The CARING (CAncer Risk and INsulin analoGues) project will obtain precise data on the incidence of cancer in diabetic patients and determine any link with use of various insulin and insulin analogues.
The study will utilise high quality prescription databases and other national data sources, integrated at European level with advanced methods of harmonising data. The study will take into account potential confounders. The project aims to determine the influence of drug dose on risk, and through a risk model, identify predictors of cancer for insulin users.
A review of published evidence combined with a study of tumour characteristics and gene expression in breast cancer tumour collections will aid understanding of potential mechanisms of cancer initiation and/or promotion by insulin.
Diabetes mellitus (DM) is a group of metabolic diseases characterised by high blood sugar, either because the pancreas does not produce enough insulin or because the body does not adequately respond to the insulin that is produced. In type 1 diabetes mellitus (T1DM), autoimmune-mediated destruction of pancreatic b-cell islets leads to absolute insulin deficiency. In type 2 diabetes mellitus (T2DM), insufficient insulin is produced, the body becomes resistant to normal or even high levels of insulin, or both. In the year 2010, approximately 285 million adults had DM worldwide (6.4% of all people), and this value is predicted to rise to around 439 million (7.7%) by 2030.
Management of DM involves the control of blood glucose and lipid concentrations, blood pressure, bodyweight and smoking, as well as regular screening for complications. One of the treatment options for diabetic patients is the use of insulin and insulin analogues.
Diabetes and cancer risk
Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age. Some cancers develop more commonly in patients with diabetes (predominantly type 2), whereas prostate cancer occurs less often in men with diabetes. The relative risks imparted by diabetes are greatest (approximately 2-fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (approximately 1.2-fold to 1.5- fold) for cancers of the colon/rectum, breast, and bladder. Other cancers (e.g., those of the lung) do not appear to be associated with an increased risk in diabetes, and the evidence for others (e.g., kidney and non-Hodgkin lymphoma) is inconclusive. Only few studies have explored links between T1DM and cancer.
Insulins and cancer risk
Insulin is a growth factor, and it is biologically plausible that high levels of endogenous insulin and/or exposure to administered insulin could stimulate neoplastic growth. A growth-promoting effect of insulin on cancer cells has been known for more than 30 years, with these findings pre-dating the commercial availability of insulin analogues or even of recombinant human insulin. The most plausible hypothesis concerning the mechanism underlying the potential link between insulin and related peptide hormones and cancer growth is that these act through the insulin and insulin like growth factor (IGF) 1 receptors to stimulate cell growth and inhibit apoptosis.
Goals per work package
Work package 1
The overall objective of WP1 is to create and maintain the conditions needed to achieve the objectives and deliverables of the CARING Project. Specific objectives are to:
• establish and maintain the governance structure of CARING
• develop the global CARING Management Plan and implement the overall strategy of the project
• issue progress reports and budget reviews
• do the day-to-day administrative and financial management of the programme
Work package 2
Objectives are to:
• conduct a systematic review on the risk of cancer and different cancer types associated with diabetes mellitus, in order to estimate the background risk of cancer in the patient population using insulins
• conduct a systematic review of clinical trials and epidemiological studies on the risk of cancer associated with the use of insulin and insulin analogues
• identify methodological issues and research gaps of available clinical trials and epidemiological studies
• conduct a systematic review of the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues
Work package 3
The overall aims are to:
• determine the advantages/disadvantages of multi-database studies over a single database study (of similar size)
• determine the statistically best design for multi-database studies
More specific aims are to:
• review statistical techniques that can be used in multi-database studies
• perform simulation studies that will evaluate the performance of different statistical techniques to deal with inter-database variability in the completeness of data, data quality and variability in exposure and outcomes
• analyze and combine the data from the different sources using different approaches for confounder control and aggregation levels
