Samantha F. Ehrlich

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.

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.

Patients Diagnosed With Diabetes Are at Increased Risk for Asthma, Chronic Obstructive Pulmonary Disease, Pulmonary Fibrosis, and Pneumonia but Not Lung Cancer

OBJECTIVE There are limited data on the risk of pulmonary disease in patients with diabetes. The aim of this study was to evaluate and compare the incidence of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer in patients with and without a diagnosis of diabetes. RESEARCH DESIGN AND METHODS We conducted a retrospective, longitudinal cohort study using the electronic records of a large health plan in northern California. Age and sex data were available for all cohort members (n = 1,811,228). Data on confounders were available for a subcohort that responded to surveys (n = 121,886), among whom Cox proportional hazards regression models were fit. RESULTS Age- and sex-adjusted incidence rates and 95% CIs were calculated for members with and without diabetes in the full cohort and the subcohort. No difference was observed for lung cancer, but the incidence of asthma, COPD, fibrosis, and pneumonia was significantly higher in those members with a diagnosis of diabetes. These differences remained significant in regression models adjusted for age, sex, race/ethnicity, smoking, BMI, education, alcohol consumption, and outpatient visits (asthma hazard ratio [HR] 1.08 [95% CI 1.03–1.12], COPD HR 1.22 [1.15–1.28], pulmonary fibrosis HR 1.54 [1.31–1.81], and pneumonia HR 1.92 [1.84–1.99]). The risk of pneumonia and COPD increased significantly with increasing A1C. CONCLUSIONS Individuals with diabetes are at increased risk of several pulmonary conditions (asthma, COPD, fibrosis, and pneumonia) but not lung cancer. This increased risk may be a consequence of declining lung function in patients with diabetes.

Racial/Ethnic Disparities in the Prevalence of Gestational Diabetes Mellitus by BMI

OBJECTIVE To examine whether the association between gestational diabetes mellitus (GDM) and BMI category varies by racial/ethnic group. RESEARCH DESIGN AND METHODS In a cohort of 123,040 women without recognized pregravid diabetes who delivered babies between 1995 and 2006 at Kaiser Permanente of Northern California, we examined racial/ethnic disparities in the prevalence of GDM by BMI category and the population-attributable risk (PAR) associated with overweight/obesity. RESULTS Among all racial/ethnic groups, the age-adjusted prevalence of GDM increased with increasing BMI (kg/m2) category. However, Asian and Filipina women had a prevalence of GDM of 9.9 and 8.5%, respectively, at a BMI of 22.0–24.9 kg/m2, whereas in Hispanic, non-Hispanic white, and African American women, the prevalence of GDM was >8.0% at a higher BMI, such as 28–30, 34–36, and ≥37 kg/m2, respectively. The estimated PARs suggest that the percentage of GDM that could be prevented if all pregnant women were of normal weight (BMI <25.0 kg/m2) ranging from 65% for African American women to only 23% among Asian women. CONCLUSIONS Clinicians should be aware that the BMI thresholds for increased risk of GDM varies by racial/ethnic group and that the risk is high even at relatively low BMI cutoffs in Asian and Filipina women. Asian women may benefit from different prevention strategies in addition to weight management.

Maternal gestational weight gain and offspring risk for childhood overweight or obesity

