FormalPara Key Points

The concentration of low-density lipoprotein (LDL) in the plasma is causally linked to atherosclerosis and its clinical sequelae.

The use of statins for LDL lowering has consistently been shown to reduce cardiovascular events and mortality.

Inhibition of PCSK9 with monoclonal antibodies lowers LDL with unprecedented efficacy and the results of outcomes studies are expected next year.

Before the results of outcome studies of PCSK9 inhibitors are available, we recommend their use in patients at extremely high risk of vascular events and with LDL cholesterol concentrations significantly above individual goals.

1 Introduction

Although cardiovascular disease (CVD) remains the leading cause of death worldwide, in recent years, a clear decrease in cardiovascular mortality has been observed [1, 2]. Some of the reasons for this positive development are improvements in the acute treatment of cardiovascular events as well as improved control of cardiovascular risk factors, especially hypercholesterolemia. Regulatory agencies such as the US FDA as well as various guidelines consider low-density lipoprotein cholesterol (LDL-C) a causal risk factor for CVD [3–7]. This causal association between LDL-C and CVD is supported by (1) experimental findings on the pathogenesis of atherosclerosis [8]; (2) associations between monogenic [9–17] and polygenic [18–22] hypercholesterolemia levels and cardiovascular events; (3) epidemiologic studies [23–25]; and (4) interventional studies with cholesterol-lowering agents such as the HMG-CoA-reductase-inhibitors (statins) [26–30] and other agents [24, 31, 32].

2 Guidelines for Lipid-Lowering Therapy

The European Atherosclerosis Society/European Society of Cardiology (EAS/ESC) European and American Heart Association/American College of Cardiology (AHA/ACC) North American guidelines focus on LDL-C as the therapeutic target of clinical relevance [4, 6, 7]. Furthermore, they agree that the higher the risk of the patient, the more intensive the treatment should be. A recent consensus statement from the ACC and the National Lipid Association (NLA) has revised the previous “fire and forget” strategy that was focused on high-dose statin therapy. The new guidance recommends clinicians treat to individualized LDL-C targets, monitor LDL-C during therapy, use maximally tolerated doses of statins, and use combination therapy with ezetimibe as second-line and PCSK9 inhibitors as third-line therapy when LDL-C targets are not reached [33]. A decrease of LDL-C levels by about 1 mmol/l (40 mg/dl) is associated with a 22 % decrease in the relative risk for coronary events [30, 34]. This reduction occurs regardless of baseline risk. The higher the baseline risk of the patient, the higher the absolute benefits of treatment. If the risk is high, for example 25 % for a coronary event in the next 10 years, then a decrease in relative risk of 20 % translates to a decrease of the absolute risk of 5 %; that would mean 20 patients would have to be treated for 10 years to prevent one event. On the other hand, if the baseline risk is only 5 % in 10 years, the absolute risk reduction would be only 1 %, meaning that 100 patients would have to be treated for 10 years to prevent one event [35]. Moreover, the relative risk reduction achieved by a specific decrease in LDL-C levels is not the same in all age groups. It is higher in younger than in older individuals [24, 36]. Therefore, the lifetime risk and an early treatment of hypercholesterolemia are the focus of the current prevention strategies [37].

In Germany in 2009, in an effort to decrease lipid-lowering drug-related expense, it was decided that lipid-lowering treatment would be reimbursed only for individuals with a risk of experiencing a cardiovascular event in the next 10 years of ≥20 % [38]. Using this arbitrary cut-off, 90 % of the population (in which ~two-thirds of the myocardial infarctions will occur) is a priori excluded from treatment. A further substantial problem with this legislative approach is that it lacks the definition of a specific method to calculate risk.

Currently, the treatment targets proposed by the ESC and the EAS guidelines are recommended in Germany [4, 6]. They suggest four risk categories: low, moderate, high, and very high (Table 1). The LDL-C treatment targets are determined using the risk estimation system SCORE (Systematic Coronary Risk Evaluation) [39], the presence of known CVD or of markedly elevated single risk factors such as diabetes, severe hypertension, familial hypercholesterolemia, and moderate to severe chronic kidney disease (CKD). For all subjects, the LDL-C treatment target is 115 mg/dl (3.0 mmol/l), for those at high risk 100 mg/dl (2.6 mmol/l), and for those at very high risk <70 mg/dl (1.8 mmol/l) [4, 6].

