Statins for Cardiac and Vascular Protection During and After Cancer Therapy

Abstract

Purpose of Review

Although cancer treatments have increased overall survival rates, the cardiovascular consequences of cancer therapy place patients at an increased risk of adverse outcomes. This manuscript presents data accumulated to date regarding cardiovascular outcomes relating to the administration of 3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitor (or statin) therapy in individuals receiving potentially cardiotoxic cancer treatments.

Recent Findings

Retrospective observational studies in humans and randomized controlled trials in animals suggest that statins may reduce cancer-specific and all-cause mortality. Further, statins may attenuate cancer therapy-induced declines in left ventricular ejection fraction (LVEF) and increases in blood pressure.

Summary

Observational studies suggest a potential attenuation in LVEF decline in patients with cancer and primary or secondary indications to receive a statin for prevention of cardiovascular events. Large randomized clinical trials are warranted to understand the efficacy and potential impacts of statin class, dosage, and duration on cardiovascular outcomes in patients treated for cancer.

INTRODUCTION

An estimated one in five patients undergoing cancer therapy will develop cardiac dysfunction, with the most common being reduced left ventricular ejection fraction (LVEF) [1]. There are several proposed mechanisms by which cancer therapy alters cardiac function, including the accumulation of toxic metabolites and reactive oxygen species [2]. In turn, the number of cardiomyocytes and subsequently mitochondrial function and oxidative phosphorylation are reduced [3]. Further, mitochondrial homeostasis and integrity are impaired, contributing to central and systemic vascular dysfunction and increased cardiovascular disease (CVD) risk. Because of this, research has focused on concurrent treatments that offer cardiac and vascular protection against left ventricular (LV) and vascular dysfunction in patients receiving treatment for cancer. In fact, the American Heart Association released a statement in 2016 regarding pharmacological agents that should be considered by healthcare providers to improve the quality of care of these patients [4].

While utilized primarily to reduce cholesterol levels, 3-hydroxy-3-methylglutarylcoenzyme-A reductase inhibitor (or statin) possess pleiotropic anti-inflammatory effects [5] that may provide a benefit during cancer therapy. Indeed, several retrospective analyses in patients with cancer indicate that statin use improves overall survival odds and deceases all-cause mortality in patients with primary or secondary indication to receive a statin to prevent a subsequent cardiovascular event, such as a myocardial infarction or stroke [6–9]. However, not all studies support these beneficial effects [10,11] and few randomized control trials exist. In addition, data regarding specific cardiac outcome measures, such as LVEF, are scarce. In this review, we will summarize cardiovascular effects of statins and discuss current evidence regarding the use of statins during and following cancer therapy.

STATIN OVERVIEW

Statins are some of the most commonly prescribed medications and are a first-line pharmacotherapy for individuals with an elevated CVD risk [12,13]. Their primary use is to lower cholesterol, particularly low-density lipoprotein (LDL), via inhibition of 3-Hydroxy-3-methylglutarylcoenzyme-A reductase (HMG-CoA reductase). However, the overall beneficial effects of statins regarding reduced CVD risk are not explained solely by decreases in LDL. Interestingly, statins also inhibit pro-atherogenic Rho-kinases [14], independent of changes in cholesterol levels. Inhibition of Rho-kinases contributes to several cardiovascular protective effects, in part, through subsequent reductions in NFkB signaling. This, in turn, enhances the activity of endothelial nitric oxide synthase and increases nitric oxide (NO) bioavailability, which stimulates troponin-1 phosphorylation and myocardial relaxation [15]. Utilizing retrospective analyses, Strand et al. reported that statin initiation was associated with less long-term pathologic increase in LV mass [16]. Additionally, statins have been shown to reduce LV dysfunction in those with heart failure [17]. This suggests that statins may play a role in long-term cardiac remodeling, potentially through a NO-induced mechanism. In addition, increases in NO have been linked to decreases in vascular inflammation and endothelial dysfunction [18]. Statins also have other downstream actions, including anti-fibrotic and anti-platelet effects. Indeed, in vitro work in endothelial cells indicated that statins have protective effects against plaque angiogenesis and rupture via reductions in COX-2 and MMP-9 activity [19]. Importantly, these beneficial impacts are still observed when CVD is already present. In addition, statins improved vascular barrier function via blocking recruitment of inflammatory leukocytes and balancing the VEGFa/ANG-PT1 expression in C57BL/6 mice with ApoE −/− infarcts [20]. Taken together, the direct and indirect actions of statins result in an overall reduction of atherosclerosis and CVD risk.

