European Heart Journal - Cardiovascular Pharmacotherapy (2017) 3, 140–146 ORIGINAL ARTICLE

doi:10.1093/ehjcvp/pvw036 Atrial fibrillation

Thiazolidinediones are associated with a

decreased risk of atrial fibrillation compared
with other antidiabetic treatment: a nationwide
cohort study

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Jannik Langtved Pallisgaard1,2*, Tommi Bo Lindhardt1,2, Laila Staerk1,2,
Jonas Bjerring Olesen1, Christian Torp-Pedersen3, Morten Lock Hansen4, and
Gunnar Hilmar Gislason1,2,5,6
1
University Hospital Gentofte and Herlev, Kildegaardsvej 28, 2900 Hellerup, Copenhagen, Denmark; 2Faculty of Health and Medical Sciences Blegdamsvej 3B, 2200, Copenhagen,
Denmark; 3Institute of Health Science and Technology, Fredrik Bajers Vej 7D, 9220 Aalborg, Denmark; 4Zealand University Hospital Roskilde, Sygehusvej 10, 4000 Roskilde,
Denmark; 5Danish Heart Foundation, Vognmagergade 7, 3. sal, 1120 Copenhagen, Denmark; and 6National Institute of Public Health University of Southern Denmark, Oster
Farimagsgade 5 A, 1353 Copenhagen, Denmark

Received 20 September 2016; revised 25 October 2016; editorial decision 28 October 2016; accepted 1 November 2016; online publish-ahead-of-print 8 November 2016

Aim The aim of this study was to investigate the association between thiazolidinediones (TZDs) vs. other antidiabetic
drugs and risk of atrial fibrillation (AF) in diabetic patients.
...................................................................................................................................................................................................
Method Diabetes mellitus (diabetes) increases the risk of AF by approximately 34%. TZD is an insulin sensitizer that also has
and results anti-inflammatory effects, which might decrease the risk of AF compared with other antidiabetic drugs. We used data
from the Danish nationwide registries to study 108 624 patients with diabetes and without prior AF who were treated
with metformin or sulfonylurea as first-line drugs. The incidence of AF was significantly lower with TZD as the second-
line antidiabetic treatment compared with other second-line antidiabetic drugs (P < 0.001). The 10 year cumulative inci-
dence [95% confidence interval (95% CI)] of AF was 6.2% (3.1–9.3%) with TZD vs. 10.2% (9.8–10.6%) with other anti-
diabetic drugs. The decreased risk of AF remained significant after adjusting for age, sex, and comorbidities with a hazard
ratio (95% CI) of 0.76 (0.57–1.00), P = 0.047 associated with TZD treatment compared with other antidiabetic drugs.
...................................................................................................................................................................................................
Conclusion Use of a TZD to treat diabetes was associated with reduced risk of developing AF compared with other antidia-
betic drugs as second-line treatment.
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Keywords Atrial fibrillation • Diabetes mellitus • Thiazolidinediones • Prevention • Complications • Glitazones

.. Thiazolidinediones (TZDs) belong to a class of peroxisome

Introduction ..
.. proliferator-activated receptor gamma activators. Binding to this
.. transcription factor alters glucose and lipid homeostasis, increases
Patients with type 2 diabetes mellitus (diabetes) have an increased ..
risk of atrial fibrillation (AF) and furthermore diabetes is a strong .. sensitivity to insulin, and decreases the inflammatory-response.9–11
..
risk factor for developing a stroke in patients with AF.1–4 The .. Despite their benefits in reducing glucose levels in diabetes, TZDs
potential mechanisms underlying the predisposition to AF in .. have been associated with heart failure leading FDA to place a black
.. box warning on TZDs. Furthermore, troglitazones have been with-
patients with diabetes are not entirely understood; however, ..
these may include inflammatory interstitial fibrosis and atrial .. drawn from the market, leaving rosiglitazone and pioglitazone the
.. only TZDs still available in the USA.12 TZDs are not recommended as
remodelling.5–8 Interventions that alter these processes might ..
reduce the risk of AF. .. first-line antidiabetic drug in international guidelines, but remains

