Pioglitazone and Risk of Chronic Obstructive Pulmonary Disease in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study

Figures & data

Table 1 Comparisons of Characteristics Between Pioglitazone Never Users and Ever Users

Characteristics	Never Users (n = 9487)		Ever Users (n = 9487)		Standardized Difference
	n	%	n	%
Basic data
Age (years)	59.44	11.82	59.41	11.19	−0.26
Sex (men)	5426	57.19	5387	56.78	−0.88
Diabetes duration (years)	6.38	2.81	6.37	2.60	−0.29
Occupation
I	3823	40.30	3834	40.41
II	2208	23.27	2211	23.31	0.12
III	1787	18.84	1732	18.26	−1.40
IV	1669	17.59	1710	18.02	1.26
Living region
Taipei	3831	40.38	3812	40.18
Northern	931	9.81	997	10.51	2.33
Central	1523	16.05	1483	15.63	−1.05
Southern	1156	12.19	1142	12.04	−0.40
Kao-Ping and Eastern	2046	21.57	2053	21.64	0.24
Major comorbidities associated with diabetes mellitus
Hypertension	7576	79.86	7536	79.44	−1.06
Dyslipidemia	8107	85.45	8073	85.10	−0.96
Obesity	529	5.58	597	6.29	2.89
Diabetes-related complications
Nephropathy	2258	23.80	2174	22.92	−2.22
Eye disease	3151	33.21	3183	33.55	0.67
Diabetic polyneuropathy	2402	25.32	2487	26.21	2.17
Stroke	2049	21.60	2032	21.42	−0.28
Ischemic heart disease	3653	38.51	3618	38.14	−0.70
Peripheral arterial disease	2135	22.50	2074	21.86	−1.54
Factors that might affect exposure/outcome
Head injury	312	3.29	286	3.01	−1.61
Parkinson’s disease	148	1.56	144	1.52	−0.20
Hypoglycemia	299	3.15	302	3.18	0.16
Tobacco abuse	338	3.56	325	3.43	−0.79
Alcohol-related diagnoses	477	5.03	479	5.05	0.19
Heart failure	1158	12.21	1137	11.98	−0.63
Gingival and periodontal diseases	8312	87.61	8316	87.66	0.11
Pneumonia	801	8.44	843	8.89	1.49
Pulmonary tuberculosis	182	1.92	178	1.88	−0.39
Osteoporosis	1321	13.92	1348	14.21	0.86
Human immunodeficiency virus infection	13	0.14	4	0.04	−4.71
Antidiabetic drugs
Insulin	269	2.84	291	3.07	1.39
Sulfonylureas	6638	69.97	6650	70.10	0.46
Metformin	7202	75.91	7129	75.14	−1.93
Meglitinide	625	6.59	638	6.72	0.56
Acarbose	1286	13.56	1282	13.51	−0.07
Medications commonly prescribed to diabetes patients or drugs that might affect exposure/outcome
Angiotensin converting enzyme inhibitors/Angiotensin receptor blockers	6869	72.40	6880	72.52	0.14
Calcium channel blockers	5058	53.32	5079	53.54	0.54
Statins	7077	74.60	7083	74.66	0.16
Fibrates	4154	43.79	4147	43.71	−0.21
Aspirin	5377	56.68	5328	56.16	−1.00
Corticosteroids	187	1.97	166	1.75	−1.62

Note: Age and diabetes duration are expressed as mean and standard deviation.

Figure 1 The step-by-step procedures applied in the enrollment of propensity score-matched pairs of ever users and never users of pioglitazone.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Figure 2 The Kaplan–Meier curves for COPD-free probability with regards to pioglitazone exposure. (A) compares pioglitazone ever users to never users (logrank test, P = 0.0014). (B) compares tertiles of cumulative duration of pioglitazone therapy to never users (logrank test, P = 0.0039).

Abbreviation: COPD, chronic obstructive pulmonary disease.

Table 2 Incidence Rates of Chronic Obstructive Pulmonary Disease and Hazard Ratios by Pioglitazone Exposure

Pioglitazone Use	Incident Case Number	Cases Followed	Person-Years	Incidence Rate (per 100,000 Person-Years)	Hazard Ratio	95% Confidence Interval	P value
Never users	359	9487	24,179.46	1484.73	1.000
Ever users	295	9487	25,265.21	1167.61	0.778	(0.667–0.908)	0.0014
Tertiles of cumulative duration of pioglitazone therapy (months)
Never users	359	9487	24,179.46	1484.73	1.000
<11.0	108	3076	8002.90	1349.51	0.904	(0.729–1.121)	0.3580
11.0–19.6	92	3163	8430.32	1091.30	0.727	(0.578–0.914)	0.0063
>19.6	95	3248	8831.99	1075.64	0.715	(0.570–0.896)	0.0036

Table 3 Joint Effects Between Pioglitazone and Risk Factors of Chronic Obstructive Pulmonary Disease

Risk Factor/Pioglitazone Use	Incident Case Number	Cases Followed	Person-Years	Incidence Rate (per 100,000 Person-Years)	Hazard Ratio	95% Confidence Interval	P value
Pneumonia (+)/Pioglitazone (-)	70	801	1950.68	3588.50	1.000
Pneumonia (+)/Pioglitazone (+)	66	843	2168.69	3043.31	0.879	(0.626–1.232)	0.4531
Pneumonia (-)/Pioglitazone (-)	289	8686	22,228.79	1300.12	0.482	(0.367–0.632)	<0.0001
Pneumonia (-)/Pioglitazone (+)	229	8644	23,096.52	991.49	0.363	(0.275–0.480)	<0.0001
P-trend							<0.0001
P-interaction							0.4333
Pulmonary TB (+)/Pioglitazone (-)	17	182	427.86	3973.29	1.000
Pulmonary TB (+)/Pioglitazone (+)	14	178	460.32	3041.38	0.686	(0.337–1.395)	0.2978
Pulmonary TB (-)/Pioglitazone (-)	342	9305	23,751.61	1439.90	0.504	(0.307–0.826)	0.0065
Pulmonary TB (-)/Pioglitazone (+)	281	9309	24,804.89	1132.84	0.395	(0.240–0.649)	0.0002
P-trend							<0.0001
P-interaction							0.7185
Tobacco abuse (+)/Pioglitazone (-)	17	338	849.32	2001.59	1.000
Tobacco abuse (+)/Pioglitazone (+)	12	325	879.70	1364.10	0.650	(0.310–1.364)	0.2549
Tobacco abuse (-)/Pioglitazone (-)	342	9149	23,330.14	1465.91	0.741	(0.453–1.214)	0.2343
Tobacco abuse (-)/Pioglitazone (+)	283	9162	24,385.51	1160.53	0.582	(0.355–0.956)	0.0325
P-trend							0.0013
P-interaction							0.6247
Any of the three (+)/Pioglitazone (-)	96	1223	2998.79	3201.29	1.000
Any of the three (+)/Pioglitazone (+)	84	1235	3227.92	2602.30	0.851	(0.634–1.142)	0.2821
All of the three (-)/Pioglitazone (-)	263	8264	21,180.67	1241.70	0.467	(0.367–0.593)	<0.0001
All of the three (-)/Pioglitazone (+)	211	8252	22,037.29	957.47	0.355	(0.277–0.455)	<0.0001
P-trend							<0.0001
P-interaction							0.5250

Abbreviation: TB, tuberculosis.