Adverse effects of statin therapy: real evidence

Aim. To provide a current view on the tolerability and safety of statin therapy. Materials and methods. The data of 73 scientific sources from Russian and foreign literature published within 1996-2018 are considered. Results. It is generally accepted that statins are first-line therapeutic agents for hypercholesterolemia and combined hyperlipidemia. Today there in growing evidence that lowering of low-density lipoprotein cholesterol levels prevents atherosclerotic diseases and reduces a risk of cardiovascular and overall mortality. Main issues of current statin therapy include a use of inadequate dosage for atherosclerotic diseases prevention, low treatment compliance and drug intolerance. In recent years the issue of statin intolerance has become of great importance. Criteria were proposed for determining an inability to tolerate statins, some experts suggest replacing definition of “statin intolerance” with the term “statin-associated side-effects”. Most discussed adverse effects due to statins include muscle-related symptoms (myalgia/myopathy), hepatotoxicity (hepatic hyperenzymemia) new-onset diabetes, dementia and cognitive impairment. Mechanisms of development of these adverse effects are still unclear. Certain factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were established. Some factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were identified. Occurrence of statin-associated side-effects depends on statin dose, a patient's age, gender, comorbidity and concomitant therapy. Many adverse effects of statins are drug class effect. At the same time each of statins has specific features of its structure, metabolism, drug interactions and pharmacokinetics. Pitavastatin belongs to the last generation of statins and it has distinct pharmacological features and neutral diabetogenic effects, etc. Risk of adverse effects due to statins is often exaggerated while benefit from the use of statins for preventing atherosclerotic diseases outweighs potential risks. Real occurrence of some adverse effects due to statin therapy requires additional evidence. Conclusion. Overall, statins have a good tolerability profile and are approved for use in the vast majority of patients who required lipid-lowering therapy.

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Alirocoumab: new perspectives of lipid-lowering therapy

Terapevticheskii arkhiv ◽

10.17116/terarkh20178912114-121 ◽

2017 ◽

Vol 89 (12) ◽

pp. 114-121

Author(s):

Zh D Kobalava ◽

S V Villevalde ◽

M A Vorobyeva

Keyword(s):

Statin Therapy ◽

Ldl Cholesterol ◽

Human Monoclonal Antibody ◽

Secondary Analysis ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Statin Intolerance ◽

Good Tolerability ◽

Long Term Study

Alirocoumab (Praluent) is a fully human monoclonal antibody against proprotein covertase subtilisin/kexin type 9 (PCSK9). The data of ODYSSEY Phases II and III clinical trials demonstrate the high efficacy of alirocoumab in lowering the level of low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia, with a considerable advantage over control groups (placebo, ezetimibe or modified statin therapy) in both monotherapy and combination therapy with statins and other lipid-lowering agents. Alirocoumab provides additional lipid-lowering effects against other atherogenic fractions of cholesterol, including non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a). The agent show high safety and good tolerability and it can be considered as the drug of choice for patients who have not reached their target LDL cholesterol levels after statin therapy and have statin intolerance and familial heterozygous hypercholesterolemia. There are now the preliminary results of a secondary analysis of data from the ODYSSEY LONG TERM study, suggesting that alirocoumab therapy may be accompanied by a lower risk of cardiovascular events. The final results will be provided after the data of a study of cardiovascular outcomes after therapy with alirocoumab versus placebo (ODYSSEY OUTCOMES) are published.

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Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

European Heart Journal ◽

10.1093/ehjci/ehaa946.3009 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R.S Wright ◽

D Kallend ◽

F.J Raal ◽

R Stoekenbroek ◽

W Koenig ◽

...

Keyword(s):

Statin Therapy ◽

Therapeutic Option ◽

Lipid Lowering ◽

Funding Source ◽

Lipid Lowering Therapy ◽

Statin Intolerance ◽

Private Company ◽

Phase 3 ◽

Absolute Reduction ◽

Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p<0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

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Exposure to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the association with neurocognitive side effects: a meta-analysis and meta-regression

European Heart Journal ◽

10.1093/ehjci/ehaa946.3339 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

B Hirsh-Raccah ◽

A Yanovsky ◽

V Rotshild ◽

H Danenberg ◽

R Eliaz ◽

...