* Corresponding author. Tel: þ45 29723117, Fax: þ45 70201282, Email: jannikjannik@gmail.com
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author 2016. For Permissions, please email: journals.permissions@oup.com.
TZD with AF vs. other antidiabetic treatment
..
option as second-line treatment for diabetes.13 TZDs may also have
potential benefits for the AF prevention in both development of new-
onset AF in patients with diabetes and in post-ablation patients.14–17
We sought to determine whether treatment with TZDs was asso-
ciated with decreased risk of AF in patients with diabetes by analysing
data from the extensive Danish nationwide cohorts.
Method
All residents of Denmark are, at birth or immigration, issued a permanent
unique civil registration number that enables individual-level linkage
between administrative registries. The Danish National Patient Register
holds information on all hospital visits of both inpatient admissions and
outpatient visits.9 Each hospitalization discharge is coded with one pri-
mary and, if appropriate, one or more secondary diagnosis codes accord-
ing to the International Classification of Diseases (ICD). Data on
pharmacy prescriptions were identified from the Danish Registry of
Medicinal Product Statistics, which has record of all drug prescriptions
dispensed by Danish pharmacies since 1995. Each drug dispensing is
coded according to the Anatomical Therapeutic Chemical system, includ-
ing the date of dispensing, quantity dispensed, strength, formulation, and
affiliation of the physician issuing the prescription. The reimbursement of
drug expenses by the Danish health care system requires all pharmacies
to register each drug dispensing in the National Prescription Registry.
Study cohort and follow-up
We included all individuals with diabetes who were treated with two dif-
ferent types of antidiabetic drugs between 2000 and 2012. Claimed pre-
scriptions of the specific types of antidiabetic drugs were identified with
first-line treatment as either metformin or sulfonylurea, and the second-
line treatment as either metformin, sulfonylurea, insulin, TZD, carbamoyl
methyl benzoic acid derivative (CBD), dipeptidyl peptidase-4 inhibitor
(DPP) or glucagon-like peptide-1 (GLP-1). We excluded all patients
below 18 and above 100 years of age and all patients with prior AF. Prior
AF was defined as a primary or secondary diagnosis of AF in both in- and
outpatients. Patients who received TZDs as second-line antidiabetic drug
entered the ‘TZD group’, and patients who received other antidiabetic
drugs than TZDs were assigned to the ‘other group’. In the study design
information on follow-up was limited to 31 December 2012; hence this
was end of study. Patients entered the study on first day they initiated the
second-line antidiabetic drug, and they were followed until end of study
(31 December 2012), last date with second-line antidiabetic drug, intro-
duction of a third-line antidiabetic drug, emigration from Denmark, death,
or AF development, whichever came first.
Comorbidities
Comorbidities were identified using ICD-8 and ICD-10 codes for stroke,
heart failure, all cancers, ischaemic heart disease, chronic obstructive pul-
monary disease, chronic kidney disease, liver disease, and vascular disease.
Claimed drug prescriptions were used to identify hyperthyroidism, hypo-
thyroidism, hypertension, and statin use. Nordic procedure codes were
used to identify prior coronary artery bypass graft (CABG) and percuta-
neous coronary intervention (PCI). Information on death came from
National Causes of Death Register (see Supplementary material online,
Table S1).
Study outcome
The study outcome was first time diagnosis of AF. This was identified
using ICD-10 codes (I48) in the Danish National Patient Register, in either
in- or outpatients and either as a primary or secondary diagnosis code.
