The SLCO1B1 c.521T>C variant (rs4149056) is not associated with muscular symptoms or PCSK9-inhibitor prescription in patients with severe hypercholesterolemia and contemporary lipid lowering therapy.

The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i.e. one in every 250 people. As HeFH is a wellknown cause of premature coronary heart disease the rigorous treatment targets for LDL-C have been established in clinical guidelines. Their achievements, even with a high dose of high efficacy statin therapy is difficult or even impossible. New strong hypolipidaemic drugs i.e. PCSK9 inhibitors have been initiated against this chalange. Both drugs, evolocumab and alirocumab, have been extensively studied in numerous phase 2 and phase 3 trials. Fewer studies with bococizumab are available until now. The PCSK9 inhibitors, as monotherapy as well in combination with statins were associated with mean LDL-C reduction about 60%. It means that the majority of patients (70-90%) with severe hypercholesterolaemia (including HeFH), treated with statins, after addition of PCSK9 inhibitors were able to achieve an LDL-C < 2.5 mmol/L (< 100 mg/dL) or < 1.8 mmol/L (< 70 mg/dL) level. Another group of patients who may benefit from PCSK9 inhibitors include those who need lipid lowering therapy, but who are statin intolerant, especially because of statin-associated muscle symptoms (SAMS). In our statement we have accepted the diagnosis of SAMS proposed recently by European Atherosclerosis Society. Today the longest clinical trial with evolocumab (11 months) was the open OSLER study, and with alirocumab ODYSSEY LONG TERM (78 weeks). In the first one the reduction of cardiovascular events by 53% (95% Cl 22-72%) was observed, and in the second one by 48% (10-69%). Neurocognitive events were reported more frequently with both drugs than with placebo. This adverse effect will be the subject of observation in ongoing studies. We still await the results of 4 ongoing large placebo controlled phase 3 trials investigating whether PCSK9 inhibitors on background of statin therapy reduce cardiovascular events. Meanwhile evolocumab, as well as alirocumab have been accepted to use in clinical practice by European Medicine Agency. In this situation the experts of Polish Society of Cardiology have prepared the statement on the use PCSK9 inhibitors with indication in the first place for HeFH patients, statin intolerant and those at high risk who are not able to reach LDL-C target level with a high potent high dose statin.

The ability to treat dyslipidemia in patients with statin-associated muscle symptoms (SAMS) is a major clinical predicament. Alternative therapies such as low-dose statins, or other lipid-modifying therapies (LMT) such as red yeast rice, ezetimibe, or berberine, have not proven to be an adequate alternative. Additionally, comprehensive clinical trials examining alternative therapy for SAMS are lacking. The discovery and understanding of proprotein convertase subtilisin/kexin type 9 (PCSK9) activity and the effects of PCSK9 inhibitors (PCSK9i) have added significant opportunities for patients with SAMS. In this chapter we will cover the results and consequences of the PCSK9i trials and one other potential future therapy, bempedoic acid, for SAMS patients.

Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. This study is registered in clinicaltrials.gov (NCT01493648).

Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the most important causative factor of atherosclerosis and associated ischemic cardiovascular diseases. The LDL receptor (LDLR) is the preferential pathway through which LDLs are cleared from the circulation. LDLs bound to the LDLR are internalized into clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the plasma membrane. See accompanying article on page 1333 Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with elevated LDL levels and premature coronary heart disease. FH is caused primarily by mutations of the LDLR or of apolipoprotein B100 (apoB100), the protein component of LDL that interacts with the LDLR. In 2003, “gain of function” mutations on a newly identified gene, proprotein convertase subtilisin/kexin type 9 ( PCSK9), were associated with FH. In 2005, a causative association was established between “loss of function” mutations in PCSK9 and low LDLC levels in 2% of the African-American population. The coronary heart disease risk in these individuals was reduced by 88%. As a result of these landmark studies (reviewed in Reference 1), PCSK9 became the subject of intensive research to discover the underlying mechanisms. PCSK9 is a serine protease mainly expressed in the liver and the intestine. It acts by reducing the amount of LDLR in hepatocytes. This was demonstrated in vitro and in mouse models …

The effects and relative mechanisms of statin usage and withdrawal on subjective and objective muscle functions are poorly known. We investigated the associations of neuromuscular junction (NMJ) degradation to muscle impairment in older adults taking statins. We recruited male controls (n =82) and statin users (n =76) for measuring handgrip strength (HGS), body composition, gait speed, short physical performance battery (SPPB), statin-associated muscle symptoms (SAMS) and plasma c-terminal agrin fragment-22 (CAF22; a marker of NMJ degradation). The statin users were evaluated at baseline, 1 year after statin usage and 6 months after statin withdrawal. One year of statin usage was associated with lower HGS, gait speed, SPPB scores and higher SAMS scores and plasma CAF22 levels (all P <.05). Conversely, 6 months after statin withdrawal, gait speed and SPPB scores were restored with a concurrent reduction in SAMS and CAF22 levels (all P <.05). Correlation analysis revealed significant correlations of plasma CAF22 with HGS, SPPB and SAMS after statin usage and withdrawal (all P <.05). Lastly, statin withdrawal also reduced the plasma creatine kinase levels (P <.05). Altogether, statin usage was associated with muscle and physical decline and an increase in CAF22 and SAMS, which were partly restored after statin withdrawal. Our findings suggest a role for NMJ plasticity in muscle restoration following statin withdrawal.

