Lewis James D, Habel Laurel, Quesenberry Charles, Mamtani Ronac, Peng Tiffany, Bilker Warren B, Hedderson Monique, Nessel Lisa, Vaughn David J, Strom Brian L, Ferrara Assiamira
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Pharmacoepidemiol Drug Saf. 2014 Jun;23(6):636-45. doi: 10.1002/pds.3619. Epub 2014 Apr 25.
The observed association between pioglitazone and bladder cancer could be causal or because of bias in the design of prior studies. We hypothesize that proteinuria testing may lead to detection bias if routine test results for proteinuria lead to a full urinalysis.
We reanalyzed patients with diabetes mellitus within Kaiser Permanente Northern California. Logistic and Cox regression adjusted for age, sex, race, and smoking were used to assess the association of proteinuria testing with pioglitazone use, subsequent full urinalysis, and diagnosis with bladder cancer.
Patients treated with pioglitazone were more likely than others with diabetes to undergo testing for proteinuria (p < 0.001). The odds of positive tests for proteinuria were higher among pioglitazone-treated patients (OR = 1.41, 95%CI 1.36-1.46). A positive proteinuria test was associated with increased odds of completing a urinalysis in the following 6 months (OR = 1.78, 95%CI 1.73-1.85). Negative and positive proteinuria test results were inversely (hazard ratio (HR) 0.63, 95%CI 0.52-0.75) and positively associated (HR 2.45, 95%CI 2.12-2.82) with bladder cancer risk, respectively. Adjustment for negative and positive proteinuria testing reduced the magnitude of association between pioglitazone and bladder cancer by only 5 to 10% (ever-exposed HR: from 1.06 to 1.01 and >4 years exposure HR: from 1.38 to 1.28).
Proteinuria testing may be a confounder in studies of pioglitazone and bladder cancer but does not fully explain the association between pioglitazone and bladder cancer in this cohort. Optimal adjustment for proteinuria testing likely requires knowledge of the test result.
观察到的吡格列酮与膀胱癌之间的关联可能是因果关系，也可能是由于既往研究设计存在偏差。我们推测，如果蛋白尿的常规检测结果导致进行全面尿液分析，那么蛋白尿检测可能会导致检测偏倚。
我们对北加利福尼亚凯撒医疗集团内的糖尿病患者进行了重新分析。采用经年龄、性别、种族和吸烟因素校正的逻辑回归和Cox回归，评估蛋白尿检测与吡格列酮使用、随后的全面尿液分析以及膀胱癌诊断之间的关联。
接受吡格列酮治疗的患者比其他糖尿病患者更有可能接受蛋白尿检测（p < 0.001）。在接受吡格列酮治疗的患者中，蛋白尿检测呈阳性的几率更高（OR = 1.41，95%CI 1.36 - 1.46）。蛋白尿检测呈阳性与在接下来6个月内完成尿液分析的几率增加相关（OR = 1.78，95%CI 1.73 - 1.85）。蛋白尿检测结果为阴性和阳性分别与膀胱癌风险呈负相关（风险比（HR）0.63，95%CI 0.52 - 0.75）和正相关（HR 2.45，95%CI 2.12 - 2.82）。对蛋白尿检测结果为阴性和阳性进行校正后，吡格列酮与膀胱癌之间关联的强度仅降低了5%至10%（曾经暴露的HR：从1.06降至1.01，暴露超过4年的HR：从1.38降至1.28）。
蛋白尿检测可能是吡格列酮与膀胱癌研究中的一个混杂因素，但并不能完全解释该队列中吡格列酮与膀胱癌之间的关联。对蛋白尿检测进行最佳校正可能需要了解检测结果。
