However, several potential caveats and methodological concerns have been raised in some of this studies including but not limited to cohort definitions, data elements and analytical approach. The possible relationship between insulin glargine and the increase of cancer risk has been a topic which has generated intense debate in recent years. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin. Conclusions Our results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population. Introduction Type 2 diabetes has been associated with an increased risk of cancer. This population indeed has a greater risk of three of the leading causes of cancer mortality such as pancreatic, colorectal and breast cancer . In addition, type 2 diabetes is associated Aleglitazar with substantial premature death rates from several types of cancer . The etiology of this excess cancer risk is poorly understood. Type 2 diabetes and cancer have common risk factors including age, race/ethnicity, obesity, physical inactivity, and tobacco use . Data from large randomized controlled trials of intensified glycemic control suggest that cancer risk is Aleglitazar not reduced by improving glycemic control in type 2 diabetes , and that both obesity and insulin resistance with or without hyperglycemia are also associated with an increased risk of cancer , . Therefore, factors other than glucose could be involved in the relationship between type 2 diabetes and cancer development. Among these factors it seems that hyperinsulinemia and/or insulin resistance could play an essential role. In Aleglitazar fact, the presence of insulin resistance and hyperinsulinemia, may accelerate tumor growth . The role of insulin in cancer promotion is suggested by studies associating circulating insulin levels and cancer of the colon, pancreas, and breast , , . The association between exogenous insulin and cancer gained attention in 2009 2009 when three observational studies evaluating cancer risks with different types of insulin were published concurrently C, fuelling speculation of an increased risk of cancer (in particular breast cancer) associated with the insulin analogue insulin glargine, due to its higher affinity for the IGF-1 receptor in comparison with human insulin. More recently, several studies have found a lack of relationship between insulin glargine and overall cancer incidence C. Apart from insulin, other glucose-lowering therapies have been involved in the relationship between type 2 diabetes and cancer. Several observational studies have suggested an increased risk of cancer or cancer mortality with sulfonylureas C. This finding could be explained by sulfonylureas capacity to increase circulating insulin levels. Glucagon-like peptide-1 Receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have also been associated with thyroid and pancreatic cancer . By contrast, metformin C Aleglitazar and thiazolidinediones (TZDs) C have been associated with a reduced risk of cancer. This association may Aleglitazar be due to the ability of these drugs to reduce insulin resistance. Given the clear relationship between type 2 diabetes and cancer incidence it seems important to dissect the potential role of any glucose-lowering therapy in the cancer risk. In DCHS2 this regard, the aim of the present study was to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population. Methods Data Source The information was obtained from the Catalan Institute of Health and electronically fielded by using the System for the Development of Research in Primary Care (SIDIAP) database. This comprises the clinical information coded in the corresponding medical records from 274 Primary Health Care Centers (PHCC) with a total of 3,414 general practitioners and with a global adult (over 15 years old) population of 7,434,632 subjects. The SIDIAP includes data from primary care electronic medical records (demographics,.