Statins are classified as either lipophilic or hydrophilic. Lipophilic statins include atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, and pitavastatin, while pravastatin and rosuvastatin are hydrophilic. While these two classes of statins similarly reduce LDL levels, there is not a consensus regarding superiority for CVD prevention and or risk reduction [21]. As mentioned previously, changes in LDL levels do not account for the overall cardioprotective effects of statins. In fact, lipophilic and hydrophilic statins have different solubility, which affect metabolic processes and potentially their pleiotropic actions. Work by Godoy et al. indicated that 48 hours of atorvastatin decreased protein kinase B (Akt) whereas pravastatin increased Akt protein expression in cardiomyocytes. Further, atorvastatin inhibited while pravastatin activated mTOR signaling. In addition, atorvastatin inhibited RhoA activation to a greater extent than pravastatin [22]. These different physiological effects need to be considered, especially during concurrent treatment, such as during cancer therapy.

STATINS AND CANCER

Early research and reviews caused concerns that statins had carcinogenic effects [23]. Indeed, a population-based case-cohort study suggested that long-term statin usage (>4 years) was associated with an increased risk of colon, bladder, and lung cancer [24]. Another case-control study observed an increased risk of breast cancer in women with obesity and taking lipophilic statins [25]. However, as more observational research became available, meta-analyses demonstrated no associations between statin use and long-term cancer risk [26] or deaths [27]. Interventional trials also began to corroborate neutral effects, as neither atorvastatin nor lovastatin administration worsened mammary carcinogenesis in rats [28]. Interestingly, a paradigm shift has occurred over the past 10 years, as a growing amount of research has suggested that statins may have protective benefits against cancer. In Danish women diagnosed with Stage I-III breast cancer, simvastatin usage was related to a reduced risk of cancer recurrence [29]. Likewise, Kwan et al. found that post-diagnosis lipophilic statin treatment reduced the risk of breast cancer recurrence [30]. Interestingly, once other factors, such as age, diabetes status, and smoking habits, were controlled for, more studies started to indicate a beneficial effect of statins to reduce breast [31], prostate [32], and colorectal cancer risk [33].

Basic research models have supported that statins modify cellular signaling in an array of cancers, including but not limited to, breast [34] and bladder [35]. This is thought to be due to, in part, reduced mevalonate levels by statins. The mevalonate pathway is involved in several cellular processes, including signaling cascades, cell respiration, and glycoprotein synthesis. In fact, carcinogenic cells may depend upon metabolites of this pathway to proliferate [36,37]. Thus, statins reduce and inhibit cellular proliferation as well as increase apoptosis of cancer cells [38,39]. Importantly, these effects are thought to be specific to cancer cells and do not negatively impact healthy cells [40].

STATINS AND CANCER THERAPY

ANIMAL SUBJECTS RESEARCH.

One of the first studies to investigate the effects of statin pretreatment on cardioprotective effects was conducted in 2009 by Riad and colleagues [41]. C57BL/10 mice received doxorubicin (DOX) with or without fluvastatin (100 mg/kg/d). Five days later, the mice that received fluvastatin had attenuated cardiac mitochondrial apoptosis, reduced inflammatory responses, and overall improved LV function compared to DOX-only mice. These antioxidative and anti-inflammatory effects of fluvastatin were corroborated in another study using C57BL/6 mice, where four DOX injections with and without daily pitavastatin (3 mg/kg) treatment was administered over 4 weeks [42]. Pitavastatin attenuated DOX-induced oxidative stress and DNA damage as well as myocyte contractile dysfunction. Similarly, lovastatin (10 mg/kg) co-treatment attenuated acute anthracycline-induced cardiotoxicity in H9c2 rat cardiomyocytes [43]. More specifically, lovastatin reduced mRNA levels of pro-fibrotic and pro-inflammatory cytokines. Further, lovastatin also mitigated DOX-induced oxidative stress and decreased LV posterior wall diameter when administered three times per week for 3 months [44]. However, ejection fraction decreases were not attenuated.