141
.. Statistical methods
.. Categorical data were presented as counts with percentages, and statisti-
..
.. cal differences were tested using v2 test and Fisher’s exact test where
.. appropriate. Continuous variables were presented as means with stand-
..
.. ard deviations for normal distributed data, and as medians with interquar-
.. tile range for non-normal distributed data. Statistical differences were
.. tested using Student’s t-test and Wilcoxon rank-sum test where appro-
..
.. priate. Cumulative incidence of AF with 95% confidence interval (95% CI)
.. was calculated using the Aalen–Johansen estimator accounting for death
... as competing risk. Statistical difference between the curves was tested
.. using Fine and Gray test. Relative risks were presented as hazard ratios
..
.. with 95% CI calculated in three Cox regression models. Model 1 was uni-
.. variate, Model 2 was adjusted for age and sex, and Model 3 was adjusted
..
.. for age, sex and comorbidities. A P-value < 0.05 was considered as statisti-
.. cally significant.
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..
.. A propensity score was calculated using information on prior stroke,
.. heart failure, all cancers, hyperthyroidism, ischaemic heart disease,
.. chronic obstructive pulmonary disease, chronic kidney disease, liver dis-
..
.. ease, vascular disease, hypertension, follow-up time, prior CABG, prior
.. PCI, and statin use. Patients in second-line treatment with TZD were
..
.. matched 1:5 with patients in second-line treatment with other antidia-
.. betic drugs with ‘exact matching’ on sex and age and ‘nearest neighbour
.. matching’ (a greedy match) on the remaining variables. Both Aalen–
..
.. Johansen cumulative incidence rates and Cox regression analyses were
.. performed on the matched cohort.
..
.. Data management and statistical analyses were conducted using R sta-
.. tistics [R Core Team (2015). R: A Language and Environment for Statistical
.. Computing. Vienna, Austria: R Foundation for Statistical Computing. URL:
..
.. http://www.R-project.org/]. Following CRAN packages were used
.. ‘tableone’, ‘riskRegression’, and ‘MatchIt’.
..
..
..
.. Ethics approval
.. In Denmark, retrospective register studies do not require approval from
..
.. the ethics committees. The Danish Data Protection Agency approved
.. this study (ref. no.: 2007-58-0015/GEH-2014-016 I-Suite no.: 02734) and
.. data were available in an anonymized format such that specific individuals
..
.. could not be identified.
..
..
..
..
.. Results
..
.. From the 311 631 patients treated with an antidiabetic drug between
..
.. 2000 and 2012, we excluded 203 007 patients (first antidiabetic drug
..
.. that was not metformin or sulfonylurea, antidiabetic mono-therapy,
.. below 18 or above 100 years of age, prior AF, or in meglitinides treat-
..
.. ment). This left us with a study cohort of 108 624 patients prescribed
.. a first-line antidiabetic drug of either metformin or sulfonylurea, and
..
.. an additional second-line antidiabetic drug of either metformin, sulfo-
.. nylurea, insulin, DPP, GLP-1, CBD, or TZD. A minority of 2658
..
.. patients entered the ‘TZD group’ and 105 966 entered the ‘other
.. group’. The selection of the study cohort is depicted in Figure 1.
..
.. Patients in the ‘TZD group’ were generally younger with a median
.. age of 59.6 years vs. 62.4 years in the ‘other group’ (P < 0.001) with
..
.. similar proportion of men and women (P = 0.14). The patients in the
.. ‘TZD group’ had less cardiovascular comorbidities at baseline: 2.3%
..
.. vs. 4.9% (P < 0.001) had heart failure, 9.9% vs. 12.9% (P < 0.001) had
.. ischaemic heart disease, and 4.3% vs. 5.6% (P < 0.005) had vascular
..
.. disease. The baseline characteristics of the study cohort are pre-
.. sented in Table 1.
142 J.L. Pallisgaard et al.

