Published Ahead of Print on June 20, 2011 as 10.1200/JCO.2011.35.1908 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.35.

1908

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Angiotensin Receptor Blockade and Risk of Cancer in Type 2 Diabetes Mellitus: A Nationwide Case-Control Study
Chia-Hsuin Chang, Jou-Wei Lin, Li-Chiu Wu, and Mei-Shu Lai
Chia-Hsuin Chang, Li-Chiu Wu, and Mei-Shu Lai, Institute of Preventive Medicine, College of Public Health; Chia-Hsuin Chang and Jou-Wei Lin, College of Medicine, National Taiwan University; Chia-Hsuin Chang, National Taiwan University Hospital, Taipei; Jou-Wei Lin, Cardiovascular Center, National Taiwan University Hospital Yun-Lin Branch, Dou-Liou City, Yun-Lin County, Taiwan. Submitted February 1, 2011; accepted April 29, 2011; published online ahead of print at www.jco.org on June 20, 2011. Supported in part by Grant No. DOH098-TD-D-113-098016 from the Taiwan Department of Health. C.-H.C. and J.-W.L. contributed equally to this work. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: Mei-Shu Lai, MD, Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; e-mail: mslai@ntu.edu.tw. 2011 by American Society of Clinical Oncology 0732-183X/11/2999-1/$20.00 DOI: 10.1200/JCO.2011.35.1908

Purpose The objective of this case-control study was to evaluate the risk of malignancy in diabetic patients who received angiotensin receptor blockers (ARBs). Patients and Methods A total of 21,750 new diabetic patients who started antihypertensive treatment were identied from the Taiwan National Health Insurance claims database during the period from July 1, 2000, to December 31, 2000. As of December 31, 2007, patients with incident cancer were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs between ARB use and cancer incidence, adjusted for other types of antihypertensive drugs, insulin, oral hypoglycemic agents, statins, and underlying diseases. Results Among the 1,281 patients with incident cancer and 5,104 controls, 333 (26.0%) and 1,341 (26.3%), respectively, received ARBs (OR, 0.98; 95% CI, 0.85 to 1.14). There was no statistically signicant association between the effect of ARBs as a class and cancer incidence after adjustment for covariates (OR, 0.94; 95% CI, 0.80 to 1.10). Among the individual ARBs, losartan decreased the risk (OR, 0.78; 95% CI, 0.63 to 0.97) and candesartan (OR, 1.79; 95% CI, 1.05 to 3.06) and telmisartan (OR, 1.54; 95% CI, 0.97 to 2.43) possibly increased the risk of occurrence of malignancy. Conclusion The results did not show an effect of ARBs as a class on increasing cancer incidence in patients with diabetes. However, there was a negative association of losartan but a positive one of candesartan and telmisartan with the overall occurrence of cancer. The underlying mechanism certainly requires further investigation. J Clin Oncol 29. 2011 by American Society of Clinical Oncology

INTRODUCTION

Antagonists of the angiotensin II type 1 receptor (or angiotensin receptor blockers [ARBs]), are widely used in the treatment of hypertension and heart failure.1-3 ARBs can be used as an alternative to angiotensin-converting enzyme (ACE) inhibitors for lowering the risk of cardiovascular events.4 A recently published meta-analysis demonstrated that ARBs were associated with a modestly increased risk of new cancer diagnosis, and telmisartan was the main ARB used as the study drug in 30,014 patients (85.7%).5 Among the specic cancers examined, only new lung cancer occurrence was signicantly higher in those assigned to receive ARBs. No statistically signicant difference in death from cancer was observed.5 The results of this meta-analysis raised a serious concern about the safety of ARBs. The nding that

there was a positive association between ARBs and cancer incidence was regarded as disturbing and provocative.6 Since the trials included in the metaanalysis were not designed to explore cancer outcomes, the post hoc nature of this meta-analysis and publication bias might have reduced the validity of the results. Therefore, urgent actions should be taken to examine the safety of ARBs.7-11 ARBs are among the antihypertensive drugs of choice for patients with diabetes.12 Recent evidence13 shows that olmesartan may reduce the occurrence of microalbuminuria, an effect independent of blood pressure reduction. ARBs have a cardiovascular protective effect in diabetic patients, particularly in those with postmyocardial infarction or heart failure,14 and a reno-protective effect in reducing proteinuria and diabetic nephropathy.15,16 However, there are currently no
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Chang et al

