Rosiglitazone may reduce non-melanoma skin cancer risk in Taiwanese

The study was approved by an ethic review board of the National Health Research Institutes with registered approval number 99274.

Since March 1995, a compulsory and universal system of health insurance (the so-called NHI) was implemented in Taiwan. All contracted medical institutes must submit computerized and standard claim documents for reimbursement. More than 99% of citizens are enrolled in the NHI, and >98% of the hospitals nationwide are under contract with the NHI. The average number of annual physician visits in Taiwan is one of the highest around the world, at approximately 15 visits per year per capita in 2009.

The National Health Research Institutes is the only organization approved, as per local regulations, for handling the NHI reimbursement databases for academic research. The databases contain detailed records on every visit for each patient, including outpatient visits, emergency department visits and hospital admission. The databases also include principal and secondary diagnostic codes, prescription orders, and claimed expenses.

The databases of all patients who had been diagnosed with diabetes and under treatment with either oral anti-diabetic agents or insulin during the period of 1996–2009 from the whole nation, and who remained enrolled in the NHI after 2006 (n = 1446414) were first retrieved. A total of 235287 patients who had ever been treated with pioglitazone were then excluded to avoid the possible contamination by its use because it may increase the risk of some cancer like bladder cancer [15]. The selected entry date was 1 January 2006. After excluding patients who had a diagnosis of diabetes after the year 2006 (n = 342351), patients who held a Severe Morbidity Card as having type 1 diabetes (n = 7120, in Taiwan, patients with type 1 diabetes were issued a so-called “Severe Morbidity Card” after certified diagnosis and they were waived for much of the co-payments), patients having a diagnosis of NMSC before 2006 (n = 6297), those who died (n = 96320) or withdrew from the NHI (n = 12502) before entry date, duplicated identification number (n = 106), and unclear information on date of birth or sex (n = 5123), a total of 886418 patients with a diagnosis of type 2 diabetes mellitus and under therapy with oral anti-diabetic agents (except pioglitazone) or insulin were recruited.

Those who had ever been prescribed with rosiglitazone before entry date were defined as ever-users; and never-users were defined as those who had never been prescribed with rosiglitazone before entry date. To evaluate whether a dose–response relationship could be seen between rosiglitazone and NMSC, the tertile cutoffs for duration of therapy in months and cumulative dose in mg were calculated from the databases and used for analyses.

An entry date at the beginning of 2006 was used based on the following reasons: 1) Because rosiglitazone was marketed in 2001 in Taiwan, this entry date, being in the middle of the marketing date of rosiglitazone in Taiwan and the ending date of the available NHI databases in 2009, provided a longest exposure of 4 to 5 years at entry and at the same time a longest follow-up duration of 4 years; and 2) The issue of bladder cancer associated with pioglitazone noted in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) was published in 2005 [16], and in 2007, the safety of rosiglitazone has been challenged with a risk of acute myocardial infarction [17]. These had caused tremendous prescription behavior changes in the physicians to withdraw thiazolidinediones including rosiglitazone and pioglitazone (troglitazone has not been marketed in Taiwan) and the patients might have stopped taking the drugs even if they were prescribed after the year 2006. Therefore, the use of a later entry date would make the estimation of the duration of therapy and cumulative dose of rosiglitazone less reliable. In addition, this would also shorten the follow-up duration for cancer incidence.

All comorbidities and covariates were determined as a status/diagnosis before the entry date. The ICD-9-CM codes for the comorbidities were [18-21]: nephropathy 580–589, hypertension 401–405, chronic obstructive pulmonary disease (a surrogate for smoking) 490–496, cerebrovascular disease 430–438, ischemic heart disease 410–414, peripheral arterial disease 250.7, 785.4, 443.81 and 440–448, eye disease 250.5, 362.0, 369, 366.41 and 365.44, obesity 278, dyslipidemia 272.0-272.4, and cancer other than NMSC 140–208 (excluding 173). Medications included sulfonylurea, metformin, insulin, and acarbose. Baseline characteristics between ever-users and never-users of rosiglitazone were compared by Chi-square test.

The incidence density of NMSC was calculated for ever-users and never-users and for different subgroups of exposure. Chi-square test was used to compare the distribution of incident cases of NMSC in ever-users versus never-users and among the different subgroups of dose–response parameters. The numerator for the incidence was the number of patients with incident NMSC during the 4-year follow-up, and the denominator was the person-years of follow-up. For ever-users, the follow-up duration was either censored at the date of NMSC diagnosis or at the date of the last record of the available reimbursement databases in individuals without incident NMSC. For never-users, the follow-up was censored at the date of rosiglitazone initiation or NMSC diagnosis or the last reimbursement record, depending on whichever occurring first. This ensured no exposure to rosiglitazone throughout the whole follow-up period until censor in the referent group of never-users.

Cox proportional hazards regression was performed to estimate the hazard ratios for NMSC for ever-users versus never-users, and for the various subgroups of dose–response parameters. The following three models were created: 1) unadjusted; 2) adjusted for age and sex; and 3) adjusted for all variables compared previously as baseline characteristics between ever-users and never-users.

The following fully adjusted models were also created as sensitivity analyses: 1) resetting the entry date to 1 January 2005; 2) deleting patients who developed NMSC within 3 months of follow-up; 3) excluding patients with a history of any cancer before 2006; 4) including pioglitazone users in the analyses; 5) using a time-dependent approach; and 6) excluding never-users of rosiglitazone and conducting the analyses only among rosiglitazone ever-users by comparing the second and third tertiles of exposure versus the first tertiles as referents.