Øystein Karlstad

Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies

Background: An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified. Objective: To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes. Data Sources: Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library. Study Eligibility Criteria (PICOS): Population: diabetes patients. Exposure: Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs. Outcome: Any incident cancer. Study Design: Cohort and case-control studies. Results: 42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer. Limitations: Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders. Conclusions: Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.

Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study

Background A trans-generational influence of prenatal tobacco smoke exposure on asthma development has been proposed but the evidence remains sparse. Methods We examined the grandmothers smoking when pregnant with the mother in relation to asthma outcomes in the grandchild (current asthma at 36 months (N=53 169, cases=3013), current asthma at 7 years (N=25 394, cases=1265) and dispensed asthma medications at 7 years in the Norwegian Prescription Database (N=45 607, cases=1787)) within the Norwegian Mother and Child Cohort Study (MoBa). We calculated adjusted RR (adj. RR) and 95% CIs using log binomial regression. Results A total of 23.5% of mothers reported that their mother smoked when pregnant with them. The grandmothers smoking when pregnant with the mother was positively associated with asthma at 36 months (adj. RR 1.15 (95% CI 1.06 to 1.24)), asthma at 7 years (adj. RR 1.21 (95% CI 1.07 to 1.37)) and dispensed asthma medications at 7 years (adj. RR 1.15 (95% CI 1.04 to 1.26)). This positive association did not differ significantly by the mothers smoking status when pregnant with the child (p values for multiplicative interaction >0.1). Conclusions The grandmothers smoking when pregnant with the mother increased the risk of asthma in the grandchild independent of the mothers smoking status. However, given limited information on the grandmothers socioeconomic status, asthma status and other factors, unmeasured confounding may be present.

High validity of mother-reported use of antiasthmatics among children: a comparison with a population-based prescription database

OBJECTIVES To examine the validity of (1) maternal questionnaire report of childrens use of antiasthmatics using a prescription database as the reference standard and (2) dispensed antiasthmatics as a measure of asthma using maternal report of childrens asthma as the reference standard. STUDY DESIGN AND SETTING A total of 3,394 children in the Norwegian Mother and Child Cohort Study aged 7 years were linked to the Norwegian Prescription Database. Maternal report of both childrens use of antiasthmatics during the preceding year and the presence of asthma was compared with data on dispensed antiasthmatics. RESULTS A total of 2,056 mothers responded and reported use of antiasthmatics during the previous year in 125 of 147 children who had been dispensed antiasthmatics (sensitivity 85.0%). Of the 1,909 children with no dispensed antiasthmatics, 1,848 had no maternal report of antiasthmatic use (specificity 96.8%). Mothers reported current asthma in 133 (6.5% of 2,056) children, including in 122 (5.9%) reported as verified by a doctor. Of these 122, 98 had been dispensed antiasthmatics during the preceding year (sensitivity 80.3%). Only 1.2% of the children without reported asthma were dispensed antiasthmatics. CONCLUSION Mother-reported use of antiasthmatics during the previous year among 7-year-old children is highly valid. Dispensed antiasthmatics would be a useful proxy for the presence of current asthma when disease data are not available.

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

IntroductionSeveral 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.MethodA 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.ResultsIn 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.ConclusionThere 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.

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

Background: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se. Objective: To examine the association between DM and cancers by a systematic review and meta-analysis according to the PRISMA guidelines. Data Sources: The systematic literature search includes Medline at PubMed, Embase, Cinahl, Bibliotek.dk, Cochrane library, Web of Science and SveMed+ with the search terms: “Diabetes mellitus”, “Neoplasms”, and “Risk of cancer”. Study Eligibility Criteria: The included studies compared the risk of cancer in diabetic patients versus non-diabetic patients. All types of observational study designs were included. Results: Diabetes patients were at a substantially increased risk of liver (RR=2.1), and pancreas (RR=2.2) cancer. Modestly elevated significant risks were also found for ovary (RR=1.2), breast (RR=1.1), cervix (RR=1.3), endometrial (RR=1.4), several digestive tract (RR=1.1-1.5), kidney (RR=1.4), and bladder cancer (RR=1.1). The findings were similar for men and women, and unrelated to study design. Meta-regression analyses showed limited effect modification of body mass index, and possible effect modification of age, gender, with some influence of study characteristics (population source, cancer- and diabetes ascertainment). Limitations: Publication bias seemed to be present. Only published data were used in the analyses. Conclusions: The systematic review and meta-analysis confirm the previous results of increased cancer risk in diabetes and extend this to additional cancer sites. Physicians in contact with patients with diabetes should be aware that diabetes patients are at an increased risk of cancer.