This study aimed to investigate the impact of the latest guidelines on the real-world clinical practice of initial lipid-lowering therapy, especially on the use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in China. All adult patients diagnosed with acute myocardial infarction in our hospital between August 31, 2018, and August 31, 2020, were divided into the following 2 groups: those patients treated before the latest guideline release, and those patients treated after the release. A propensity score-matched method was used, and logistic regression was used to assess the association with intensive statin, ezetimibe and PCSK9 inhibitor usage together with treatment results between the 2 groups. A total of 325 patients were enrolled in this study, including 141 patients who were admitted before the release of the latest guideline and 184 patients who were admitted after the release. After a median follow-up time of 8.20 months, the mean low-density lipoprotein cholesterol was 1.87 ± 0.59 mmol/L (1.87 ± 0.55 in the before group vs 1.88 ± 0.62 in the after group, P = .829). After propensity score matching, the initial usage of intensive statin therapy was decreased after guideline release without statistical significance (17.00% vs 28.00%, P = .090), whereas the usage of ezetimibe and PCSK9 inhibitors was increased (19.00% vs 8.00%, P = .039; and 10.00% vs 3.00%, P = .085, respectively). In logistic regression models, the release of the guideline was associated with a statistically significantly increased use of ezetimibe (odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.21, 3.02; P = .005), a marginally decreased use of intensive statins (OR: 0.68; 95% CI: 0.45, 1.03; P = .069) and a marginally increased use of PCSK9 inhibitors (OR: 1.31; 95% CI: 0.98, 1.76; P = .068). In this single-center, real-world data analysis, after the release of the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines, an increasing number of patients with a recent acute myocardial infarction were initially receiving ezetimibe and PCSK9 inhibitors.

This article aims to review the spectrum of statin-associated muscle symptoms (SAMS), the consequences of downtitration of statin therapy on cardiovascular events, the published trials of nonstatin therapy in patients who report SAMS, and to provide a framework for future trials in SAMS patients. SAMS is reported in 10-25% of patients prescribed statin therapy; however, the few patients enrolled in randomized, double-blind, controlled clinical trials (RCTs) discontinue statin therapy due to adverse events. Several possible reasons for this discrepancy in clinical practice versus RCTs may results from patient selection in clinical trials that excludes patients with characteristics that increase the risk of SAMS, widespread use of higher intensity statins in low-risk populations that evaluated in nearly all RCTs, and perceptions concerning harm of statin therapy. Clinical trials of nonstatin therapy have shown that most patients tolerate statin therapy upon repeat challenge, and thus better tools are needed to more accurately identify SAMS patients and enroll these patients in RCTs of nonstatin therapy. Clinical trials in patients who report SAMS have shown better tolerability of certain classes of nonstatin therapy. Low rates of recurrent SAMS in double-blind rechallenge have led some to challenge the concept of statin muscle intolerance. However, patients with perceived SAMS downtitrate their statin therapy and suffer more cardiovascular events. A revised paradigm for evaluation of SAMS is proposed.

High-intensity statins are recommended for all patients with familial hypercholesterolemia (FH) and non-statin lipid lowering therapies (LLTs) are indicated when there is an inadequate response to statins 1, 2 . In the pre-PCSK9 inhibitor (PCSK9i) era only about 40% of FH patients achieved an LDL-C level 3 . Partly based on the need for additional therapeutic options in high-risk FH patients, PCSK9 inhibitors were approved for treatment of heterozygous and homozygous FH in 2015. Nevertheless, emerging anecdotal data suggest that access to non-statin LLTs has been a challenge for FH patients though this has not been systematically evaluated. The FH Optimal Care of the US (FOCUS) study was designed by The FH Foundation to assess current treatment patterns of FH patients, and allowed us to assess rejection rates of PCSK9 inhibitors in those with FH or ASCVD.

Recently, the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) published a consensus paper giving guidance on the definition and management of statin-associated muscle symptoms (SAMS), as well as the use of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in very high-risk patients. The occurrence of SAMS can have a major negative impact on treatment adherence and, consequently, on the prognosis of cardiovascular diseases. In addition, both the ESC guidelines on the prevention of cardiovascular disease (CVD) in clinical practice with sections addressing global strategies to minimise the burden of CVD at population and individual levels, and the 2016 ESC/EAS guideline for the management of dyslipidaemias, focus on evaluation and treatment of SAMS. The release of these guidelines was a source of great interest to clinicians, as new emergent therapies, such as the PCSK9 inhibitors, have been approved for the treatment of dyslipidaemias: recently, both the US Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) approved the use of PCSK9 inhibitors as add-ons for the treatment of hypercholesterolaemia in cases where low-density lipoprotein cholesterol (LDL-C) target levels could not be reached with maximum tolerated statin doses alone, or instead of statins in the event of SAMS. Because of the relatively high cost of these new therapies, physicians need to justify the use of PCSK9 inhibitors by demonstrating that their high-risk patients' LDL-C levels have remained high (1) despite a well-conducted, but insufficiently effective high-intensity statin therapy (e.g. rosuvastatin 10-20 mg or atorvastatin 40-80 mg), or (2) in the event of the patient developing side effects, in particular severe SAMS, during treatment with at least three statins. In addition to SAMS, the use of PCSK9 inhibitors may be considered in patients with documented atherosclerotic cardiovascular disease or in patients with familial hypercholesterolaemia and poorly controlled LDL-C under the combination of maximum tolerated stain and ezetimibe.

Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance.Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMGCoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies.Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effec tive therapeutic strategy for hyperlipidaemia in patients with statin intolerance.

Interactions Between Statins, Exercise, and Health: A Clinical Update

Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association

No benefit of vitamin D supplementation on muscle function and health-related quality of life in primary cardiovascular prevention patients with statin-associated muscle symptoms: A randomized controlled trial

Statin Intolerance and Noncompliance: An Empiric Approach

Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.