LIFESTAT - Living with statins
LIFESTAT is an interdisciplinary project that leverages approaches and knowledge from health science, the humanities and the social sciences to analyse the impact of statin use on health, life-style and well-being in a large cohort of Danish citizens. The impetus for the study is the fact that 600,000 Danes take statins in order to maintain good health and to avoid cardiovascular disease by counteracting high blood levels of cholesterol. Almost 40% of these individuals are in “primary prevention”, being treated pharmacologically for this risk factor alone. The potential benefit of treatment with statins should be considered in light of evidence that statin-use has serious and prevalent unintended side-effects, including skeletal muscle cell death, muscle pain (myalgia), and lower exercise tolerance which in turn prohibit healthy habits. Furthermore, glucose intolerance (a risk factor for type 2 diabetes) may be induced.
In collaboration with an SME (Zora Biosciences, Finland) we will develop a blood biomarker forstatin induced myalgia in patients. We will investigate the biological consequences of statin treatment of high blood cholesterol and the patient’s perception of disease risk. Furthermore, we will investigate the interplay between general practitioners – their patients – and the media, with focus on disease risk perception and the statin-users health seeking behaviours (compliance with prescriptions, use of general practitioners and other health professionals, and use of hospital services).
This defines what LIFESTAT is about: the complicated intertwining of medical knowledge with the promotion of healthy living with or without medication and choice of life style as a moral as well as a medical imperative.
HYPERCHOLESTEROLEMIA AND STATIN USE IN DENMARK
Simvastatin is the most commonly prescribed statin, a class of drugs that inhibit hydroxyl-methyl-glutaryl coenzyme A reductase, thereby blocking biosynthesis of cholesterol in the liver. Simvastatin and other statins are prescribed for individuals with elevated low-density lipoprotein cholesterol (LDL-C) and/or total cholesterol, because these clinical parameters are viewed as a risk factor for CVD, even in the absence of other health problems or risk factors, such as previous myocardial infarction, diabetes or hypertension. Fig. 1 shows the number of individuals taking statins in Denmark from 2006 to 2013.
Approximately 40% of the prescriptions for statins are issued for primary prevention of elevated cholesterol by general practitioners to patients without bodily symptoms or signs 1. Only the number indicating cholesterol level makes the risk of heart attack and stroke visible. The lack of symptoms is likely to be of importance for patients’ adherence to treatment as is adverse effects. A number of factors, such as information in mass media and changes in life circumstances, may affect the decision to take the treatment
TREATMENT GUIDELINES FOR HYPERCHOLESTEROLMIA
The guidelines 2-4 indicate preventive treatment with statins is appropriate in individuals with >10% predicted risk of a major vascular event within 5 years, while, some, but not all opinion-leaders advocate a 5% threshold 3, 5. Nevertheless, statin therapy failed to reduce all-cause mortality in a meta-study of 65,229 patients without CVD, some of whom had diabetes 6. Similarly, a Cochrane review analysis, which included some studies in which more than 10% of the patients had history of CVD, showed only 0.5% reduction in all-cause mortality, indicating that for every 200 patients taking statins daily for 5 years, 1 death would be prevented 7. These data suggest that more conservative use of statins to prevent CVD in otherwise healthy individuals at low risk for future CVD may be warranted.
Rhabdomyolysis (skeletal muscle cell death) is an infrequent but serious side-effect of statin use, that can on rare occasion lead to acute renal failure and death ( i.e., 1.5 deaths per 1.000.000 prescriptions 8). Statin use is much more frequently associated with muscle dysfunction, including myalgia (muscle pain), cramps, and weakness. The reported incidence of myalgia varies from 1% (pharmaceutical company reports) to as high as 75% in statin-treated athletes 8, 9. Mild to severe myalgia is a strong disincentive to regular exercise, and because regular exercise is one of the critical life-style approaches to preventing CVD and reducing blood cholesterol, this is a significant major down-side of statin use. Regular exercise is also effective in preventing and treating obesity and type 2 diabetes, which themselves are risk factors for CVD 10.
