Advertisement

Drugs - Real World Outcomes

, Volume 6, Issue 3, pp 133–140 | Cite as

Post-authorisation Safety Study of Pioglitazone Use and Safety Endpoints of Interest in Denmark After Direct Healthcare Professional Communication

  • Javier Cid RuzafaEmail author
  • Sinna Pilgaard Ulrichsen
  • Dimitri Bennett
  • Vera Ehrenstein
Open Access
Short Communication
  • 346 Downloads

Abstract

Introduction

A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values.

Methods

This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011–2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated.

Results

There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone.

Conclusions

Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.

Key Points

A drug utilisation study in Denmark was requested by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) and conducted to assess compliance with prescribing information following pioglitazone labelling changes on haematuria, bladder cancer and guidance on monitoring treatment effectiveness approved in Europe in July 2011.

The number of pioglitazone users in Denmark was low and decreased over time.

Based on the small numbers of pioglitazone users in Denmark over a 4-year period, no inference can be made confidently on the risks of heart failure, bladder cancer or haematuria from exposure to pioglitazone treatment.

1 Introduction

Pioglitazone is an oral drug of the thiazolidinedione class that is indicated for glycaemic control in type 2 diabetes mellitus (T2DM) [1]. Pioglitazone is usually prescribed as second-line therapy in combination with metformin [2, 3, 4].

A potential excess risk of bladder cancer (BC) associated with pioglitazone exposure was identified in patients in the PROspective pioglitAzone Clinical Trial In macrovascular Events (PROactive) trial. In PROactive, cases of BC were reported in 14 patients treated with pioglitazone (n = 2605) versus six on placebo (n = 2633) over an average observation time of 34.5 months. After blinded review, 11 cases were excluded as they could not plausibly be related to treatment (six pioglitazone vs. three placebo) [5]. The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) confirmed in July 2011 that pioglitazone is a “valid treatment option for certain patients with T2DM”, while acknowledging “that there is a small increased risk of BC in patients taking these medicines” [6]. Prescribers were advised not to use pioglitazone-containing medicines in patients with concurrent or a history of BC or with uninvestigated macroscopic haematuria, and to start elderly patients on the lowest possible dose, as they are at a higher risk of BC, as well as heart failure (HF) [7].

A Direct Healthcare Professional Communication (DHPC) was sent to Danish prescribers on 11 August 2011 providing information on updated pioglitazone labelling. According to data from Danish health registers, in 2011 there were 306,624 patients with diabetes, and 90% of them had T2DM [8, 9]. According to published statistics by the Danish Health Data Authority, in 2011 there were 310 pioglitazone users in Denmark, compared with 350, 380 and 255 in 2008, 2009 and 2010, respectively [10]. This drug utilisation study in Denmark was conducted to assess compliance with prescribing information following pioglitazone labelling changes on haematuria, BC and guidance on monitoring treatment effectiveness approved in Europe in July 2011.

This study had the following aims:
  1. 1.

    To describe the number of incident and prevalent users of pioglitazone in Denmark after the DHPC on 11 August 2011 and their glucose-lowering treatment patterns.

     
  2. 2.

    To quantify the number and proportion of pioglitazone users (incident and prevalent separately) who ceased pioglitazone treatment following a diagnosis of BC or following uninvestigated macroscopic haematuria.

     
  3. 3.

    To estimate the incidence rate of HF in incident and prevalent pioglitazone users who had no prior history of HF.

     
  4. 4.

    To describe glycated haemoglobin (HbA1c) results and other parameters relevant to the effectiveness of T2DM treatment and discontinuation of pioglitazone use due to therapy failure.

     

2 Methods

2.1 Study Design

We conducted a cohort study describing patient characteristics available at index date to assess indicators of pioglitazone utilisation, and a descriptive analysis of the patient cohort over the follow-up period to address the other objectives. Index date was the date of first dispensing of pioglitazone or insulin between 11 August 2011 and 31 December 2015 for incident users and 11 August 2011 for prevalent users. Pioglitazone and insulin are two alternative second-line therapies that can be added to metformin and lifestyle changes [11]. Results from insulin users are included to provide context for interpreting findings in pioglitazone.