Patients with diabetes, July 1 to December 31, 2000 (N = 595,276)

Excluded: Prior diagnosis of diabetes, January 1 to June 30, 2000 Age < 30 or > 100 years Potential type 1 diabetes

(n = 546,328) (n = 1,141) (n = 37)

Inception patients with type 2 diabetes potentially eligible for study inclusion (n = 47,770)

Excluded: Patients did not receive any antihypertensive medication from July 1, 2000, to December 31, 2007 (n = 6,982) Patients received antihypertensive medication from January 1 to June 30, 2000 (n = 18,103)

Fig 1. CONSORT diagram. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

New users of ACE inhibitors/ARBs or other antihypertensive medications from July 1, 2000, to December 31, 2007 (n = 22,685)

Patients already had prevalent cancer recorded in the National Cancer Registry at or before antihypertensive treatment initiation (n = 935)

Patients with type 2 diabetes receiving antihypertensive treatment in the cohort Patients with incident cancer included in the analysis Controls matched on age, sex, diabetes duration, and antihypertensive treatment duration by risk set sampling

(n = 21,750) (n = 1,281)

(n = 5,104)

data concerning the association of ARBs and cancer risk in patients with diabetes.17-19 Therefore, our objective was to conduct a nationwide case-control study to assess the incidence of malignancies associated with ARBs among the general diabetic population in Taiwan.
PATIENTS AND METHODS
Data Source The Taiwan National Health Insurance (NHI) database includes outpatient visits, hospital admissions, prescriptions, disease, and vital status for 99% of the population of 23 million in Taiwan. We established the longitudinal medical history of each beneciary by linking several computerized administrative claims data sets and the National Cancer and Death Registry. The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee. Diabetic Cohort All patients records with any diabetes diagnostic codes (International Classication of Diseases, 9th Revision, Clinical Modication [ICD-9-CM] code 250 and A code 181) in the claims database between January 1, 2000, and December 31, 2000, were retrieved. An algorithm that included age, number of
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outpatient visits, number of hospitalizations, and the hospital level was used to identify potential diabetic patients with improved accuracy. This denition of diabetes was evaluated by a study sampling 9,000 patients with a diagnosis of diabetes in the NHI claims data in 2000. Validation of this algorithm demonstrated a high level of sensitivity and positive predictive value (93.2% and 92.3%, respectively). A total of 640,173 patients were identied by the algorithm. Among them, 115,364 patients had newly diagnosed diabetes. Patients were followed from the date of diagnosis of diabetes in 2000 to death, disenrollment from NHI, or December 31, 2007, with a median time of 7.4 years. A total of 24,695 patients (21.4%) died; only 322 (0.3%) were lost to follow-up. Study Groups We analyzed data from 595,276 patients with diabetes from July 1, 2000, to December 31, 2000, and their records from diagnosis and pharmacy prescription les from January 1, 2000, to June 30, 2000, were checked for study eligibility criteria. First, we excluded patients age younger than 30 and older than 100 years, those who had a hospital admission with a discharge diagnosis of insulin-dependent diabetes mellitus (ICD-9-CM code 250.x1 or 250.x3), or those who had type 1 diabetes. We further restricted our study base to those who started antihypertensive treatment between July 1, 2000, and December 31, 2007 (Fig 1). Patients who had a history of cancer recorded in the National Cancer Registry any time before the initiation of antihypertensive treatment
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Angiotensin Receptor Blockade and Cancer Risk

