Editorial (Thematic Issue: Novel Data on the Pathogenesis of Atherosclerosis, Treatment Targets, and New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors)

Title:Editorial (Thematic Issue: Novel Data on the Pathogenesis of Atherosclerosis, Treatment Targets, and New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors)

Volume: 20 Issue: 40

Author(s): Vasilios G. Athyros, Konstantinos Tziomalos, Niki Katsiki and Dimitri P. Mikhailidis

Affiliation:

Keywords: Cardiovascular disease, dyslipidaemia, novel lipid lowering treatments, statins, PCSK6 antibodies, microRNA, ideal CVD health.

Abstract: Cardiovascular disease (CVD) claims more lives than any other disease in the Western World [1]. In US, it is estimated that there was a decline in CVD-related deaths from 1980 to 2000 [1,2]. Nearly half (44%) of this drop resulted from population-wide risk factor reduction (smoking), whereas another (47%) resulted from medical treatment targeting patients at risk or with established atherosclerosis [1,2]. In contrast, only 5% of the reduction in deaths was estimated to be due to revascularization in patients with established CVD [1,2]. No changes in the dietary intake of fat (total, saturated and polyunsaturated) and cholesterol were recorded from 1988-1994 to 2007-2008 [3]. However, the age-adjusted use of cholesterol-lowering medications increased from 1.6 to 12.5% (P < 0.001) [3]. Data suggest that changes in dietary fat intake had minimal contribution to the observed trend in mean concentrations of total cholesterol, while the increased use of cholesterollowering medications was estimated to account for most of the change [3]. The INTERHEART study showed that 9 CVD risk factors - smoking, dyslipidemia, diabetes mellitus (DM), hypertension, abdominal obesity, stress, poor diet, physical inactivity, and excess alcohol consumption - are associated with > 90% of the CVD risk [4]. All the above suggest that despite the substantial effort to inform the public on the benefit of modifying reversible CVD risk factors this has no practical effect, because people are not keen to change their lifestyle on a longterm basis. This led the Centers for Disease Control to design the Million Hearts Initiative, an effort aimed to prevent 1 million myocardial infarctions and strokes over the next 5 years [1, 5]. Moreover, this contributed in embracing the concept of ideal CVD health by the American Heart Association (AHA) among its strategic goals for 2020 [6]. This concept was intended to focus on the promotion of a healthy lifestyle and the adoption of a multi-factorial pharmacological intervention, aimed to improve the CV health of all Americans by 20%, in order to reduce deaths from myocardial infarctions and strokes by 20% by 2020 [6]. All the above seem to have played a significant role in the composition of the new ACC/AHA lipid guidelines [7]. As stated by the authors of the guidelines, they focused on statins and only briefly mentioned other hypolipidemic drugs, because only statins have shown a clearly defined clinical benefit [7]. Also, the ACC/AHA guidelines risk assessment was based on an equation that appears to overestimate CVD risks by 75-150%, roughly doubling the actual risk [7-9]. Based on the new ACC/AHA guidelines, it is probable that 40-50% of the 46 million middle-aged Americans targeted for statin treatment by the ACC/AHA guidelines do not actually need these drugs [7,9]. It may have been the aim of the panel to protect the US population from a greater CVD incidence that is a consequence of the ever increasing prevalence of obesity [10]. By 2015, the prevalence of CVD in US will be 38% [10]. Obesity, hypertension, dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) are driving CVD risks [10]. Despite the fact that 70% of US adults are overweight or obese, diet quality continues to deteriorate, leading to the fact that at present more than half of US adults have significant lipid abnormalities [10]. All the above point to the necessity to further inform physicians about CVD risk factors and update the information on the pathogenesis and the recent (as well as the near future) advances in the treatment of dyslipidemias and atherosclerosis. In this issue of the Journal, several articles consider recent advances in novel and established CVD risk factors, mainly those related to lipids, aiming to prevent or treat fatal or non-fatal CVD. The current and future therapeutic options targeting residual CVD risk have been summarized in a multidisciplinary manner. Familial hypercholesterolemia (FH) is a fairly common hereditary lipid disorder that is characterized by a marked increase in low-density lipoprotein cholesterol (LDL-C) levels and premature CVD [11]. The diagnosis of FH is usually based on LDL-C levels, clinical signs and the family history; genetic testing can also be used to confirm the diagnosis [11]. The emphasis of treatment is now on the 4 classes of newer and promising lipid-lowering drugs already or yet to be, available for the treatment of FH. The apolipoprotein-B synthesis inhibitors (mipomersen - as a weekly subcutaneous injection), and the microsomal transfer protein inhibitors (lomitapide - oral administration) have already been approved for homozygous FH (HoFH) and are commercially available in US and Europe, but it remains uncertain whether they will obtain approval for use in patients with heterozygous FH (HeFH) or in the general population [11]. The problem with these drugs is that, besides local irritation at the injection site (for mipomersen), there exists a risk of hepatotoxicity and fat accumulation in the liver; a black box warning exists for both mipomersen and lomitapide regarding the risk for transaminase elevations and hepatic steatosis [11]. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades the LDL receptor, are in phase 3 trials, and are expected to be commercially available within the next two years [11]. At present, they seem to have an excellent safety profile, while local irritations and liver related side-effects are not reported [11]. With anti PCSK9 antibodies, the LDL receptor has a longer life and removes greater amounts of LDL-C from the blood. Evolocumab and alirocumab (PCSK9 inhibitors administered as a subcutaneous injection every 2- 4 weeks) seem to be able to treat HeFH or reduce the need for LDL apheresis in some forms of HoFH that have a degree of LDL receptor function [11]. On the other hand, specific high density lipoprotein cholesterol (HDL-C) defects may lead to atherosclerosis and in this case only genetic intervention may be of help [12]. The cholesterol ester transfer protein (CETP) inhibitors, which substantially increase HDL-C, had off-target side-effects and 2 of them (torcetrapib and dalcetrapib) have been withdrawn from phase III trials. Anacetrapib and evacetrapib continue to be investigated [12]. At present several HDL-raising agents are being evaluated, including two CETP inhibitors, gene therapies, enzyme replacement therapies, Apo AI mimetics, antagonists against some microRNAs (miRs) and peroxisome proliferator-activated receptors (PPAR)-based therapies [12]. Triglycerides (TGs) are likely to play a role in atherogenesis and significantly increase CVD risk. Hypertriglyceridemia in the fasting or postprandial state, related to a high non-HDL-C level, represents a metabolic disorder due to insulin resistant (IR) states such as inappropriate lifestyle, obesity, MetS and T2DM [13]. The latest guidelines by the Joint European Societies recognize the importance of treating hypertriglyceridemia to prevent CVD and acute pancreatitis, with fibrates being the first choice in drug therapy after lifestyle changes [13]. However, it is not only the quantity of lipid CVD risk factors that matters; the quality of lipoprotein particles also plays a role in atherogenesis. Small dense LDL (sdLDL) sub-fractions are highly atherogenic and small HDL particles may not perform reverse cholesterol transfer as effectively as other HDL fractions [14,15]. From dyslipidemia defined by the routine markers (i.e. total cholesterol, LDL-C, HDL-C and TGs) to atherosclerosis there are a number of steps involving other molecules such as lipoprotein-associated phospholipase A2 (Lp-PLA2), also named as platelet-activating factor (PAF)- acetylhydrolase [16]. Lp-PLA2 is a 45-kDa protein of 441 amino acids, and it is one of several PAF acetylhydrolases; in the blood it travels mainly with LDL, while less than 20% is associated with HDL [16]. It is an enzyme produced by inflammatory cells and it hydrolyzes oxidized phospholipids in LDL. It is considered a marker of atherosclerosis but it may also play an important role in the pathogenesis of atherogenesis [16]. An advantage of this marker is the low biological variation and high vascular specificity [16]. In contrast to LDL-Lp-PLA2, the clinical relevance of HDL-Lp-PLA2 has not been extensively explored, despite data supporting an antiatherogenic role of this enzyme. In a recent prospective study involving patients with overt CVD, HDL-Lp-PLA2 was inversely associated with future cardiac mortality, independently of conventional risk factors [16]. Specific LDL-Lp-PLA2 inhibitors are already available and are being evaluated [16]. Mixed dyslipidemia is an increasingly common lipid disorder across different ethnic groups especially with increasing IR as a result of obesity, MetS and T2DM. The presence of TG-rich lipoproteins and increased sdLDL particles, well known as the atherogenic lipid triad or dyslipidemia, is higher in many ethnic groups including Indian Asians [17]. In high risk populations, such as South Asians, where genetic factors interplay with the environment to lead to premature CVD, early and aggressive intervention is required. Awareness of the problem and lifestyle intervention such as increased physical activity and dietary modification are likely to improve the lipid profile and reduce other CVD risk factors [17]. Moreover, lipid lowering therapies have an important role especially in high risk individuals as they have been proved to reduce CVD morbidity and mortality [17]. With regard to the relation between lifestyle and CVD risk, low to moderate alcohol consumption is associated with beneficial effects on CVD risk. This effect may be mediated by reducing the risk for several metabolic diseases and modifying established and emerging vascular risk factors. In contrast, heavy and binge drinking has been related to increased risk of all the above metabolic conditions, leading to increased CVD risk [18]. Data from a