Electronic Supplementary Material 2 s3

Electronic supplementary material 2

Supplementary tables

Article title: Fibrate and risk of cancer in tissues with a high PPAR-α concentration: a nested case-controls study

Journal name: Drug Safety

Authors: Francesco Salvo, Fabienne Bazin, Aude Kostrzewa, Christian Bandre, Philip Robinson, Nicholas Moore, Bernard Bégaud, Antoine Pariente.

Corresponding Author: Francesco Salvo, Université de Bordeaux, INSERM U657

146, Rue Léo Saignat, Bâtiment 1A Zone nord Site Carreire, BP36, 33076 Bordeaux Cedex, France

Elements included in this Online Resource:

· eTable 1;

· eTable 2;

· eTable 3;

· eTable 4;

· eTable 5;

· eTable 6;

· eTable 7;

· eTable 8;

· eTable 9.

· eTable 10.

· eTable 11.

eTable 1. List of codes of the International Classification of Diseases, 10th version (ICD-10) used to identify cases of the cancers of interest

Cancer type / ICD-10 codes
Melanoma / C43*
Non-Melanoma skin cancer / C44*
Thyroid cancer / C73
Pancreas cancer / C25*
Kidney cancer / C64
Bladder cancer / C67*

eTable 2. List of ATC codes used to identify comorbidities used for cases and controls matching

Comorbidity / ICD-10 codes
Type 1 diabetes / E10*
Type 2 diabetes / E11*
Alcoholic liver disease / K70*
Toxic liver disease / K71*
Hepatic failure / K72*
Chronic hepatitis / K73*, B18*
Fibrosis and cirrhosis of liver / K74*
HIV and its complications / B20*, B21*, B22*, B23*, B24
Schistosomiasis / B65*
Heart failure / I50*
Cardiac ischemic disorders / I20*, I21*, I22*, I23*, I24*, I25*
Atherosclerosis, arterial embolism and thrombosis / I70*, I74*
Chronic obstructive pulmonary disease / J40*, J41*, J42*, J43*, J44*
Asthma / J45*, J46*

eTable 3. Drugs used as covariates: ATC codes used for identification of exposed patients and defined categories of exposure according to cumulated use in Delivered Daily Doses (DDD).

Drugs / ATC codes / DDD / Exposure categories
Aspirin -
Antiplatelet / B01AC06, C10BX01, C10BX02, C10BX04 / 1 tablet / a. Non-exposed
b. 1 - 179 DDD
c. 180 - 729 DDD
d. ≥ 730 DDD
Aspirin -
Painkiller / N02BA01, N02BA51, N02BA71 / 3 g / a. Non-exposed
b. < 14 DDD
c. ≥ 14 DDD
Statins / a. Non-exposed
b. 1 - 364 DDD
c. 365 - 912 DDD
d. 913 - 1459 DDD
e. ≥ 1460 DDD
Simvastatin / C10AA01, C10BA02 / 30 mg
Pravastatin / C10AA03, C10BA03, C10BX01, C10BX02, C10BX04 / 30 mg
Lovastatin / C10AA02, C10BA01 / 45 mg
Fluvastatin / C10AA04 / 60 mg
Atorvastatin / C10AA05, C10BX03 / 20 mg
Rosuvastatin / C10AA07 / 10 mg
Insulins / A10A* / 40 U / a. Non-exposed
b. 1 - 59 DDD
c. ≥ 60 DDD
Metformin / A10BA02, A10BD02, A10BD03, A10BD05, A10BD07, A10BD08, A10BD10, A10BD11 / 2 g / a. Non-exposed
b. 1 - 269 DDD
c. ≥ 270 DDD
Pioglitazone / A10BG03, A10BD06, A10BD05, A10BD09 / 30 mg / a. Non-exposed
b. Exposed (≥ 1 DDD)
Sulfonamides / a. Non-exposed
b. 1 - 1094 DDD
c. ≥ 1095 DDD
Glibenclamide / A10BB01, A10BD02 / 2 tablets
Glibornuride / A10BB04 / 38 mg
Carbutamide / A10BB06 / 0.75 mg
Glipizide / A10BB07 / 10 mg
Gliclazide / A10BB09 / 60 mg
Glimepiride / A10BB12 / 2 mg
Dipeptidyl peptidase 4 (DPP-4) inhibitors / a. Non-exposed
b. Exposed (≥ 1 DDD)
Sitagliptin / A10BH01, A10BD07 / 100 mg
Vidagliptin / A10BH02, A10BD08 / 100 mg
Saxagliptin / A10BH03 / 5 mg
Glucagon-like peptide-1 agonist (GLP-1 agonist) / a. Non-exposed
b. Exposed (≥ 1 DDD)
Exenatide / A10BX04 / 15 mcg
Liraglutide / A10BX07 / 1.2 mg
Glinides / a. Non-exposed
b. Exposed (≥ 1 DDD)
Repaglinide / A10BX02 / 4 mg
Nateglinide / A10BX03 / 360 mg