were also excluded. As a result, the study cohort encompassed 21,750 patients with newly diagnosed type 2 diabetes (Fig 1). All individuals in the study cohort with the rst occurrence of any cancer were included as cases and were further classied according to specic sites of cancer, including liver, colorectal, lung, urologic (kidney, renal pelvis, ureter, and urinary bladder), breast, prostate, gastric, and pancreatic cancers through a linkage to the National Cancer Registry. Risk-set sampling, matched on age (within 5 years), sex, diabetes duration at cancer diagnosis, and antihypertensive treatment duration (within 30 days) were used to nd controls from the study cohort. Controls could not have cancer diagnosis within 1 year after matched cases date of cancer diagnosis. Up to four controls were selected for each case. Exposure Ascertainment and Covariate Adjustment The main exposure of interest was ARB therapy. The use of ACE inhibitors was chosen as a comparator for the same indications as ARBs. We collected information on prescribed drug types (according to the Anatomic Therapeutic Chemical [ATC] classication system code C09CA for ARBs), dosage, date of prescription, supply days, and total number of drug pills dispensed from the outpatient pharmacy prescription database. For each patient, we estimated the mean daily dose by multiplying cumulative number of pills dispensed by the dose prescribed divided by the follow-up duration of risk from the date of initiating antihypertensive treatment to cancer diagnosis. Data were presented as the number of dened daily doses (DDDs; 50 mg for losartan, 80 mg for valsartan, 150 mg for irbesartan, 8 mg for candesartan, and 40 mg for telmisartan). Other medication included ACE inhibitors, beta blockers, calcium channel blockers, thiazides, other antihypertensive agents, various types of oral hypoglycemic agents and insulins, statins, and aspirin. Other information collected included age, sex, comorbidities, and monthly income level as a proxy of socioeconomic status. Statistical Analysis Conditional logistic regression was used to estimate the crude and adjusted odds ratio (OR) and 95% CI for the association between ARBs (and ACE inhibitors) and cancer risk. Potential risk factors, including socioeconomic status (monthly income level), diabetic complications, comorbidities at cancer diagnosis, and medication use, were incorporated into the model. In the multivariable analysis, we used several variable selection schemes, including forward selection, backward elimination, stepwise selection, and including all covariates in the model, and found results were similar (Appendix Table A1, online only). Therefore, we presented results only from the stepwise selection to control for variables with P values less than .10 for model entry and more than .05 for removal. Furthermore, we divided the person-time product into current use, recent use (from drug discontinuation to cancer diagnosis 6 months), and past use (from drug discontinuation to cancer diagnosis 6 months) by using nonuse as the reference. In the dose- and duration-response analyses, we calculated the ORs for higher ( 0.5 DDD/d) and lower mean daily dose ( 0.5 DDD/d) and for cumulative treatment duration 3, 2 to 3, 1 to 2, and 1 years. The longest duration subgroup was thus designed specically to examine the late cancers (ie, excluding the cancers during the rst 3 years of exposure) in patients with at least 3 years of exposure. To show the impact of cumulative exposure, we further stratied the subjects into high, intermediate, and low tertiles of the cumulative dose, dened as a product of dose and duration. The cancer risk associated with ARB use was assessed in each tertile. In a separate analysis, we further stratied patients on the basis of specic sites of cancer. Potential dose and duration responses were explored when a statistically signicant association with a specic cancer site was found. A two-sided P value less than .05 was considered to be statistically signicant. Approximately 35% of participants claimed at lease one prescription for ARBs. Assuming that a correlation coefcient for ARB use between case and control was 0.5 and an OR was 1.5, a study of 1,280 cases and four controls for each case would have a power 80% at .05.
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RESULTS