..
.. In the interaction analyses, sex, age, hypertension status, statin use,
.. and ischaemic heart disease were investigated and no interactions/
..
.. effect modification were found (Figure 6). In the matched analysis, the
.. propensity scores were matched 99.99%, and age and sex were
..
.. matched 100% making the mean propensity scores practically identi-
.. cal in the two groups. Subsequently testing between baseline charac-
..
.. teristics showed no significant difference between the ‘TZD group’
.. and the 1:5 matched ‘other group’ (see Supplementary material
..
... online, Table S2). The cumulative incidence of AF was significantly
.. lower (P < 0.001) in the ‘TZD group’ with 6.2% compared with the
.. ‘other group’ with 10.4% after 10 years. This decreased risk was also
..
.. found in the Cox regression analysis with an HR of 0.60 (95% CI 0.
.. 45–0.80), P <_ 0.001 in the ‘TZD group’ with the ‘other group’ as
..
.. reference.

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..
..
..
..
..
..
Discussion
..
.. This nationwide study found that additional second-line treatment
.. with TZD was associated with 24% lower risk of developing AF com-
..
.. pared with other second-line antidiabetic drugs.
.. This study is the largest study to investigate the association
..
.. between TZD and the risk of developing AF with TZD as second-
.. line antidiabetic drug. This is an important point because guidelines
..
.. do not recommend TZD as first-line treatment but as additional
.. second-line antidiabetic drug, and this makes our study clinically
..
.. more relevant compared with studies investigating TZD as first-line
.. drug. International guidelines on diabetes patients recommend met-
Figure 1 The study flowchart. AF, atrial fibrillation; TZD, thiazoli- ..
.. formin as the preferred first-line antidiabetic drug,13 and this was
dinedione; Met, metformin; SU, sulfonylurea; Insu, insulin; DPP, .. investigated in a subgroup analysis with patients exclusively in metfor-
dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1; ..
CBD, carbamoyl methyl benzoic acid derivative.
.. min treatment as first-line drug. In this subgroup analysis, TZD was
.. associated with a decreased risk of AF of 31% compared with other
..
.. antidiabetic drugs. This association with TZD and decreased risk of
The incidence of AF was significantly lower in the ‘TZD group’ .. AF is even stronger than found in the main analysis with a 24%
..
(P < 0.001) with a 10 year cumulative incidence of AF of 6.2% (95% CI .. decreased risk.
3.1–9.3%) compared with 10.2% (95% CI 9.8–10.6%) in the ‘other
.. Our study is also the first to investigate TZD vs. individual antidia-
..
group’ (Figure 2). In the Cox proportional hazard models patients .. betic drugs one by one. In these analyses all HRs were <1, indicating a
treated with TZD had significantly lower risk of AF with an HR of 0.58
.. decreased risk of AF with TZD compared with all of the other indi-
..
(95% CI 0.44–0.77), P < 0.001 in the univariate model. Adjustment atte- .. vidual antidiabetic drugs. Notably, significant results were only found
nuated this association, but it remained significant at 0.72 (95% CI
.. with sulfonylurea and insulin as reference. The patients treated with
..
0.54–0.94), P = 0.018 after adjusting for age and sex and after full .. TZD in our study suffered from less heart failure, prior stroke, ischae-
adjustment it was still significant at 0.76 (95% CI 0.57–1.00), P = 0.047
..
.. mic heart disease, and vascular disease than patients in both the sulfo-
(Figure 3). The lower risk of AF in patients treated with TZD was .. nylurea and insulin subgroup. These comorbidities are all strong
..
present irrespective of the specific second-line antidiabetic drugs .. predictors of AF, and although our statistical models were fully
with all point estimates being below 1.0 indicating decreased risk of .. adjusted for these risk factors, it can still be argued that the decreased
..
AF with TZD (Figure 4). Significant associations were only found with .. risk of AF could to some extend be attributed to the younger and
insulin and sulfonylurea. .. healthier TZD group. As TZD has a black box warning from FDA,
..
In a sensitivity analysis, we identified a subgroup of patients receiv- .. because TZDs were found associated with worsening in heart failure
ing exclusively metformin as first-line antidiabetic drug and either sul- .. among diabetes patients, clinicians might be more reluctant with pre-
..
fonylurea, insulin, DPP, GLP-1, CBD or TZD as additional second- .. scribing TZD in patients with heart failure.
line additional antidiabetic drug (n = 54077). In this subgroup, the .. The evidence regarding TZD and risk of developing AF has only
..
cumulative incidence of AF was also significantly lower (P = 0.004) in .. been investigated in a few other studies. A recent nationwide study by
the ‘TZD group’ with 4.4% compared with the ‘other group’ with .. Chao et al.,16 who investigated TZD treatment associated with risk of
..
9.8% after 10 years (Figure 5). This decreased risk was also found in .. AF in 12 065 diabetic patients, found a decreased risk of developing
the Cox regression analysis after adjusting age, sex and comorbidities .. AF with TZD compared with no-TZD with an HR of 0.69 (95% CI
..
with an HR of 0.69 (95% CI 0.50–0.96), P = 0.026 in the ‘TZD group’ .. 0.49–0.91), P = 0.028. The direction and magnitude of the HR found
with the ‘other group’ as reference.
.. compliments in our study of 0.76 (95% 0.57–1.00), P = 0.047.
TZD with AF vs. other antidiabetic treatment 143

Table 1 Baseline characteristics of the ‘TZD group’ and ‘Other group’

TZD Other P-value

....................................................................................................................................................................................................................
N 2658 105 966
First line metformin 2163 (81.4) 51 914 (49.0) <0.001
First line sulfonylurea 495 (18.6) 54 052 (51.0) <0.001
Men, n (%) 1507 (56.7) 61 610 (58.1) 0.141
Age, median (IQR) 59.59 (50.6–67.5) 62.40 (53.6–71.2) <0.001
Age categories <0.001
<40 202 (7.6) 5146 (4.9)
40–64 1628 (61.2) 56 414 (53.2)
65–74 555 (20.9) 26 671 (25.2)
>74 273 (10.3) 17 735 (16.7)