2.2 Data Sources

This study was conducted using prospectively collected data from:
  1. 1.

    The Danish Civil Registration System, which since 1968 has provided unique identifiers for linkage, date of birth, sex and vital status [12, 13].

     
  2. 2.

    The Danish National Patient Registry, which since 1977 has included information on hospital admission and discharge dates with discharge diagnoses, and from 1995 outpatient specialist clinic visits were included (diagnoses coded using the International Classification of Diseases 10th Revision [ICD-10] from 1994 onwards) [14, 15].

     
  3. 3.

    The Danish Health Services Prescription Database, which holds information on reimbursed dispensings, including purchase date, Anatomical Therapeutic Chemical classification code and package size for every reimbursed dispensing at a community pharmacy since 2004 [16].

     
  4. 4.

    The Clinical Laboratory Information Systems research database, which contains laboratory test results of patients in North and Central Denmark Regions (approximately one-third of the population in Denmark) [17].

     

2.3 Study Population and Period

The source population was the entire population from Denmark (for laboratory data, it was residents of the North and Central Denmark regions). Incident users of pioglitazone were patients with a diagnosis of T2DM (ICD-10 E11) in their baseline period (from 1995 up to index date), one or more dispensings of pioglitazone between 11 August 2011 and 31 December 2015, and no dispensing of pioglitazone in the 12 months before index date. Prevalent users of pioglitazone were patients with a diagnosis of T2DM, one or more dispensings of pioglitazone from 11 August 2011 to 31 December 2015, and at least one pioglitazone dispensing in the 12 months before 11 August 2011. Incident and prevalent insulin user cohorts were similarly defined.

Patients were excluded if they had a diagnosis of type 1 diabetes mellitus (T1DM) in their record or were diagnosed with T2DM before 40 years of age (to prevent incorrectly capturing T1DM misdiagnosed in the database). Patients in the insulin cohorts were also excluded if they had a pioglitazone dispensing recorded during the 12 months prior to their study period, and they were censored and included into the corresponding pioglitazone cohort if a pioglitazone dispensing was observed during the study period.

The follow-up period for each patient extended from index date to the earliest date of death, emigration or end of study period (31 December 2015) or first pioglitazone dispensing (for the insulin users who switched to the incident pioglitazone users group during the study period).

2.4 Study Variables

Exposure of interest to pioglitazone or insulin starts at index date and duration of exposure (dispensing length) is computed from the number of days supplied, based on the dispensed amount and the corresponding defined daily dose (DDD). Duration of exposure from subsequent dispensing is similarly computed, starting at each dispensing date. Exposure ends at the time of treatment discontinuation, switch to another glucose-lowering medication (GLM), or end of follow-up.

Treatment patterns identified in the applicable cohorts were:
  1. 1.

    First-line pioglitazone treatment: Use of pioglitazone without previous GLM in the 12 months prior or longer. First-line insulin treatment was similarly defined.

     
  2. 2.

    Persistence: Continued treatment for at least 12 months after index date.

     
  3. 3.

    Discontinuation of pioglitazone therapy: Absence of new pioglitazone dispensing for 180 days after the expiration of the DDD supplied in all pioglitazone dispensings.

     
  4. 4.

    Overlap of dispensing drug supplies: Two different prescriptions with days of supply overlapping.

     
  5. 5.

    Switch of medication: A dispensing of another GLM than the one received at index date (pioglitazone or insulin), without overlap and within 60 days after expiry of the last dispensing.

     
  6. 6.

    Augmentation/co-medication: A dispensing during the study period of a GLM (other than pioglitazone/insulin as applicable) with at least 1 day’s overlap with the pioglitazone or insulin dispensing. First augmentation was recorded.

     

Co-morbidities and endpoints of interest were HF (defined as a recorded code for HF plus initiation of a loop diuretic within 90 days of diagnosis), BC, haematuria (excluding or including recurrent haematuria), and uninvestigated macroscopic haematuria (patients with a recording of haematuria, but without a subsequent laboratory urine assessment, antibiotic treatment, magnetic resonance imaging of the bladder, ultrasounds, urinary calculi, or referral to a hospital-based urologist; required to be within the prior 90 days).