Table 1 Target values for low-density lipoprotein cholesterol (LDL-C) according to the European Atherosclerosis Society/European Society of Cardiology guidelines for the management of dyslipidemias [6] and cardiovascular disease prevention [4]
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3 Drug Therapy

3.1 Statins

Statins have consistently reduced cardiovascular events and are therefore, together with lifestyle modifications, the treatment of choice [4, 6, 7, 27, 30]. However, in some cases, statin monotherapy is not sufficient. One reason for this is that statins decrease LDL-C levels in a dose-dependent but not linear manner. The doubling of a statin dose is associated with an only ~6 % further decrease in LDL-C. Figure 1 shows the degrees of LDL-C reduction achieved with various statins [26, 40, 41]. In some patients with very high untreated LDL-C levels, LDL-C treatment targets cannot be achieved, even with the highest statin doses [42]. This is very commonly seen in patients with familial hypercholesterolemia [43, 44].

Fig. 1
figure 1

Effects of statins on low-density lipoprotein cholesterol (LDL-C). X-axis: statins and their daily doses in mg. ATOR atorvastatin, FLUVA fluvastatin, LOVA lovastatin, PITA pitavastatin PRAVA pravastatin, ROSU rosuvastatin, SIMVA simvastatin [40, 41]

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Statins are generally very well tolerated, and their good safety profile has been clearly documented over the years. However, they do have potential side effects such as abdominal discomfort; small, reversible increases in the transaminases; and muscle symptoms that, when present, may limit compliance with therapy [45–47]. Muscle complaints occur in 5–30 % of statin-treated patients. Predisposing factors are older age, infections, hypothyroidism, decreased renal function, liver disease, operations and muscle trauma, diabetes, alcohol consumption, pre-existing muscle disease, or use of specific concomitant medications [45–47]. Although the vast majority of patients with statin-associated muscle symptoms can eventually tolerate a statin at a low dose, many of these patients cannot reach their LDL-C treatment targets.

Moreover, statins increase the risk of developing type 2 diabetes by ~10 % [48]. However, the decrease in total and cardiovascular mortality associated with statin use clearly outweighs the disadvantage of potentially developing diabetes. Furthermore, the benefits of statin use in patients with diabetes have also been demonstrated. Therefore, statins are indicated in all patients with diabetes.

If the LDL-C treatment target is not achieved with the maximally tolerated statin dose, a combination therapy is indicated, with ezetimibe as first choice because the combination of simvastatin and ezetimibe has been shown to decrease the risk for myocardial infarction and stroke [32]. Other options include bile acid sequestrants and fibrates. Monoclonal antibodies against PCSK9 can also be used when the LDL-C levels remain significantly above the treatment target after two (some authors propose three) statins have been tried at their maximally tolerated dose.

3.2 Ezetimibe

Ezetimibe inhibits the Niemann-Pick C1 like 1 (NPC1L1) protein, a specific transporter of cholesterol, thus reducing cholesterol and plant sterol absorption [49]. The absorption of triglycerides and fat-soluble vitamins is not affected. Ezetimibe at a dose of 10 mg per day can decrease cholesterol absorption by 50 %. However, the decrease in circulating LDL-C levels is only ~20 % because of a compensatory increase in cholesterol synthesis in the liver [50]. Ezetimibe is mainly used in combination with statins. In SHARP (Study of Heart and Renal Protection), 9270 patients with CKD received either simvastatin 20 mg plus ezetimibe 10 mg daily or placebo. LDL-C was decreased by an average of 33 mg/dl (0.85 mmol/l) and the major atherosclerotic events by 17 % [51].

In the IMPROVE-IT trial, 18,141 patients with acute coronary syndrome and LDL-C <125 mg/dl (3.2 mmol/l) were treated with simvastatin 40 mg or simvastatin 40 mg plus ezetimibe 10 mg daily. The median average LDL-C levels in the group treated with simvastatin monotherapy was 70 mg/dl (1.8 mmol/l), and in the group treated with simvastatin plus ezetimibe it was 55 mg/dl (1.63 mmol/l). The event rate for the primary endpoint, a composite of cardiovascular death, myocardial infarction, unstable angina pectoris requiring hospitalization, coronary revascularization, or stroke, at 7 years was 32.7 % in the simvastatin–ezetimibe group, and 34.7 % in the simvastatin-monotherapy group. This translates to a relative risk reduction of 6.4 % (p = 0.016) in the intention-to-treat event rate of the composite primary endpoint and is consistent with the expected effect size. There was no decrease in cardiovascular or total mortality. The combination therapy potently reduced repeated events [52]. The study shows that a decrease in LDL-C is safe and beneficial irrespective of the mechanism through which the LDL-C is being lowered.