THE INTERDISCIPLINARITY OF THE PROBLEM
This is a collaborative project between the social sciences, the humanities and the health sciences. The overall aim is to produce new knowledge about patients living with a widespread condition, elevated cholesterol in the blood, which is not in itself life threatening. The project encompasses an everyday condition for a large group of Danes. Through an interdisciplinary effort, we will provide new knowledge about the relationship between the use of statins as a primary preventive treatment, people’s knowledge of the risk of CVD associated with raised cholesterol levels, and how patients gain information about possible side-effects of their treatment and use it in their everyday lives.
LIFESTAT addresses the following overall research questions:
- How is statin treatment affecting identity and self-perception?
- How will information on personal biological values and knowledge on cholesterol and statins affect the patients contact with health service providers?
- In what ways and in which forms is knowledge on statins and cholesterol disseminated to the general public?
- How do patients seek out and process information about ways of living with statins?
- What is the pathophysiological mechanism behind statin induced myalgia?
- How does statin treatment impact muscular function?
- To what extent is the use of statins affected by the development of comorbidity, various life events, information in mass media and experience of symptoms?
- Which factors modify compliance?
- What is the frequency of adverse effects in a general practice population?
Patients that fulfil defined inclusion and exclusion criteria will be recruited from General Practice clinics in Copenhagen. The vast majority of these patients are being treated on basis of the HeartScore risk estimation system that offers direct estimation of the ten-year risk of fatal cardiovascular disease in a format suited to the constraints of clinical practice 2 (www.HeartScore.org). Most patients will be in primary prevention with statins, but some substudies will include secondary prevention as well. In addition large cohorts (some nationwide) will be followed via registers. As a basis we will recruit 200 statin users and 200 age- and sex-matched healthy controls. For the Survey (see below) an additional 400 subjects will be included. To avoid confounding population effects, only participants of European ancestry will be included because there is variability in the clinical response to statins among different ethnicity 11. A staggered recruitment will be implemented, according to initiation of sub-projects, and all participants will as a minimum complete the Survey questionnaire.
APPROACH – A MEDICAL, SOCIAL AND PERSONAL PERSPECTIVE ON HEALTH AND HEALTHY LIFE-STYLE
Specific Aim 1: The Human Technology Interface
One goal of LIFESTAT is to consider the social and personal impact of the enhanced possibilities to monitor own blood cholesterol (and e.g. blood pressure and glucose) 12 and the media attention cholesterol is given. It is important to understand the impact of technology and medical knowledge on human lives and life-styles 13, 14, which we refer to here as “the human technology interface.” We would like to know: “Why do individuals choose to take or not take prescription medication?” and “Why do individuals chose to proactively monitor, or to neglect to monitor, their cholesterol level, weight, exercise habits and diet?” We will use well established qualitative methods to study the everyday life of a sub-cohort of 50 individuals; we will also use ethnographic methods such as interviews 15 and participant observation 16, as well as structured focus group discussions on cholesterol and statin-use 17. These methodologies yield qualitative output, which will be evaluated in context with other outcomes of a baseline survey questionnaire.
Specific Aim 2: Information, Dissemination and Media Use/Impact
This part of LIFESTAT will examine availability, use and impact of information on statins on people’s daily life. A survey instrument will be used to collect data from all subjects in the study cohort. In addition, a comprehensive textual analysis consisting of a quantitative content and qualitative discourse analyses will be carried out on articles published in Danish-language newspapers within the last three years relevant to healthy life-style, cholesterol, exercise and statin use. The goal is to increase our understanding how information disseminated to the public impact on the individual citizen as patient, pharmaceutical user, and personal risk manager. We will try to determine how Danish citizens view themselves: 1) as an informed ‘expert patient’; 2) as a risk manager (i.e., weighing advantage and disadvantages of living with or without statins); or 3) as a ‘security seeker.’ Surveys and interviews conducted under Aim 2 will shed light on living with statins, coping with a disease/risk factor, information and technology utilization.
Specific Aim 3: Statins, Muscle Pathology and Exercise.