Other variables of interest included patient sex, age, co-morbidities, GLM and laboratory test results data (HbA1c and lipid profile).

2.5 Statistical Analysis

Numbers of incident and prevalent pioglitazone and insulin users in the T2DM cohort were reported and their characteristics described using summary statistics. Duration of pioglitazone use after index date was described as the median and the mean (standard deviation [SD]) number of months.

The number and proportion (%) of incident pioglitazone users after 11 August 2011 with a history of BC (ever) or uninvestigated macroscopic haematuria (within the prior 90 days) were assessed. The number of patients with a new diagnosis of BC or haematuria who ceased or continued pioglitazone treatment after the DHPC on 11 August 2011 was calculated.

The number and proportion (%) of patients with HF occurring after index date (excluding patients with prior HF) were calculated. Incidence rates for HF during and after treatment with pioglitazone and co-medication with insulin were calculated. All estimates were provided with 95% confidence intervals (CIs).

For patients with available laboratory data, most recent levels in the 12 months pre-index date and over 6 months post-index date, HbA1c levels (mean [SD]) and lipid levels (LDL, HDL, plasma triglycerides, total cholesterol) were described.

Selected analyses were stratified by age (< 65 and ≥ 65 years) and sex; all analyses were conducted using SAS software, version 9.2 (Cary, NC, USA).

Recent regulations from the data-source custodians in Denmark require masking counts of < 5 and the corresponding relative frequencies, whether observed or computable from the remaining data, to prevent identification of individuals.

3 Results

In 2011, 2012, 2013, 2014 and 2015, the numbers of persons with at least one community pharmacy dispensing of pioglitazone were, respectively, 310, 250, 215, 155 and 100 [10]. Between 11 August 2011 and 31 December 2015, the following groups were identified: 80 incident pioglitazone users; 17,699 incident insulin users; 140 prevalent pioglitazone users and 13,183 prevalent insulin users. Demographic characteristics, co-morbidities and co-medications of the four study cohorts at index date are described (Table 1).
Table 1

Patient demographics, co-morbidities and co-medications at index date

 

Incident pioglitazone users

Incident insulin users

Prevalent pioglitazone users

Prevalent insulin users

N

%

N

%

N

%

N

%

No. of users

80

100.0

17,699

100.0

140

100.0

13,183

100.0

< 65 years

47

58.7

7556

42.7

59

42.1

5525

41.4

≥ 65 years

33

41.2

10,143

57.3

81

57.9

7658

58.1

Men

45

56.2

10,800

61.0

87

62.1

7796

59.1

Women

35

43.7

6899

39.0

53

37.9

5387

40.9

Age (median, P25–P75, years)

62.4 (55.5–69.3)

67.2 (58.4–75.4)

66.0 (58.2–74.1)

66.8 (60.2–74.1)

Alcohol disorders

5

6.3

975

5.5

< 5

2.x

485

3.7

Heart failure

< 5

≤ 5.0a

1949

11.0

7

5.0

931

7.1

Bladder cancer

0

0.0

139

0.8

0

0.0

66

0.5

Haematuria (inclusive)

< 5

≤ 5.0

1135

6.4

11

7.8

573

4.35

Uninvestigated haematuria

0

0.0

11

0.1

0

0.0

< 5

0.0

Hypertension

26

32.5

7570

44.8

58

41.4

4989

37.8

Chronic kidney disease

< 5

≤ 5.0

969

5.5

< 5

< 1.5

305

2.3

Myocardial infarction

< 5

≤ 5.0

1752

9.9

7

5.0

1043

7.9

Lipid-lowering agents

60

75.0

13,604

76.9

122

87.1

11,434

86.7

Antiplatelet agents

37

46.3

10,186

57.6

63

45.0

8318

63.1

Diuretics

38

47.5

10,111

57.1

75

53.6

7630

57.9

Beta blockers

22

27.5

7458

42.1

45

32.1

4948

37.5

Calcium channel blockers

32

40.0

7939

44.9

64

45.7

6308

47.9

ACE inhibitors

46

57.5

10,830

61.2

94

67.1

8919

67.7

AR blockers

53

66.3

13,044

73.7

120

85.7

10,785

81.8

Insulins and analogues

< 5

≤ 5.0

17,699

100.0

6

4.29

13,183

100.0

ACE angiotensin-converting enzyme, AR angiotensin II receptor

aCertain values or their proportions masked to avoid identification of individuals

