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Current and Emerging Uses of Statins in Clinical Therapeutics
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Current and Emerging Uses of Statins in Clinical Therapeutics

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 48621

Special Issue Editor

Prof. Dr. Steen Larsen

E-Mail Website
Guest Editor
1. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
2. Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
Interests: exercise training; mitochondria; skeletal muscle; humans

Special Issue Information

Dear Colleagues,

Statins are one of the most sold drugs worldwide. Atherosclerosis is a major risk factor for cardiovascular disease (CVD), and statin therapy is used in the prevention of CVD. Statins are usually well tolerated, but some adverse effects are seen. One of the most common adverse-effects is muscle pain ranging from myalgia to rhabdomyolysis. In 2012, the US Food and Drug Administration (FDA) added to the safety labels of statins that a potential increased risk of elevated blood glucose concentrations and a new-onset of diabetes were observed with statin treatment. The mechanisms behind these adverse effects are unknown.

This Special Issue from Journal of Clinical Medicine will focus on the use of statins clinical therapeutics and the adverse effects seen with statin treatment.

Dr. Steen Larsen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Statin
  • Skeletal muscle
  • Glucose tolerance
  • Myalgia

Published Papers (7 papers)

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Research

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12 pages, 1289 KiB  
Article
Assessment of the Efficacy of Lowering LDL Cholesterol with Rosuvastatin 10 mg in Four Korean Statin Benefit Groups as per ACC/AHA Guidelines (NewStaR4G)
by Kyung-Jin Kim, Junghan Yoon, Kyung Heon Won, Sang-Wook Lim, In-Ho Chae, Sung Yun Lee, Sang-Wook Kim and Hyo-Soo Kim
J. Clin. Med. 2020, 9(4), 916; https://doi.org/10.3390/jcm9040916 - 27 Mar 2020
Cited by 4 | Viewed by 7406
Abstract
The American College of Cardiology and American Heart Association (ACC/AHA) guidelines identified four statin benefit groups on the basis of atherosclerotic cardiovascular disease risk reduction and proposed statin therapy by evidence-based intensity. Although these guidelines used randomized controlled trials with hard outcomes as [...] Read more.
The American College of Cardiology and American Heart Association (ACC/AHA) guidelines identified four statin benefit groups on the basis of atherosclerotic cardiovascular disease risk reduction and proposed statin therapy by evidence-based intensity. Although these guidelines used randomized controlled trials with hard outcomes as exclusive evidence for its recommendations, a limited number of studies conducted in Asian countries makes its application of treatment strategy, intensity, and statin doses uncertain in these population. This prospective, multicenter study aimed to evaluate the efficacy of rosuvastatin 10 mg in the four statin benefit groups requiring high- or moderate-intensity statin therapy according to the ACC/AHA guidelines in the Korean population. The primary endpoint was percentage reduction in low-density lipoprotein (LDL) cholesterol. Secondary endpoints were percentage reduction in other lipids and achievement of ≥50% reduction in LDL cholesterol. Rosuvastatin 10 mg lowered LDL cholesterol by 61.4 mg/dL, a 44.9% decrease from baseline after eight weeks. Reduction of LDL cholesterol ≥50% was achieved in 46.3% of patients. Rosuvastatin 10 mg was generally well tolerated. In the Korean population, rosuvastatin 10 mg was favorable and tolerant in lowering LDL cholesterol in the four statin benefit groups requiring high- or moderate-intensity statin therapy according to the ACC/AHA guidelines. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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17 pages, 652 KiB  
Article
Statin and Cancer Mortality and Survival: An Umbrella Systematic Review and Meta-Analysis
by Gwang Hun Jeong, Keum Hwa Lee, Jong Yeob Kim, Michael Eisenhut, Andreas Kronbichler, Hans J. van der Vliet, Jae Il Shin and Gabriele Gamerith
J. Clin. Med. 2020, 9(2), 326; https://doi.org/10.3390/jcm9020326 - 23 Jan 2020
Cited by 27 | Viewed by 5778
Abstract
The aim of this study is to provide an overview and understand the strength of evidence and the extent of potential biases and the validity of claimed associations between the use of statins and cancer mortality or survival. We performed a comprehensive umbrella [...] Read more.
The aim of this study is to provide an overview and understand the strength of evidence and the extent of potential biases and the validity of claimed associations between the use of statins and cancer mortality or survival. We performed a comprehensive umbrella review of meta-analyses and systematically appraised the relevant meta-analyses of observational studies on the associations between statin use and cancer mortality or survival in various kinds of cancer. We searched the PubMed database and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval, heterogeneity, and also examined small study effects and 95% prediction intervals for effect sizes, and the level of evidence was determined from the criteria. Regarding cancer mortality, statin use showed convincing evidence for an association with a reduced cancer-specific mortality rate for colorectal cancer. Four associations with reduced all-cause mortality (for breast cancer, colorectal cancer, endocrine-related gynecological cancer, and ovarian cancer) had a suggestive evidence. Moreover, analyses in nine cancers showed a weak level of evidence, while the remaining 15 did not indicate significant changes in either direction. Although there was a preventive effect of statin on cancer mortality in some cancer types, the evidence supporting the use of statins to reduce cancer mortality or survival was low. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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23 pages, 7791 KiB  
Article
Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE Cascade Suppresses TNF-α-Induced Lung Inflammation
by Chih-Chung Lin, Wei-Ning Lin, Rou-Ling Cho, Chien-Chung Yang, Yi-Cheng Yeh, Li-Der Hsiao, Hui-Ching Tseng and Chuen-Mao Yang
J. Clin. Med. 2020, 9(1), 226; https://doi.org/10.3390/jcm9010226 - 15 Jan 2020
Cited by 26 | Viewed by 3509
Abstract
Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule [...] Read more.
Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule (ICAM)-1 expression were determined using real-time PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated using pharmacological inhibitors or specific small interfering RNA (siRNA)s. Interaction between Nrf2 and the antioxidant response element (ARE) binding site for the HO-1 promoter was determined by chromatin immunoprecipitation (ChIP) assay. Results: Upregulation of HO-1 by MVS attenuated the tumor necrosis factor (TNF)-α-stimulated ICAM-1 expression associated with THP-1 adhesion to HPAEpiCs. These inhibitory effects of HO-1 were reversed by tin protoporphyrin (SnPP)IX or by transfection with HO-1 siRNA. MVS-induced HO-1 expression was mediated via NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation. Activation of Nox2/ROS further stimulated the phosphorylation of p47phox, proto-oncogene tyrosine-protein kinase (c-Src), platelet-derived growth factor receptor (PDFGR)α, protein kinase B (Akt), and Nrf2, which were inhibited by siRNAs. Pretreatment with pharmacological inhibitors, including diphenyleneiodonium (DPI), apocynin (APO), N-acetyl-L-cysteine (NAC), PP1, AG1296, or LY294002, reduced the MVS-activated Nrf2 nuclear-translocation binding to the ARE on the HO-1 promoter. Conclusions: MVS-induced HO-1 is, at least in part, mediated through a p47phox/Nox2/ROS-dependent activation of c-Src/PDGFRα/PI3K/Akt-regulated Nrf2/ARE axis and suppresses the TNF-α-mediated inflammatory responses in HPAEpiCs. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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12 pages, 217 KiB  
Article
Dissimilar Effects of Anagliptin and Sitagliptin on Lipoprotein Subclass in Standard or Strong Statin-Treated Patients with Type-2 Diabetes Mellitus: A Subanalysis of the REASON (Randomized Evaluation of Anagliptin versus Sitagliptin on Low-Density LipoproteiN Cholesterol in Diabetes) Trial
by Hiroyuki Hirai, Moritake Higa, Takeshi Morimoto, Mio Sakuma, Osamu Arasaki, Takashi Nomiyama, Koichi Node, Shinichiro Ueda and Michio Shimabukuro
J. Clin. Med. 2020, 9(1), 93; https://doi.org/10.3390/jcm9010093 - 30 Dec 2019
Cited by 3 | Viewed by 2913
Abstract
The effects of antidiabetic agents on lipoprotein subclasses are assumed to be pivotal, but this assumption has not been studied. We evaluated lipoprotein subclasses in patients, randomly selected from REASON (Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes) Trial [...] Read more.
The effects of antidiabetic agents on lipoprotein subclasses are assumed to be pivotal, but this assumption has not been studied. We evaluated lipoprotein subclasses in patients, randomly selected from REASON (Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes) Trial participants, with type-2 diabetes treated with either anagliptin or sitagliptin. We measured total cholesterol (TC) and triglycerides (TG) in 4 (chylomicron (CM), very low-density lipoprotein (VLDL), low density lipoprotein (LDL), and high-density lipoprotein (HDL)) lipoprotein classes and 20 (2 CM, 5 VLDL, 6 LDL, and 7 HDL) lipoprotein subclasses. Between 0 and 52 weeks, TC and TG in lipoprotein and the lipoprotein subclass were distributed differently in patients treated with anagliptin and sitagliptin. The preferable changes in TC and TG levels were observed dominantly in the anagliptin-treated group under standard statin therapy, but the benefits were observed in both the anagliptin- and sitagliptin-treated groups, at least partially under strong statin therapy. In future studies, the atherogenic properties of lipoprotein subclasses might be considered when employing antidiabetic dipeptidyl peptidase-4 (DPP-4) inhibitors, especially in patients with type-2 diabetes who are at risk of atherosclerotic cardiovascular disease (ASCVD) or are undergoing statin treatment. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
13 pages, 992 KiB  
Article
Low Levels of Low-Density Lipoprotein Cholesterol and Mortality Outcomes in Non-Statin Users
by Ki-Chul Sung, Ji Hye Huh, Seungho Ryu, Jong-Young Lee, Eleonora Scorletti, Christopher D Byrne, Jang Young Kim, Dae Sung Hyun and Sang-Baek Ko
J. Clin. Med. 2019, 8(10), 1571; https://doi.org/10.3390/jcm8101571 - 01 Oct 2019
Cited by 30 | Viewed by 16847
Abstract
We aimed to test the association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD), cancer, and all-cause mortality in non-statin users. A total of 347,971 subjects in Kangbuk Samsung Health Study (KSHS.57.4% men, mean follow up: 5.64 ± 3.27 years) were tested. [...] Read more.
We aimed to test the association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD), cancer, and all-cause mortality in non-statin users. A total of 347,971 subjects in Kangbuk Samsung Health Study (KSHS.57.4% men, mean follow up: 5.64 ± 3.27 years) were tested. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES, 182,943 subjects). All subjects treated with any lipid-lowering therapy and who died during the first 3 years of follow up were excluded. Five groups were defined according to baseline LDL-C concentration (<70, 70–99, 100–129, 130–159, ≥160 mg/dL). A total of 2028 deaths occurred during follow-up in KSHS. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55–2.47), CVD mortality (HR 2.02, 1.11–3.64), and cancer mortality (HR 2.06, 1.46–2.90) compared to the reference group (LDL 120–139 mg/dL). In the validation cohort, 2338 deaths occurred during follow-up. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44–2.28) compared to the reference group. Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD, and all-cause mortality. These findings suggest that more attention is needed for subjects with no statin-induced decrease in LDL-C concentrations. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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16 pages, 1275 KiB  
Article
Effect of Statin on Cancer Incidence: An Umbrella Systematic Review and Meta-Analysis
by Gwang Hun Jeong, Keum Hwa Lee, Jong Yeob Kim, Michael Eisenhut, Andreas Kronbichler, Hans J. van der Vliet, Sung Hwi Hong, Jae Il Shin and Gabriele Gamerith
J. Clin. Med. 2019, 8(6), 819; https://doi.org/10.3390/jcm8060819 - 08 Jun 2019
Cited by 28 | Viewed by 4787
Abstract
Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed [...] Read more.
Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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Review