Clinical studies report that statin therapy is frequently associated with muscle weakness and reduced aerobic capacity. However, the data are limited, largely anecdotal and somewhat inconsistent 18, 19. Thus, standardized muscle strength assessments and quantitative measures of aerobic capacity in a well-defined cohort are lacking. We found reduced hand-grip strength in middle-aged healthy individuals after 2 weeks of statin use, independent of reported myalgia and that statins diminish mitochondrial function and the amount of a central protein in the respiratory chain (Q10) 20. In aim 3, the link between statin use and muscle dysfunction will be evaluated with an array of quantitative measures of muscle strength & fitness. LIFESTAT Aim 3 will collect extensive quantitative biochemical, anthropometric and functional data on all study subjects. Glucose metabolism and insulin secretion capacity as well as mitochondrial respiratory capacity will be assessed via blood samples and muscle biopsies. The tissue samples will form the basis for identification of a myalgia biomarker in collaboration with Zora Biosciences.
Specific Aim 4: To explore motives and barriers for patient compliance and adverse effects connected to statin treatment in general practice.
Qualitative studies have shown that patients’ use of statins depend on perceived benefits and side effects, but nonclinical cues may be of equal importance: patients may balance the use of statin against existing routines and triggers from everyday life 21. Our knowledge about the factors that affect patients’ use of statins is, however, limited. To what extent is the use of statins affected by factors such as 1) patient’s experience of symptoms 2) various life events 3) development of comorbidity and 4) knowledge about adverse effects? It is of major clinical importance to examine the influence of patient characteristics such as education and social position. Statins have well known adverse effects, but the incidence is debated 22. We will study these questions using data in Danish national registries, the Danish General Practice Database and in our cohorts of incident user of statins identified in general practice by means of information obtained from questionnaires. Data will be analysed using various epidemiologic designs: cohort, case-control and case-crossover. The case-crossover design will specifically be used for identifying transient triggers associated with non-compliance.
A survey disseminated to the entire project cohort will provide background data on the demographic composition (age, sex, civil status, children, family, education, income, occupation, and residence). The survey questionnaire will provide the basis for answering specific research questions on: the individual patients’ knowledge sources for health issues in general and for cholesterol in particular; opinions of and decision-making in relation to the use of statins; changes in bodily practices and the use of new measurement technologies. Moreover, the survey will provide information on the subjects’ physical activity and self-reported health (internationally recognized and well validated survey instruments SF12 and International Physical Activity Questionnaire (IPAQ), respectively).
The media function as sources of information and knowledge are an important arena for communication of health issues 23 and hence for decision making. In particular, the Internet has become a popular place for people looking for health and medical information 24, 25. Consequently, the survey will include the media’s role in patients’ searching for information and knowledge on health, cholesterol and statins. Key questions concern which media, when and how often they consult media on health issues and on cholesterol, compared to visiting the physician, and how much time they spend seeking health information. The survey will provide an initial picture of why and how people use media as knowledge sources.
Overall, the survey will provide a quantitative picture of the role that media, public policy and technology play in relation to the choices that people make about statin use.
Database and Registry Analyses
The database will serve as the nucleus of LIFESTAT where all final data are stored. The controlled design of the LIFESTAT project will allow a direct comparison of the effect of intensive measurements and information on health seeking behaviours in the intervention group and the control group. By using personal identity numbers, it is possible to link these data with national registry data, including information on socio-economic status (education, income and occupation); use of prescribed drugs (the Danish Drug Registry); registration of compliance and adverse effects (the Danish General Practice Database); use of general practitioners and other health professionals (the National Health Insurance Registry); and use of hospital services (the National Hospital Registry). We have profound extensive experience in developing and using these kinds of linked data bases.
The database will allow analysis of contacts to health services and intake of prescribed drugs during a period before (the last 5 years), during the LIFESTAT project and during a follow-up period of several years – comparing the statin users and control groups and including biological indicators, age, gender and socio-economic variables as possible modifiers.
All biological material, including DNA, will be stored in a biobank. We will not establish it ourselves, rather we will take advantage of the already established Copenhagen University Biobank for Experimental research (www.cube.ku.dk). This Biobank invites all UCPH researchers to make use of their facilities.