Median follow-up time on pioglitazone after index date was 5.3 months for incident and 26.2 months for prevalent pioglitazone users. Mean [SD] follow-up time after index date was 8.3 [9.2] months for incident and 23.5 [14.3] months for prevalent pioglitazone users. Pioglitazone was rarely the first-line GLM. During follow-up, 65.0% of incident and 65.7% of prevalent pioglitazone users switched to another GLM, and 80.0% or more in both pioglitazone cohorts had augmentation with another GLM. Among 80 incident pioglitazone users, 23 (28.8%) discontinued pioglitazone during the follow-up; among 140 prevalent pioglitazone users, 29 (20.7%) discontinued pioglitazone during follow-up (Table 2).
Table 2

Antidiabetic treatment patterns of pioglitazone users after index date

 

Incident pioglitazone users

Prevalent pioglitazone users

N

%

N

%

No. of users in study period

80

100.0

140

100.0

First-line pioglitazone

< 5a

≤ 5.0

14

10.0

Persistence

18

22.5

99

70.7

Discontinuation

23

28.8

29

20.7

Switching

52

65.0

92

65.7

Augmentation

64

80.0

125

89.3

Duration of pioglitazone treatment until discontinuation (median, P25–P75, in months)

4.3 (1.4–13.1)

25.0 (10.9–28.9)

Duration of pioglitazone treatment until switching (median, P25–P75, in months)

4.6 (1.6–11.4)

26.2 (9.1–28.8)

Duration of pioglitazone treatment until augmentation (median, P25–P75, in months)

0.3 (0.0–1.0)

0.9 (0.4–1.6)

aCertain values or their portions masked to avoid identification of individuals

There was no history of BC (since 1995) or uninvestigated macroscopic haematuria (within 90 days of index date) in either of the pioglitazone cohorts. History of any haematuria (since 1995) was seen in less than five of the 80 incident and in 11 of the 140 prevalent pioglitazone users. There was no new diagnosis of BC among incident pioglitazone users during the follow-up and among prevalent pioglitazone users less than five cases were recorded, all of them after treatment with pioglitazone had been stopped. During follow-up, no cases of uninvestigated macroscopic haematuria were noticed.

There were less than five cases of HF among 77 pioglitazone incident users (incidence rate of 9/1000 person-years [95% confidence interval (CI): 2, 34]) and less than five cases of HF among 133 pioglitazone prevalent users without a history of HF (incidence rate of 2/1000 person-years [95% CI: 0, 13]).

HbA1c measurements (Table 3) preceding the index date were present in 95.0% of incident and 92.3% of prevalent pioglitazone users. Median HbA1c at index date was 8.8% and 7.6% in the incident and prevalent insulin cohorts, respectively. Considering HbA1c ≥ 7.5% as inadequate glycaemic control, 61.8% of pioglitazone users were inadequately controlled.
Table 3

Laboratory test results among users of pioglitazone with measurements pre-index and 6 months post-index (North and Central Denmark Regions)

Median (P25–P75)

Incident pioglitazone users

Prevalent pioglitazone users

Pre-index

 HbA1c (%)

7.8 (7.5–8.9)

7.5 (6.9–8.2)

 LDL (mmol/L)

2.1 (1.7–2.4)

1.9 (1.6–2.7)

 HDL (mmol/L)

1.2 (0.9–1.6)

1.2 (1.0–1.4)

 Plasma triglycerides (mmol/L)

2.2 (1.6–2.7)

1.8 (1.2–2.2)

 Total cholesterol (mmol/L)

4.3 (3.9–4.6)

4.2 (3.5–4.7)

6 months post-index

 HbA1c (%)

7.7 (7.0–8.9)

7.4 (6.9–8.1)

 LDL (mmol/L)

