Current Drug Safety - Volume 8, Issue 5, 2013

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mechanistic speculations based on epidemiological association studies, a few randomized controlled trials (several unpublished), or non-human studies (cell cultures or animal studies).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.

Background: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se. Objective: To examine the association between DM and cancers by a systematic review and meta-analysis according to the PRISMA guidelines. Data Sources: The systematic literature search includes Medline at PubMed, Embase, Cinahl, Bibliotek.dk, Cochrane library, Web of Science and SveMed+ with the search terms: “Diabetes mellitus”, “Neoplasms”, and “Risk of cancer”. Study Eligibility Criteria: The included studies compared the risk of cancer in diabetic patients versus non-diabetic patients. All types of observational study designs were included. Results: Diabetes patients were at a substantially increased risk of liver (RR=2.1), and pancreas (RR=2.2) cancer. Modestly elevated significant risks were also found for ovary (RR=1.2), breast (RR=1.1), cervix (RR=1.3), endometrial (RR=1.4), several digestive tract (RR=1.1-1.5), kidney (RR=1.4), and bladder cancer (RR=1.1). The findings were similar for men and women, and unrelated to study design. Meta-regression analyses showed limited effect modification of body mass index, and possible effect modification of age, gender, with some influence of study characteristics (population source, cancer- and diabetes ascertainment). Limitations: Publication bias seemed to be present. Only published data were used in the analyses. Conclusions: The systematic review and meta-analysis confirm the previous results of increased cancer risk in diabetes and extend this to additional cancer sites. Physicians in contact with patients with diabetes should be aware that diabetes patients are at an increased risk of cancer.

Background: An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified. Objective: To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes. Data Sources: Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library. Study Eligibility Criteria (PICOS): Population: diabetes patients. Exposure: Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs. Outcome: Any incident cancer. Study Design: Cohort and case-control studies. Results: 42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer. Limitations: Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders. Conclusions: Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.

Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies.

Objective: This study was set out to determine whether metformin use influences survival in breast cancer patients treated with antidiabetic drugs as compared to non-users. Research Design and Methods: We used data from the Danish national registries (1996-2008) to identify adult female patients diagnosed with breast cancer who were prescribed antidiabetic medication. We performed multivariate Coxproportional hazard regression to assess all-cause and breast cancer-specific mortality risks associated with metformin exposure. In a secondary analysis, we stratified use of metformin according to the cumulative number of prescriptions. Results: Of the 1058 breast cancer patients 349 died during follow-up, with breast cancer listed as the primary cause of death for 152 cases. Compared to non-use, current metformin treatment was associated with a significant reduction in overall mortality (adjusted HR 0.74, 95% CI, 0.58-0.96). For breast cancer-specific mortality, a non-significant risk reduction (adjusted HR 0.88, 95% CI, 0.59-1.29) was observed, which became significant after stratification according to cumulative number of prescriptions. An increased risk of both overall and breast cancer-specific mortality was observed in the first 12 months after discontinuation of metformin. Conclusions: We observed a nonsignificant reduction in breast cancer-specific mortality associated with metformin exposure among breast cancer patients treated with antidiabetic drugs. However, our findings suggest that long-term metformin use may have a beneficial effect on survival in patients with breast cancer. Further confirmation of these findings is needed.

Background: Pioglitazone, a drug for the treatment of type 2 diabetes mellitus has been associated with bladder cancer in observational studies. Diabetes mellitus itself has also been linked with bladder cancer. The objective was to estimate the risk of bladder cancer for diabetic patients using thialozidinediones (TZDs) compared with patients in other treatment stages of the disease. Methods: We performed a population-based cohort study (1996-2007) in the Danish National Health Registers. Oral antidiabetic drug users (n=179,056) were matched 1:3 by sex and year of birth to non-users. Hazard ratios (HRs) of bladder cancer were estimated using Cox proportional hazards models. Time-dependent adjustments were made for age, comorbidity, and drug use. Four different treatment stages were defined: current use of either a biguanide or a sulfonylureum (stage 1), current use of a biguanide and a sulfonylureum at the same time (stage 2), current use of TZDs (stage 3) and current use of insulin (stage 4). Results: Compared with non-diabetic controls, patients using antidiabetic medication experienced a 1.3-fold increased risk of bladder cancer (adjusted HR 1.3 [95%CI 1.2-1.4]). No major differences were observed between the different treatment stages. The risk of bladder cancer varied between 1.2 [95%CI 1.0-1.4] in stage 4 and 1.4 [95%CI 1.3-1.6] in stage 1. The risk of bladder cancer with TZD use (stage 3) was similar to the other groups (adjusted HR 1.3 [95%CI 0.6-2.7]). Interpretation: The association between TZD use and bladder cancer is probably confounded by the underlying disease.

Introduction: Drug-induced cancer risk is of increasing interest. Both observational studies and data from clinical trials have linked several widely used treatments to cancer. When a signal for a potential drug-cancer association is generated, substantiation is required to assess the impact on public health before proper regulatory action can be taken. This paper aims to discuss challenges of exploring drug-associated cancer outcomes by post-hoc analyses of Randomised controlled trials (RCTs) designed for other purposes. Methodological Challenges to Consider: We set out to perform a post-hoc nested case-control analysis in the ADVANCE trial in order to examine the association between insulin use and cancer. We encountered several methodological challenges that made the results difficult to interpret, including short duration of exposure of interest, lack of power, and correlation between exposure and potential confounders. Considering these challenges, we concluded that using the data would not enlighten the discussion about insulin use and cancer risk and only serve to further complicate any understanding. Therefore, we decided to use our experience to illustrate methodological challenges, which need to be addressed when re-analysing trial data for cancer related outcomes. Conclusion: Substantial amount of information on cancer outcomes is available from RCTs. Hence, making use of such data could save time and spare patients from inclusion in further trials. However, methodological challenges must be addressed to enhance the likelihood of reliable conclusions. Advantages of post-hoc analyses of RCTs include quality of data collected and sometimes randomisation to exposure of interest. Limitations include confounding and sample size, which is fixed to suit the purposes of the trial, insufficient duration of exposure and identification of underlying biological mechanisms relating treatment to cancer to formulate the most appropriate post-hoc study design.