Tiffany Peng

Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone: Interim report of a longitudinal cohort study

OBJECTIVE Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes. RESEARCH DESIGN AND METHODS This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking. RESULTS The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9–1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [1.03–2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage. CONCLUSIONS In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.

Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes

IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

A Pregnancy and Postpartum Lifestyle Intervention in Women With Gestational Diabetes Mellitus Reduces Diabetes Risk Factors: A feasibility randomized control trial

OBJECTIVE To pilot, among women with gestational diabetes mellitus (GDM), the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program. The intervention was delivered by telephone, and support for breastfeeding was addressed. RESEARCH DESIGN AND METHODS The goal was to help women return to their prepregnancy weight, if it was normal, or achieve a 5% reduction from prepregnancy weight if overweight. Eligible participants were identified shortly after a GDM diagnosis; 83.8% consented to be randomly assigned to intervention or usual medical care (96 and 101 women, respectively). The retention was 85.2% at 12 months postpartum. RESULTS The proportion of women who reached the postpartum weight goal was higher, although not statistically significant, in the intervention condition than among usual care (37.5 vs. 21.4%, absolute difference 16.1%, P = 0.07). The intervention was more effective among women who did not exceed the recommended gestational weight gain (difference in the proportion of women meeting the weight goals: 22.5%, P = 0.04). The intervention condition decreased dietary fat intake more than the usual care (condition difference in the mean change in percent of calories from fat: −3.6%, P = 0.002) and increased breastfeeding, although not significantly (condition difference in proportion: 15.0%, P = 0.09). No differences in postpartum physical activity were observed between conditions. CONCLUSIONS This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight. Strategies to help postpartum women overcome barriers to increasing physical activity are needed.

Trends in Postpartum Diabetes Screening and Subsequent Diabetes and Impaired Fasting Glucose Among Women With Histories of Gestational Diabetes Mellitus A report from the Translating Research Into Action for Diabetes (TRIAD) Study

OBJECTIVE—The purpose of this study was to examine trends in postpartum glucose screening for women with gestational diabetes mellitus (GDM), predictors of screening, trends in postpartum impaired fasting glucose (IFG) and diabetes, and diabetes and pre-diabetes detected by postpartum fasting plasma glucose (FPG) versus a 75-g oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS—This was a cohort study of 14,448 GDM pregnancies delivered between 1995 and 2006. Postpartum screening was defined as performance of either an FPG or OGTT at least 6 weeks after delivery and within 1 year of delivery. RESULTS—Between 1995 and 2006, the age- and race/ethnicity-adjusted proportion of women who were screened postpartum rose from 20.7% (95% CI 17.8–23.5) to 53.8% (51.3–56.3). Older age, Asian or Hispanic race/ethnicity, higher education, earlier GDM diagnosis, use of diabetes medications during pregnancy, and more provider contacts after delivery were independent predictors of postpartum screening. Obesity and higher parity were independently associated with lower screening performance. Among women who had postpartum screening, the age- and race/ethnicity-adjusted proportion of IFG did not change over time (24.2 [95% CI 20.0–27.8] in 1995–1997 to 24.3 [22.6–26.0] in 2004–2006), but the proportion of women with diabetes decreased from 6.1 (95% CI 4.2–8.1) in 1995–1997 to 3.3 (2.6–4.0) in 2004–2006. Among women who received an OGTT in 2006, 38% of the 204 women with either diabetes or pre-diabetes were identified only by the 2-h glucose measurements. CONCLUSIONS—Postpartum screening has increased over the last decade, but it is still suboptimal. Compared with FPGs alone, the 2-h values identify a higher proportion of women with diabetes or pre-diabetes amenable to intervention.

