Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.
Würtz Peter,Wang Qin,Soininen Pasi,Kangas Antti J,Fatemifar Ghazaleh,Tynkkynen Tuulia,Tiainen Mika,Perola Markus,Tillin Therese,Hughes Alun D,Mäntyselkä Pekka,Kähönen Mika,Lehtimäki Terho,Sattar Naveed,Hingorani Aroon D,Casas Juan-Pablo,Salomaa Veikko,Kivimäki Mika,Järvelin Marjo-Riitta,Davey Smith George,Vanhala Mauno,Lawlor Debbie A,Raitakari Olli T,Chaturvedi Nish,Kettunen Johannes,Ala-Korpela Mika
Journal of the American College of Cardiology
BACKGROUND:Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. OBJECTIVES:This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. METHODS:Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. RESULTS:Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03). CONCLUSIONS:Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.
Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte.
Sniderman Allan D,Kiss Robert Scott,Reid Thomas,Thanassoulis George,Watts Gerald F
Clinical science (London, England : 1979)
Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change. Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with the conventional model of cholesterol homeostasis within the liver, but are consistent with a new model of regulation, the multi-channel model, which postulates that different lipoprotein particles enter the hepatocyte by different routes and have different metabolic fates within the hepatocyte. The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.
Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol.
Jiang Shi-You,Li Hui,Tang Jing-Jie,Wang Jie,Luo Jie,Liu Bing,Wang Jin-Kai,Shi Xiong-Jie,Cui Hai-Wei,Tang Jie,Yang Fan,Qi Wei,Qiu Wen-Wei,Song Bao-Liang
Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.
Interpretation of the evidence for the efficacy and safety of statin therapy.
Collins Rory,Reith Christina,Emberson Jonathan,Armitage Jane,Baigent Colin,Blackwell Lisa,Blumenthal Roger,Danesh John,Smith George Davey,DeMets David,Evans Stephen,Law Malcolm,MacMahon Stephen,Martin Seth,Neal Bruce,Poulter Neil,Preiss David,Ridker Paul,Roberts Ian,Rodgers Anthony,Sandercock Peter,Schulz Kenneth,Sever Peter,Simes John,Smeeth Liam,Wald Nicholas,Yusuf Salim,Peto Richard
Lancet (London, England)
This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.
The controversies of statin therapy: weighing the evidence.
Jukema J Wouter,Cannon Christopher P,de Craen Anton J M,Westendorp Rudi G J,Trompet Stella
Journal of the American College of Cardiology
The debate whether statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are safe to use has been raging since their introduction in 1987. Statins are generally well tolerated and are believed to have minimal adverse effects. However, individual, specific rare adverse events have been reported, such as elevations of liver enzymes, muscle aches, and very rarely, rhabdomyolysis. Discontinuation and/or reduction in the dose of the statin usually leads to resolution of these side effects. Recently, however, debate has focused on the possible negative long-term effects of statin treatment on cognitive decline, the incidence of cancer, and the development of diabetes mellitus. Recently, the U.S. Food and Drug Administration has expanded the warning for statins with a statement that statin use may lead to cognitive impairment. In this review, we discuss all levels of evidence, from case reports to large randomized controlled clinical trials, for the possible adverse effects of statins on cognitive decline, cancer, and diabetes. After careful consideration of all discussed scientific evidence, we conclude that there is no increased risk of cognitive decline or cancer with statin use. However, statin use is related to a small increased risk of type 2 diabetes mellitus. In view of the overwhelming benefit of statins in the reduction of cardiovascular events, we believe the small absolute risk for development of diabetes is outweighed by the cardiovascular benefits in patients for whom statin therapy is recommended. We, therefore, suggest that clinical practice for statin therapy should not be changed on the basis of the most recent Food and Drug Administration informational warnings.
Recommendations for (Discontinuation of) Statin Treatment in Older Adults: Review of Guidelines.
van der Ploeg Milly A,Floriani Carmen,Achterberg Wilco P,Bogaerts Jonathan M K,Gussekloo Jacobijn,Mooijaart Simon P,Streit Sven,Poortvliet Rosalinde K E,Drewes Yvonne M
Journal of the American Geriatrics Society
OBJECTIVES:As a person's age increases and his/her health status declines, new challenges arise that may lead physicians to consider deprescribing statins. We aimed to provide insight into recommendations available in international cardiovascular disease prevention guidelines regarding discontinuation of statin treatment applicable to older adults. DESIGN:We systematically searched PubMed, EMBASE, EMCARE, and the websites of guideline development organizations and online guideline repositories for cardiovascular disease prevention guidelines aimed at the general population. We selected all guidelines with recommendations (instructions and suggestions) on discontinuation of statin treatment applicable to older adults, published between January 2009 and April 2019. In addition, we performed a synthesis of information from all other recommendations for older adults regarding statin treatment. Methodological quality of the included guidelines was appraised using the appraisal of guidelines for research & evaluation II (AGREE II) instrument. RESULTS:Eighteen international guidelines for cardiovascular disease prevention in the general adult population provided recommendations for statin discontinuation that were applicable to older adults. We identified three groups of instructions for statin discontinuation related to statin intolerance, and none was specifically aimed at older adults. Three guidelines also included suggestions to consider statin discontinuation in patients with poor health status. Of the 18 guidelines included, 16 made recommendations regarding statin treatment in older adults, although details on how to implement these recommendations in practice were not provided. CONCLUSION:Current international cardiovascular disease prevention guidelines provide little specific guidance for physicians who are considering statin discontinuation in older adults in the context of declining health status and short life expectancy. J Am Geriatr Soc 68:417-425, 2020.
