Use of postmenopausal hormone therapy and risk of Alzheimer's disease in Finland : nationwide case-control study

OBJECTIVES To compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer's disease. DESIGN Nationwide case-control study. SETTING Finnish national population and drug register, between 1999 and 2013. PARTICIPANTS All postmenopausal women (n= 84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer's disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n= 84 739), matched by age and hospital district, were traced from the Finnish national population register. INTERVENTIONS Data on hormone therapy use were obtained from the Finnish national drug reimbursement register. MAIN OUTCOME MEASURES Odds ratios and 95% confidence intervals for Alzheimer's disease, calculated with conditional logistic regression analysis. RESULTS In 83 688 (98.8%) women, a diagnosis for Alzheimer's disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer's disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (noreth isterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer's disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01). CONCLUSIONS Long term use of systemic hormone therapy might be accompanied with an overall increased risk of Alzheimer's disease, which is not related to the type of progestogen or the age at initiation of systemic hormone therapy. By contrast, use of vaginal estradiol shows no such risk. Even though the absolute risk increase for Alzheimer's disease is small, our data should be implemented into information for present and future users of hormone therapy.Peer reviewe

Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study.

OBJECTIVES: Describe and compare the risk of cardiovascular and non-cardiovascular mortality in patients whose antidiabetic therapy is modified to include pioglitazone compared with an alternative antidiabetic medication at the same stage of disease progression. RESEARCH DESIGN AND METHODS: This exploratory linked database cohort analysis used pooled health and mortality data from three European countries: Finland, Sweden and the UK. Propensity score together with exact matching was used to match 31 133 patients with type 2 diabetes first prescribed pioglitazone from 2000 to 2011, to 31 133 patients never prescribed pioglitazone. Exact matching variables were treatment stage, history of diabetes, diabetes complications and cardiovascular disease, and year of cohort entry. Mean follow-up time was 2.60 (SD 2.00) and 2.69 (SD 2.31) years in the pioglitazone and non-pioglitazone-exposed groups, respectively. Crude cause-specific mortality rates were ascertained. Association with pioglitazone use was estimated using Cox proportional hazards models adjusted a priori for country, age, sex, the propensity score quintile and time-dependent variables representing use of antidiabetic drugs. Stepwise testing identified no additional confounders to include in adjusted models. RESULTS: The crude mortality rate was lower in the pioglitazone-exposed group than the non-exposed group for both cardiovascular and non-cardiovascular mortality. Adjusted HRs comparing pioglitazone to alternative antidiabetic exposure were 0.58 (95% CI 0.52 to 0.63) and 0.63 (95% CI 0.58 to 0.68) for cardiovascular and non-cardiovascular mortality, respectively. A protective effect associated with pioglitazone was also found for all specific cardiovascular causes. CONCLUSIONS: This analysis suggests that pioglitazone is associated with a decrease in both cardiovascular and non-cardiovascular mortality. Results should be interpreted with caution due to the potential for residual confounding in this exploratory analysis. Further studies, specifically designed to test the association between pioglitazone use and patient-focused outcomes, are suggested. STUDY REGISTRATION NUMBER: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; EUPAS3626)

All-Cause and Cause-Specific Mortality among Users of Basal Insulins NPH, Detemir, and Glargine

Background Insulin therapy in type 2 diabetes may increase mortality and cancer incidence, but the impact of different types of basal insulins on these endpoints is unclear. Compared to the traditional NPH insulin, the newer, longer-acting insulin analogues detemir and glargine have shown benefits in randomized controlled trials. Whether these advantages translate into lower mortality among users in real life is unknown. Objective To estimate the differences in all-cause and cause-specific mortality rates between new users of basal insulins in a population-based study in Finland. Methods 23 751 individuals aged >= 40 with type 2 diabetes, who initiated basal insulin therapy in 2006-2009 were identified from national registers, with comprehensive data for mortality, causes of death, and background variables. Propensity score matching was performed on characteristics. Follow-up time was up to 4 years (median 1.7 years). Results 2078 deaths incurred. With NPH as reference, the adjusted HRs for all-cause mortality were 0.39 (95% CI, 0.30-0.50) for detemir, and 0.55 (95% CI, 0.44-0.69) for glargine. As compared to glargine, the HR was 0.71 (95% CI, 0.54-0.93) among detemir users. Compared to NPH, the mortality risk for both cardiovascular causes as well as cancer were also significantly lower for glargine, and especially for detemir in adjusted analysis. Furthermore, the results were robust in various sensitivity analyses. Conclusion In real clinical practice, mortality was substantially higher among users of NPH insulin as compared to insulins detemir or glargine. Considering the large number of patients who require insulin therapy, this difference in risk may have major clinical and public health implications. Due to limitations of the observational study design, further investigation using an interventional study design is warranted.Peer reviewe

Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries

Introduction: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. Objective: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. Methods: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005–2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel–Haenszel (MH) meta-analyses. Results: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98–1.34) for major congenital malformations and 1.72 (1.02–2.91) for stillbirth, which attenuated to 1.25 (0.74–2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03–1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67–1.42) for autism spectrum disorders, and 1.00 (0.78–1.29) for intellectual disability. Conclusions: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.publishedVersio

Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries.