3.3 Monoclonal Antibodies against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is synthesized mainly in the liver but also in the kidneys, small intestine, and brain. In the plasma, PCSK9 circulates either bound to LDL or as free PCSK9 and regulates the catabolism of the LDL receptors [53]. Mutations of the PCSK9 gene, which increase its function (gain of function) cause an increased catabolism of the LDL receptors and are a cause, albeit rare, of familial hypercholesterolemia [53–55]. On the other hand, other PCSK9 gene variants cause decreased function of the gene. These are associated with lower LDL-C levels than those of the general population and incur a significantly decreased risk for the development of coronary heart disease [18]. When PCSK9 binds to the LDL receptor on the liver cell surface, the receptor can no longer dissociate itself from LDL-C in the endosome and both, LDL-C and LDL receptor, are catabolized in the lysosomes [53]. This decreases the amount of LDL receptors on the liver cell surface and subsequently increases LDL-C concentrations (Fig. 2). Statins increase the secretion of PCSK9, which in vivo may decrease the effects of statins [56–60]. Therefore, it seems reasonable to combine statins with PCSK9 antibodies. There is evidence that PCSK9 may also modulate other lipoprotein receptors [53], such as the very low-density lipoprotein (VLDL) receptor, the apolipoprotein E (ApoE)-receptor 2 (LRP8), and LRP1 [61–63]. Since lipoprotein(a) can be catabolized via these receptors [64], this is one of several potential explanations why PCSK9 antibodies, unlike statins, also decrease lipoprotein(a). Another proposed explanation for this effect would be that inhibition of PCSK9 suppresses the assembly of this lipoprotein. Further beneficial effects of PCSK9 inhibition independent from its effects on the lipoprotein receptors have been postulated, such as effects on inflammation and endothelial dysfunction [65].

Fig. 2
figure 2

Mechanism of action of PCSK9 antibodies (from Catapano and Papadopoulos [118]). a LDL binds to the LDL-Rs at the cell surface. The complexes of LDL and LDL-R are concentrated in specific areas of the cell membrane, the so-called coated pits. After their internalization, LDL and LDL-R dissociate in the endosome. The LDL-R then leaves the endosome and returns to the cell membrane before the former fuses with the lysosomes. There, the protein component of LDL is hydrolyzed and the LDL-C-associated cholesterol esters are catabolized with the help of the lysosomal acid lipase into fatty acids and cholesterol. The round-trip of the LDL-R to the endosome and back to the cell surface lasts about 12 min (of which, 3 min are spent in the cell and cell membrane, respectively and 6 min in the coated pits). Each LDL-R recirculates about 100 times in its life span. Free cholesterol can be used for the synthesis of cell membranes, steroid hormones, or—in the liver—for the synthesis of bile acids. It also suppresses the expression of LDL-Rs and HMG-CoA reductase and activates ACAT, an enzyme that esterifies free cholesterol for storage. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly synthesized in the liver cells and regulates the degradation of the LDL-R. PCSK9 circulates in the blood either as free PCSK9 or bound on LDL. When PCSK9 binds to the LDL–LDL-R complex on the liver surface, a dissociation of the receptor is no longer possible, and they are both catabolized. This decreases the expression of the LDL-R and consequently increases the circulating LDL-C levels. b Monoclonal antibodies against PCSK9 bind circulating PCSK9, block the degradation of the LDL receptors, and thus increase the catabolism of LDL. LDL low-density lipoprotein, LDL-C low-density lipoprotein cholesterol, LDL-R LDL receptor

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In 2015, two fully human monoclonal antibodies against PCSK9, alirocumab and evolocumab, were approved for use in patients. They bind circulating PCSK9 (Fig. 2) and decrease LDL-C concentrations by ~50 to 60 %, triglycerides by 1–18 %, and lipoprotein(a) by 23–31 % [66–68]. Other approaches to inhibit PCSK9 are in development, such as small interfering RNA (siRNA) [66–70], antisense oligonucleotides [71–73], and competitive inhibitors [63, 74].