The mean number of antihypertensive agents was 3.16, and the mean daily dosage was 0.74 DDD/d. Approximately 54% of the patients received prescriptions for ACE inhibitors and 36% received ARBs, with similar proportions of patients diagnosed with hypertension (25.8% to 27.6%), nephropathy (4.3% to 4.9%), and congestive heart failure (1.6% to 1.7%). The mean cumulative treatment duration was 603 days for ARBs, and the mean daily dosage was 0.28 DDD/d. During the study period, valsartan (37.8%), losartan (29.2%), and irbesartan (19.9%) were the most commonly used ARBs. A total of 1,281 incident cancer cases were identied. Liver (22%), colorectal (15%), lung (11%), and urologic cancer (6%) were the most common sites. Table 1 summarizes the characteristics of the cases and 5,104 age- and sex-matched controls. Cancer cases were more likely to have diabetic retinopathy, neuropathy, and nephropathy and chronic kidney, liver, and lung diseases, but less cardiovascular disease. The prescription pattern was also reported in Table 1. In the univariate analyses, we did not nd any signicant association between ARBs and overall cancer incidence (Table 2). The risk estimate slightly decreased after controlling for potential confounding variables (OR, 0.94; 95% CI, 0.80 to 1.10). However, there was a trend toward a negative association of overall cancer incidence with higher mean daily dosage ( 0.5 DDD/d; OR, 0.85; 95% CI, 0.64 to 1.12) and with longer cumulative treatment duration (2 to 3 years; OR, 0.70; 95% CI, 0.43 to 1.16), but statistical signicance was not reached. In those who had 3 years of exposure to ARBs, we found no evidence of increased risk for late cancer occurrence (OR, 1.00; 95% CI, 0.64 to 1.58). In the cumulative dose analysis, there was a trend toward a decreased risk of cancer in those with the higher cumulative dose (Table 2). In the stratied analyses, no signicant association between ARB use and individual sites of cancer was found (Table 3). Specically, there was no association of ARBs with either urologic or pancreatic cancer. Among individual ARBs, losartan decreased the risk (OR, 0.78; 95% CI, 0.63 to 0.97) and candesartan (OR, 1.79; 95% CI, 1.05 to 3.06) and telmisartan (OR, 1.54; 95% CI, 0.97 to 2.43) possibly increased the risk of occurrence of malignancy (Table 4). The number of patients with cancer exposed to individual ARBs was too small to allow us to precisely evaluate the risks for specic sites of cancer.

DISCUSSION

The results have demonstrated a null association between the effect of ARBs as a class and overall cancer incidence in diabetic patients in Taiwan. However, the association with the overall occurrence of cancer varied across individual ARBs. In our analysis, neither current use, recent use, nor past use affected the neutral association with overall risk of cancer. However, increased mean daily dosage of ARBs ( 0.5 DDD/d) was associated with a 26% lower risk of cancer, indicating a protective effect from cancer occurrence with higher ARB dosages. A similar trend was also observed when the cumulative dose, dened as the product of dose and duration, increased. The risk reduction substantially diminished
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Chang et al

Table 1. Characteristics, Comorbidities, and Medication Use Among Cases and Controls (n Characteristic Age at cancer diagnosis, years (mean SD) Male Diagnosis year 2000 2001 2002 2003 2004 2005 2006 2007 Duration of diabetes at cancer diagnosis, years (mean SD) Socioeconomic status (monthly income), New Taiwan dollars 17,280 17,281-22,800 22,801-28,800 28,801-36,300 36,301-45,800 45,800 Comorbidities Cardiovascular disease Peripheral vascular disease Cerebrovascular disease Retinopathy Neuropathy Nephropathy Depression Chronic kidney disease Chronic liver disease Chronic lung disease Charlsons index (mean SD) Medication used before cancer diagnosis Biguanides Sulfonylurea Alpha-glucosidase inhibitors Thiazolidinediones Glinides No. of oral antidiabetic agents (mean SD) Fast-acting human insulin Insulin glargine Statins Aspirin ACE inhibitors Angiotensin receptor blockers Beta blockers Calcium channel blockers Thiazides Other antihypertensive agents No. 66.21 Cases 1,281) % 10.91 63.31 No. 66.12 Controls (n 5,104) % 10.81 63.24 Crude OR Reference 1.05 1.12 0.77 0.77 0.70 0.86 1.01 1.10 1.22 1.09 1.45 0.93 1.53 1.70 1.25 1.28 0.87 1.02 1.26 0.95 1.40 1.02 1.88 0.94 0.86 1.08 0.97 0.98 1.25 1.15 1.32 1.27 95% CI

51 123 162 156 194 201 185 209 3.92

2.07 38.25 45.28 6.09 4.29 3.20 2.89 84.62 5.54 25.29 21.16 36.07 61.59 6.17 8.67 49.65 17.95 3.03 62.06 76.42 12.80 11.32 13.35 1.25 37.47 0.39 23.73 43.48 52.22 26.00 55.74 65.73 20.84 23.97