Participants, organisation and management
MANAGEMENT & ORGANISATION
The PI/project manager of LIFESTAT is professor F. Dela. He has attracted considerable external funding and he has extensive leadership experience in research and research administration (former vice-dean at the Medical Faculty). A steering committee will be formed (PI + associate professor Christa Lykke Christensen (Dept. of Media, Cognition, and Communication; Faculty of Humanities) + professor Jakob Kragstrup (Research Unit for General Practice, Faculty of Health and Medical Sciences). The steering committee will meet monthly, with additional ad hoc meetings, as needed. The main purpose of the steering committee is to ensure continuing progress along the research lines, with the initial focus on patient recruitment, survey and database construction. Later the focus will shift to promoting progress on joint publications from the PI, co-PIs and their colleagues and collaborators. Key researchers in LIFESTAT are listed in enclosure C.
A Scientific Advisory Board (SAB) of internationally recognized researchers has been formed (all confirmed): Professor Paul Greenhaff, School of Biomedical Sciences, University of Nottingham, UK. + Assistant professor Jeremy Greene, M.D., Ph.D., Dept. of History of Science & Harvard Medical School, USA + Professor Kevin B. Wright, Ph.D., Dept. of Communication, Saint Louis University, USA. The SAB meeting will take place at least once per year.
Anticipated results and impact related to both science and society
A pathway analysis of cholesterol synthesis reveals that the statins interact and diminish the synthesis of molecules essential for optimal mitochondrial function, but the functional impact is uncertain at this point. It is also possible that statins may have more profound effects on cell biology than hitherto thought. Thus, mitochondrial nucleotide pool imbalance and genome instability (e.g. deletions, mutations and rearrangements of mtDNA) can be quantified in biobanked samples. In selected cases, full mitochondrial genome sequencing will be performed. If deemed appropriate, nuclear genome instability and indicators of genotoxic stress will be investigated. The potential negative impact of statin on glucose homeostatis may have huge impact on medical practice, and the mechanism will be uncovered in LIFESTAT.
With the collection of DNA from a large cohort that is extremely well characterized with respect to medical records, in-depth phenotypical characteristics (both biological and social) as well as media using behaviour, we have a unique opportunity to study the relationship between these parameters and genetic traits. Some studies have already been done in this field, but they all suffer from lack of high quality data on phenotypical characteristics. However, one study on single-nucleotide-polymorphisms has found that the SLCO1B1 gene is strongly associated with statin induced myopathy 11. At least four other candidate genes have been identified relating to myalgia, and with the data base we will build, it would be a matter of course to follow these known genes by the regular candidate gene approach. However, our material also allows for a search for unknown genes by use of genome-wide-associationstudies (GWAS).
The possibility for the discovery of a biomarker for statin induced side-effects (muscle weakness, myalgia, and impaired mitochondrial capacity is quite good. With the size of the proposed research endeavour, including the fact that we will obtain biological samples from all subjects and fully characterize the phenotype (questionnaire survey; muscle tests), there is a potential for finding a biomarker. Such a biomarker is commercially interesting, and the collaboration with the well-established SME (Zora Biosciences, Finland) testifies also the business perspectives of the present proposal.
Statins are currently the most prescribed drugs in Denmark, Europe and the USA. In Denmark, statin use increased 52% from 2006 to 2010, with an associated cost of 400 MKr per year. In the USA, approximately 25% of adults >45 years old reported using a prescription statin in the last 30 days, and the fraction of the population taking statins increased 10-fold from 1988 to 2008 8. Approximately 240.000 patients in DK are in the “primary prevention” group and the predicted health benefit on a societal level is small (i.e., ≤0.5% reduction in all-cause mortality). Furthermore, the possibility of negative side-effects, including mild to severe loss of muscle function, may outweigh the potential benefit of statin use for some patient groups, by limiting tolerance for moderate to strenuous exercise. The unique interdisciplinary LIFESTAT approach will not only collect data on human health and behaviour, but will also explore the impact of culturally-pervasive medical knowledge on patient expectations. The patient perspective of statin treatment will produce useful knowledge to clinical practice. LIFESTAT results and outcomes are thus expected to be relevant not only to Danish society, but to also be generalizable to many other countries within and outside of Europe/North America 11, 12, 24, 26.
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