eTable 4. Estimation of the association between exposure to fibrates and melanoma.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / 0.83 / 0.86
Non-exposed / 1 / 1
<550 / 0.88 [0.49; 1.57] / 0.87 [0.48; 1.57]
≥550 / 0.89 [0.53; 1.49] / 0.92 [0.54; 1.55]
Statins / 0.51 / 0.44
Non-exposed / 1 / 1
<365 / 0.81 [0.50; 1.31] / 0.80 [0.49; 1.32]
≥ 365 and < 913 / 1.29 [0.80; 2.10] / 1.32 [0.81; 2.17]
≥ 913 and < 1460 / 1.33 [0.79; 2.22] / 1.37 [0.81; 2.33]
≥1460 / 1.05 [0.68; 1.63] / 1.08 [0.68; 1.70]

*Adjusted for exposure to: aspirin-cardiovascular, aspirin-painkiller or antipyretic, statins, insulines, metformin, pioglitazone, sulfamides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and glinides.

eTable 5. Estimation of the association between exposure to fibrates and non-melanoma skin cancers.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / <0.01 / 0.01
Non-exposed / 1 / 1
<550 / 0.92 [0.73; 1.15] / 0.90 [0.71; 1.13]
≥550 / 1.32 [1.12; 1.56] / 1.35 [1.14; 1.60]
Statins / 0.22 / 0.15
Non-exposed / 1 / 1
<365 / 1.03 [0.85; 119] / 0.99 [0.82; 1.19]
≥ 365 and < 913 / 0.95 [0.77; 1.18] / 0.94 [0.75; 1.16]
≥ 913 and < 1460 / 1.17 [0.95; 1.44] / 1.17 [0.95; 1.44]
≥1460 / 1.17 [1.00; 1.37] / 1.19 [1.00; 1.40]

eTable 6. Estimation of the association between exposure to fibrates and thyroid cancers.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / 0.75 / 0.76
Non-exposed / 1 / 1
<550 / 1.05 [0.57; 1.93] / 0.87 [0.45; 1.67]
≥550 / 0.79 [0.41; 1.51] / 0.80 [0.40; 1.57]
Statins / 0.14 / 0.12
Non-exposed / 1 / 1
<365 / 1.40 [0.87; 2.27] / 1.46 [0.89; 2.39]
≥ 365 and < 913 / 1.15 [0.61; 2.19] / 1.00 [0.50; 1.98]
≥ 913 and < 1460 / 1.05 [0.50; 2.18] / 0.99 [0.47; 2.12]
≥1460 / 1.94 [1.16; 3.25] / 1.92 [1.11; 3.33]