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15 pages, 1789 KiB  
Review
Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications
by Armita Mahdavi Gorabi, Nasim Kiaie, Saeideh Hajighasemi, Maciej Banach, Peter E. Penson, Tannaz Jamialahmadi and Amirhossein Sahebkar
J. Clin. Med. 2019, 8(12), 2051; https://doi.org/10.3390/jcm8122051 - 22 Nov 2019
Cited by 65 | Viewed by 6786
Abstract
In addition to their cholesterol-lowering effects, statins are associated with pleiotropic effects including improvements in heart failure (HF), reduced blood pressure, prevention of the rupture of atherosclerotic plaques and improved angiogenesis. In addition to these cardiovascular benefits, statins have been implicated in the [...] Read more.
In addition to their cholesterol-lowering effects, statins are associated with pleiotropic effects including improvements in heart failure (HF), reduced blood pressure, prevention of the rupture of atherosclerotic plaques and improved angiogenesis. In addition to these cardiovascular benefits, statins have been implicated in the treatment of neurological injuries, cancer, sepsis, and cirrhosis. These cholesterol-independent beneficial effects of statins are predominantly mediated through signaling pathways leading to increased production and bioavailability of nitric oxide (NO). In this review, the mechanistic pathways and therapeutic effects of statin-mediated elevations of NO are described and discussed. Full article
(This article belongs to the Special Issue Current and Emerging Uses of Statins in Clinical Therapeutics)
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