1.9 (1.5–2.4)

2.0 (1.5–2.9)

 HDL (mmol/L)

1.2 (0.9–1.5)

1.3 (1.1–1.4)

 Plasma triglycerides (mmol/L)

2.1 (1.5–2.8)

1.8 (1.3–2.6)

 Total cholesterol (mmol/L)

3.9 (3.5–4.8)

4.1 (3.5–5.0)

HbA1c glycated haemoglobin, LDL low-density lipoprotein, HDL high-density lipoprotein

4 Discussion

This study reports on drug utilisation and incidence of safety endpoints of interest for patients with T2DM using pioglitazone after risk-minimisation measures were implemented by the EMA [6]. Because of the small number of observed pioglitazone users, no inference can be made regarding the incidence of endpoints of interest during follow-up in association with pioglitazone treatment. Approximately two-thirds of pioglitazone users had suboptimal glycaemic control. Since the DHPC in Denmark, the number of persons with at least one pioglitazone outpatient dispensing declined from 310 in 2011 to 100 in 2015. This is suggestive of clinicians responding to the new risk minimisation measures. Similar DHPC were issued in other European countries [18, 19, 20]. One study undertaken on several European healthcare data sources from Finland, the Netherlands, Sweden and the UK, in response to a request by EMA, reported 61,587 patients exposed to pioglitazone among 940,294 eligible patients in the period up to 2011, prior to the DHPC [21].

Over recent years multiple studies have reported results on the risk of BC on patients with diabetes exposed to pioglitazone, some of them suggesting an increased risk [22, 23, 24, 25] and some suggesting no risk [21, 26, 27, 28, 29]. Controversy remains [30], although the Food and Drug Administration (FDA) concluded that “Discrepant findings between studies, as well as between interim and final reports of the Kaiser Permanente Northern California and PROactive studies, combined with limitations in study design and the inherent difficulty of investigating moderate effect sizes in long latency endpoints, render the totality of evidence inconclusive” [31]. Treatment with pioglitazone is not recommended for patients with a medical history of BC or uninvestigated macroscopic haematuria. The lowest starting dose of pioglitazone is recommended for elderly patients.

The association between exposure to pioglitazone and increased incidence of HF has been described [32, 33] but not confirmed compared with other GLMs [34, 35, 36], and pioglitazone should not be used in patients with a history of HF [37] because it can cause dose-dependent fluid retention, which may exacerbate or precipitate HF [38].

Observational studies from real-world settings contribute to improved understanding of the effectiveness and safety of medicines in routine clinical practice [21, 39, 40]. Results from these studies supplement data from clinical trials and contribute to informed decisions.

The most important limitation of the analysis reported here is the small number of pioglitazone users, precluding meaningful inferences and resulting in high uncertainty around point estimates. This limitation derives from the declining number of pioglitazone users over the study period. Therefore, the current study size is not as large as originally expected. Future studies with a longer inclusion period or adding data from other countries could accrue larger numbers of pioglitazone users and produce precise estimates. Nevertheless, making findings of this European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) registered study publicly available contributes to full disclosure of results and future research efforts [41, 42].

As in similar studies, there are potential sources of systematic error. Selection bias is expected to be negligible because the Danish medical registries routinely capture data representing the entire population of Denmark. We are also confident about lab test data, which were only partially available, since Danish regions generally can be considered representative of the Danish population in terms of demographic and socioeconomic characteristics as well as healthcare utilization and medication use [43]. Information bias may have resulted from relying on dispensing information and the inability to ascertain the actual drug intake and its timing. Nevertheless, T2DM is a chronic condition requiring glucose-lowering treatment, including pioglitazone; hence, we assume that there is high correlation between drug dispensing and actual use. However, the exact time of treatment initiation or discontinuation is expected to be somehow misclassified. Additionally, interpretation of results and comparisons to other studies need to take into account the treatment pattern definitions used in the current study. Data on smoking status or body mass index were not recorded in the data sources we used; obesity diagnoses based only on hospital record information are likely to result in prevalence estimates discrepant with the true prevalence of obesity in the target study population. The presence of some risk factors for BC among pioglitazone users (e.g. smoking and occupational exposures) could not be assessed.

