OBJECTIVE -Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer.RESEARCH DESIGN AND METHODS -This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided.RESULTS -We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 Ϯ 1.9 years (means Ϯ SD). The mean age for the cohort was 63.4 Ϯ 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1-1.6]; P ϭ 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5-2.4; P Ͻ 0.0001).CONCLUSIONS -Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk. Diabetes Care 29:254 -258, 2006A number of epidemiologic studies have identified an increased risk of development of cancer in people with type 2 diabetes (1-14). The association appears to be mediated through the metabolic syndrome (also known as the insulin resistance syndrome). The metabolic syndrome is present in almost onehalf of all older individuals and is a condition associated with hyperinsulinemia, insulin resistance, and a predilection to type 2 diabetes (15).There is also evidence that impaired glucose tolerance and insulin resistance may lead to an increased risk of cancer (16). Insulin is a growth-promoting hormone with mitogenic effects (17,18). Several animal studies, complemented by case studies in humans, have demonstrated the critical role of insulin-like growth factor in all stages of mammalian growth (19). Thus, it has been suggested that hyperinsulinemia combined with insulin resistance might promote carcinogenesis (16,20 -23).Despite the recognition of the potential link between type 2 diabetes and cancer, very little is known about the role that antidiabetic therapies might have on this relationship. This role is particularly noteworthy because there are treatments for diabetes that increas...

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 glucoselowering 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.

Aims/hypothesis Despite the vast body of epidemiological literature on the risk of cancer in people with diabetes, few studies have examined the pattern of cancer risk during different time windows following diabetes onset. The objective of the study was to examine the risks of sitespecific cancer in people with incident type 2 diabetes during different time windows following diabetes onset. Methods This was a population-based retrospective cohort study. The study period was 1 April 1994 to 31 March 2006; censoring occurred at 31 March 2006, at death or on departure from British Columbia, Canada. Using linked health databases, we identified incident cohorts with and without diabetes, who were matched by age, sex and index year. Following a minimum 2-year cancer washout period, first site-specific cancers were identified prospectively in both cohorts. Results Within 3 months following diabetes onset, participants with diabetes had significantly increased risks of colorectal, lung, liver, cervical, endometrial, ovarian, pancreatic and prostate cancers. After the initial 3-month period, the risks for colorectal (HR 1.15, 95% CI 1.05, 1.25), liver (HR 2.53, 95% CI 1.93, 3.31) and endometrial (HR 1.58, 95% CI 1.28, 1.94) cancers remained significantly elevated compared with those without diabetes. The diabetes cohort remained at increased risk of pancreatic cancer in later years, but followed a different pattern: HR 3.71 at 3 months-1 year, 2.94 at 1-2 years, 1.78 at 2-3 years and 1.65 at 3-10 years (p value for all <0.01). After an initial period of elevated risk, men with type 2 diabetes subsequently had a decreased risk of prostate cancer (HR 0.82, 95% CI 0.76, 0.88). Conclusions/interpretation People with type 2 diabetes are at increased risk of select cancers; this risk is particularly elevated at the time of diabetes onset, which is likely to be due to increased ascertainment.

Aims/hypothesis We 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. Methods This 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. Results We 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/interpretation Our 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.

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Aims/hypothesis The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach.Methods Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of Electronic supplementary material The online version of this article (doi:10.1007/s00125-014-3456-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. -014-3456-9 pioglitazone. These were then pooled using fixed and random effects meta-regression. Results Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). Conclusions/interpretation The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.Diabetologia (2015) 58:493-504 DOI 10.1007/s00125

Aims/hypothesis The 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. Methods We 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. Results

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