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Stroke, n (%) 123 (4.6) 7657 (7.2) <0.001
Heart failure, n (%) 62 (2.3) 5236 (4.9) <0.001
Cancer, n (%) 155 (5.8) 9260 (8.7) <0.001
Hyperthyroidism, n (%) 47 (1.8) 1890 (1.8) 1.000
Ischaemic heart disease, n (%) 263 (9.9) 13 627 (12.9) <0.001
Chronic obstructive pulmonary disease, n (%) 98 (3.7) 6145 (5.8) <0.001
Chronic kidney disease, n (%) 20 (0.8) 1522 (1.4) 0.002
Liver disease, n (%) 32 (1.2) 2583 (2.4) <0.001
Vascular disease, n (%) 115 (4.3) 5955 (5.6) 0.005
Hypertension, n (%) 1334 (50.2) 51 335 (48.4) 0.079
Antiadrenergic drug, n (%) 121 (4.6) 3953 (3.7) 0.031
Diuretics, n (%) 1166 (43.9) 45 193 (42.6) 0.217
RAS inhibitors, n (%) 1564 (58.8) 59 218 (55.9) 0.003
Loop diuretics, n (%) 532 (20.0) 24 059 (22.7) 0.001
Beta-blockers, n (%) 836 (31.5) 33 365 (31.5) 0.987
Statin, n (%) 1541 (58.0) 56 176 (53.0) <0.001
Coronary artery bypass grafting, n (%) 45 (1.7) 2518 (2.4) 0.026
Percutaneous coronary intervention, n (%) 80 (3.0) 4403 (4.2) 0.004

‘TZD group’ is patients with thiazolidinedione as second-line antidiabetic drug. ‘Other group’ is patients with metformin, sulfonylurea, insulin, DPP, GLP-1, or CBD as second-
line antidiabetic drug.

..
.. The PROactive study (PROspective pioglitAzone Clinical Trial In
.. macroVascular Events) was a randomized controlled trial investigating
..
.. the risk of cardiovascular events in patients with diabetes treated with
.. pioglitazone vs. placebo.18 The study showed a non-significant
..
.. (P = 0.374) decreased risk of developing AF between the two groups.
.. The reason for this lack of significance could be low incidence of AF
..
.. (2%) or that AF was not a predefined endpoint in the study.
.. Thiazolidinedione and risk of developing AF have also been investi-
..
.. gated in patients with high risk of AF after cardiothoracic surgery and
.. after ablation.14,15 In the study investigating patients after cardio-
..
.. thoracic surgery, 40 diabetic patients in treated with TZD patients vs.
..
.. 144 diabetic patients not treated with TZD were enrolled, and a
.. non-significant decreased risk of developing AF was found with an
..
.. adjusted odds ratio of 0.80 (95% CI 0.32–1.99), P = 0.63. Although
.. the odds ratio was non-significant, it still suggests that TZD could
..
.. have a protective effect towards AF, and the direction and magnitude
.. of the odds ratio is similar to the HR found in our study. In the abla-
..
Figure 2 Cumulative incidence of atrial fibrillation with TZD and .. tion study, the risk of recurrent atrial tachycardia was investigated in
other antidiabetic treatment. Aalen–Johansen cumulative incidence
.. diabetic patients randomized to pioglitazone vs. not in treatment
..
of AF in the ‘TZD group’ and the ‘other group’. The model takes .. with pioglitazone. With an odds ratio of 0.32 (95% CI 0.12–0.86),
into account competing risk of death. P-value from Fine and Gray .. P = 0.024 pioglitazone was found to both decrease the risk of atrial
competing risks regression model.
144 J.L. Pallisgaard et al.

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Figure 3 Cox hazard ratio of atrial fibrillation in the ‘TZD group’ with ‘other group’ as reference. The ‘fully adjusted’ model is adjusted for age, sex,
stroke, heart failure, all cancer, hyperthyroidism, ischaemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, liver disease,
vascular disease, hypertension, statin use, prior CABG, and prior PCI.

Figure 4 Cox hazard ratio of risk of atrial fibrillation for the individual antidiabetic drugs with the individual antidiabetic drugs as reference. The
model is adjusted for age, sex, stroke, heart failure, all cancer, hyperthyroidism, hypothyroidism, ischaemic heart disease, chronic obstructive pulmo-
nary disease, chronic kidney disease, liver disease, vascular disease, hypertension, statin use, prior CABG, and prior PCI. TZD, thiazolidinedione; met,
metformin; SU, sulfonylurea; insu, insulin; DPP, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1; CBD, carbamoyl methyl benzoic acid
derivative.

