Abstract
Background: Statin intolerance refers to the inability of a patient to tolerate statin therapy, presenting muscle aches, pains, weakness and muscle inflammation. Thus, numerous patients are not treated with suitable statin-based therapy or take only very low doses. As a result, the desired decrease in low-density lipoprotein cholesterol (LDL-C) is not achieved, resulting in patients at a high risk for cardiovascular events, requiring an alternative lipid-lowering treatment. Common treatments manage to reduce the LDL-C level by up to 20%. Recently, new alternative treatment options have been proved to lower the LDL-C level by up to 70%. These treatment strategies are based on human monoclonal antibodies against protein convertase subtilisin/kexin 9 (PCSK9). Materials and Methods: Herein, we review the efficiency of anti-PCSK9 in treatment of hypercholesterolemic patients with statin intolerance. We focused on the use of PCSK9 inhibitors in statin-intolerant patients and we estimated the clinical results concerning the reduction of the mean LDL-C concentration and the side effects that were observed. Results: In the majority of cases, treatment strategy based on PCSK9 was successful and achieved the end-points. Conclusion: PCSK9 inhibition can be considered as a treatment of option for lipid-lowering in statin-intolerant patients.
Statin-based therapies are indicated for lowering low-density lipoprotein cholesterol (LDL-C) concentrations and are considered to be a safe option for the majority of patients with elevated LDL. However, a wide range of adverse effects have been attributed to this kind of treatment, indicating statin intolerance. Side effects derived from statin treatment in patients with statin intolerance are muscle symptoms, nausea, dyspepsia and headache and affect patients’ quality of life (1, 2). Various risk factors have been reported, setting patients at a high risk of presenting statin-induced myopathy. The most common risk factors are advanced age, frailty, genetic factors and co-morbidities (3, 4). Moreover, an important factor that affects the risk of developing myopathy is the dosage used, an increased dose results in higher risk.
Concerning the current treatment options for statin-intolerant patients, when statin-based therapy results in adverse side-effects, a washout period is recommended. If symptoms recede, a lower dose of the same statin is recommended. If the patient does not tolerate the given statin, an alternative statin should be considered. The most efficient and potent statins with a long half-life that can be recommended at low doses are atorvastatin, simvastatin, and rosuvastatin; Iess efficient drugs are fluvastatin and pravastatin (5, 6).
Additionally, non-statin therapies have been proven to lower the LDL-C level. For example, ezetimibe reduces LDL-C by 15-20%, by inactivating the Niemann-Pick C1-like 1 protein (NPC1L1) receptor, having few side-effects and being associated with reduced cardiovascular events in combination with a statin therapy (7-9). Other non-statin lipid-lowering therapies include bile acid sequestrants such as cholestyramine and colesevelam. Although these agents are poorly tolerated when they are given at increased doses, they are able to reduce the LDL-C level synergistically with statins (10).
The newest class of agents that are used in statin-intolerant patients are inhibitors of protein convertase subtilisin/kexin type 9 (PCSK9), which have been proven to significantly reduce the LDL-C level. The most commonly used drugs of this category are two monoclonal antibodies, evolocumab and alirocumab. Regarding the molecular pathway, when the LDL-C level in blood is increased, the monoclonal antibody attaches to PCSK9 and as a result, inhibits the interaction between it and the LDL receptor. PCSK9 inhibition results in increased expression of LDL receptors and therefore the LDL-C concentration is reduced. Importantly, these drugs have also been reported to reduce the rate of cardiovascular events (11-16).
The aim of this review was to investigate the utilization of PCSK9 inhibitors in statin-intolerant patients with muscle-related side-effects. The safety and the effectiveness of these agents was assessed.
Materials and Methods
This review article was based on a systematic search conducted in MEDLINE (via PubMed) library in order to retrieve articles focusing on use of PCSK9 inhibitors in statin-intolerant patients. The search strategy was based on the use of key words such as anti-PCSK9 antibodies, statin intolerance, evolocumab, alirocumab and hypercholesterolemia. A total of 61 records were identified. Some of them were only abstracts, whereas others were not completely relevant to the topic. These articles were excluded. Following removal of the duplicates, 10 records remained. The full-text articles assessed for eligibility were 10 and none of them was excluded. The inclusion process is presented in Figure 1.
PRISMA flow diagram for the current literature review.
Results
In 2012, Giugliano et al. conducted a trial in which the efficiency and the safety of evolocumab, a human monoclonal IgG2 antibody, as a PCSK9 inhibitor were assessed in statin-intolerant hypercholesterolemic patients (Table I) (17). During this study, 631 patients aged 18-80 years on a stable statin dose with hypercholesterolemia were randomly treated with subcutaneous injections of different doses of evolocumab or placebo every 2 weeks or 4 weeks. After 12 weeks, not only was the mean LDL-C level reduced but also no dose-related or dose-frequency-related increase in side-effects were reported. In contrast, in another study, although the LDL-C concentration was reduced, four serious complications were reported during the evolocumab treatment: Coronary artery disease, acute pancreatitis, hip fracture, and syncope, while myalgia was the main treatment-related side-effect during the study, occurring in 15.6% of the patients (Table I) (18).