Cohort Study of Pioglitazone and Cancer Incidence in Patients With Diabetes

OBJECTIVE To explore whether treatment with pioglitazone was associated with risk of incident cancer at the 10 most common sites (prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma [NHL], pancreas, kidney/renal pelvis, rectal, and melanoma). RESEARCH DESIGN AND METHODS A cohort study of 252,467 patients aged ≥40 years from the Kaiser Permanente Northern California Diabetes Registry was conducted. All prescriptions for diabetes medications were identified by pharmacy records. Cox proportional hazards models were used to examine the association between risk of incident cancer and ever use, duration, dose, and time since initiation of pioglitazone (modeled as time-dependent variables). RESULTS In models adjusted for age, sex, year of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, and use of other diabetes medications, the hazard ratio (HR) for each cancer associated with ever use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. There was a suggestion of an increased risk of melanoma (HR 1.3 [95% CI 0.9–2.0]) and NHL (1.3 [1.0–1.8]) and a decreased risk of kidney/renal pelvis cancers (0.7 [0.4–1.1]) associated with ever use of pioglitazone. These associations were unaltered with increasing dose, duration, or time since first use. CONCLUSIONS We found no clear evidence of an association between use of pioglitazone and risk of the incident cancers examined. Because the maximum duration of follow-up was fewer than 6 years after the initiation of pioglitazone, longer-term studies are needed.

Treatment intensification and risk factor control: toward more clinically relevant quality measures.

Background:Intensification of pharmacotherapy in persons with poorly controlled chronic conditions has been proposed as a clinically meaningful process measure of quality. Objective:To validate measures of treatment intensification by evaluating their associations with subsequent control in hypertension, hyperlipidemia, and diabetes mellitus across 35 medical facility populations in Kaiser Permanente, Northern California. Design:Hierarchical analyses of associations of improvements in facility-level treatment intensification rates from 2001 to 2003 with patient-level risk factor levels at the end of 2003. Patients:Members (515,072 and 626,130; age >20 years) with hypertension, hyperlipidemia, and/or diabetes mellitus in 2001 and 2003, respectively. Measurements:Treatment intensification for each risk factor defined as an increase in number of drug classes prescribed, of dosage for at least 1 drug, or switching to a drug from another class within 3 months of observed poor risk factor control. Results:Facility-level improvements in treatment intensification rates between 2001 and 2003 were strongly associated with greater likelihood of being in control at the end of 2003 (P ≤ 0.05 for each risk factor) after adjustment for patient-and facility-level covariates. Compared with facility rankings based solely on control, addition of percentages of poorly controlled patients who received treatment intensification changed 2003 rankings substantially: 14%, 51%, and 29% of the facilities changed ranks by 5 or more positions for hypertension, hyperlipidemia, and diabetes, respectively. Conclusions:Treatment intensification is tightly linked to improved control. Thus, it deserves consideration as a process measure for motivating quality improvement and possibly for measuring clinical performance.

Metformin Use and Lung Cancer Risk in Patients with Diabetes

Methodologic biases may explain why observational studies examining metformin use in relation to lung cancer risk have produced inconsistent results. We conducted a cohort study to further investigate this relationship, accounting for potential biases. For 47,351 patients with diabetes ages ≥40 years, who completed a health-related survey administered between 1994 and 1996, data on prescribed diabetes medications were obtained from electronic pharmacy records. Follow-up for incident lung cancer occurred from January 1, 1997, until June 30, 2012. Using Cox regression, we estimated lung cancer risk associated with new use of metformin, along with total duration, recency, and cumulative dose (all modeled as time-dependent covariates), adjusting for potential confounding factors. During 428,557 person-years of follow-up, 747 patients were diagnosed with lung cancer. No association was found with duration, dose, or recency of metformin use and overall lung cancer risk. Among never smokers, however, ever use was inversely associated with lung cancer risk [HR, 0.57; 95% confidence interval (CI), 0.33–0.99], and risk appeared to decrease monotonically with longer use (≥5 years: HR, 0.48; 95% CI, 0.21–1.09). Among current smokers, corresponding risk estimates were >1.0, although not statistically significant. Consistent with this variation in effect by smoking history, longer use was suggestively associated with lower adenocarcinoma risk (HR, 0.69; 95% CI, 0.40–1.17), but higher small cell carcinoma risk (HR, 1.82; 95% CI, 0.85–3.91). In this population, we found no evidence that metformin use affects overall lung cancer risk. The observed variation in association by smoking history and histology requires further confirmation. Cancer Prev Res; 8(2); 174–9. ©2014 AACR.

Proteinuria testing among patients with diabetes mellitus is associated with bladder cancer diagnosis: potential for unmeasured confounding in studies of pioglitazone and bladder cancer

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.