• explore heterogeneity between countries, characteristics of databases and healthcare systems
Work package 4
The objectives are to:
• study the influence of potential confounders on the association between insulin (type, dose, duration) and cancer risk in observational studies in the literature
• identify potential confounders available in the databases and quantify the strength of their association with insulin use and cancer risk, individually and combined
• quantify the influence of the available confounders on the association between insulin use and cancer risk in the databases, individually and combined
• develop methods for external adjustment for unmeasured confounders in databases with missing information on certain confounders
• do sensitivity analyses of risk estimates using external adjustment for confounders of single country/single database studies
Work package 5
The aims are to:
• determine whether diabetic breast cancer patients have a specific breast cancer subtype defined by clinically used immunohistochemical tumour markers
• study whether diabetic breast cancer patients have a specific tumour profile (or tumour subtype) compared to non-diabetic breast cancer patients, and whether this may be related to specific pathways (e.g. IGF), using CGH profiling
• study whether the use of insulin and insulin analogues are related to specific pathways in breast tumours of diabetic patients
Work package 6
Objectives are to:
• determine associations between new insulin and insulin analogues use and risk of cancer and different cancer types. Exposure effects of daily dosage, time and/or intensity of insulin treatment on the likelihood of developing cancer will be studied
• study the hazard patterns of cancer risk associated with the use of insulin and insulin analogues
• develop a clinical risk score for the prediction of cancer in users of insulin and insulin analogues
Work package 7
The aims are to:
• raise awareness of the project among key stakeholders and influencers
• communicate the findings of the project to the scientific community, regulators, policymakers and to the healthcare sector across Europe
• interact with related national, European and international projects for mutual benefit concerning exchange of research expertise and dissemination of results
Utrecht University (Netherlands)
The Utrecht Pharmacoepidemiology Group is part of the Utrecht Institute for Pharmaceutical Sciences of the Utrecht University and is one of the leading academic groups in the world in the interface between pharmacoepidemiology, pharmacovigilance and drug innovation. The profile of the group includes new methods on drug channelling, exposure ascertainment, rare events, adjustment for confounding, record linkage, pharmacogenetics and implications for public health and weighing of benefits and drugs that are already on the market. More information can be found at www.uu.nl/science/pharmacoepidemiology.
Aarhus University Hospital (Denmark)
The Research Unit at Aarhus University Hospital has extensive experience in pharmaco-epidemiology including analyses of patients with diabetes and outcomes in patients treated with various anti-diabetic medications. All participants are trained specialists in endocrinology and thus have extensive clinical and research experience with patients with diabetes. Furthermore, this partner possesses extensive experience in working with Danish register data from all available sources. More information can be found at www.auh.dk.
Norwegian Institute of Public Health (Norway)
The Department of Pharmacoepidemiology at the Norwegian Institute of Public Health (NIPH) is running the nationwide Norwegian Prescription Database (NorPD). The research unit has access to and wide experience in handling and analyzing data from the different population-based data sources (health registries and comprehensive health surveys) in Norway. In addition, NIPH is running other nationwide health registries and comprehensive health surveys which may be linked to NorPD. The WHO Collaborating Centre for Drug Statistics Methodology, which classifies drug substances according to the ATC system and assigns defined daily doses (DDDs), is also a part of the department. More information can be found at www.fhi.no.
Karolinska Institute (Sweden)
The Centre for Pharmacoepidemiology performs pharmacoepidemiological research and provides expert knowledge and consultation on pharmacoepidemiology to society, authorities and industry. It is located at the Clinical Epidemiology Unit at the Department of Medicine at Karolinska Institute, Stockholm, Sweden. It includes 15 senior researchers with experiences in epidemiology, pharmacoepidemiology, biostatistics, pharmacovigilance and drug utilisation. The centre has taken an active part in the creation of European and Nordic networks (ENCePP and NorPEN). More information can be found at www.karolinska.se.