186 516 635 614 805 786 756 806 3.92

2.06 38.15 42.81 5.39 5.49 4.13 4.04 86.32 5.43 23.51 18.14 34.25 53.33 6.54 5.84 37.23 14.95 2.02 65.11 76.02 10.62 11.81 9.99 1.19 24.49 0.41 26.23 41.71 53.04 26.27 50.72 62.85 16.87 20.28

0.92 to 1.21 0.85 to 1.47 0.57 to 1.06 0.54 to 1.09 0.48 to 1.02 0.72 to 1.03 0.78 to 1.33 0.95 to 1.28 1.05 to 1.43 0.96 to 1.24 1.27 to 1.65 0.72 to 1.21 1.22 to 1.93 1.50 to 1.93 1.06 to 1.47 1.25 to 1.32 0.76 to 0.99 0.88 to 1.19 1.04 to 1.53 0.78 to 1.17 1.16 to 1.69 0.97 to 1.08 1.65 to 2.15 0.36 to 2.50 0.74 to 1.00 0.95 to 1.23 0.85 to 1.10 0.85 to 1.14 1.10 to 1.42 1.00 to 1.31 1.13 to 1.55 1.09 to 1.48

4.56

3.23

1.76

1.74

Abbreviations: ACE, angiotensin-converting enzyme; OR, odds ratio; SD, standard deviation.

to 15% when other factors were adjusted for, and the statistical significance disappeared. Our nding is comparable with another more recent meta-analysis20 showing that, in 15 trials, there was no excess of cancer incidence with ARB therapy compared with that in controls (OR, 1.00; 95% CI, 0.95 to 1.04). One explanation for this nding of null association is that cancer risk associated with ARBs might not be a class effect, and
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examining different ARBs as a group will dilute the risk estimates for individual drugs. Despite several meta-analyses of randomized controlled trials that were not designed to explore cancer incidence as the primary outcome measure,5,20,21 there were few long-term trials that enrolled a sufcient number of patients to evaluate the potential risk associated with individual ARBs. Thus, welldesigned epidemiologic studies that examine large computerized
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Angiotensin Receptor Blockade and Cancer Risk

Table 2. Risk of Overall Cancer Associated With Use of ACE Inhibitors or ARBs in Patients With Diabetes Receiving Antihypertensive Treatment ACE Inhibitors Variable Nonuse Any use Current use Recent use Past use Mean daily dosage 0.5 DDD/d 0.5 DDD/d Cumulative duration, years 3 2-3 1-2 1 Cumulative dose High Intermediate Low Cases Controls Crude OR 612 669 187 163 319 134 535 2,397 2,707 695 558 1,454 569 2,138 Ref. 0.97 1.05 1.15 0.85 0.92 0.99 95% CI Ref. 0.85 to 1.10 0.87 to 1.26 0.94 to 1.40 0.72 to 0.99 0.75 to 1.14 0.86 to 1.13 Adjusted OR Ref. 0.99 1.00 1.14 0.84 1.04 0.97 95% CI Ref. 0.86 to 1.14 0.81 to 1.23 0.92 to 1.41 0.71 to 1.00 0.83 to 1.29 0.84 to 1.12 Cases Controls Crude OR 948 333 141 62 130 70 263 3,763 1,341 548 270 523 374 967 Ref. 0.98 1.02 0.91 0.99 0.74 1.09 ARBs 95% CI Ref. 0.85 to 1.14 0.84 to 1.25 0.68 to 1.21 0.80 to 1.22 0.56 to 0.97 0.92 to 1.28 Adjusted OR Ref. 0.94 0.96 0.84 0.89 0.85 0.99 95% CI Ref. 0.80 to 1.10 0.77 to 1.19 0.62 to 1.14 0.71 to 1.12 0.64 to 1.12 0.83 to 1.17

43 43 92 491 232 223 214

156 137 342 2,072 901 893 913

1.10 1.26 1.07 0.94 1.02 0.98 0.92

0.77 to 1.58 0.87 to 1.82 0.83 to 1.37 0.82 to 1.07 0.85 to 1.22 0.83 to 1.17 0.77 to 1.10