OBJECTIVE The objective of the study was to evaluate the association between gestational weight gain, per the 2009 Institute of Medicine (IOM) recommendations, and offspring overweight/obesity at 2-5 years of age. STUDY DESIGN This was a prospective cohort study of 4145 women who completed a health survey (2007-2009) and subsequently delivered a singleton at Kaiser Permanente Northern California (2007-2010). Childhood overweight/obesity was defined as a body mass index (BMI) z-score of the 85th percentile or greater of the Centers for Disease Control and Prevention child growth standards. Gestational weight gain was categorized according to the 2009 IOM recommendations. Logistic regression was used; meeting the IOM recommendations was the referent. RESULTS Exceeding the IOM recommendations was associated with a 46% increase in odds of having an overweight/obese child (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.17-1.83), after adjusting for maternal prepregnancy BMI, race/ethnicity, age at delivery, education, child age, birthweight, gestational age at delivery, gestational diabetes, parity, infant sex, total metabolic equivalents, and dietary pattern. The OR (95% CI) for childhood overweight/obesity among women gaining below the IOM recommendations was 1.23 (0.88-1.71). The associations between gaining outside the IOM recommendations and childhood obesity were stronger among women with a normal prepregnancy BMI (OR, 1.63; 95% CI, 1.03-2.57) (below); OR, 1.79; 95% CI, 1.32-2.43) (exceeded). CONCLUSION Gestational weight gain outside the IOM recommendations is associated with increased odds of childhood overweight/obesity, independent of several potential confounders and mediators. Gestational weight gain had a greater impact on childhood overweight/obesity among normal-weight women, suggesting that the effect may be independent of genetic predictors of obesity.

Change in Body Mass Index Between Pregnancies and the Risk of Gestational Diabetes in a Second Pregnancy

OBJECTIVE: To estimate the association between interpregnancy change in body mass index (BMI) and the risk of gestational diabetes mellitus (GDM) in a second pregnancy. METHODS: In a retrospective cohort analysis of 22,351 women, logistic regression models provided adjusted estimates of the risk of GDM in women gaining 3.0 or more 2.0–2.9, and 1.0–1.9 BMI units, or losing 1.0–2.0 and more than 2.0 units between pregnancies (one BMI unit corresponds to 5.9 pounds for the average height [5 feet 4 inches] of the study population). Women with stable BMIs (±1.0 BMI unit) comprised the reference. RESULTS: For those with GDM in the first pregnancy, the age-adjusted risk of GDM in the second pregnancy was 38.19% (95% confidence interval [CI] 34.96–41.42); for those whose first pregnancy was not complicated by GDM, the risk was 3.52% (95% CI 3.27–3.76). Compared with women who remained stable, interpregnancy BMI gains were associated with an increased risk of GDM in the second pregnancy (odds ratio [OR] 1.71 [95% CI 1.42–2.07] for gaining 1.0–1.9 BMI units; OR 2.46 [95% CI 2.00–3.02] for 2.0–2.9 BMI units; and OR 3.40 [95% CI 2.81–4.12] for 3.0 or more BMI units). The loss of BMI units was associated with a lower risk of GDM only among women who were overweight or obese in the first pregnancy (OR 0.26 [95% CI 0.14–0.47] for the loss of at least 2.0 BMI units). In overweight and obese women, those with GDM in the first pregnancy that did not develop the condition again gained fewer BMI units than those experiencing recurrent GDM (mean change 0.66 [95% CI 0.25–1.07] compared with 2.00 [95% CI 1.56–2.43] BMI units, respectively). CONCLUSION: Interpregnancy increases in BMI between the first and second pregnancy increases a womans risk of GDM pregnancy. LEVEL OF EVIDENCE: II

Low Prepregnancy Adiponectin Concentrations Are Associated With a Marked Increase in Risk for Development of Gestational Diabetes Mellitus

OBJECTIVE To examine whether circulating total and high–molecular weight (HMW) adiponectin concentrations, measured before pregnancy, are associated with subsequent risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up exam (1984–1996) with a serum sample obtained and who had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case subjects were the 256 women who developed GDM. Two control subjects were selected for each case and matched for year of blood draw, age at exam, age at pregnancy, and number of intervening pregnancies. RESULTS Compared with the highest quartile of adiponectin, the risk of GDM increased with decreasing quartile (odds ratio [OR] 1.5 [95% CI 0.7–2.9], 3.7 [1.9–7.2], and 5.2 [2.6–10.1]; Ptrend <0.001) after adjustment for family history of diabetes, BMI, parity, race/ethnicity, cigarette smoking, and glucose and insulin concentrations. Similar estimates were observed for HMW (Ptrend <0.001). The combined effects of having total adiponectin levels below the median (<10.29 mg/mL) and being overweight or obese (BMI ≥25.0 kg/m2) were associated with a sevenfold increased risk of GDM compared with normal-weight women with adiponectin levels above the median (OR 6.7 [95% CI 3.6–12.5]). CONCLUSIONS Prepregnancy low adiponectin concentrations, a marker of decreased insulin sensitivity and altered adipocyte endocrine function, is associated with reduced glucose tolerance during pregnancy and may identify women at high risk for GDM to target for early intervention.