Keyword(s):

Side Effects ◽

Adverse Effects ◽

Meta Analysis ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Proprotein Convertase ◽

Pcsk9 Inhibitors ◽

Lowering Therapy ◽

Meta Regression ◽

Meta Analyses

Abstract Background Lipid lowering therapy may be associated with impaired cognitive function. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse effects remains unclear. Purpose To assess the neurocognitive safety of PCSK9 inhibitors using meta-analysis and meta-regression of randomized controlled trials (RCTs). Methods PubMed (MEDLINE), Embase and Cochrane library were searched. RCTs that reported assessments of neurocognitive outcomes of participants using PCSK9 inhibitors, with a duration of follow up of at least six months were included. The results of the search were screened by two independent reviewers. Any disagreements were resolved by consensus. The research was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for meta-analyses. Results were pooled using random-effects models. The primary safety outcome of this analysis was defined as the reported incidence of neurocognitive adverse effects. Results Results of 21 trials were included in the analysis. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. No significant difference in the incidence of neurocognitive side effects between the treatment and control groups was identified (RR=1.01, 95% CI: 0.86–1.19, I2=3%). Same results were seen in separate analysis for each of the medicines (Alirocumab- RR=0.88, 95% CI: 0.72–1.08, I2=0%, Evolocumab- RR=1.42, 95% CI: 0.74–2.73, I2=55%). In a meta-regression analysis there was no statistically significant association between the assessed and the risk for neurocognitive side effects. Conclusions Pooled results of our meta-analysis and meta-regression clearly show that the exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse events. Due to the increasing proportion of patients using lipid-lowering therapy these results are positively reassuring. However, more data from long-term outcomes studies is needed to further evaluate the effect of longer exposure to PCSK9 inhibitors Funding Acknowledgement Type of funding source: None

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Statin Intolerance: Diagnosis and Management

Indian Journal of Cardiovascular Disease in Women WINCARS ◽

10.1055/s-0037-1607193 ◽

2017 ◽

Vol 02 (03) ◽

pp. 014-020

Author(s):

Roopali Khanna ◽

Dandu Himanshu

Keyword(s):

Adverse Effects ◽

Clinical Symptoms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Pcsk9 Inhibitors ◽

Statin Intolerance ◽

Artery Disease ◽

Statin Dose

AbstractStatins are the main cornerstone in the treatment of coronary artery disease. Statins not only reduce the cardiovascular events but also significantly reduce the all-cause mortality. Due to adverse effects of statins, 20 to 30% of patients discontinue statins without consulting the physician. Most common adverse effects reported are muscle symptoms. Studies have shown that the majority of these patients can tolerate statin upon rechallenge. Alternative statin dosing, alternate-day statin, or twice-weekly statin dosing are different strategies to be given before changing to nonstatin lipid-lowering therapy. The newer nonstatin lipid-lowering drugs (ezetimibe, PCSK9 inhibitors) can be added if the low-density lipoprotein (LDL) target level can be achieved despite the maximally tolerated statin dose. This article reviews the etiology, clinical symptoms, and management of statin intolerance.

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The problem of safety of lipid-lowering therapy

Kardiologiia ◽

10.18087/cardio.2505 ◽

2019 ◽

Vol 59 (5S) ◽

pp. 13-26

Author(s):

M V. Zykov

Keyword(s):

Adverse Effects ◽

Renal Dysfunction ◽

Key Words ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Statin Intolerance ◽

Lowering Therapy ◽

Online Databases ◽

Highly Effective

This study focused on analysis of current publications evaluating safety of lipid-lowering therapy. Search for literature was performed on websites of cardiological societies and online databases, including PubMed, EMBASE, and eLibrary by the following key words: statins, statin intolerance, lipid-lowering therapy, statin safety, and statin аdverse effects. The focus is on statins, in view of the fact that they are the most commonly prescribed, highly effective and safe drugs for primary and secondary cardiovascular prophylaxis. This review consistently summarized information about myopathies, hepatic and renal dysfunction, potentiation of DM, and other possible adverse effects of lipid-lowering therapy. The author concluded that despite the high safety of statins acknowledged by all international cardiological societies, practicing doctors still continue unreasonably cancel statins, exposing the patient under even greater danger. Information about the corresponding author:

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Lower is better: ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy

Reviews in Health Care ◽

10.7175/rhc.v7i1.1263 ◽

2016 ◽

Vol 7 (1) ◽

pp. 17-25

Author(s):

Cezary Wójcik

Keyword(s):