eTable 7. Estimation of the association between exposure to fibrates and pancreas cancer.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / 0.29 / 0.31
Non-exposed / 1 / 1
<550 / 1.17 [0.77; 1.76] / 1.28 [0.83; 1.98]
≥550 / 1.28 [0.92; 1.77] / 1.23 [0.87; 1.74]
Statins / 0.25 / 0.21
Non-exposed / 1 / 1
<365 / 0.99 [0.71; 1.37] / 0.86 [0.61; 1.23]
≥ 365 and < 913 / 0.63 [0.41; 0.98] / 0.62 [0.39; 1.01]
≥ 913 and < 1460 / 0.79 [0.51; 1.21] / 0.67 [0.42; 1.07]
≥1460 / 0.91 [0.66; 1.24] / 0.87 [0.62; 1.22]

eTable 8. Estimation of the association between exposure to fibrates and bladder cancer.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / 0.27 / 0.24
Non-exposed / 1 / 1
<550 / 1.07 [0.79; 1.45] / 1.05 [0.77; 1.43]
≥550 / 1.24 [0.96; 1.61] / 1.26 [0.96; 1.64]
Statins / 0.20 / 0.29
Non-exposed / 1 / 1
<365 / 1.09 [0.83; 1.43] / 1.01 [0.76; 1.34]
≥ 365 and < 913 / 1.18 [0.88; 1.59] / 1.10 [0.81; 1.49]
≥ 913 and < 1460 / 0.98 [0.72; 1.34] / 0.93 [0.68; 1.28]
≥1460 / 1.29 [1.04; 1.61] / 1.25 [1.00; 1.58]

eTable 9. Estimation of the association between exposure to fibrates and kidney cancer.

OR [95%CI] Crude / p / OR [95%CI] Adjusted* / p
Fibrates / 0.04 / 0.19
Non-exposed / 1 / 1
<550 / 1.52 [1.02; 2.29] / 1.38 [0.91; 2.10]
≥550 / 1.38 [0.97; 1.98] / 1.28 [0.86; 1.82]
Statins / 0.09 / 0.22
Non-exposed / 1 / 1
<365 / 1.22 [0.85; 1.76] / 1.13 [0.78; 1.64]
≥ 365 and < 913 / 1.62 [1.13; 2.33] / 1.49 [1.02; 2.17]
≥ 913 and < 1460 / 0.89 [0.56; 1.42] / 0.90 [0.56; 1.44]
≥1460 / 1.05 [0.73; 1.50] / 0.96 [0.66; 1.40]

eTable 10. Adjusted Estimation of the association between exposure to fibrates and cancers of tissues with high PPAR-α concentration in non-statin users.

Drugs / Cases
N= 1,838 (%) / Controls
N= 18,218 (%) / OR (95%CI)
Adjusted* / p
Fibrates / 0.007
Non-exposed / 1559 (84.8) / 15927 (87.4) / 1
<550 Defined Daily Doses / 67 (3.6) / 670 (3.7) / 1.00 (0.76-1.32)
≥550 Defined Daily Doses / 212 (11.5) / 1621 (8.9) / 1.31 (1.10-1.54)

*Adjusted for exposure to: aspirin-cardiovascular, aspirin-painkiller or antipyretic, insulines, metformin, pioglitazone, sulfamides, Dipeptidyl Peptidase-4 inhibitors, Glucagon-Like Peptide-1 agonists, glinides.

eTable11. Adjusted Estimation of the association between exposure to fibrates and cancers of tissues with high PPAR-α concentration in statin-users.

Drugs / Cases
N= 1,493 (%) / Controls
N= 13,242 (%) / OR (95%CI)
Adjusted* / p
Fibrates / 0.37
Non-exposed / 1177 (78.8) / 10595 (80.0) / 1
<550 Defined Daily Doses / 157 (10.5) / 1403 (10.6) / 1.02 (0.84-1.24)
≥550 Defined Daily Doses / 159 (10.6) / 1244 (9.4) / 1.15 (0.95-1.39)