Alirocumab is available in doses of 75 and 150 mg every 2 weeks, and evolocumab is available in doses of 140 mg every 2 weeks or 420 mg every 4 weeks (all administered subcutaneously) (Table 2). Both antibodies have been tested for efficacy and safety in a large number of studies (Table 3). Their effects are present either as monotherapy or co-administered with other lipid-lowering medications (statins up to their maximal dose or ezetimibe), and are not affected by diet modifications. Their efficacy has been tested and proven in various populations, such as those with statin intolerance [75, 76], familial hypercholesterolemia [77, 78], or those at high cardiovascular risk [79–81]. PCSK9 antibodies are well tolerated. The most common side effects are injection site reactions, nasopharyngitis, upper respiratory tract infections, nausea, and back pain, and—in some studies—also headache and fatigue. There was a statistically non-significant trend for more neurocognitive side effects in those using monoclonal antibodies against PCSK9 than in those receiving standard therapy [81, 82]. However, until now, no correlation between LDL-C levels under treatment and neurocognitive symptoms could be established. The question whether the use of PCSK9 antibodies is associated with cognitive side effects is specifically examined in the Ebbinghaus study with evolocumab [83].

Table 2 Monoclonal antibodies against PCSK9 available in Germany
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Table 3 Phase III studies with antibodies against PCSK9
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In ODYSSEY Long Term, some effects of alirocumab on the levels of the fat-soluble vitamins E and K, which are almost exclusively transported in LDL, were observed [81]. More precisely, subjects in the group treated with alirocumab rather than those in the control group had circulating levels of vitamin E and K below the normal range; the concentrations of other fat-soluble vitamins and hormones remained unchanged. Likewise, in the DESCARTES study, absolute vitamin E levels decreased in the evolocumab-treated patients by 16 % after 52 weeks of treatment but actually increased by 19 % when normalized for cholesterol. No adverse effects were seen in steroid or gonadal hormones [84–86].

Long-term data on the safety of PCSK9 antibodies are currently sparse. However, it is reassuring that individuals who completely lack PCSK9 because of genetic mutations (loss-of function homozygotes) exhibit no pathologic phenotype, suggesting the long-term safety of very low PCSK9- and LDL-C serum concentrations [87, 88]. More information regarding the clinical efficacy and safety of PCSK9 antibodies will be provided by the long-term endpoint trials currently under way: FOURIER for evolocumab and ODYSSEY OUTCOMES for alirocumab. The results of the FOURIER trial are expected mid-2016. This study included approximately 27,000 patients who had experienced either a myocardial infarction or a stroke plus one major or at least two minor cardiovascular risk factors and LDL-C ≥70 mg/dl while receiving the maximally tolerated statin dose with or without ezetimibe. The primary endpoint is a composite of cardiovascular death, myocardial infarction, and hospitalization for unstable angina or coronary revascularization. ODYSSEY OUTCOMES included 18,000 patients with recent acute coronary syndrome. The primary endpoint is a composite of cardiovascular death, myocardial infarction, and hospitalization for unstable angina or stroke. Results are expected in 2018.

In the meantime, post hoc analyses of the phase III trials with evolocumab and alirocumab have been published and show promising findings regarding cardiovascular endpoints. In ODYSSEY Long Term, after 24 weeks of treatment, the cumulative incidence of cardiovascular events in the alirocumab group was ~50 % lower than in the group receiving standard therapy (1.7 vs. 3.3 %; hazard ratio 0.52, p = 0.02) [81]. Similar findings were shown in the post hoc analysis of the OSLER 1 and OSLER 2 studies with evolocumab. They also found a ~50 % decrease in the incidence of cardiovascular events (Fig. 3) [82]. Moreover, a recent meta-analysis of studies with PCSK9 antibodies showed a significant decrease, even in total mortality [66]. Altogether, while awaiting the results of the long-term endpoint trials, this preliminary evidence suggests one can be optimistic about the therapeutic potential of PCSK9 antibodies.

Fig. 3
figure 3

a Incidence of cardiovascular events in the OSLER studies (adapted from Sabatine et al. [82]). Cardiovascular events include death from cardiovascular causes, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. b Incidence of cardiovascular events in the ODYSSEY Long Term study (adapted from Robinson et al. [81]). Death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization

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In Germany, two monoclonal antibodies are commercially available. They are both approved for a very wide spectrum of indications (Table 2). Although the effect of PCSK9 antibodies on clinical endpoints has not yet been proven, it is very likely—based on currently available data—that they may indeed decrease cardiovascular events. Given their high cost, we consider it prudent at this point to prescribe it only for patients at very high cardiovascular risk and after all other lipid-lowering agents (at least statins and ezetimibe) have been tried at their maximally tolerated dose. Moreover, the LDL-C level should be significantly and reproducibly higher than the treatment target. Since LDL-C levels may vary between measurements because of analytical and pre-analytical factors, the LDL-C values should be measured again at least once before PCSK9 therapy is initiated.

