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)

The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis

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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

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)

Etiological aspects of gastroesophageal cancers : An epidemiological approach

Aims: The aims of this thesis were to study the association of overall dietary habits, duodenal ulcer and gastric ulcer diseases, as two models of Helicobacter pylori (H. pylori) infection and the development of gastroesophageal cancers to further explore the etiology of these malignancies. Moreover, the association between parity, a proxy for high level of female hormones, and stomach cancer risk was studied to shed light on the enigma of male predominance in this cancer. Methods: In a nationwide population-based case-control study in Sweden with 165 esophageal squamous cell carcinoma, 185 esophageal adenocarcinoma and 258 cardia cancer cases and 815 randomly selected controls we estimated relative risks associated with dietary patterns. Furthermore, cohorts of 61,548 and 81,379 unoperated patients with duodenal ulcer and gastric ulcer, respectively, recorded in the Swedish Inpatient Register since 1965, were followed and standardized incidence ratios were estimated for esophageal cancer by histology, compared with the Swedish general population. We also followed cohorts of 59,550 and 79,412 unoperated patients with duodenal ulcer and gastric ulcer, respectively, plus 12,840 patients with partial gastric resection and 8,105 with vagotomy, recorded since 1970. We estimated relative risks for stomach cancer by anatomical subtype compared to the Swedish general population for unoperated cohorts, whereas relative risks were estimated among operated patients relative to unoperated ones with the same ulcer type. Finally, in a case-control study, nested within a cohort of Swedish women born in 1925 or later, with 286 cardia cancer and 2,498 non-cardia stomach cancer as well as corresponding 1,430 and 12,490 controls, we investigated the relationship between parity and risk of stomach cancer by anatomic subsite. Results: A healthy diet tended to moderately decrease the risk of esophageal and cardia cancers, Western diet increased risks of cardia cancer and esophageal adenocarcinoma, whereas a dietary pattern characterized by high beer and liquor intake significantly increased the risk of squamous-cell carcinoma of the esophagus. We observed that patients with duodenal ulcer had a significant 70% excess risk of esophageal adenocarcinoma, a nonsignificant small excess risk of esophageal squamous cell carcinoma, a halved risk of noncardia cancer, and a risk of cardia cancer slightly above expectation. Gastric ulcer was unrelated to esophageal adenocarcinoma but linked to 80% increased risk of esophageal squamous cell carcinoma, and doubled risks for both anatomical types of stomach cancer. Duodenal ulcer patients who underwent gastric resection had a 60% risk elevation for noncardia cancer compared to unoperated ones. Vagotomy was associated with a greater risk in the first 10 years, but this excess disappeared with further follow-up. Resected gastric ulcer patients had a 40% risk reduction for non-cardia cancer relative to their unoperated peers. We found no association between parity and risk of non-cardia stomach cancer comparing everparous women with nulliparous, whereas a statistically significant 30% risk reduction for postmenopausal cardia cancer was noted among ever-parous women relative to nulliparous. Conclusions: Overall dietary habits seem to play an important role in the carcinogenesis of esophageal and cardia cancer. The well-established strong inverse association of H. pylori seropositivity and risk of esophageal adenocarcinoma does not pertain to all infections. The duodenal ulcer related protection against stomach cancer does not seem to affect cardia cancer. It seems that the pattern of stomach colonization and/or the clinical consequences in the stomach might play a pivotal role in the long term outcome of H. pylori infection. With gastric resection, risks are shifted toward normality, regardless of underlying ulcer type. Exposure to female sex hormones is not associated with protection against stomach cancer and does not seem to explain the male predominance for such cancer. However the observed moderate inverse relationship between parity and cardia cancer might be mediated by other factors than hormonal