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. 2017 May 29;5(1):e000364.
doi: 10.1136/bmjdrc-2016-000364. eCollection 2017.

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

Helen Strongman  1 , Pasi Korhonen  2 , Rachael Williams  1 , Shahram Bahmanyar  3 , Fabian Hoti  2 , Solomon Christopher  2 , Maila Majak  2 , Leanne Kool-Houweling  4 , Marie Linder  3 , Paul Dolin  5 , Edith M Heintjes  4
Affiliations

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

Helen Strongman et al. BMJ Open Diabetes Res Care. .

Abstract

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.

Keywords: Electronic Medical Records; Mortality; Pioglitazone; Type 2 Diabetes.

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Conflict of interest statement

Competing interests: All authors have completed the Unified CompetingInterest form at (available on request from the corresponding author) and declare that PK, FH,SC, and MM are employed by EPID Research, EH is and LKH was employed by PHARMOInstitute, RW and HS are employed by CPRD, and ML and SB are employed byKarolinska Institute. EPID Research, PHARMO Institute, CPRD and KarolinskaInstitute perform commissioned pharmacoepidemiological studies and thus theiremployees have been and currently are working in collaboration with severalpharmaceutical companies (including Takeda). PD is employed by Takeda

Figures

Figure 1
Figure 1
Kaplan-Meier plot of association of exposure to pioglitazone with all-cause mortality in patients with type 2 diabetes. Never: never exposed to pioglitazone. Ever: exposed to pioglitazone.
Figure 2
Figure 2
Number of events, the crude incidence rate, and the crude and adjusted HR with 95% CI for the association between pioglitazone use and all-cause mortality. Crude model: pioglitazone exposure variable and a dataset identifier. Adjusted model: Crude model plus, age, gender, use of metformin, use of sulphonylureas, use of insulin, and use of other antidiabetic drugs, all exact matching variables, propensity scores as quintiles, all propensity score variables evaluated at cohort entry date.
Figure 3
Figure 3
Adjusted HRs with 95% CI for the association between pioglitazone use and all-cause mortality for each dataset. The HRs and 95% CIs are presented in the original scale and the figure is plotted in the log scale. FIN, Finland; SWE, Sweden; United Kingdom GP, UK general practitioner; UK GP-HOSP, UK linked dataset; NL HOSP, Netherlands hospital data; NL GP, NL general practitioner.
Figure 4
Figure 4
Adjusted HRs with 95% CI for the association between pioglitazone use and all-cause mortality stratified by key variables. CED, cohort entry date; CHF, congestive heart failure; TZD, thiazolidinedione.
See this image and copyright information in PMC

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