Hydrophilic statins may also be cardioprotective during cancer therapy. Indeed, pre-treatment of rosuvastatin for one month prior to a single high-dose exposure of DOX mitigated the increase in systolic and diastolic blood pressure, heart rate, and caspase-3 protein levels in Wister rat cardiomyocytes compared to control [45]. Another study also identified that 4 weeks of co-administration of rosuvastatin resulted in less LV fibrosis and improved cardiac function, as determined by higher maximum LV +dP/dt and lower -dP/dt [46]. While it was beyond the scope of these studies to identify the mechanism(s) that attenuated cardiac injury and LV dysfunction, the suppression of DOX-induced oxidative stress likely played a role. Certainly, recent data suggest that rosuvastatin prevents increases in high sensitivity C-reactive protein (hsCRP) and N-terminal pro hormone B-type natriuretic peptide in Sprague Dawley rats treated with DOX and/or trastuzumab [47]. Further, rosuvastatin decreased LV end-systolic volume and the area of myocardial fibrosis compared to control. Taken together, the data produced via animal studies support that both lipophilic and hydrophilic statins offer protection against acute and chronic cardiac damage induced by cancer therapy.

HUMAN SUBJECTS RESEARCH.

Collectively, observation studies in humans has aligned with animal data in that statin usage during and following cancer therapy is associated with both cancer-specific and all-cause mortality. One of the first retrospective analyses was conducted by Seicean et al. [48]. Sixty-seven patients on continuous statin therapy were compared with 134 matched patients who were not on statins during anthracycline-based chemotherapy (Anth-bC). Cancer-related mortality as well as incident heart failure were significantly lower in the statin group compared to those who were statin naive approximately 2 years after initiating cancer treatment. These results mirror data from an observational study in which patients with breast cancer, leukemia, or lymphoma who were taking simvastatin (n=9) or atorvastatin (n=5) during Anth-bC had no changes in 6-month LVEF compared to a 7% decline in those who were not on a statin (n=37) [49]. In this study, a subset analysis highlighted that there was a statin dose-response, in which patients who were on higher dosages (40–80 mg/d) had an increase in LVEF compared to individuals on lower dosages (10 to 20 mg/d) who demonstrated a slight decrease. The individuals on statin therapy in both studies were older and often had an increased number of co-morbidities (type 2 diabetes, hypertension, dyslipidemia) compared to non-statin users.

This demographic profile was also observed in a retrospective study by Calvillo-Argüelles et al. in HER2+ breast cancer patients [50]. Despite this, patients on a statin (n=43) had a median LVEF change of 0% around 11 months following trastuzumab, while individuals not on a statin (n=86) had an absolute decline of 6%. Importantly, the difference in final LVEF remained after adjusting for potential confounders, suggesting that statin therapy was independently associated with a lower risk of cardiotoxicity. Likewise, another study showed that in patients with breast cancer, chronic statin usage protected against significant declines in LVEF 6 months after receiving DOX compared to those not receiving a statin [51]. It is important to note that these data were compared within each group (statin, non-statin) and not between, highlighting that when directly compared, there may not be a beneficial effect of statins on LVEF.

