Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

A combinatorial approach to electronic healthcare records in pharmacoepidemiology

There is a need to know when multi-country observational studies are useful and how they should be performed and interpreted, because there are no well-established methods to deal with the combination of data from several independent electronic healthcare registries. The overall aim of this thesis was to explore the value of using data from multiple countries when estimating the risk of fractures for patients with multiple sclerosis (MS) and the risk of fractures for patients exposed to thiazolidinediones (TZDs). Data were retrieved from three different electronic healthcare registries: the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers linked to the Danish MS Registry. Our studies of MS and fractures indicate that increased awareness of the risk of hip fracture is warranted in patients with MS. Attention should particularly be paid for MS patients aged 30–69 and for more disabled patients (i.e., who have a higher expanded disability status scale score). The use of antidepressants further increased fracture risks. The results for patients with MS exposed to glucocorticoids (GCs) were conflicting, although generally the link between GC use and fracture risk has been well established. A clinical risk score for fracture risk estimation may be a starting point for the communication of an individual’s fracture risk in patients with MS, such as the FRAX score or the score presented in one of the chapters of this thesis, which includes MS as a risk factor. A measurement of the bone mineral density may be the next step to determine if preventative treatment, such as bisphosphonates, strontium ranelate, raloxifene or denosumab, is indicated. Other possible interventions are the intake of calcium and vitamin D tablets, and the prevention of falls. Treatment with TZDs in diabetic patients has been associated with a relatively small increased fracture risk for women. If a patient has several other risk factors for fracture, such as a previous fracture, exposure to GCs, or a higher age, a fracture risk assessment may be considered. If this assessment shows an absolute fracture risk that is substantial, then discontinuation of TZD use may be an option. However, this involves a benefit-risk assessment between the best treatment option for diabetes and the risk of fractures. Multi-country studies add valuable insights to the field of observational research. Whether they are worth the effort depends on the specific exposure and outcome being investigated, the quality and completeness of data recording in the separate registries, the ability to gain access to individual patient data if needed and the willingness to invest time and money. When different registries are combined, a crucial step is to investigate the features of these separate registries and the characteristics of patients. Ideally, there should be as much consistency as possible between data from the different sources in terms of study design and definitions of exposure, outcome and risk factors before combining the data. Access to individual patient data is therefore a major strength for a multi-country study

A combinatorial approach to electronic healthcare records in pharmacoepidemiology

There is a need to know when multi-country observational studies are useful and how they should be performed and interpreted, because there are no well-established methods to deal with the combination of data from several independent electronic healthcare registries. The overall aim of this thesis was to explore the value of using data from multiple countries when estimating the risk of fractures for patients with multiple sclerosis (MS) and the risk of fractures for patients exposed to thiazolidinediones (TZDs). Data were retrieved from three different electronic healthcare registries: the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers linked to the Danish MS Registry. Our studies of MS and fractures indicate that increased awareness of the risk of hip fracture is warranted in patients with MS. Attention should particularly be paid for MS patients aged 30–69 and for more disabled patients (i.e., who have a higher expanded disability status scale score). The use of antidepressants further increased fracture risks. The results for patients with MS exposed to glucocorticoids (GCs) were conflicting, although generally the link between GC use and fracture risk has been well established. A clinical risk score for fracture risk estimation may be a starting point for the communication of an individual’s fracture risk in patients with MS, such as the FRAX score or the score presented in one of the chapters of this thesis, which includes MS as a risk factor. A measurement of the bone mineral density may be the next step to determine if preventative treatment, such as bisphosphonates, strontium ranelate, raloxifene or denosumab, is indicated. Other possible interventions are the intake of calcium and vitamin D tablets, and the prevention of falls. Treatment with TZDs in diabetic patients has been associated with a relatively small increased fracture risk for women. If a patient has several other risk factors for fracture, such as a previous fracture, exposure to GCs, or a higher age, a fracture risk assessment may be considered. If this assessment shows an absolute fracture risk that is substantial, then discontinuation of TZD use may be an option. However, this involves a benefit-risk assessment between the best treatment option for diabetes and the risk of fractures. Multi-country studies add valuable insights to the field of observational research. Whether they are worth the effort depends on the specific exposure and outcome being investigated, the quality and completeness of data recording in the separate registries, the ability to gain access to individual patient data if needed and the willingness to invest time and money. When different registries are combined, a crucial step is to investigate the features of these separate registries and the characteristics of patients. Ideally, there should be as much consistency as possible between data from the different sources in terms of study design and definitions of exposure, outcome and risk factors before combining the data. Access to individual patient data is therefore a major strength for a multi-country study

The Risk of Colorectal Cancer in Patients With Type 2 Diabetes: Associations With Treatment Stage and Obesity