University of Tampere (Finland)
Tampere School of Public Health (TSPH) is the largest public health school in Finland. The school is responsible for the master’s programmes in public health and health sciences. The department of epidemiology has been an essential component within the school since the beginning and it has currently two full-time professors and a senior assistant professor, as well as three-part time professors. Annually, 5-10 PhD degrees are completed in the discipline. Cancer epidemiology is a prominent field with the department, with a long tradition of close collaboration with the Finnish Cancer Registry including shared positions. More information can be found at www.uta.fi.
University of Helsinki (Finland)
The University of Helsinki has the widest range of disciplines in Finland. The number of faculties is eleven. The University concentrates on high-level scientific research and researcher education. Scientific research is also the basis of the teaching provided by the University. The University has strong international connections. It has some 80 cooperation agreements with universities on different continents. The University researchers are in great demand as experts in international scientific communities, meetings and publications. Besides Helsinki, the University has operations at 20 localities throughout Finland. More information can be found at www.helsinki.fi/university.
Netherlands Cancer Institute (Netherlands)
The Netherlands Cancer Institute (NKI) is the only Dutch Cancer Centre combining hospital and research laboratories in a single independent organisation. The institute has a strong translational research programme. Support facilities include a comprehensive patient and tumour registry, biometrics, a microarray facility, a core facility Molecular Pathology and biobanking, and confocal and digital analysis facilities. The division of Pathology, including the subdivisions of Molecular Pathology and Psychosocial research and Epidemiology has a long standing interest and experience in translational research. The Department of Epidemiology focuses on the aetiology of hormone-related female cancers , the long-term adverse effects of cancer treatment and on gene-environment interactions in the aetiology of breast cancer. The Pathology department and the subdivision of molecular pathology have extensive experience with tumour profiling by gene- expression micro-array and CGH. More information can be found at www.nki.nl.
• De Bruin ML, Sturkenboom MC, Grimaldi LM, Simo R. European Initiatives To Study Adverse Events of Treatments for Diabetes Mellitus. Pharmacoepidemiol Drug Saf. 2012; 21 (SUPPL. 3): 338. Please see http://onlinelibrary.wiley.com/doi/10.1002/pds.3324/abstract
• Vestergaard P, Starup-Linde J. Diabetes, cancer and treatment - a mini-review. Curr Drug Saf. 2013 Dec; 8(5): 292-5. Please see http://www.ncbi.nlm.nih.gov/pubmed/24215309
• Starup-Linde J, Karlstad O, Eriksen SA, Vestergaard P, Bronsveld HK, de Vries F, Andersen M, Auvinen A, Haukka J, Hjellvik V, Bazelier MT, Boer Ad, Furu K, De Bruin ML. CARING (CAncer Risk and INsulin analoGues): The Association of Diabetes Mellitus and Cancer Risk with Focus on Possible Determinants - A Systematic Review and a Meta-Analysis. Curr Drug Saf. 2013 Dec; 8(5): 296-332. Please see http://www.ncbi.nlm.nih.gov/pubmed/24215312
• Karlstad O, Starup-Linde J, Vestergaard P, Hjellvik V, Bazelier MT, Schmidt MK, Andersen M, Auvinen A, Haukka J, Furu K, de Vries F, De Bruin ML. Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies. Curr Drug Saf. 2013 Dec; 8(5): 333-48. Please see http://www.ncbi.nlm.nih.gov/pubmed/24215311
• Peeters PJ, Bazelier MT, Vestergaard P, Leufkens HG, Schmidt MK, de Vries F, De Bruin ML. Use of metformin and survival of diabetic women with breast cancer. Curr Drug Saf. 2013 Dec; 8(5): 357-63. Please see http://www.ncbi.nlm.nih.gov/pubmed/24215316
Dr. Marie L De Bruin,
Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Dr. Marloes Bazelier,
Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Division of Pharmacoepidemiology & Clinical Pharmacology
David de Wied Building
3584 CG Utrecht