Samantha L. Bowker

Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure

Aims/hypothesisWe explored the relationship between glucose-lowering agents and cancer mortality rates in type 2 diabetes patients, hypothesising a decreased risk of cancer mortality with metformin use and a dose–risk gradient for insulin therapy.MethodsThis was a population-based cohort study using administrative data from Saskatchewan Health, Canada. We identified new users of metformin or sulfonylureas from 1 January 1991 to 31 December 1996, with follow-up until death, departure from the province or 31 December 1999. Cox regression analyses were used to estimate the HR of death from cancer, accounting for time-varying exposure to metformin, sulfonylurea, and exogenous insulin therapy.ResultsWe identified 10,309 new users of metformin or sulfonylurea. The average follow-up was 5.4 (1.9) years, during which 407 (4.0%) cancer deaths occurred. Adjusting for age, sex and chronic disease score, the adjusted HR for metformin use was 0.80 (95% CI 0.65–0.98) compared with sulfonylurea monotherapy users. Adjusted HRs for subsequent insulin use were 2.22 (0.99–5.00), 3.33 (2.26–4.89) and 6.40 (4.69–8.73) for <3, 3 to 11 and ≥12 insulin dispensations/year, respectively, compared with patients not on insulin. We observed a similar risk gradient among the sub-cohort of new insulin users.Conclusions/interpretationOur results support previous reports of a decreased risk of cancer outcomes associated with metformin use relative to sulfonylurea monotherapy. We also provide new evidence of a gradient of cumulative insulin dispensations and cancer mortality rates.

Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence

Substantial evidence suggests that people with type 2 diabetes have an increased risk of developing several types of cancers. These associations may be due to a number of direct and indirect mechanisms. Observational studies of these associations, including the potential role for glucose-lowering therapy, are being increasingly reported, but face a number of methodological challenges. This paper is the first of two review papers addressing methodological aspects underpinning the interpretations of links between diabetes and cancer, and suggests potential approaches to study designs to be considered in observational studies. This paper reviews factors related to cancer incidence in the diabetic population; the second paper relates to studies of cancer mortality.

Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis

Background: Patients with type 2 diabetes have a 40% increased risk of bladder cancer. Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review and meta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones. Methods: We searched key biomedical databases (including MEDLINE, Embase and Scopus) and sources of grey literature from inception through March 2012 for published and unpublished studies, without language restrictions. We included randomized controlled trials (RCTs), cohort studies and case–control studies that reported incident bladder cancer among people with type 2 diabetes who ever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione. Results: Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case–control study. The total number of patients was 2 657 365, of whom 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100 000 person-years. The one RCT that reported on pioglitazone use found no significant association with bladder cancer (risk ratio [RR] 2.36, 95% confidence interval [CI] 0.91–6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04–1.26; I2 = 0%) and of pioglitazone specifically (pooled RR 1.22, 95% CI 1.07–1.39; I2 = 0%) showed significant associations with bladder cancer. No significant association with bladder cancer was observed in the two RCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34–2.23; I2 = 0%). Interpretation: The limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone, are associated with an increased risk of bladder cancer among adults with type 2 diabetes.

Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials

Aims/hypothesisThe purpose of this study was to explore the relationship between hyperglycaemia in type 2 diabetes and risk of cancer incidence or cancer mortality. We were interested to determine if data from major randomised controlled trials would support a hypothesis that improving glycaemic control may reduce the risk of cancer outcomes.MethodsWe included major randomised controlled trials conducted with an overall aim of intensified glycaemic control in type 2 diabetes. We abstracted data from published papers and supplemental material and conducted separate meta-analyses of cancer mortality and cancer incidence.ResultsFour trials reported cancer mortality for the intensive (222 events in 53,892 person-years) and standard control (155 events in 38,743 person-years) arms (UK Prospective Diabetes Study [UKPDS] 33, UKPDS 34, Action to Control Cardiovascular Risk in Diabetes [ACCORD] and Veterans Affairs Diabetes Trial [VADT]); the summary risk ratio for cancer mortality was 1.00 (95% CI 0.81–1.24; I2 = 0%). Excluding the UKPDS metformin trial resulted in a pooled risk estimate of 1.03 (95% CI 0.83–1.29; I2 = 0%). Three trials reported cancer incidence for the study arms (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], PROspective pioglitAzone Clinical Trial In macroVascular Events [PROactive], Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes [RECORD]) with 357 events in 47,974 person-years with improved glycaemic control and 380 events in 45,009 person-years in the control arms; the pooled risk ratio for cancer incidence was 0.91 (95% CI 0.79–1.05; I2 = 0%).Conclusions/interpretationData from large randomised controlled trials of intensified glycaemic control suggest that cancer risk is not reduced by improving glycaemic control in type 2 diabetes. These data therefore do not support the hypothesis that hyperglycaemia is causally linked to increased cancer risk.

Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin Response to Farooki and Schneider

We thank Farooki and Schneider (1) for their comments on our recently published article (2) on diabetes treatments and cancer-related mortality. As we had indicated (2), we agree with Drs. Farooki and Schneider that additional clinical data would aid our understanding of pathophysiologic mechanisms. Clinical intervention studies may be optimal in obtaining such pathophysiologic data. However, such studies may be impractical given the large numbers of patients required …

Thiazolidinedione use and cancer incidence in type 2 diabetes: A systematic review and meta-analysis

AIMS Evidence suggests thiazolidinediones (TZDs) may modify the relationship between type 2 diabetes and cancer incidence. We aimed to summarize data from randomized controlled trials (RCTs) and observational studies to examine risk of overall and site-specific cancers with TZD use in individuals with type 2 diabetes. METHODS We searched 12 key biomedical databases and seven grey literature sources up to June 2011, without language restrictions. We performed separate meta-analyses according to cancer site and study design, comparing ever-use to never-use of TZDs, and pioglitazone alone. RESULTS The search yielded 1338 unique citations; we included four RCT, seven cohort and nine nested case-control studies, contributing data from 2.5 million people. Estimates from observational studies suggested any TZD use was associated with a decreased risk of colorectal (pooled RR: 0.93, 95%CI 0.87-1.00, P=0.04, I(2)=30%), lung (pooled RR: 0.91, 95%CI 0.84-0.98, P=0.02, heterogeneity (I(2))=35%) and breast (pooled RR: 0.89, 95%CI 0.81-0.98, P=0.02, I(2)=44%) cancer. Risk of overall cancer with TZD use was not significantly modified in RCTs (pooled RR: 0.92, 95%CI 0.79-1.07, P=0.26, I(2)=0%) or observational studies (pooled OR: 0.95, 95%CI 0.78-1.16, P=0.63, I(2)=70%). Pioglitazone use was, however, associated with a decreased risk of overall cancer (colorectal, lung, breast, prostate and renal sub-sites combined) in observational studies (pooled RR: 0.95, 95%CI 0.91-0.99, P=0.009, I(2)=0%). CONCLUSIONS Our findings suggest that use of TZDs is associated with a modest but significantly decreased risk of lung, colorectal and breast cancers. Results were limited by the paucity of studies designed to answer our research question. Further evaluation of TZD use, cancer risk factors and potential confounders is required.

Insulin use and cancer risk in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies

AIMS To determine whether data from observational studies supports the hypothesis of an increased risk of overall and site-specific cancer among individuals with diabetes using exogenous insulin therapies. METHODS We conducted a comprehensive search of nine key biomedical databases for all years up to December 2011, restricted to the English language. Data from cohort and nested case-control studies were included in random effects meta-analyses of site-specific and overall cancer incidence comparing ever use and new use of: (1) insulin to no insulin and; (2) insulin glargine to other insulins. RESULTS The search yielded 3052 unique citations, of which 19 were selected for inclusion, representing data for 1,332,120 people and 41,947 cancers. Pancreatic cancer risk was increased among new users of insulin (RR: 3.18, 95%CI: 3.27-3.71, I(2)=32%). New use of insulin glargine was associated with an increased risk of pancreatic cancer (RR: 1.63, 95%CI: 1.05-2.51, I(2)=0%) and prostate cancers (RR: 2.68, 95%CI: 1.50-4.79, I(2)=0%) but a decreased risk of colorectal cancer (RR: 0.78, 95%CI: 0.64-0.94, I(2)=15%). CONCLUSION New use of insulin or insulin glargine was associated with an increased risk of pancreatic cancer, possibly due to reverse causality. New use of insulin glargine was associated with a decreased risk of colorectal cancer but an increased risk of prostate cancer. Our results should be interpreted with caution due to limitations of included studies.