Statin use after radiation treatment in cancer patients has also been studied. A 15% relative risk reduction in cerebrovascular and cardiovascular events was observed after radiotherapy in patients with thorax and head or neck cancer, even after adjusting for several risk factors, including but not limited to age, sex, type 2 diabetes, dyslipidemia, hypertension, and heart failure [52]. While this study did not reach the statistically significant threshold for this 15% decrease, it does suggest another potential use of statins in patients treated for cancer. Additionally, these data, along with a recent meta-analysis [53], suggest that statins attenuate cardiac dysfunction and reduce CVD.

A recent retrospective cohort study included female breast cancer patients undergoing Anth-bC with or without trastuzumab [54]. Individuals were classified as statin users if at least two scripts were filled in the year prior to treatment initiation and were matched 1:1 with non-statin users. Following Anth-bC, statin users had significantly lower 5-year heart failure hospital presentations compared to non-statin users (1.2% vs 2.9%). This was also observed following Anth-bc and trastuzumab treatment, as statin users tended to have a lower overall incidence compared to non-statin exposed individuals (2.7% vs 3.7%). In a similar design, Feng and Qin [55] completed an observational study that included only females who had filled at least two statin scripts in the year prior to cancer treatment. Utilizing the Australian Cancer Database, 38,195 females with either breast cancer, colorectal cancer, or melanoma were included to investigate the impact of medication adherence. It was observed that each 10% increase in 1-year statin adherence was inversely associated with cancer-specific mortality. A strength of this study was that the type of statin (lipo- vs hydrophilic) was also characterized. Interestingly, the reduction in mortality was more pronounced in the lipophilic compared to hydrophilic statins. Similarly, lung cancer patients who were treated with statins before and after diagnosis, particularly lipophilic statins, had more protective associations compared to hydrophilic statins. However, overall all-cause mortality was comparable between the two classes of statins [56].

Not all studies agree that statins provide a cardiovascular benefit during and following cancer therapy. Indeed, a retrospective study that included patients with newly diagnosed colorectal, breast, prostate, or bladder cancer (n=17,372) did not report any improvement in 3-year cancer-specific or overall survival in individuals also on statin therapy [11]. However, a key difference in this study was that all individuals included had initiated statin use within 6 months of diagnosis. Further, the authors postulated that several prior studies were confounded by selection and immortal time biases and produced results that were favorable for statin use. Nonetheless, these data suggest that the duration of statin use prior to cancer therapy may impact cardio-protection.

One of the first randomized control trials for statin usage during cancer therapy was conducted by Acar et al [57]. Forty patients undergoing Anth-bC were randomized to 6 months of concurrent therapy (Anth-bc + 40 mg/d atorvastatin) or routine Anth-bC. Atorvastatin prevented an increase in high-sensitivity C-reactive protein, preserved ejection fraction, attenuated increases in systolic and diastolic diameters, and had a significantly smaller decrease in LVEF compared to the control. Comparable results were also observed utilizing rosuvastatin, a hydrophilic statin. Females with recently diagnosed breast cancer scheduled to undergo Anth-bC were randomized to either control on combinational therapy with rosuvastatin (20 mg/d) for 6 months. Anthr-bC negatively affected LVEF, global longitudinal strain, LV diastolic function and filling pressures, as well as left atrial diameter in the control group. However, rosuvastatin attenuated these negative effects as no significant changes were observed [58]. Taken together, these data suggest that while statins may not increase cardiovascular function, they do provide protection from cancer therapy-induced declines (Figure 1). Although, it is likely that additional cardiovascular benefits are not being captured due to the follow-up period (e.g. 6 months vs 2 years).

Figure 1.

Four studies detailing the effects of statins on left ventricular ejection fraction changes during trastuzumab with or without anthracyclines (Calvillo-Argüelles et al. [50]) or anthracycline therapy only (Acar et al. [57], Cotenimitkhun et al. [49], Nabati et al. [58]). Participants had breast cancer [49,50,58], leukemia [49], or lymphoma [49]. One study did not classify the type of cancer [57]. Data are presented as means with 95% confidence intervals. *Indicates a randomized-controlled trial. LVEF = left ventricular ejection fraction.