The risk of large for gestational age across increasing categories of pregnancy glycemia.

OBJECTIVE We sought to estimate the risk of large for gestational age (LGA) across categories of glucose tolerance. STUDY DESIGN In a cohort of 89,141 participants, women without gestational diabetes mellitus (GDM) were categorized by their screening and diagnostic test results; those with GDM were categorized as meeting the National Diabetes Data Group or only the American Diabetes Association (ADA) criteria. Multivariable logistic regression models estimated the risk of LGA; screening values 5.5-6.0 mmol/L comprised the referent. RESULTS In women without GDM, the odds ratio for LGA was 1.89 (95% confidence interval [CI], 1.45-2.45) for fasting, 1.57 (95% CI, 1.31-1.89) for 1-hour, 1.60 (95% CI, 1.33-1.93) for 2-hour, and 1.62 (95% CI, 1.23-2.14) for 3-hour values meeting the ADA time point-specific thresholds. CONCLUSION For GDM identified in a 2-step procedure, our findings support the use of isolated abnormal fasting values according to the ADA threshold in identifying women who could benefit from treatment.

A pragmatic cluster randomized clinical trial of diabetes prevention strategies for women with gestational diabetes: design and rationale of the Gestational Diabetes’ Effects on Moms (GEM) study

BackgroundWomen with gestational diabetes (GDM) are at high risk of developing diabetes later in life. After a GDM diagnosis, women receive prenatal care to control their blood glucose levels via diet, physical activity and medications. Continuing such lifestyle skills into early motherhood may reduce the risk of diabetes in this high risk population. In the Gestational Diabetes’ Effects on Moms (GEM) study, we are evaluating the comparative effectiveness of diabetes prevention strategies for weight management designed for pregnant/postpartum women with GDM and delivered at the health system level.Methods/DesignThe GEM study is a pragmatic cluster randomized clinical trial of 44 medical facilities at Kaiser Permanente Northern California randomly assigned to either the intervention or usual care conditions, that includes 2,320 women with a GDM diagnosis between March 27, 2011 and March 30, 2012. A Diabetes Prevention Program-derived print/telephone lifestyle intervention of 13 telephonic sessions tailored to pregnant/postpartum women was developed. The effectiveness of this intervention added to usual care is to be compared to usual care practices alone, which includes two pages of printed lifestyle recommendations sent to postpartum women via mail. Primary outcomes include the proportion of women who reach a postpartum weight goal and total weight change. Secondary outcomes include postpartum glycemia, blood pressure, depression, percent of calories from fat, total caloric intake and physical activity levels. Data were collected through electronic medical records and surveys at baseline (soon after GDM diagnosis), 6 weeks (range 2 to 11 weeks), 6 months (range 12 to 34 weeks) and 12 months postpartum (range 35 to 64 weeks).DiscussionThere is a need for evidence regarding the effectiveness of lifestyle modification for the prevention of diabetes in women with GDM, as well as confirmation that a diabetes prevention program delivered at the health system level is able to successfully reach this population. Given the use of a telephonic case management model, our Diabetes Prevention Program-derived print/telephone intervention has the potential to be adopted in other settings and to inform policies to promote the prevention of diabetes among women with GDM.Trial registrationClinical Trials.gov number, NCT01344278.