Comorbidities in an asthma population 8-29 years old: a study from the Norwegian Prescription Database

To examine the occurrence of chronic diseases and antimicrobial treatment in an asthma population 8–29 years old, compared with the general population.

Prenatal and infant paracetamol exposure and development of asthma: the Norwegian Mother and Child Cohort Study

BACKGROUND Paracetamol exposure has been positively associated with asthma development. The relative importance of prenatal vs infant exposure and confounding by indication remains elusive. We examined the association of prenatal and infant (first 6 months) paracetamol exposure with asthma development while addressing confounding by indication. METHODS We used information from the Norwegian Mother and Child Cohort Study, including 53169 children for evaluation of current asthma at 3 years, 25394 for current asthma at 7 years and 45607 for dispensed asthma medications at 7 years in the Norwegian Prescription Database. We calculated adjusted relative risks (adj. RR) and 95% confidence intervals (CI) using log-binomial regression. RESULTS There were independent modest associations between asthma at 3 years with prenatal paracetamol exposure (adj. RR 1.13; 95% CI: 1.02-1.25) and use of paracetamol during infancy (adj. RR 1.29; 95% CI: 1.16-1.45). The results were consistent for asthma at 7 years. The associations with prenatal paracetamol exposure were seen for different indications (pain, respiratory tract infections/influenza and fever). Maternal pain during pregnancy was the only indication that showed an association both with and without paracetamol use. Maternal paracetamol use outside pregnancy and paternal paracetamol use were not associated with asthma development. In a secondary analysis, prenatal ibuprofen exposure was positively associated with asthma at 3 years but not asthma at 7 years. CONCLUSIONS This study provides evidence that prenatal and infant paracetamol exposure have independent associations with asthma development. Our findings suggest that the associations could not be fully explained by confounding by indication.

Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort

Rationale: A potential adverse effect of high folate intake during pregnancy on childrens asthma development remains controversial. Objectives: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. Methods: This study included eligible children born 2002‐2006 from the Norwegian Mother and Child Cohort Study, a population‐based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log‐binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Measurements and Main Results: Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06‐1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241‐366 &mgr;g/d) and nearly all took at least 400 &mgr;g/d of supplemental folic acid (median, 500; interquartile range, 400‐600 &mgr;g/d). Conclusions: In this large prospective population‐based cohort with essentially complete follow‐up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children.

Prescribing of Drugs for Attention-Deficit Hyperactivity Disorder in Opioid Maintenance Treatment Patients in Norway

Background: Attention-deficit hyperactivity disorder (ADHD) is a risk factor for the development of substance use disorders. Treatment of ADHD with psychostimulants in patients on opioid maintenance treatment (OMT) has been restricted in Norway. We examined the use of prescribed drugs for ADHD in OMT patients and assessed co-medication with other psychotropics. Methods: Data were drawn from the nationwide Norwegian Prescription Database (NorPD), which includes all prescriptions filled at pharmacies. The study population included subjects ≥18 years on OMT during 2008-2010. Results: In 2010, 6,116 patients received OMT and 2.8% of these also received ADHD drugs. This percentage is seven times greater than that in the gender- and age-specific general population of Norway. The prevalence was higher in the youngest patients, while there was no gender difference. Methylphenidate was the most commonly used drug for ADHD in OMT patients, followed by atomoxetine. 60% of OMT patients filled at least one prescription for antidepressants, anxiolytics or hypnotics, and percentages were similar for users and non-users of ADHD drugs. Conclusion: Treatment with ADHD drugs was higher in OMT patients than expected from the general population, but was relatively low compared to the prevalence of ADHD in patients with substance use disorders reported in the literature.

Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium

Importance Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety. Objective To examine the risk of congenital malformations associated with intrauterine exposure to stimulants. Design, Setting, and Participants Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017. Exposures Methylphenidate and amphetamines dispensed during the first trimester. Main Outcomes and Measures Major congenital malformations and subgroup of cardiac malformations. Results In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64). Conclusions and Relevance These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.