A cross-sectional study of health-related quality of life deficits in individuals with comorbid diabetes and cancer

BackgroundNumerous studies have identified a reduced health related quality of life (HRQL) in patients that have either diabetes or cancer. We assessed the HRQL burden in patients with these comorbid conditions, postulating that they would have even greater HRQL deficits.MethodsData from the Public Use File of the Canadian Community Health Survey (PUF CCHS) Cycle 1.1 (September 2000–November 2001) were used for this analysis. The total sample size of the CCHS PUF is 130,880 individuals. We used the Health Utilities Index Mark 3 (HUI3) to assess HRQL in patients with: 1) comorbid diabetes and cancer, 2) diabetes alone, 3) cancer alone, and 4) no diabetes or cancer. Analysis of covariance was used to compare the mean overall HUI3 score, controlling for age, sex, marital status, body mass index (BMI), physical activity level, smoking status, education level, depression status, and other chronic conditions.ResultsWe identified 113,587 individuals (87%) with complete data for the analysis. The comorbid diabetes and cancer group were older and a larger proportion reported being obese, inactive, having less than a secondary education and more chronic conditions when compared to the other three cohorts (p < 0.0001). However, the diabetes and cancer cohort was less likely to be depressed (p < 0.0001). Overall HUI3 scores were significantly lower for the diabetes and cancer group (unadjusted mean (SD): 0.67 (0.30)), compared to diabetes (0.78 (0.27)), cancer (0.78 (0.25)), and the reference group (0.89 (0.18)) (p < 0.0001). After adjusting for covariates, the comorbid diabetes and cancer group continued to have significantly lower overall HUI3 scores than the reference group (unstandardized mean difference: -0.11, 95% CI: -0.13 to -.0.09) (p < 0.0001).ConclusionIndividuals with diabetes and cancer had a clinically important and significantly lower HRQL than those with either condition alone. A better understanding of the relationship between diabetes and cancer, and their associated comorbidities, complications, and HRQL deficits may have important implications for prevention and management strategies.

Risk of Breast Cancer After Onset of Type 2 Diabetes Evidence of detection bias in postmenopausal women

OBJECTIVE To examine the risk of breast cancer in pre- and postmenopausal women with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a population-based retrospective cohort study. Cox regression, stratified by pre- (<55 years) and postmenopausal (≥55 years) status, was used to estimate hazard ratios (HRs) for breast cancer, during earlier (0–3 months) and later (3 months to 10 years) time windows after diabetes index date. RESULTS Compared with women without T2D, HRs for breast cancer were 0.95 (95% CI 0.48–1.86; P = 0.88) and 1.31 (0.92–1.86; P = 0.14) in pre- and postmenopausal women with T2D, respectively, in the early time window, and 0.92 (0.75–1.13; P = 0.45) and 1.00 (0.90–1.11; P = 0.93) in pre- and postmenopausal women with T2D, respectively, in the later time window. CONCLUSIONS We observed a trend toward an increased risk of breast cancer in postmenopausal women with T2D, but only in the time period immediately after diabetes index date.

Lack of insurance coverage for testing supplies is associated with poorer glycemic control in patients with type 2 diabetes

Background: Public insurance for testing supplies for self-monitoring of blood glucose is highly variable across Canada. We sought to determine if insured patients were more likely than uninsured patients to use self-monitoring and whether they had better glycemic control. Methods: We used baseline survey and laboratory data from patients enrolled in a randomized controlled trial examining the effect of paying for testing supplies on glycemic control. We recruited patients through community pharmacies in Alberta and Saskatchewan from Nov. 2001 to June 2003. To avoid concerns regarding differences in provincial coverage of self-monitoring and medications, we report the analysis of Alberta patients only. Results: Among our sample of 405 patients, 41% had private or public insurance coverage for self-monitoring testing supplies. Patients with insurance had significantly lower hemoglobin A1c concentrations than those without insurance coverage (7.1% v. 7.4%, p = 0.03). Patients with insurance were younger, had a higher income, were less likely to have a high school education and were less likely to be married or living with a partner. In multivariate analyses that controlled for these and other potential confounders, lack of insurance coverage for self-monitoring testing supplies was still significantly associated with higher hemoglobin A1c concentrations (adjusted difference 0.5%, p = 0.006). Interpretation: Patients without insurance for self-monitoring test strips had poorer glycemic control.