plethora of studies show that apoB levels and the apoB/apoA-I ratio are strongly and independently associated with CVD risk compared with conventional lipids, lipoproteins and lipid ratios [19]. However, there are some drawbacks. ApoB has not been evaluated as a primary treatment target in statin trials, but several post-hoc analyses of statin trials suggest that apoB may not only be a risk marker but also a better treatment target than LDL-C. Also, apoB has not been included in algorithms for calculation of global risk [19]. Even after LDL-C goal attainment, there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the reninangiotensin system (RAS) was investigated. Data from clinical trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone [20]. This benefit is probably related to effects of the two drug categories on endothelial function, vascular inflammation and atheromatous plaques [20]. These effects are, at least in part, driven by mediators, the miRs, which are implicated in the pathogenesis and clinical manifestations of atherosclerosis [20]. Some miRs are favorably affected by statins and others by RAS inhibition. However, a miR family (miR-146a/b), related to coronary artery plaque destabilization is beneficially affected by the statin and RAS inhibition combination only [20]. These data suggest that statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, MetS, and/or T2DM to achieve full clinical benefit [20]. Most of the actions described above are mediated through the “pleiotropic” effects of statins. Indeed it seems that many lipid-lowering agents, mainly statins, exert anti-inflammatory, antithrombotic and antihypertensive actions, which appear to be mostly independent from their effects on the lipid profile [21]. These “pleiotropic” actions may contribute to the observed reduction in CVD events [21]. Regarding other lipid-lowering agents, it is unclear whether the effects on inflammation, thrombosis or blood pressure play a role in their antiatherogenic potential. Adherence to statin treatment is not ideal because it depends on many factors such as the health system, physician education, patient awareness and patient willingness to comply on a long-term basis [22]. Discontinuation of statins after an acute coronary event is associated with higher total mortality and this may represent a biological rebound and/or a risk-treatment mismatch phenomenon, where treatment is withdrawn from very ill patients. It is increasingly apparent that statin non-adherence is an important modifiable risk factor for CV outcomes, and all efforts should be made to improve adherence to statin therapy in both primary and secondary preventions [22]. There are several interventions targeting different barriers to statin adherence; the most successful strategy should capitalize on the physician-patient partnership, and may involve tailoring the intervention to the patient’s need and non-adherence risk assessment, as opposed to a program integrating different strategies [22]. While awaiting further research, at present statin use should only be withdrawn under judicious clinical supervision [22]. There might also be a problem with iatrogenic dyslipidemia, after administration of drugs for other diseases. Some hypoglycemic medications, most notably rosiglitazone, can be associated with dyslipidemia [23]. Antihypertensive medications reduce CVD risk, but some, such as diuretics or older beta-blockers, can cause hypertriglyceridemia [23]. Estrogens administered orally can be associated with a severe hypertriglyceridemia. Currently-used antipsychotic medications have a significant association with hypertriglyceridemia, IR, obesity, MetS and T2DM. Clinicians must be aware of the dyslipidemias caused by these medications and know how to manage them, even in many cases treating a secondary dyslipidemia with another medication as in the case of HIV infection rather than trying to switch treatment of the infection [23].All the traditional CVD risk factors such as hypertension, dyslipidemia, obesity, MetS, DM, and smoking can lead to early arterial stiffness (AS) which has been linked with an increased risk of CVD events [24]. AS increases with aging; early vascular aging is a contributor to CVD events [24]. Statins can reduce AS not only in patients with dyslipidemia but also in those with a variety of CVD risk factors, such as hypertension, obesity, MetS, and T2DM [24]. The effects of combining statins with antihypertensive drugs or other strategies to attenuate arterial aging are very promising but need further investigation [24]. Finally, the future holds significant promise [25] for example, the use of human monoclonal antibodies against PCSK9 [25,26]. These drugs are suitable for statin intolerant or resistant patients, HeFH, some forms of HoFH, increased Lp(a), and as co-administration with statins in patients that cannot reach their lipid goals [26]. Another example is silencing specific miRs, related with the pathogenesis of atherosclerosis and its clinical manifestations, using specific antisense oligonucleotides, some of which are already available at an experimental level [25,26]. Finally, repairing or silencing genes implicated in hyperlipidemia and/or atherosclerosis though genetic engineering holds promise [25,26]. This