OBJECTIVE:  To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes. DESIGN:  Retrospective cohort study using propensity score matched cohorts. SETTINGS:  Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths. PARTICIPANTS:  Patients with type 2 diabetes who initiated pioglitazone (n=56 337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317 109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation. MAIN OUTCOME MEASURES:  Hazard ratios and 95% confidence intervals were estimated by Cox's proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed. RESULTS:  In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40 000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort). CONCLUSIONS:  This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period. TRIAL REGISTRATION:  Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626)

Pioglitazone and risk of mortality in patients with type 2 diabetes: results from a European multidatabase cohort study.

OBJECTIVES: Estimate and compare the risk of mortality in patients whose antidiabetic therapy is modified to include pioglitazone compared with an alternative antidiabetic medication at the same stage of disease progression. DESIGN: Retrospective cohort study. SETTING: Pooled analysis of clinical data collected from primary and/or secondary care settings in four European countries: Finland, The Netherlands, Sweden and the UK . PARTICIPANTS: 56 337 patients with type 2 diabetes mellitus first prescribed pioglitazone between 2000 and 2011, and 56 337 patients never prescribed pioglitazone matched by treatment stage, history of diabetes, diabetes complications and cardiovascular disease, and year of cohort entry using exact and propensity score matching. Patients were followed-up for a mean of 2.90 (SD 2.21) and 2.83 (SD 2.37) years in the pioglitazone-exposed and non-pioglitazone-exposed groups, respectively. OUTCOMES: All-cause mortality ascertained from clinical or registry data. Mortality was a planned secondary outcome in a study primarily studying the association of pioglitazone use with bladder cancer risk. RESULTS: The crude overall mortality rate per 10 000 patient years was 206 (95% CI 199 to 213) in the pioglitazone-exposed group and 448 (95% CI 438 to 458) in the non-pioglitazone-exposed group. The crude HR comparing pioglitazone to alternative antidiabetic exposure was 0.46 (95% CI 0.45 to 0.48). This reduced in magnitude to 0.67 (95% CI 0.64 to 0.70) following further adjustment for matching variables, propensity scores, age, gender and time-dependent variables representing use of alternative antidiabetic drugs. CONCLUSIONS: In this large observational cohort study of patients with type 2 diabetes, pioglitazone exposure was associated with a statistically significant decrease in the risk of all-cause mortality across four European countries. Results should be interpreted with caution due to the potential for residual confounding. PROTOCOL REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

Clustering of serotypes in a longitudinal study of Streptococcus pneumoniae carriage in three day care centres

<p>Abstract</p> <p>Background</p> <p><it>Streptococcus pneumoniae </it>(pneumococcus) causes a wide range of clinical manifestations that together constitute a major burden of disease worldwide. The main route of pneumococcal transmission is through asymptomatic colonisation of the nasopharynx. Studies of transmission are currently of general interest because of the impact of the new conjugate-polysaccharide vaccines on nasopharyngeal colonisation (carriage). Here we report the first longitudinal study of pneumococcal carriage that records serotype specific exposure to pneumococci simultaneously within the two most important mixing groups, families and day care facilities.</p> <p>Methods</p> <p>We followed attendees (N = 59) with their family members (N = 117) and the employees (N = 37) in three Finnish day care centres for 9 months with monthly sampling of nasopharyngeal carriage. Pneumococci were cultured, identified and serotyped by standard methods.</p> <p>Results</p> <p>Children in day care constitute a core group of pneumococcal carriage: of the 36 acquisitions of carriage with documented exposure to homologous pneumococci, the attendee had been exposed in her/his day care centre in 35 cases and in the family in 9 cases. Day care children introduce pneumococci to the family: 66% of acquisitions of a new serotype in a family were associated with simultaneous or previous carriage of the same type in the child attending day care. Consequently, pneumococcal transmission was found to take place as micro-epidemics driven by the day care centres. Each of the three day care centres was dominated by a serotype of its own, accounting for 100% of the isolates of that serotype among all samples from the day care attendees.</p> <p>Conclusion</p> <p>The transmission of pneumococci is more intense within than across clusters defined by day care facilities. The ensuing micro-epidemic behaviour enhances pneumococcal transmission.</p