1.29 1.28 1.09 0.94 1.11 1.03 0.93

0.87 to 1.91 0.87 to 1.89 0.83 to 1.43 0.82 to 1.09 0.91 to 1.35 0.85 to 1.24 0.77 to 1.11

29 21 52 231 87 120 126

137 125 251 828 444 448 449

0.82 0.65 0.82 1.10 0.76 1.06 1.11

0.54 to 1.25 0.40 to 1.05 0.60 to 1.12 0.93 to 1.30 0.59 to 0.98 0.85 to 1.31 0.90 to 1.37

1.00 0.70 0.81 1.02 0.83 0.98 1.06

0.64 to 1.58 0.43 to 1.16 0.59 to 1.13 0.85 to 1.22 0.64 to 1.09 0.77 to 1.23 0.84 to 1.33

NOTE. Recent use, from drug discontinuation to cancer diagnosis 6 months; past use, from drug discontinuation to cancer diagnosis 6 months. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DDD, dened daily dose; OR, odds ratio; Ref., reference. Multivariable model with stepwise selection of covariates, including ACE inhibitors, ARBs, beta blockers, calcium channel blockers, thiazide, other antihypertensive agents, fast-acting human insulins, chronic liver disease, biguanides, nephropathy, glinides, retinopathy, cardiovascular disease, statins, and socioeconomic status. Dened as a product of dose and duration.

health databases may provide useful information, although the current analysis for a single-drug effect must be considered exploratory. In our analysis, losartan was indeed the only drug that was associated with a decreased overall risk of cancer. Angiotensin II signicantly accelerates S phase progression. In turn, losartan blocks endogenous angiotensin II and signicantly suppresses proliferation of pancreatic adenocarcinoma. Losartan also inhibits cell growth, decreases c-myc expression, and increases apoptosis.22,23 Moreover, losartan interferes with angiogenesis by decreasing the expression of angiogenic factor receptors.24,25 However, this potential antineoplastic agent was under-represented in the clinical trials selected in the meta-analysis by Sipahi et al.5 Telmisartan, one of the least frequently used ARBs in Taiwan, was again found to be associated with an increased risk of new

cancer diagnosis. However, the mechanism is still unknown.5 Alternatively, in vivo studies showed that telmisartan mediated potent antiproliferative effects and might be a potential target for prevention and treatment in prostate cancer.26 Since most patients in the meta-analysis by Sipahi et al5 (85.7%) received telmisartan, we speculated that the nding of a modestly increased risk of new cancer diagnosis might be based mainly on the combination of telmisartan and ramipril.5 However, our analysis did not support this hypothesis because there was no detrimental effect of ACE inhibitors on increasing risk of cancer. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial3 reported a signicant increase in risk of fatal cancers in patients randomly assigned to candesartan compared with placebo (2.3% v 1.6%; P .038). An increased risk in overall incidence of

Table 3. Risk of Different Site of Cancer Associated With Use of ACE Inhibitors or ARBs in Patients With Diabetes Receiving Antihypertensive Treatment Type of Cancer Liver Colorectal Lung Urologic Breast Prostate Gastric Pancreatic ACE Inhibitors Cases 142 109 74 39 33 24 34 15 Controls Crude OR 596 433 282 157 160 115 139 63 0.90 1.02 1.10 0.99 0.64 0.68 0.95 0.91 95% CI 0.69 to 1.18 0.73 to 1.41 0.75 to 1.61 0.58 to 1.67 0.37 to 1.12 0.37 to 1.25 0.55 to 1.63 0.41 to 2.01 Adjusted OR 1.03 0.87 1.10 1.32 0.72 0.74 0.87 0.18 95% CI 0.73 to 1.45 0.60 to 1.27 0.71 to 1.69 0.69 to 2.53 0.38 to 1.38 0.34 to 1.64 0.45 to 1.68 0.04 to 0.84 Cases 68 52 34 22 14 13 17 9 Controls Crude OR 298 220 150 79 80 57 77 22 0.87 0.92 0.86 1.16 0.58 0.87 0.83 1.86 ARBs 95% CI 0.63 to 1.20 0.64 to 1.33 0.56 to 1.32 0.66 to 2.04 0.29 to 1.15 0.42 to 1.82 0.44 to 1.54 0.77 to 4.50 Adjusted OR 0.96 0.75 0.80 1.10 0.63 1.04 0.65 0.68 95% CI 0.64 to 1.44 0.49 to 1.14 0.49 to 1.30 0.56 to 2.18 0.28 to 1.41 0.42 to 2.60 0.32 to 1.34 0.14 to 3.21