Although recent data surrounding the cardioprotective role of statins are promising, there is a need for more randomized clinical trials. A recently completed trial at Tampere University Hospital investigated the effects of atorvastatin (80 mg/d) administration prior to radical prostatectomy. While atorvastatin did not lower prostate cancer proliferation rate compared to control [59], post-hoc analyses indicated that atorvastatin decreased prostatic steroidomic profiles without any reported serious adverse events [60]. A phase II clinical trial (R01-HL118740) was recently completed by our lab (Hundley) and is in the process of data analysis. The PREVENT (preventing anthracycline cardiovascular toxicity with statins) study randomized females receiving Anth-bC to either a placebo or daily atorvastatin (40 mg/d) for 6 months (NCT01988571). In addition to changes in 6-month LVEF, this study conducted a follow-up visit at 24 months to investigate longer-term effects of statin co-administration during cancer therapy [61]. Two phase II clinical trials are currently being conducted and are expected to be completed in 2022 and 2023, respectively. The first is being conducted at Johns Hopkins University where females with breast cancer are openly randomized to either combinational DOX and simvastatin therapy (40 mg/d) or DOX only for 25 weeks (NCT02096588). This study will provide additional insight into changes in global longitudinal strain, tolerability and safety of simvastatin, and recurrence free survival [62]. The other is a double-blind study investigating whether daily atorvastatin preserves LVEF at 12 months in adults with Non-Hodgkin and Hodgkin lymphoma undergoing DOX (NCT02943590). This trial will also provide valuable data regarding changes in global longitudinal strain (3 months), myocardial fibrosis (6 months), and the number of cardiac events (2 years) [63].

FUTURE DIRECTIONS

Most of the work conducted with combinational statin therapy have been performed in adults with current cancer diagnoses. However, one in every 640 young adults (20–39 yr) is a survivor of a childhood malignancy [64], which further elevates CVD risks [65]. One study by Marlatt et al. investigated the impact of placebo (n=6) compared to daily atorvastatin (n=9; 40 mg/d) for 6 months in young adult survivors of childhood acute lymphoblastic leukemia or Non-Hodgkin’s lymphoma [66]. Although there were no significant treatment effects on vascular outcomes, a significant decrease in peak brachial artery flow mediated dilation was observed in the placebo group. This study was comprised of a small sample size and likely lacked overall power to detect differences between the groups. However, these data hold promise for future studies to investigate statin use in childhood cancer survivors. In addition to expanding research into this population, future research is needed in regard to combinational therapies, such as statins with metformin or hypertensive medications. As discussed previously, the majority of cancer patients studied to date have possessed indications for receiving a statin as they have several CVD risk factors, including type 2 diabetes and hypertension. These individuals receive substantive care in addition to statins and it remains uncertain as to whether therapies in addition to statins that are administered to prevent cardiovascular disease contribute to the cardiovascular benefits observed in patients receiving statins during treatment. In 12,700 high-risk prostate patients identified through the SEER-Medicare database, a statin alone or in combination with metformin reduced all-cause and prostate cancer mortality. Interestingly, the effects were more pronounced in post-diagnosis users. Further, in contrast to prior research, the effects of lipophilic compared to hydrophilic as well as low vs high potency statins were not statistically different [67]. In addition, studies in rats showed a combination of rosuvastatin with candesartan significantly attenuated worsening longitudinal strain [47]. Taken together, these data support a complementary approach in future studies to identify therapies that work in tandem to prevent and/or reduce CVD.

CONCLUSION

In conclusion, statin usage during cancer therapy appears associated with decreases in cancer-specific and all-cause mortality. Statins do not appear to increase cancer risk, are well tolerated, and have a well-documented history of reducing CVD risk. Although statins do not increase LVEF, the attenuation of LVEF declines seems present among patients with primary or secondary indications to receive a statin, independent of cancer incidence. Future research is needed in the form of randomized controlled trials to identify duration- and dosage-specific effects of statins on acute and chronic outcomes of cardiac and vascular function to reduce CVD-related deaths in cancer survivors.