Trends and racial and ethnic disparities in the prevalence of pregestational type 1 and type 2 diabetes in Northern California: 1996–2014

BACKGROUND: Despite concern for adverse perinatal outcomes in women with diabetes mellitus before pregnancy, recent data on the prevalence of pregestational type 1 and type 2 diabetes mellitus in the United States are lacking. OBJECTIVE: The purpose of this study was to estimate changes in the prevalence of overall pregestational diabetes mellitus (all types) and pregestational type 1 and type 2 diabetes mellitus and to estimate whether changes varied by race‐ethnicity from 1996–2014. STUDY DESIGN: We conducted a cohort study among 655,428 pregnancies at a Northern California integrated health delivery system from 1996–2014. Logistic regression analyses provided estimates of prevalence and trends. RESULTS: The age‐adjusted prevalence (per 100 deliveries) of overall pregestational diabetes mellitus increased from 1996–1999 to 2012–2014 (from 0.58 [95% confidence interval, 0.54–0.63] to 1.06 [95% confidence interval, 1.00–1.12]; Ptrend <.0001). Significant increases occurred in all racial‐ethnic groups; the largest relative increase was among Hispanic women (121.8% [95% confidence interval, 84.4–166.7]); the smallest relative increase was among non‐Hispanic white women (49.6% [95% confidence interval, 27.5–75.4]). The age‐adjusted prevalence of pregestational type 1 and type 2 diabetes mellitus increased from 0.14 (95% confidence interval, 0.12–0.16) to 0.23 (95% confidence interval, 0.21–0.27; Ptrend <.0001) and from 0.42 (95% confidence interval, 0.38–0.46) to 0.78 (95% confidence interval, 0.73–0.83; Ptrend <.0001), respectively. The greatest relative increase in the prevalence of type 1 diabetes mellitus was in non‐Hispanic white women (118.4% [95% confidence interval, 70.0–180.5]), who had the lowest increases in the prevalence of type 2 diabetes mellitus (13.6% [95% confidence interval, –8.0 to 40.1]). The greatest relative increase in the prevalence of type 2 diabetes mellitus was in Hispanic women (125.2% [95% confidence interval, 84.8–174.4]), followed by African American women (102.0% [95% confidence interval, 38.3–194.3]) and Asian women (93.3% [95% confidence interval, 48.9–150.9]). CONCLUSIONS: The prevalence of overall pregestational diabetes mellitus and pregestational type 1 and type 2 diabetes mellitus increased from 1996–1999 to 2012–2014 and racial‐ethnic disparities were observed, possibly because of differing prevalence of maternal obesity. Targeted prevention efforts, preconception care, and disease management strategies are needed to reduce the burden of diabetes mellitus and its sequelae.

Abstract 2274: Metformin use and risk of lung cancer in patients with diabetes.

Observational studies suggest that cancer incidence is lower in patients with type 2 diabetes treated with metformin, relative to patients treated with other diabetes medications. The few studies to examine metformin use in relation to lung cancer risk, however, have produced inconsistent results. To clarify this relationship, we conducted a retrospective cohort study of 50,722 adults aged 40 years or older included in the Kaiser Permanente Northern California Diabetes Registry, who completed a mailed survey administered in 1994 to 1996 on health-related traits and behaviors. All prescribed diabetes medications were identified for each patient from pharmacy records. Patients were followed for lung cancer from 1997 to 2009, with a median follow-up of 8.1 years. Using Cox regression, with age as the time scale, rate ratios (RR) and 95% confidence intervals (CI) were calculated to estimate risk of lung cancer associated with new use of metformin, adjusted for sex, race/ethnicity, smoking status, income, education level, diabetes duration, baseline measures of hemoglobin A1c and creatinine, and ever use of other types of diabetes medications. Measures of metformin use, along with ever use for each type of diabetes medication, were modeled as time-dependent variables. During 389,887 person-years of follow-up, 685 patients were diagnosed with lung cancer. The adjusted RR for ever use of metformin was 0.95 (95% CI, 0.79-1.14). For duration of metformin use, the adjusted RRs for Citation Format: Lori C. Sakoda, Ninah S. Achacoso, Charles P. Quesenberry, Tiffany Peng, Samantha F. Ehrlich, Assiamira Ferrara, Laurel A. Habel. Metformin use and risk of lung cancer in patients with diabetes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2274. doi:10.1158/1538-7445.AM2013-2274