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Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study
  1. Helen Strongman1,
  2. Solomon Christopher2,
  3. Maila Majak2,
  4. Rachael Williams1,
  5. Shahram Bahmanyar3,
  6. Marie Linder3,
  7. Edith M Heintjes4,
  8. Dimitri Bennett5,
  9. Pasi Korhonen2,6,
  10. Fabian Hoti6
  1. 1 Clinical Practice Research Datalink (CPRD), London, UK
  2. 2 EPID Research, Helsinki, Finland
  3. 3 Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden
  4. 4 PHARMO Institute, Utrecht, The Netherlands
  5. 5 Department of Pharmacoepidemiology, Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts, USA
  6. 6 EPID Research, Espoo, Finland
  1. Correspondence to Dr Fabian Hoti; fabian.hoti{at}


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).

  • mortality
  • Pioglitazone
  • Cardiovacsular Disease(s)

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  • Contributors All authors planned and designed this post-hoc analysis. SC, MM, ML, RW and HS performed the data management and data analysis, and all authors interpreted the data. All authors drafted the manuscript, revised the paper critically for important intellectual content and approved the final version of the manuscript. PK supervised the analysis and is the guarantor.

  • Funding Takeda Develop­ment Centre Europe Ltd.

  • Competing interests PK, FH, SC and MM are employed by EPID Research, EMH is employed by PHARMO Institute, RW and HS are employed by CPRD, and ML and SB are employed by Karolinska Institute. EPID Research, PHARMO Institute, CPRD and the Centre for Pharmacoepidemiology (CPE) at Karolinska Institute perform commissioned pharmacoepidemiological studies and thus their employees have been and currently are working in collaboration with several pharmaceutical companies (including Takeda). DB is employed by Takeda Pharmaceutical Company Limited.

  • Ethics approval In Finland, the study protocol was approved by the Ethical Review Board of the Hjelt Institute, University of Helsinki Medical Faculty (Dnro 96/13/00/2013). The research permission numbers to use the data were obtained from Statistics Finland (Dnro TK/53-373-13), National Institute for Health and Welfare (Dnro THL/634/5.05.00/2016), Social Insurance Institute (Dnro Kela 25/522/2013), Population Register Centre (Dnro 726/410/13). In Sweden, the study was approved by the Regional Ethical Review Board at Karolinska Institute in Stockholm, Sweden. DNR: 2011/82-31/3, 2011/752-323 and 2013/347-32. In the UK, the study protocol was reviewed and approved by the Independent Scientific Advisory Committee (ISAC) which considers and provides advice to the Medicines and Healthcare products Regulatory Agency on research projects which propose the use of data obtained from the CPRD (ISAC protocol numbers 13_044 and 14_065). In the Netherlands, the PHARMO compliance committee approved use of the PHARMO Database Network for the study and confirmed no ethics approval was needed.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Criteria and process for sharing the analytical country specific datasets and meta-analysis dataset for third parties are defined in the study protocol available at the ENCePP E-Register of Studies.

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