessment of lipophilic vs hydrophilic statin therapy in acute myocardial infarction – ALPS-AMI study. Circ J. (2015) 79:161–8. 10.1253/circj.CJ-14-0877 [] [[PubMed]
  • 60. Kim MC, Ahn Y, Jang SY, Cho KH, Hwang SH, Lee MG, et al. . Comparison of clinical outcomes of hydrophilic and lipophilic statins in patients with acute myocardial infarction. Korean J Intern Med. (2011) 26:294–303. 10.3904/kjim.2011.26.3.294 ] [
  • 61. Bytyçi I, Bajraktari G, Bhatt DL, Morgan CJ, Ahmed A, Aronow WS, et al. . Hydrophilic vs lipophilic statins in coronary artery disease: a meta-analysis of randomized controlled trials. J Clin Lipidol. (2017) 11:624–37. 10.1016/j.jacl.2017.03.003 [] [[PubMed]
  • 62. Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J. (2010) 74:818–26. 10.1253/circj.CJ-10-0110 ] [
  • 63. Bulhak AA, Gourine AV, Gonon AT, Sjoquist PO, Valen G, Pernow J. Oral pre- treatment with rosuvastatin protects porcine myocardium from ischaemia/reperfusion injury via a mechanism related to nitric oxide but not to serum cholesterol level. Acta Physiol Scand. (2005) 183:151–9. 10.1111/j.1365-201X.2004.01392.x [] [[PubMed]
  • 64. Wolfrum S, Grimm M, Heidbreder M, Dendorfer A, Katus HA, Liao JK, et al. . Acute reduction of myocardial infarct size by a hydroxymethyl glutaryl coenzyme A reductase inhibitor is mediated by endothelial nitric oxide synthase. J Cardiovasc Pharmacol. (2003) 41:474–80. 10.1097/00005344-200303000-00017 [] [[PubMed]
  • 65. Sahebkar A, Kotani K, Serban C, Ursoniu S, Mikhailidis DP, Jones SR, et al. . Statin therapy reduces plasma endothelin-1 concentrations: a meta-analysis of 15 randomized controlled trials. Atherosclerosis. (2015) 241:433–42. 10.1016/j.atherosclerosis.2015.05.022 [] [[PubMed]
  • 66. Eun MY, Jung JM, Choi KH, Seo WK. Statin effects in atrial fibrillation-related stroke: a systematic review and meta-analysis. Front Neurol. (2020) 11:589684. 10.3389/fneur.2020.589684 ] [
  • 67. Pastori D, Baratta F, Di Rocco A, Farcomeni A, Del Ben M, Angelico F, et al. . Statin use and mortality in atrial fibrillation: a systematic review and meta-analysis of 100,287 patients. Pharmacol Res. (2021) 165:105418. 10.1016/j.phrs.2021.105418 [] [[PubMed]
  • 68. Bonsu KO, Kadirvelu A, Reidpath DD. Statins in heart failure: do we need another trial?Vasc Health Risk Manag. (2013) 9:303–19. 10.2147/VHRM.S44499 ] [
  • 69. McKenney JM. Pharmacologic characteristics of statins. Clin Cardiol. (2003) 26 (4 Suppl. 3):III32–38. 10.1002/clc.4960261507 ] [
  • 70. Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, et al. . Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. (2015) 11:1–23. 10.5114/aoms.2015.49807 ] [
  • 71. Mueller AM, Liakoni E, Schneider C, Burkard T, Jick SS, Krähenbühl S, et al. . The risk of muscular events among new users of hydrophilic and lipophilic statins: an observational cohort study. J Gen Intern Med. (2021). 10.1007/s11606-021-06651-6. [Epub ahead of print]. [] [[PubMed]
  • 72. Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, et al. . Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms?Drug Discov Today. (2017) 22:85–96. 10.1016/j.drudis.2016.09.001 [] [[PubMed]
  • 73. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther. (2005) 19:403–14. 10.1007/s10557-005-5686-z [] [[PubMed]
  • 74. Climent E, Benaiges D, Pedro-Botet J. Statin treatment and increased diabetes risk. Possible mechanisms. Clin Investig Arterioscler. (2019) 31:228–32. 10.1016/j.arteri.2018.12.001 [] [[PubMed]
  • 75. Fong CW. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies. Eur J Med Chem. (2014) 85:661–74. 10.1016/j.ejmech.2014.08.037 [] [[PubMed]
  • 76. Mach F, Ray KK, Wiklund O, Corsini A, Catapano AL, Bruckert E, et al. . Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J. (2018) 39:2526–39. 10.1093/eurheartj/ehy182 ] [
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