In patients with familial hypercholesterolemia [45] without cardiovascular events, the treatment target is an LDL-C value of <100 mg/dl. In our opinion, PCSK9 antibodies should be considered if the LDL-C values are ≥160 mg/dl under maximally tolerated conventional treatment.

Figure 4 and Table 4 show, based on results of the LURIC (Ludwigshafen Risk and Cardiovascular Health) study [89], that the risk for cardiovascular death in patients with CVD particularly depends on the number of their comorbidities.

Fig. 4
figure 4

Total mortality (a) and cardiovascular mortality (b) in 2272 clinically stable subjects in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study without (n = 732) or with angiographically documented coronary heart disease (n = 1540) [89]. CVD was diagnosed if there was at least one lesion in a coronary artery that resulted in a ≥20 % reduction in lumen diameter. CVD + 0: no, CVD + 1 to CVD + 4: one to four of the following co-morbidities: familial hypercholesterolemia [90], previous myocardial infarction, diabetes mellitus [91], impaired renal function (calculated glomerular filtration rate <60 ml/min/1.72 m2) [92], moderate to severe heart failure (New York Heart Association classification III and IV). CVD cardiovascular disease

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Table 4 Total and cardiovascular mortality in 2272 clinically stable participants of the LURIC study, including patients without or with coronary heart disease (documented angiographically) [89]
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Therefore, in “secondary prevention” (patients with CVD, particularly with unequivocally diagnosed coronary heart disease), we propose treatment with PCSK9 antibodies if the LDL-C, under well-documented, maximally tolerated conventional lipid-lowering pharmacotherapy, remains ≥130 mg/dl and at least two of the following factors are present:

  • familial hypercholesterolemia [90].

  • previous myocardial infarction, clinically evident progression of coronary heart disease, or atherosclerosis of other vessels.

  • diabetes mellitus [91].

  • moderate to severe CKD (glomerular filtration rate [GFR] <60 ml/min/1.73 m2) [92].

  • heart failure (mainly ischemic) New York Heart Association (NYHA) classification III–IV.

This preliminary stratification is easy to use in clinical practice and can of course be modified in individual cases within the frame set by the approved indications for PCSK9 antibodies. For instance, patients in whom coronary heart disease progresses exceptionally quickly (e.g. repeated myocardial infarctions) and who do not reach LDL-C goals despite other lipid-lowering medicines may qualify for instant initiation of treatment. If the criteria proposed above are used, ~1 % (shaded fields in Table 5) of the patients with coronary heart disease would be considered as candidates for treatment with PCSK9 antibodies (on top of the maximally tolerated lipid-lowering therapy). Assuming a prevalence of 6 million patients with coronary heart disease in Germany [93], this would include 60,000 patients, which is approximately the patient population with an indication for LDL apheresis according to the guidance of the Federal Joint Committee.

Table 5 Distribution of low-density lipoprotein cholesterol in 1543 clinically stable patients of the LURIC study with coronary heart disease and various co-morbidities [89]
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Currently, the annual cost of PCSK9 antibody treatment in Germany is around €8500 per patient. Since even treating 60,000 patients would place a significant cost burden on the healthcare system, we sought to obtain a rough estimate of the cost effectiveness of treatment in terms of life-years saved. In this analysis, we assumed that patients with coronary heart and two comorbidities were treated either with conventional, maximal lipid-lowering therapy or, in addition, with PCSK9 antibodies. Cardiovascular mortality at 10 years was set at approximately 35 % in the conventional treatment group and 50 % lower with a PCKS9 antibody, with no effect on non-cardiovascular causes of death. We also accounted for cost savings from the prevention of non-fatal coronary and cerebrovascular events using a ratio of three non-fatal events per one fatal event and costs of €13,000 and €47,000 per non-fatal myocardial infarction or non-fatal cerebrovascular event, respectively. This provisional calculation resulted in costs per life-year saved of ~€100,000. We wish to emphasize that an in-depth health economic analysis is beyond the scope of this review article and will truly be appropriate only after the results of the ongoing outcome trials with PCSK9 antibodies have become available. In the meantime, it should be considered that the expenses for LDL apheresis, and consequentially the costs per life-years saved, are four to five times higher than for PCSK9 antibody therapy.