Statin Therapy ◽

Heart Association ◽

Lipid Lowering ◽

Atherosclerotic Cardiovascular Disease ◽

Lipid Lowering Therapy ◽

Pcsk9 Inhibitors ◽

Level Of Evidence ◽

Cholesterol Guidelines ◽

Pcsk9 Inhibition ◽

Current Guidelines

The focus of 2013 cholesterol guidelines to prevent atherosclerotic cardiovascular disease (ASCVD) released by American College of Cardiology (ACC) and American Heart Association (AHA) is the administration of high intensity statin therapy to specific four groups of patients, which were found to benefit the most from such therapy. They no longer promote achieving specific LDL-C goals with a combination therapy involving statins and other drugs, as advocated by the former ATP-III guidelines as well as current guidelines of European Atherosclerosis Society, International Atherosclerosis Society or National Lipid Association. Such approach has been dictated by the strict reliance on randomized controlled trials as the only acceptable level of evidence. However, since publication of the 2013 ACC/AHA guidelines, cardiovascular benefits of ezetimibe added to statin therapy have been established. Moreover, the advent of PCSK9 inhibitors, providing a powerful supplement and/or alternative to statin therapy, further complicates the therapeutic horizon in dyslipdiemias. It is very likely that a new set of ACC/AHA guidelines will be published in 2016, with a return of specific LDL-C and Non-HDL-C goals of therapy as well as integration of drugs other than statins. As the treatment of dyslipidemias becomes more complex, the need for the subspecialty of clinical lipidology to be officially recognized becomes more evident.

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Abstract 13787: Efficacy of Lowering Low-density Lipoprotein Cholesterol in Elderly Subjects: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Circulation ◽

10.1161/circ.142.suppl_3.13787 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Baris Gencer ◽

Nicholas A Marston ◽

KyungAh Im ◽

Peter S Sever ◽

Anthony C Keech ◽

...

Keyword(s):

Statin Therapy ◽

Coronary Revascularization ◽

The Elderly ◽

Lipid Lowering ◽

Elderly Subjects ◽

Lipid Lowering Therapy ◽

Vascular Events ◽

Randomized Controlled ◽

Lowering Therapy ◽

Myocardial Infraction

Introduction: The clinical benefit from LDL-C lowering therapy in the elderly remains debated. Aim: To synthesize the efficacy of lowering LDL-C in patients aged ≥75 years in the light of most recently published data. Methods: Medline database was searched for the most recent evidence (2015-2020). The key inclusion criterion was a randomized controlled cardiovascular outcome trial testing an LDL-C lowering therapy with data available in patients aged ≥75 years at randomization. For efficacy, we meta-analyzed the risk ratio (RR) of major vascular events (a composite of cardiovascular (CV) death, myocardial infarction, stroke or coronary revascularization) per 1-mmol/L reduction in LDL-C. Results: Among 244,090 patients from 29 trials, 21,492 (8.8%) were elderly; 11,750 from statin trials, 6209 from ezetimibe trials, and 3533 from PCSK9 inhibitor trials. Median follow-up ranged from 2.2-6.0 years. LDL-C lowering therapy significantly reduced major vascular events (n=3519) in the elderly by 26% per 1-mmol/L LDL-C reduction (RR 0.74 [0.61-0.89], P=0.002), which was at least as good as the magnitude of effect seen in the non-elderly patients (RR 0.85 [0.78-0.92]; P interaction =0.24). Amongst the elderly, the RR was similar for statin (0.81 [0.70-0.94]) and non-statin therapy (0.67 [0.47-0.95]; P interaction =0.60). The benefit of LDL-C lowering in the elderly was observed for each component of the composite, including CV death (RR 0.85 [0.73-0.996], P=0.045), myocardial infraction (RR 0.80 [0.70-0.92], P=0.001), stroke (RR 0.71 [0.58-0.87], P=0.001) and coronary revascularization (RR 0.78 [0.63-0.96], P=0.017). Conclusion: In patients 75 years and older, lipid-lowering therapy is as effective in reducing CV events as it is in younger adults. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin therapy, in the elderly.

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Abstract 111: Assessing Statin Therapy and Lipid Profile Goals 6 Months After Percutaneous Coronary Intervention at a Veterans Hospital

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.6.suppl_1.a111 ◽

2013 ◽

Vol 6 (suppl_1) ◽

Author(s):

Dmitry Blumenkrants ◽

Saifullah M Siddiqui ◽

Karthik Challa ◽

Amit Ladani ◽

Adhir Shroff

Keyword(s):

Percutaneous Coronary Intervention ◽

Statin Therapy ◽

Coronary Intervention ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Percutaneous Coronary ◽