5 Conclusions

In summary, based on the small numbers of pioglitazone users in Denmark over a 4.4-year period, risk estimates of BC or HF or haematuria from exposure to pioglitazone treatment are small and imprecise because of low occurrence.

Notes

Acknowledgements

The authors would like to thank Sophie Graham and Chang Lu for editorial support and Dr Reimar W. Thomsen for clinical advice.

Compliance with Ethical Standards

Availability of data and material

The data that support the findings of this study are hosted by the population-based registries in Denmark described in the Methods section and can be accessed through the corresponding application procedure.

Conflict of interest

JCR is an employee of Evidera, a PPD business unit. DB is an employee of Takeda Pharmaceutical Company Limited. SPU and VE are salaried employees of Aarhus University/Aarhus University Hospital.

Ethics approval and consent to participate

This is a registry-based study committed with European Health Authorities, which uses anonymized data from secondary data sources and requires no patient contact. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Funding

This work was supported by the Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, through Evidera, and through a research grant to and administered by Aarhus University.

Author contributions

JCR, SPU, VE and DB made substantial contributions to the conception and design of the study. VE and SPU processed the data and conducted the statistical analyses. All authors interpreted the data. JCR wrote the first draft of the manuscript. All authors critically revised the manuscript, provided final approval and agree to be accountable for all aspects of the work.