For both medical reasons and based on the phrasing of the Policy Methods of Contractual Medical Care (Richtlinie Methoden vertragsärztliche Versorgung) of the Federal Joint Committee (Gemeinsamer Bundesausschuss) of 16 May 2015 (http://www.g-ba.de/downloads/62-492-1022/MVV-RL_2015-02-19_iK-2016-05-16.pdf), we therefore suggest that LDL apheresis should be considered only if LDL-C cannot adequately be lowered within a period of at least 12-months during which diet, oral lipid-lowering therapy, and PCSK9 antibodies have been tried. A rather justified exception applies for patients with homozygous familial hypercholesterolemia. In these patients, LDL apheresis can be initiated before other treatments have been tried [94].

3.4 Other Lipid-Lowering Agents

Nicotinic acid is no longer available in Germany, after the studies AIM-HIGH [95] and HPS2-THRIVE (Heart Protection Study 2- Treatment of HDL [high-density lipoprotein] to Reduce the Incidence of Vascular Events) [96] showed that adding nicotinic acid to statins does not bring any significant clinical benefit to patients. Moreover, in the HPS2-THRIVE study, the group receiving nicotinic acid experienced severe side effects more often, including intracranial and gastrointestinal bleeding, myopathies, infections, and diabetes.

The orally administered bile acid sequestrants are therapeutic options for the treatment of severe hypercholesterolemia or statin intolerance. However, they are often not well tolerated because of gastrointestinal side effects. Bile acid sequestrants were evaluated in LRC-CPPT (Lipid Research Clinics Coronary Primary Prevention Trial) and were shown to reduce CVD events in the patients studied [97]. Whether the addition of bile acid sequestrants to statins reduces clinical endpoints remains unclear. Fibrates can be used as monotherapy for the treatment of hypertriglyceridemia or in combination with other lipid-lowering agents in patients with mixed dyslipidemia. The effects of fibrates on cardiovascular endpoints is disputed, but recent studies examining a potential benefit when added to statins had negative results [98]. Mipomersen is an antisense oligonucleotide against Apo-B that is administered subcutaneously and decreases LDL-C by up to 30 % [99]. It is approved in the USA but not in Europe for the treatment of homozygous hypercholesterolemia. Lomitapide is an oral inhibitor of the microsomal triglyceride transfer protein (MTP) and decreases LDL-C by ≥40 % [100]. The most important side effect of lomitapide is a considerable increase in liver fat (hepatic steatosis). It is approved only for the treatment of homozygous hypercholesterolemia both in Europe (since 2013) and in the USA (since 2012). Its effect on cardiovascular endpoints is unknown. The cholesterylester transfer protein (CETP) inhibitors were assumed to decrease cardiovascular events since they robustly increase HDL-cholesterol (HDL-C) levels. However, this hope has not been realized until now. The development of torcetrapib was stopped in 2006 after the phase III trial ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) showed that it significantly increased both total and cardiovascular mortality [101]. The endpoint trial Dal-OUTCOMES (dalcetrapib 600 mg vs. placebo in patients with acute coronary syndrome) was stopped prematurely for futility in May 2012 [102]. An endpoint trial with evacetrapib [103] was also stopped prematurely in October 2015 [104]. The REVEAL (Randomized Evaluation of the Effects Anacetrapib through Lipid modification) study with anacetrapib is ongoing [105].

4 Conclusions

Regarding LDL-C, there is compelling evidence for the ‘the lower—the better’ thesis. Statins in addition to dietary and lifestyle changes remain the primary therapeutic option to reduce LDL-C. There is now also a solid scientific basis for initiation of treatment with ezetimibe in patients who do not reach LDL-C goals with the maximally tolerated dose of a potent statin. Although endpoint studies are not yet completed, there is mounting evidence that PCSK9 antibodies markedly reduce not only LDL-C but also cardiovascular risk. However, even in the absence of the results of the long-term endpoint trials, the initiation of PCSK9 antibodies is justified and sufficiently founded in patients at very high cardiovascular risk whose serum LDL-C levels are very high despite optimal oral lipid-lowering therapy.