Clinical trials conducted in the current literature review.
Another antibody to PCSK9, alirocumab, has also been investigated. Moriarty et al., presented a study in which alirocumab was compared to ezetimibe in patients at cardiovascular risk with statin intolerance due to muscle side-effects (Table I) (19). During this study, 361 patients were treated with subcutaneous and oral placebo for 4 weeks. Patients in whom muscle-related symptoms were observed were excluded. The rest of the patients were randomized to alirocumab, alirocumab plus placebo, ezetimibe, ezetimibe plus placebo, atorvastatin or atorvastatin plus placebo for 24 weeks. According to the clinical findings, alirocumab resulted in greater LDL-C reductions compared to ezetimibe in statin-intolerant patients, while fewer skeletal-muscle side-effects were observed compared to atorvastatin. In line with these findings, the ODYSSEY DM-DYSLIPIDEMIA randomized trial investigated the safety and efficiency of alirocumab in individuals with type 2 diabetes mellitus and mixed dyslipidemia taking the maximally tolerated dose of statin (Table I) (20). A total of 413 individuals were randomized to receive 75-150 mg alirocumab every 2 weeks or lipid-lowering common treatment including no additional lipid-lowering therapy, fenofibrate, ezetimibe, omega-3 fatty acid, and nicotinic acid. Alirocumab proved to be more efficient in reducing the mean non-HDL-C, LDL-C (−43.0%), apolipoprotein B (−32.3%), and total cholesterol (−24.6%). In addition, it was generally well-tolerated and the incidence of treatment-related adverse events were similar to other study cohorts.
In addition, Teramoto et al. investigated the efficiency of alirocumab in lowering LDL-C (Table I) (21). In this study, 163 patients with hypercholesterolemia were randomized to a placebo-controlled study. During the 12-week therapy period, patients will be randomized equally to receive alirocumab subcutaneously (150 mg/4 weeks), placebo (150 mg/4 weeks), alirocumab (150 mg/2 weeks), or placebo (150 mg/2 weeks). The clinical results, the safety and tolerability of alirocumab will be reported in the future.
Cho et al. conducted a trial in which evolocumab was compared to ezetimibe in hypercholesterolemic patients with statin-associated muscle symptoms (Table I) (22). During this study, 307 patients with elevated LDL-C were tested in a 12-week study. Patients were randomized to evolocumab plus ezetimibe (2: 1). The mean LDL-C level was 4.99 mmol/l. Several statin-related complications were observed: Myalgia in 80% of patients, weakness in 39%, and more serious complications in 20%. Moreover, another study group investigated the safety and efficiency of evolocumab up to 2 years in patients with statin intolerance (Table I) (23). During this study, 382 statin-intolerant patients were tested and re-randomized to evolocumab at a dose of 140 mg weekly or 420 mg monthly (2: 1) or to a standard therapy. After year 1, 98% of the patients had been treated with evolocumab plus a standard therapy. The mean LDL-C concentration was 4.97-5.02 mmol/l (range=192-194 mg/dl). A reduction of 13% was observed in patients treated with the standard therapy and 57% in patients treated with evolocumab plus standard therapy in the first year, and 59% in patients treated with evolocumab plus standard therapy in the second year. Regarding adverse effects, muscle-related events were observed in 16% of patients treated with the standard therapy, and in 14% of those treated with evolocumab plus the standard therapy at year 1, and in 11% of the patients treated with evolocumab plus the standard therapy at year 2. According to the clinical findings, evolocumab plus the standard therapy was shown to be safe, tolerable, and efficient for up to 2 years in statin-intolerant patients.
In the same year, Nissen et al., reported on the efficiency of evolocumab compared to ezetimibe in hypercholesterolemic patients during a 24-week trial (Table I) (24). Patients treated with 420 mg evolocumab monthly compared to 10 mg ezetimibe daily managed to attain LDL-C <70 mg/dl. As a result, evolocumab gave promising results compared with ezetimibe in statin-intolerant patients and allowed researchers to better understand the potential role of PCSK9 inhibitors in the treatment of these challenging patients.
Sbrana et al. enrolled 18 individuals, with a mean age of 62 years, with hypercholesterolemia, cardiovascular disease, and statin intolerance (Table I) (25). The efficiency of PCSK9 inhibitors was investigated. Evolocumab was administered to 15 patients, and alirocumab to three. After 3 months of therapy, a decrease in total cholesterol, LDL-C and Lp(a) levels was achieved. Importantly, in five patients, the level of LDL-C was reduced to <70 mg/dl, seven presented LDL-C levels between 71 and 100 mg/dl, and six continued to have LDL-C levels above 100 mg/dl. Adverse side-effects occurred in two patients treated with evolocumab. According to the results, PCSK9 inhibitors were found to be novel therapeutic tools for statin-intolerant patients with hypercholesterolemia. However, deeper investigation is needed.