Core Measure ◽

Study Population ◽

Artery Disease

Background: Patients undergoing percutaneous coronary intervention (PCI) represent a high-risk cohort for cardiovascular events. Lipid lowering therapy is an established core measure of secondary prevention in coronary artery disease management. The NCEP-ATPIII advises a minimum LDL level < 100 mg/dL in patients with coronary heart disease (CHD). However, further research suggests that an LDL < 70 is more desirable in this population to further reduce adverse CHD endpoints. Methods: We conducted a retrospective, observational study on all patients undergoing PCI at an urban Veterans Hospital from September 2004 to December 2011. Statin use and lipid profiles at 6 months post-PCI were compared to pre-PCI values. Results: A total of 1052 unique patients had PCI during the study period. Approximately 70% of patients were on statins at baseline, which improved to 88% at 6 months post-PCI (p < 0.0001). LDL levels improved significantly when compared to pre-PCI levels, from a mean of 97.2 to 85.1 (p < 0.0001). With regards to NCEP-ATPIII guidelines, the proportion of the study population that met minimum LDL goals (<100) post-PCI increased from 59% to 76% (p < 0.0001). The percentage of patients meeting ideal goals for LDL (<70) increased from 23% to 33% (p < 0.0001). Conclusion: In patients who have undergone PCI, there was significant improvement in LDL levels. At six months, there was an increase in usage of statin therapy. Furthermore there was a statistically significant increase in adherence to NCEP-ATIII guidelines at both the minimum and ideal LDL levels on follow-up after PCI.

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P829The impact of APOC3 and APOE gene polymorphisms on response to statin therapy in acute myocardial infarction

European Heart Journal ◽

10.1093/eurheartj/ehz747.0428 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Teterina ◽

A Geraskin ◽

P Potapov ◽

L Babaeva ◽

A Pisaryuk ◽

...

Keyword(s):

Myocardial Infarction ◽

Statin Therapy ◽

Gene Polymorphisms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Genetic Studies ◽

Apoc3 Gene ◽

Pronounced Reduction

Abstract Background and aim Many genetic studies have been reported about the association between APOE, APOC3 gene polymorphisms and response to statin therapy in myocardial infarction, but results remain controversial. The aim of this study was to investigate the association between SNP rs7412 (APOE), rs2854117 (APOC3), rs2854116 (APOC3) and lipid-lowering effect of atorvastatin and rosuvastatin in patients with myocardial infarction. Methods Polymorphism of genes APOE (rs7412), APOC3 (rs2854117 and rs2854116) was determened. Lipid profile was determined on admission and after 1 year of treatment. Results 78 patients with myocardial infarction treated with maximal tolerated dose of atorvastatin or rosuvastatin were included. More pronounced reduction of lipid levels was associated with of T allele of rs7412 (APOE), p<0,05. ANOVA demonstrated greater low-density lipoprotein and total cholesterol decrease in patients with combination of genes CT/TT (rs7412, APOE) and CC (rs2854117, APOC3) genotypes, CT/TT (rs7412, APOE) and CT (rs2854116, APOC3) genotypes. Conclusion The genetic variants of APOC3 and APOE are useful markers and can be use to predict response to lipid-lowering therapy with statin in myocardial infarction.

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P5015Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events: A meta-analysis

European Heart Journal ◽

10.1093/eurheartj/ehz746.0193 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

I Dykun ◽

R Mincu ◽

M Totzeck ◽

T Rassaf ◽

A A Mahabadi

Keyword(s):

Myocardial Infarction ◽

Relative Risk ◽

Statin Therapy ◽

Risk Reduction ◽

Cardiovascular Events ◽

Ldl Cholesterol ◽

Meta Analysis ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Lowering Therapy

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors allow for reduction in LDL-cholesterol in addition to statin therapy. Purpose To perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe or PCSK-9 inhibitor in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of November 2018, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were “ezetimibe”, “evolocumab”, “alirocumab”, or “bococizumab” and “cardiovascular events”. Results A total of 100,610 patients from 9 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, SIPRE I, SPIRE II, ODYSSEY LONG TERM, OSLER-1 and OSLER-2, HIJ-PROPER) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 18% risk reduction in cardiovascular events (OR [95% CI]: 0.82 [0.75–0.89]). Effect sizes were similar for myocardial infarction (0.84 [0.76–0.92]) and even more pronounced for ischemic stroke (0.77 [0.67–0.83]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.94 [0.85–1.05]). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Comparing efficacy of LDL-reduction and relative risk redaction of cardiovascular events, a linear relationship was observed (figure). Figure 1. Correlation of reduction of LDL-cholesterol at one year with relative risk reduction (95% confidence interval) of cardiovascular events in included trials. Conclusion Intensified LDL-lowering therapy with ezetimibe or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. There is a linear relationship between LDL reduction and cardiovascular risk reduction, confirming the beneficial effects of LDL lowering therapy beyond statins in secondary prevention.

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