Aim: To conduct a systematic review of the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues.
Material and methods: The review was developed according to the PRISMA guidelines. A systematic search of Pubmed was performed using the key words: "insulin analogue", "insulin derative", "insulin homologue", "glargine", "Lantus", "degludec", "tresiba", "NPH", "lispro", "humalog", "detemir", "levemir", "glulisine", "apidra", "aspart", "novolog", "insulin treatment", "diabetes treatment", "insulin therapy" or "diabetes therapy" combined with "neoplasia", "tumor", "cancer", "carcinoma", "malignan*", "carcinog*" or " mitoge*". Eligible studies were those reporting on potential biological mechanisms, studies reporting on statistical or epidemiological associations were excluded.
Results: Per October 8, 2013, the search produced 28,276 hits in Pubmed. All studies were either mechanistic speculations based on epidemiological association studies, a few randomized controlled trials (several unpublished), or non-human studies (cell cultures or animal studies). The evidence level in human terms was low.
Conclusion: In general many studies on pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues exist. However, the level of evidence of a causal association between diabetes and the treatment of diabetes and cancer is low.