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; OR, odds ratio. Multivariable model with stepwise selection of covariates, including ACE inhibitors, ARBs, beta blockers, calcium channel blockers, thiazide, other antihypertensive agents, fast-acting human insulins, chronic liver disease, biguanides, nephropathy, glinides, retinopathy, cardiovascular disease, and statins, and socioeconomic status.

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Chang et al

Table 4. Risk of Overall Cancer Associated With Any Use of Individual ARB in Patients With Diabetes Receiving Antihypertensive Treatment Drug Type Valsartan Losartan Irbesartan Candesartan Telmisartan Cases Controls 166 127 84 22 29 698 571 328 47 74 Crude OR 0.94 0.87 1.02 1.91 1.58 95% CI 0.78 to 1.13 0.71 to 1.07 0.79 to 1.31 1.14 to 3.19 1.01 to 2.45 Adjusted OR 0.90 0.78 0.97 1.79 1.54 95% CI 0.74 to 1.09 0.63 to 0.97 0.74 to 1.26 1.05 to 3.06 0.97 to 2.43

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; OR, odds ratio. Multivariable model with stepwise selection of covariates, including individual ARBs, ACE inhibitors, beta blockers, calcium channel blockers, thiazide, other antihypertensive agents, fast-acting human insulins, chronic liver disease, biguanides, nephropathy, glinides, retinopathy, cardiovascular disease, and statins, and socioeconomic status.