Finally, Shapiro et al., conducted a trial, in which LDL-C and Lp(a) lowering by evolocumab was investigated (Table I) (26). In this study, 895 patients with hypercholesterolemia, or statin intolerance participated in a 12-week study. Baseline mean level of LDL-C was 133.6 mg/dl and the median Lp(a) level was 46.4 mg/dl. A discordant response was detected in 165 patients. Moreover, the prevalence of discordance increased when considering those with baseline Lp(a) concentrations >30 mg/dl (26.5%) or >50 mg/dl (28.6%). On the basis of these data, high prevalence of discordance in LDL-C and Lp(a) reduction in the case of evolocumab was demonstrated. As a result, evolocumab provides promising results that need further investigation.
Discussion
Statin intolerance is a common problem among patients treated with statins (27). These patients, being unable to tolerate statin therapy, present muscle-related complications. Therefore, various alternatives treatment options have been reported in order to reduce the LDL-C concentration (28-32). PCSK9 inhibitors have been shown to resulted in a decrease of LDL-C level by up to 70% and have been approved for patients with primary hypercholesterolemia, for patients with statin intolerance and for patients with atherosclerotic cardiovascular disease requiring LDL-C lowering (33, 34).
According to a published review, PCSK9 inhibitors have been a preferred treatment for patients with statin intolerance (35, 36). In particular, two monoclonal antibodies, evolocumab and alirocumab, are considered as treatment of choice, resulting in LDL-C reduction >50%. Arilocumab is associated with a low rate of muscle complications, while evolocumab is related to significantly great reduction of LDL-C concentrations without presenting muscle-related adverse events.
In a recent review, it was suggested that in patients with statin intolerance, presenting muscle pain, treatment with another statin should be recommended (37). The most effective and tolerable statins that patients can be treated with are atorvastatin and rosuvastatin. Moreover, an alternative agent for patients who are not able to tolerate any of the statins is ezetimibe. However, this review also suggests that if LDL cholesterol targets are not achieved, PCSK9 inhibitors may be a valuable option. In patients at high risk of cardiovascular events, these inhibitors can be considered as a suitable treatment tool, resulting in good results.
On the other hand, there have been reports arguing against treatment with PCSK9 inhibitors, such as evolocumab, in statin-intolerant patients (38). In these studies, it was indicated that although preliminary clinical findings were promising, long-term outcomes were controversial, as PCSK9 inhibitors have not yet been proved to reduce cardiovascular events. Moreover, it was suggested that PCSK9 inhibitors are themselves associated with muscle-related adverse effects. Additionally, PCSK9 inhibitor-based therapies are costly and, as a result, are an inappropriate treatment option. According to their findings cardiovascular and noncardiovascular mortality was reduced in patients receiving statin-based therapy, while PCSK9 inhibitors need further investigation as LDL-C lowering therapy.
Recently a review suggested that the better choice for statin-intolerant patients is the re-initiation of therapy with an alternative statin which is related to better persistence (39). Higher tolerance is linked to atorvastatin and rosuvastatin. Restarting therapy based on a different statin may allow clinicians to achieve better therapy selection. Given that statin-taking behaviors may differ, this review recommended that restarting therapy with a different statin can lead to better outcomes. However, innovative strategies need to be undertaken to improve statin compliance.
Studies that will primarily test the effects of monoclonal antibodies to PCSK9 on long-term cardiovascular results should be conducted in order to determine whether the documented LDL-C reduction and various other promising impacts on short-term clinical findings lead to long-term cardiovascular benefit (40). The promising and meaningful evidence of the clinical benefits provided of these agents should lead to cost-effectiveness analyses. Whether this treatment option is effective for cardiovascular risk reduction remains to be determined. The expected novel insights from ongoing trials will notably influence future suggestions of these promising therapies for challenging statin-intolerant patients.
Conclusion
In conclusion, numerous studies have been published about the usefulness of PCSK9 inhibition as a treatment option for lipid-lowering in statin-intolerant patients. However, further clinical trials should be conducted and deeper investigation is needed concerning the safety and the efficiency of this treatment option.
Footnotes
Authors’ Contributions
Savvanis S. and Diamantis E. designed the study. Voutyritsa E., Farmaki P. and Patsouras A. wrote the article. Voutyritsa E., Farmaki P., Diamantis E., Quiles-Sánchez LV. and Kyriakos G. collected the data. Quiles-Sánchez LV., Kyriakos G. Stelianidi A. offered scientific advice. Diamantis E., Damaskos C., Garmpi A., Garmpis N. revised the article. Savvanis S. was the supervisor.
This article is freely accessible online.
Conflicts of Interest
The Authors report no conflicts of interest in this work.
- Received August 1, 2020.
- Revision received August 31, 2020.
- Accepted September 7, 2020.
- Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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