References

  1. 1.
    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42.  https://doi.org/10.1007/s00125-014-3460-0.CrossRefPubMedGoogle Scholar
  2. 2.
    Christensen DH, Rungby J, Thomsen RW. Nationwide trends in glucose-lowering drug use, Denmark, 1999–2014. Clin Epidemiol. 2016;8:381–7.  https://doi.org/10.2147/clep.s113211.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Morgan CL, Poole CD, Evans M, Barnett AH, Jenkins-Jones S, Currie CJ. What next after metformin? A retrospective evaluation of the outcome of second-line, glucose-lowering therapies in people with type 2 diabetes. J Clin Endocrinol Metab. 2012;97(12):4605–12.  https://doi.org/10.1210/jc.2012-3034.CrossRefPubMedGoogle Scholar
  4. 4.
    Datta-Nemdharry P, Thomson A, Beynon J, Donegan K. Patterns of anti-diabetic medication use in patients with type 2 diabetes mellitus in England and Wales. Pharmacoepidemiol Drug Saf. 2017;26(2):127–35.  https://doi.org/10.1002/pds.4092.CrossRefPubMedGoogle Scholar
  5. 5.
    Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.  https://doi.org/10.1016/S0140-6736(05)67528-9.CrossRefGoogle Scholar
  6. 6.
    European Medicines Agency (EMA). European Medicines Agency recommends new contra-indications and warnings for pioglitazone to reduce small increased risk of bladder cancer. 2011. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001311.jsp&mid=WC0b01ac058004d5c1. Accessed 28 Jun 2017.
  7. 7.
    European Medicines Agency (EMA). Questions and answers on the review of pioglitazone containing medicines (Actos, Glustin, Competact, Glubrava and Tandemact). Outcome of a procedure under Article 20 of Regulation (EC) No 726/2004. 2011. https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-review-pioglitazone-containing-medicines-actos-glustin-competact-glubrava_en.pdf. Accessed 15 Apr 2019.
  8. 8.
    Green A, Sortso C, Jensen PB, Emneus M. Incidence, morbidity, mortality, and prevalence of diabetes in Denmark, 2000–2011: results from the Diabetes Impact Study. Clin Epidemiol. 2013;2015:7421–30.  https://doi.org/10.2147/CLEP.S88577.CrossRefGoogle Scholar
  9. 9.
    Jorgensen ME, Kristensen JK, Reventlov Husted G, Cerqueira C, Rossing P. The Danish adult diabetes registry. Clin Epidemiol. 2016;8:429–34.  https://doi.org/10.2147/clep.s99518.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Medstat.dk. 2017. http://medstat.dk/. Accessed 18 Jun 2019.
  11. 11.
    Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203.  https://doi.org/10.2337/dc08-9025.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pedersen CB. The Danish civil registration system. Scand J Public Health. 2011;39(7 Suppl):22–5.  https://doi.org/10.1177/1403494810387965.CrossRefGoogle Scholar
  13. 13.
    Schmidt M, Pedersen L, Sorensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol. 2014;29(8):541–9.  https://doi.org/10.1007/s10654-014-9930-3.CrossRefPubMedGoogle Scholar
  14. 14.
    Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sorensen HT. The Danish national patient registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–90.  https://doi.org/10.2147/clep.s91125.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health. 2011;39(7 Suppl):30–3.  https://doi.org/10.1177/1403494811401482.CrossRefGoogle Scholar
  16. 16.
    Johannesdottir SA, Horvath-Puho E, Ehrenstein V, Schmidt M, Pedersen L, Sorensen HT. Existing data sources for clinical epidemiology: the Danish national database of reimbursed prescriptions. Clin Epidemiol. 2012;4:303–13.  https://doi.org/10.2147/clep.s37587.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Grann AF, Erichsen R, Nielsen AG, Froslev T, Thomsen RW. Existing data sources for clinical epidemiology: the clinical laboratory information system (LABKA) research database at Aarhus University, Denmark. Clin Epidemiol. 2011;3:133–8.  https://doi.org/10.2147/clep.s17901.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Agenzia Italiana del Farmaco (AIFA). L’Agenzia Europea dei Medicinali raccomanda nuove controindicazioni e avvertenze per pioglitazone al fine di ridurre il lieve aumento di rischio di cancro alla vescica. 2011. http://www.agenziafarmaco.gov.it/sites/default/files/comunicato_stampa_pioglitazone.pdf. Accessed 15 Apr 2019.
  19. 19.
    Lilly, Takeda. Comunicacion Directa a los Profesionales de la Salud sobre la asociacion de pioglitazona con un ligera incremento del Riesgo de Cancer de Vejiga. 2011. https://sinaem.agemed.es/CartasFarmacovigilanciaDoc/2011/PIOGLITAZONA_CANCER_VEJIGA_30julio2011.pdf. Accessed 15 Apr 2019.
  20. 20.
    Takeda UK Ltd. Direct Healthcare Professional Communication on pioglitazone and a small increased risk of Urinary Bladder Cancer. 2011. https://www.hpra.ie/docs/default-source/Safety-Notices/dhpc-letter-roi-27july2011.pdf?sfvrsn=0. Accessed 15 Apr 2019.
  21. 21.
    Korhonen P, Heintjes EM, Williams R, Hoti F, Christopher S, Majak M, et al. Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. BMJ. 2016;354:i3903.  https://doi.org/10.1136/bmj.i3903.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645.  https://doi.org/10.1136/bmj.e3645.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013;30(9):1026–32.  https://doi.org/10.1111/dme.12144.CrossRefPubMedGoogle Scholar