Statin-Associated Side Effects.
Thompson Paul D,Panza Gregory,Zaleski Amanda,Taylor Beth
Journal of the American College of Cardiology
Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are well tolerated, but associated with various statin-associated symptoms (SAS), including statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are "statin-associated symptoms" because they are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of statin users. Clinically important muscle symptoms, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the statin treatment, and using alternative lipid-lowering therapy.
Safety and efficacy of statin therapy.
Adhyaru Bhavin B,Jacobson Terry A
Nature reviews. Cardiology
The 2013 ACC/AHA guidelines on blood cholesterol management were a major shift in the delineation of the main patient groups that could benefit from statin therapy and emphasized the use of higher-intensity statin therapies. In 2016, an expert consensus panel from the ACC recommended the use of nonstatin therapies (ezetimibe and PCSK9 inhibitors) in addition to maximally tolerated statin therapy in individuals whose LDL-cholesterol and non-HDL-cholesterol levels remained above certain thresholds after statin treatment. Given the substantial benefits of statin therapies in both primary and secondary prevention of cardiovascular disease, their long-term safety has become a concern. The potential harmful effects of statin therapy on muscle and liver have been known for some time, but new concerns have emerged regarding the risk of new-onset diabetes mellitus, cognitive impairment and haemorrhagic stroke associated with the use of statins and the risks of achieving very low levels of LDL cholesterol. The increased media attention on the adverse events associated with statins has unfortunately led to statin therapy discontinuation, nonadherence to therapy or concerns about initiating statin therapy. In this Review, we explore the safety of statin therapy in light of the latest evidence and provide clinicians with reassurance about the safety of statins. Overwhelming evidence suggests that the benefits of statin therapy far outweigh any real or perceived risks.
Ward Natalie C,Watts Gerald F,Eckel Robert H
There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread use, discontinuation and nonadherence remains a major gap in both the primary and secondary prevention of atherosclerotic cardiovascular disease. The major reason for statin discontinuation is because of the development of statin-associated muscle symptoms, but a range of other statin-induced side effects also exist. Although the mechanisms behind these side effects have not been fully elucidated, there is an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies. In this article, we review the mechanisms and clinical importance of statin toxicity and focus on the evaluation and management of statin-associated muscle symptoms.
Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.
Natarajan Pradeep,Young Robin,Stitziel Nathan O,Padmanabhan Sandosh,Baber Usman,Mehran Roxana,Sartori Samantha,Fuster Valentin,Reilly Dermot F,Butterworth Adam,Rader Daniel J,Ford Ian,Sattar Naveed,Kathiresan Sekar
BACKGROUND:Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis. METHODS:We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage). RESULTS:Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; <0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; =0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others ( for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque. CONCLUSIONS:Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.
Prevalence and Predictors of Cholesterol Screening, Awareness, and Statin Treatment Among US Adults With Familial Hypercholesterolemia or Other Forms of Severe Dyslipidemia (1999-2014).
Bucholz Emily M,Rodday Angie Mae,Kolor Katherine,Khoury Muin J,de Ferranti Sarah D
BACKGROUND:Familial hypercholesterolemia (FH) and other extreme elevations in low-density lipoprotein cholesterol significantly increase the risk of atherosclerotic cardiovascular disease; however, recent data suggest that prescription rates for statins remain low in these patients. National rates of screening, awareness, and treatment with statins among individuals with FH or severe dyslipidemia are unknown. METHODS:Data from the 1999 to 2014 National Health and Nutrition Examination Survey were used to estimate prevalence rates of self-reported screening, awareness, and statin therapy among US adults (n=42 471 weighted to represent 212 million US adults) with FH (defined using the Dutch Lipid Clinic criteria) and with severe dyslipidemia (defined as low-density lipoprotein cholesterol levels ≥190 mg/dL). Logistic regression was used to identify sociodemographic and clinical correlates of hypercholesterolemia awareness and statin therapy. RESULTS:The estimated US prevalence of definite/probable FH was 0.47% (standard error, 0.03%) and of severe dyslipidemia was 6.6% (standard error, 0.2%). The frequency of cholesterol screening and awareness was high (>80%) among adults with definite/probable FH or severe dyslipidemia; however, statin use was uniformly low (52.3% [standard error, 8.2%] of adults with definite/probable FH and 37.6% [standard error, 1.2%] of adults with severe dyslipidemia). Only 30.3% of patients with definite/probable FH on statins were taking a high-intensity statin. The prevalence of statin use in adults with severe dyslipidemia increased over time (from 29.4% to 47.7%) but not faster than trends in the general population (from 5.7% to 17.6%). Older age, health insurance status, having a usual source of care, diabetes mellitus, hypertension, and having a personal history of early atherosclerotic cardiovascular disease were associated with higher statin use. CONCLUSIONS:Despite the high prevalence of cholesterol screening and awareness, only ≈50% of adults with FH are on statin therapy, with even fewer prescribed a high-intensity statin; young and uninsured patients are at the highest risk for lack of screening and for undertreatment. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high-risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.