cancer associated with candesartan was also found in Taiwan. To the best of our knowledge, there were no reports of association of valsartan and irbesartan with cancer before our analysis, which showed a neutral relationship. No information was available about olmesartan and eprosartan in the NHI claims data set. Huang et al27 conducted a related retrospective cohort study by analyzing data from a random sample of 5% of all patients in the Taiwan NHI database. Without restricting their sample to diabetic patients, they included patients with newly diagnosed hypertension from 1998 to 2006 to examine their incident cancer occurrence. It was not clearly reported whether the diagnosis of cancer was validated, whether patients were censored at death or disenrollment from NHI, and how concomitant antihypertensive agents were controlled in the multivariable adjusted analysis. The authors compared ever use of ARB with never use (in fact a mixture of different antihypertensive treatments) and found an implausibly low risk for all kinds of cancer and for all types of ARBs.27 This nding of overestimation of treatment effect was probably due to immortal time bias.28 Because ARBs have entered into Taiwans market since 1998, an increasing number of hypertensive patients started or switched to ARB therapy as the study proceeded. The authors dened cohort entry as the date of hypertension diagnosis. Compared with ARB never users who received other antihypertensive therapy, ARB users who switched from other antihypertensive treatments they had taken for years had longer cancer-free follow-up time because malignancy could not occur during this period by their denition of exposure. This speculation was further supported by their ndings showing that the more recently introduced ARBs were associated with more pronounced benecial effect. Instead, in our study, we used a time-matched, nested casecontrol design to reduce immortal time bias.28 Cancer cases and controls were matched on duration of diabetes and of antihypertensive treatment, and their cumulative exposures to different antihypertensive medications were compared. Hepatocellular carcinoma, one of the most incident, prevalent, and lethal malignancies in Taiwan, is regarded as a late-stage sequel of chronic infection with hepatitis B or C. The development of hepatocellular carcinoma almost exclusively follows the sequence of chronic hepatic inammation, cirrhosis of the liver, repair and regeneration of hepatic cells, and carcinogenesis.29-31 Despite the large number of cases of liver cancer, there was no signicant association with ARBs.
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The strengths of this case-control study include the enrollment of all patients with newly diagnosed diabetes who started antihypertensive drug useinTaiwan.Thedatarepresentthetrueprescriptionpatterninageneral diabetic population rather than a randomized allocation of patients in clinical trials. Cancer cases were veried by record linkage through the National Cancer Registry. We used a new user study design and matched cases and controls on the duration of diabetes and antihypertensive treatment to reduce potential selection bias.28,32 The study has some limitations. First, besides the most incident cancers (liver, colorectal, and lung cancer), the number of cases of individual cancer was relatively low. We did not nd an association between individual ARBs and specic cancers (eg, losartan and lung cancer, telmisartan and lung cancer, telmisartan and prostate cancer).2,5,26 Second, the number of cases associated with candesartan and telmisartan was small and therefore the CIs of the OR were wide. The point estimates of ORs (77% increased risk for candesartan and 53% increased risk for telmisartan) had a larger value than previously known moderate increased cancer risk (8% to 11%), but these estimates were derived from different measures (OR v relative risk) and might not be precise enough.5 Third, we also noticed that there might be an increased cancer incidence in diabetic patients receiving alphaglucosidase inhibitors, glinides, fast-acting human insulin, and other types of antihypertensive agents. Biguanides and statins might be associated with lower occurrence of malignancy. Some of these associations have been reported before, but the others denitely require further investigations.33 Fourth, smoking status could not be obtained from the claims database. However, since NHI covers almost the whole population of Taiwan and the reimbursement policy is universally the same, it is unlikely that the smoking status would affect the prescription of ARBs. Smoking is an important risk factor for cancer but probably could not explain the association. Fifth, the evidence derived from a case-control study is generally lower than that from randomized trials or cohort studies because case-control study design is subject to many biases related to selection of cases and controls, confounding adjustment, and assessment of outcomes. Despite our meticulous study design and adequate control of confounding factors, a key limitation is that bias could still remain if there are unmeasured or unknown confounders. In conclusion, the results did not show a class effect of ARBs on increasing cancer incidence in diabetic patients. However, the association with the overall occurrence of cancer varied across individual drugs. Further investigation is required to demonstrate the relative risk between ARBs and specic types of cancer.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conicts of interest.

AUTHOR CONTRIBUTIONS
Conception and design: Chia-Hsuin Chang, Jou-Wei Lin Administrative support: Li-Chiu Wu, Mei-Shu Lai Collection and assembly of data: Li-Chiu Wu Data analysis and interpretation: Chia-Hsuin Chang, Jou-Wei Lin, Li-Chiu Wu, Mei-Shu Lai Manuscript writing: All authors Final approval of manuscript: All authors
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Angiotensin Receptor Blockade and Cancer Risk

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Appendix

Table A1. Adjusted OR of Overall Cancer Associated With Any Use of ACE Inhibitors or ARBs in Patients With Diabetes Receiving Antihypertensive Treatment by Different Multivariable Models Antihypertensive Treatment ACE inhibitors ARBs Model 1 OR 0.99 0.94 95% CI 0.86 to 1.14 0.80 to 1.10 OR 0.98 0.93 Model 2 95% CI 0.86 to 1.13 0.80 to 1.09 OR 0.99 0.94 Model 3 95% CI 0.86 to 1.13 0.80 to 1.10 OR 0.98 0.93 Model 4 95% CI 0.86 to 1.13 0.79 to 1.09

NOTE. Covariates common to all models: ACE inhibitors, ARBs, beta blockers, calcium channel blockers, thiazide, other antihypertensive agents, fast-acting human insulins, glinides, statins, chronic liver disease, nephropathy, retinopathy, cardiovascular disease, and socioeconomic status. Model 1: Multivariable model with stepwise selection (P .10 for entry; P .05 for stay) of covariates, including biguanides. Model 2: Multivariable model with forward selection (P .15 for entry) of covariates, including biguanides, depression, and chronic kidney disease. Model 3: Multivariable model with backward elimination (P .10 for stay) of covariates, including sulfonylurea, alpha-glucosidase inhibitors, and oral anti-diabetic agents. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; OR, odds ratio.

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