  24. 24.
    Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia. 2012;55(7):1953–62.  https://doi.org/10.1007/s00125-012-2538-9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zhu Z, Shen Z, Lu Y, Zhong S, Xu C. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2012;98(1):159–63.  https://doi.org/10.1016/j.diabres.2012.05.006.CrossRefPubMedGoogle Scholar
  26. 26.
    Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone and the risk of bladder cancer: a meta-analysis. Diabetes Ther. 2017.  https://doi.org/10.1007/s13300-017-0273-4.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Levin D, Bell S, Sund R, Hartikainen SA, Tuomilehto J, Pukkala E, et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia. 2015;58(3):493–504.  https://doi.org/10.1007/s00125-014-3456-9.CrossRefPubMedGoogle Scholar
  28. 28.
    Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA. 2015;314(3):265–77.  https://doi.org/10.1001/jama.2015.7996.CrossRefPubMedGoogle Scholar
  29. 29.
    Wei L, MacDonald TM, Mackenzie IS. Pioglitazone and bladder cancer: a propensity score matched cohort study. Br J Clin Pharmacol. 2013;75(1):254–9.  https://doi.org/10.1111/j.1365-2125.2012.04325.x.CrossRefPubMedGoogle Scholar
  30. 30.
    Faillie JL, Hillaire-Buys D. Examples of how the pharmaceutical industries distort the evidence of drug safety: the case of pioglitazone and the bladder cancer issue. Pharmacoepidemiol Drug Saf. 2016;25(2):212–4.  https://doi.org/10.1002/pds.3925.CrossRefPubMedGoogle Scholar
  31. 31.
    Hampp C, Pippins J. Pioglitazone and bladder cancer: FDA’s assessment. Pharmacoepidemiol Drug Saf. 2017;26(2):117–8.  https://doi.org/10.1002/pds.4154.CrossRefPubMedGoogle Scholar
  32. 32.
    Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007;30(11):2773–8.  https://doi.org/10.2337/dc07-0717.CrossRefPubMedGoogle Scholar
  33. 33.
    Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7(1):e013927.  https://doi.org/10.1136/bmjopen-2016-013927.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Breunig IM, Shaya FT, McPherson ML, Snitker S. Development of heart failure in Medicaid patients with type 2 diabetes treated with pioglitazone, rosiglitazone, or metformin. J Manag Care Spec Pharm. 2014;20(9):895–903.  https://doi.org/10.18553/jmcp.2014.20.9.895.CrossRefPubMedGoogle Scholar
  35. 35.
    Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46(2):145–54.  https://doi.org/10.1007/s00592-008-0090-3.CrossRefPubMedGoogle Scholar
  36. 36.
    Filion KB, Joseph L, Boivin JF, Suissa S, Brophy JM. Thiazolidinediones and the risk of incident congestive heart failure among patients with type 2 diabetes mellitus. Pharmacoepidemiol Drug Saf. 2011;20(8):785–96.  https://doi.org/10.1002/pds.2165.CrossRefPubMedGoogle Scholar
  37. 37.
    European medicines Agency (EMA). Questions and answers on the benefits and risks of rosiglitazone and pioglitazone. 2007. https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-benefits-risks-rosiglitazone-pioglitazone_en.pdf. Accessed 15 Apr 2019.
  38. 38.
    Takeda. Takeda Announces Completion of the Pioglitazone Post-Marketing Commitment and Submission of Results to the EMA, the FDA and the PMDA. 2015. https://www.takeda.com/newsroom/newsreleases/2015/takeda-announces-completion-of-the-pioglitazone-post-marketing-commitment-and-submission-of-results-to-the-ema-the-fda-and-the-pmda/. Accessed 15 Apr 2019.
  39. 39.
    Rodriguez A, Reviriego J, Karamanos V, del Canizo FJ, Vlachogiannis N, Drossinos V, et al. Management of cardiovascular risk factors with pioglitazone combination therapies in type 2 diabetes: an observational cohort study. Cardiovasc Diabetol. 2011;10:18.  https://doi.org/10.1186/1475-2840-10-18.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Williams R, de Vries F, Kothny W, Serban C, Lopez-Leon S, Chu C, et al. Cardiovascular safety of vildagliptin in patients with type 2 diabetes: a European multi-database, non-interventional post-authorization safety study. Diabetes Obes Metab. 2017;19(10):1473–8.  https://doi.org/10.1111/dom.12951.CrossRefPubMedGoogle Scholar
  41. 41.
    Siddiqi N. Publication bias in epidemiological studies. Cent Eur J Public Health. 2011;19(2):118–20.CrossRefPubMedGoogle Scholar
  42. 42.
    Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol. 2000;53(2):207–16.CrossRefPubMedGoogle Scholar
  43. 43.
    Henriksen DP, Rasmussen L, Hansen MR, Hallas J, Pottegard A. Comparison of the five Danish regions regarding demographic characteristics, healthcare utilization, and medication use—a descriptive cross-sectional study. PLoS One. 2015;10(10):e0140197.  https://doi.org/10.1371/journal.pone.0140197.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Real World Evidence, EvideraLondonUK
  2. 2.Department of Clinical Epidemiology, Institute of Clinical MedicineAarhus UniversityAarhus NDenmark
  3. 3.Department of PharmacoepidemiologyTakeda Pharmaceutical Company LimitedCambridgeUSA

Personalised recommendations