has already been carried out in animal models [25,26]. Aspects of New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors are not Covered in this Issue. It is not feasible in a single issue of the Journal to comment on all novel developments in lipid- and non- lipid-related treatment of the clinical manifestations of atherosclerosis. Some remain to be analyzed in future issues of the Journal. However, we will briefly mention some of these topics in this editorial. A major issue is the administration of statins in patients with chronic liver diseases (CLD), such as non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B (HBV), chronic hepatitis C (HCV), and primary biliary cirrhosis (PBC). Until recently this was a “forbidden fruit” [27]. However, the Liver Expert Panel of the National Lipid Association Statin Safety Task Force clearly stated that this is not so [27], and that liver-related side-effects are uncommon during statin therapy; increased serum activities of liver enzymes, mainly alanine transaminase (ALT) are reported in 0.5% of patients, while acute liver failure is seen in 1 case/1 million patient-years [27]. The incidence of these adverse effects in patients with CLD, HBV, HCV, PBC and NAFLD is likely to be low suggesting that CLD does not induce liver-related statin intolerance [27]. In fact in chronic viral hepatitis, statin treatment facilitates clearance of virus B or C by antiviral drugs, and reduces the risk for cirrhosis and hepatocellular carcinoma [28]. Statins can enhance NAFLD resolution and reduce the excess CVD risk related with NAFLD [29,30]. It has also been shown that statin therapy in patients with HBV, after the acute phase, is safe [31], while in patients with chronic HCV infection statins may contribute to the quicker clearance of the virus from the blood through the reduction of HCV mRNA [28,31]. Statins are also safe and have a beneficial effect in the prognosis of PBC [32] and they also reduce the risk of cirrhosis [27] and hepatocellular carcinoma [33]. Besides liver-related morbidity and mortality, statin treatment may also exert a substantial beneficial effect on CVD risk in patients with NAFLD [34-38]. In the GREACE (n = 1600) and ATTEMPT (n = 1,123) prospective survival studies, atorvastatin treatment not only contributed to NAFLD resolution (reduction in liver enzyme activities and ultrasonographic resolution of fatty liver), but also reduced the associated CVD risk twice as much as in those without NAFLD at baseline [34-36]. These results were supported by a post hoc analysis of the IDEAL (n = 8,888) trial [37], and by a pilot biopsy-based study with rosuvastatin monotherapy [38]. High CVD risk patients with NAFLD should probably not be deprived of statin treatment, because of the fear of liver enzyme elevation [27,35,37]. Another issue is the use of statins in elderly patients. Data suggest that statin treatment is safe in older patients and that the clinical benefit (in terms of relative risk reduction of CVD mortality as well as CVD morbidity) increases with increasing patient age [39,40]. This is because the percentage and the absolute number of CVD events prevented are increasingly higher with older patients [39]. This seems to be so even if only CVD and total mortality in the very elderly patients (>80 years old) are taken into consideration [41]. Another issue is statin administration in patients with impaired renal function. Patients with chronic kidney disease (CKD) are exposed to excess CVD risk [42], to the extent that CKD is considered as a CHD equivalent [43]. Statins are necessary in the treatment of these patients; however, most of these drugs are cleared in the kidney and should not be prescribed in patients with CKD stage 3 or greater [44]. Less than 2% of atorvastatin or fluvastatin are metabolized in the kidneys and these could be prescribed in any stage of CKD [44]. In the GREACE study, CHD patients that were not treated with a statin, glomerular filtration rate (GFR) declined over a period of 3 years, while atorvastatin treatment not only prevented this decline but significantly improved renal function, and substantially reduced the additional CVD risk, in a manner independent of its hypolipidemic effect [45]. Even the periprocedural statin administration in CVD patients undergoing percutaneous coronary intervention or CKD patients undergoing angiography, with or without intervention may prevent contrast-induced acute kidney injury [46]. The relationship between statins and CKD may be quite complex [47,48]. There is also a need to consider the role of lipid lowering drugs other than statins (e.g. ezetimibe and colesevelam) [49,50]. In conclusion, recent advances in the pathophysiology of atherosclerosis and novel drug options will result in a more effective treatment of atherosclerotic disease. Hopefully, residual CVD will decrease but it is unlikely that we will become immortal!

Cite this article as:

Athyros G. Vasilios, Tziomalos Konstantinos, Katsiki Niki and Mikhailidis P. Dimitri, Editorial (Thematic Issue: Novel Data on the Pathogenesis of Atherosclerosis, Treatment Targets, and New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors), Current Pharmaceutical Design 2014; 20 (40) . https://dx.doi.org/10.2174/1381612820666140622201940