..
tachycardia recurrence and as a significant predictor of absence of .. regarding efficacy and safety of TZD treatment and AF risk is needed,
atrial tachycardia after ablation. .. and future randomized controlled trails could be considered in order
..
Our study supports the existing evidence of a decreased risk of AF .. to investigate this.
in diabetes patients treated with TZD, and it contributes with the ..
..
largest cohort study investigating this to date. Furthermore, our study ..
offers novel information on the clinically relevant question regarding .. Limitations
..
the risk of AF with TZD as additional antidiabetic drug to metformin. .. The main limitation of this study is inherent in our observational
This is a very important notion as this is the most clinically relevant .. design of the study and lack of clinical information and randomization
..
use of TZD. Our finding implies increased use of TZD, and prescrip- .. to treatment groups. Albeit the models are adjusted for known con-
tion with TZD as additional second-line antidiabetic drug to metfor-
.. founders, there is still a challenge with residual confounding in the
..
min is according with current guidelines. Notably, our study is .. observational design that can affect the results. To compensate this,
registry based and therefore all findings are associations. Knowledge
.. we performed propensity score-matched analyses. In the matched
TZD with AF vs. other antidiabetic treatment 145

..
analyses, we found an even greater association between TZD and .. The follow-up period was 12 years, and it was a limitation that
decreased risk of AF with an HR of 0.60 (95% CI 0.45–0.80), .. patients included near the study end (31 December 2012) had
..
P < 0.001 than we found in our main analyses with an HR of 0.76 .. decreased risk-time to develop AF, which could have underestimated
(95% CI 0.57–1.00), P = 0.047. .. the cumulative incidences of developing AF depicted in Figures 2 and
..
.. 5. The method of identifying AF with ICD codes does not identify
.. patients with unrecognized AF, or patients attending their general
..
.. practitioner; hence there is a risk of misclassification. On the other
.. hand, the risk of including false-positive patients is very limited, as the
..
.. method of identifying AF in our study is validated with a positive pre-
.. dictive value of 92.6%.19 Using anti-arrhythmic drugs as proxies for
..
.. AF is a method that has not yet been validated in the Danish registers.
.. Although this method could decrease the proportion of false-nega-
..
.. tive AF events in our study, the tradeoff could be introduction of
.. false-positive AF events.
..

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.. One of the strengths of our study is that the National Prescription
..
.. Register is linked to the partial reimbursement policy for drug
.. expenses by the national health security system and has been shown
..
.. to be accurate and reduce the risk of surveillance bias.20,21 In
.. Denmark healthcare is tax financed and is available for every citizen
..
.. without charge, and by including the entire Danish population, we
.. avoided selection bias. The utility of TZDs in treatment of patients
..
.. with diabetes has declined in the past decade largely due to adverse
.. effects of fluid retention. Although there has been a decline, TZD
..
.. may still be the right choice of antidiabetic drug for some patients
.. where good glucose control is hard to achieve with other antidiabetic
..
Figure 5 Aalen–Johansen cumulative incidence of AF in the ‘TZD .. drugs.
group’ and the ‘other group’ in patients exclusively treated with .. In conclusion, treatment with TZD as second-line antidiabetic
metformin as first-line antidiabetic drug. The model takes into
..
.. drug in patients with diabetes is associated with decreased risk of AF
account competing risk of death. P-value from Fine and Gray com- .. compared with treatment with other antidiabetic drugs.
peting risks regression model. ..
..
..
.

Figure 6 Interaction analysis for sex, age, hypertension, statin, and ischaemic heart disease. Presented are both events/patients; incidence rates per
100 person years, Cox hazard ratio in the ‘TZD group’ with ‘other group’ as reference. The model is adjusted for age, sex, stroke, heart failure, all
cancer, hyperthyroidism, hypothyroidism, ischaemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, vas-
cular disease, hypertension; statin use, prior CABG, and prior PCI. In the last column is the P-value for interaction.
146
..
Supplementary material ..
..
Supplementary material is available at European Heart Journal – ..
..
Cardiovascular Pharmacotherapy online. ..
..
..
..
Funding ..
J.L.P. and L.S. have received research funding from Boehringer-Ingelheim.
..
..
G.H.G. is supported by an unrestricted clinical research scholarship from ..
the Novo Nordisk Foundation. He has ownership of stocks in Novo ..
..
Nordisk Pharmaceuticals, which produce glucose-lowering drugs. ..
..
Conflict of interest: none declared.
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