OBJECTIVE To assess the risk of colorectal cancer associated with type 2 diabetes, as compared with a nondiabetic reference population, and to study additional associations between treatment stage and duration of obesity and colorectal cancer risk. RESEARCH DESIGN AND METHODS We conducted an observational population-based cohort study within the Clinical Practice Research Datalink (1987-2012). All patients (>= 18 years) with at least one prescription for an antidiabetic drug (n = 300,039) were matched (1: 1) by birth year, sex, and practice to a comparison cohort without diabetes. Cox proportional hazards models were used to derive adjusted hazard ratios (HRs) for colorectal cancer associated with type 2 diabetes. Within the diabetic cohort, associations of colorectal cancer with treatment stages and duration of obesity (BMI >= 30 kg/m(2)) were studied. RESULTS After amedian follow-up of 4.5 years, 2,759 cases of colorectal cancer were observed among the diabetic study population. Type 2 diabetes was associated with a 1.3-fold increased risk of colorectal cancer (HR 1.26 [95% CI 1.18-1.33]). Among diabetic patients, no association was found with treatment stages. A trend of increased colorectal cancer risk was observed with longer duration of obesity. Risk of colorectal cancer was significantly increased for patients with recorded duration of obesity of 4-8 years (HR 1.19 [1.06-1.34]) and >8 years (1.28 [1.11-1.49]). CONCLUSIONS Type 2 diabetes is associated with a moderately increased risk of colorectal cancer. Among diabetic patients, an increased risk was observed for patients who suffered from obesity for a total duration of 4 years or more

Risk of bladder cancer in patients with diabetes: a retrospective cohort study

OBJECTIVE: The objective of this study was to examine the association between diabetes, and both urinary bladder cancer (UBC) risk and mortality. METHODS: We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) linked to the Office of National Statistics (ONS). Patients diagnosed with diabetes mellitus type 1 or 2, or using antidiabetic drugs (ADDs), were compared to matched non-diabetic controls. Cox proportional hazards models were used to estimate the risk and mortality of UBC. We adjusted for age, sex, smoking status and body mass index. RESULTS: The cohort included 329 168 patients using ADD, and 307 315 controls with 1295 and 1071 patients, respectively, diagnosed as having UBC during follow-up. The adjusted HRs of UBC were 0.77 (95% CI 0.57 to 1.05) and 1.04 (95% CI 0.96 to 1.14) for type 1 and 2 diabetes, respectively. These results were similar if we restricted our analysis to an inception cohort. We noticed a small increased risk during the first year after diagnosis (HR=1.26 (95% CI 1.05 to 1.52)), which could be explained by detection bias. There was no influence of the severity of diabetes as measured by the glycated haemoglobin. Mortality of UBC was not increased for patients with either type 1 (HR=0.95 (95% CI 0.39 to 2.34)) or type 2 diabetes (HR=1.16 (95% CI 0.91 to 1.46)). CONCLUSIONS: Neither the risk of UBC nor the mortality from UBC was increased in patients with type 1 and patients with type 2 diabetes in the CPRD data

The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study

Objective To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls. Methods All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987-2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591). Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use. Results At diagnosis of AS, the proportion of patients with an EAM was 11.4% for AAU, 4.4% for psoriasis and 3.7% for IBD. Incidence rates of EAMs were 8.9/ 1000 person-years for AAU, 3.4/1000 person-years for psoriasis and 2.4/1000 person-years for IBD in AS. The 20-year cumulative incidence was 24.5%, 10.1% and 7.5%, respectively. Risks of EAMs were 1.5-fold to 16-fold increased versus controls, with an adj HR of 15.5 (95% CI 11.6 to 20.7) for AAU, adj HR of 1.5 (95% CI 1.1 to 1.9) for psoriasis and adj HR of 3.3 (95% CI 2.3 to 4.8) for IBD. For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS. Conclusions The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls. Hazard patterns are different for each of the EAMs

Multiple sclerosis and fracture risk: traditional meta-analysis versus mega-analysis of individual patient data

Introduction The aim of this systematic review was to evaluate the difference between a traditional meta-analysis and a mega-analysis of individual patient data when combining observational studies. Materials and methods We used data from two studies that evaluated the risk of fracture in patients with multiple sclerosis using the British General Practice Research Database and the Danish National Health Registries. The published results were pooled together in an inverse-variance fixed effect meta-analysis. Using patient level data, we made the study populations as comparable as possible regarding the index date, calendar time, selection of incident/prevalent patient and follow-up. The individual patient data of these populations were combined in a mega-analysis. Cox proportional hazards models were used to estimate hazard ratios of fracture, adjusted for shared confounders. Results A traditional meta-analysis of the original studies resulted in pooled adjusted hazard ratios of 1.13 [95%CI 1.03–1.23] for any fracture, hazard ratio 1.22 [95%CI 1.07–1.41] for osteoporotic fracture, and hazard ratio 2.47 [95%CI 1.72–3.53] for hip fracture. The mega-analysis of individual patient data showed an adjusted hazard ratio of 1.20 [95%CI 1.12−1.28] for any fracture, hazard ratio 1.36 [95%CI 1.24–1.50] for osteoporotic fracture, and hazard ratio 3.27 [95%CI 2.65–4.04] for hip fracture. The traditional meta-analysis of the original studies showed significant heterogeneity, which disappeared in a meta-analysis that pooled the two more comparable studies together. This meta-analysis yielded similar results as the mega-analysis with individual patient data. Conclusion A crucial step in performing a multi-country study is to reduce the level of heterogeneity between studies as much as possible before combining the data