***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: OBJECTIVE Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer . The present study is aim ed at assessing the long-term association of different insulin analogues with  cancer incidence . RESEARCH DESIGN AND METHODS A nested case-control study data set was generated from the cohort study data set ( n = 1,340 insulin-treated diabetic out patients ) by sampling control subjects from the risk sets . For each case subject , the control subjects ( up to five ) were chosen r and omly from those members of the cohort who are at risk for the same follow-up time of the case subject . Five-year age classes , sex , and BMI classes ( < 18.5 , 18.5–24.9 , 25–29.9 , and ≥30 kg/m2 ) were considered as additional categorical matching variables . RESULTS During a median follow-up of 75.9 months ( interquartile range 27.4–133.7 ) , 112 case subjects of incident cancer were compared with 370 matched control subjects . A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects ( 0.24 IU/kg/day [ 0.10–0.39 ] versus 0.16 IU/kg/day [ 0.12–0.24 ] , P = 0.036 ) . Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score , other types of insulin administration , and metformin exposure ( odds ratio 5.43 [ 95 % CI 2.18–13.53 ] , P < 0.001 ) . No association between incident cancer and insulin doses was found for human insulin or other analogues . CONCLUSIONS The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer Aims /hypothesisIn the light of a report suggesting that insulin glargine may increase cancer occurrence , the EASD asked us to perform this study . Methods We followed 114,841 individuals who had a prescription dispensed for insulin between 1 July and 31 December 2005 . From 1 January 2006 to 31 December 2007 , we noted the occurrence of malignancies . Seven different nationwide registers were used to obtain information on insulin exposure , outcome and possible confounders ; these were linked using the unique personal identity number assigned to every Swedish resident . Results After adjustment for age and , when appropriate , sex , users of insulin glargine alone ( no other types of insulin ) , compared with users of types of insulin other than insulin glargine , had an RR of 1.99 ( 95 % CI 1.31–3.03 ) for breast cancer , 0.93 ( 95 % CI 0.61–1.40 ) for gastrointestinal cancer , 1.27 ( 95 % CI 0.89–1.82 ) for prostate cancer and 1.07 ( 95 % CI 0.91–1.27 ) for any type of malignancy . Adjustment for age , smoking , BMI , age at onset of diabetes , age at birth of first child , cardiovascular disease and oestrogen use gave an RR for breast cancer of 1.97 ( 95 % CI 1.29–3.00 ) . The 95 % CIs crossed 1.0 for the RR calculated in all analyses of users of insulin glargine in combination with other types of insulin . Conclusions /interpretationIn Sweden , during 2006 and 2007 , women using  insulin glargine alone ( no other types of insulin ) had an increased incidence rate of breast cancer as compared with women using types of insulin other than insulin glargine . This result may be due to a r and om fluctuation ; the possibilities for examining validity are limited , and no statistically significant results were obtained for any other individual cancer site or for the outcome ‘ all malignancies ’ . No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study OBJECTIVE Epidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed . We aim ed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN ( Outcome Reduction with Initial Glargine Intervention ) trial . RESEARCH DESIGN AND METHODS The ORIGIN trial is an international , long-term , r and omized two-by-two factorial study comparing insulin glargine with st and ard care and n-3 fatty acids with placebo ( double blind ) in people with dysglycemia at high risk for cardiovascular events . The primary outcome measure ( cancer sub study ) was the occurrence of any new or recurrent adjudicated cancer . Cancer mortality and cancer subtypes were also analyzed . RESULTS Among 12,537 people ( mean age 63.5 years , SD 7.8 ; 4,388 females ) , 953 developed a cancer event during the median follow-up of 6.2 years . In the glargine and st and ard care groups , the incidence of cancers was 1.32 and 1.32 per 100 person-years , respectively ( P = 0.97 ) , and in the n-3 fatty acid and placebo groups , it was 1.28 and 1.36 per 100 person-years , respectively ( P = 0.39 ) . No difference in the effect of either intervention was noted within predefined subgroups ( P for all interactions ≥0.17 ) . Cancer-related mortality and cancer-specific outcomes also did not differ between groups . Postr and omization HbA1c levels , glucose-lowering therapies ( including metformin ) , and BMI did not affect cancer outcomes . CONCLUSIONS Insulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes , including cancer-specific mortality . Exposure to glucose-lowering therapies , including metformin , and HbA1c level during the study did not alter cancer risk BACKGROUND The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events , but such a possibility has not been formally tested . METHODS We r and omly assigned 12,537 people ( mean age , 63.5 years ) with cardiovascular risk factors plus impaired fasting glucose , impaired glucose tolerance , or type 2 diabetes to receive insulin glargine ( with a target fasting blood glucose level of ≤95 mg per deciliter [ 5.3 mmol per liter ] ) or st and ard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design . The results of the comparison between insulin glargine and st and ard care are reported here . The co primary outcomes were nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure . Microvascular outcomes , incident diabetes , hypoglycemia , weight , and cancers were also compared between groups . RESULTS The median follow-up was 6.2 years ( interquartile range , 5.8 to 6.7 ) . Rates of incident cardiovascular outcomes were similar in the insulin-glargine and st and ard-care groups : 2.94 and 2.85 per 100 person-years , respectively , for the first co primary outcome ( hazard ratio , 1.02 ; 95 % confidence interval [ CI ] , 0.94 to 1.11 ; P=0.63 ) and 5.52 and 5.28 per 100 person-years , respectively , for the second co primary outcome ( hazard ratio , 1.04 ; 95 % CI , 0.97 to 1.11 ; P=0.27 ) . New diabetes was diagnosed approximately 3 months after therapy was stopped among 30 % versus 35 % of 1456 participants without baseline diabetes ( odds ratio , 0.80 ; 95 % CI , 0.64 to 1.00 ; P=0.05 ) . Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years . Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the st and ard-care group . There was no significant difference in cancers ( hazard ratio , 1.00 ; 95 % CI , 0.88 to 1.13 ; P=0.97 ) . CONCLUSIONS When used to target normal fasting plasma glucose levels for more than 6 years , insulin glargine had a neutral effect on cardiovascular outcomes and cancers . Although it reduced new-onset diabetes , insulin glargine also increased hypoglycemia and modestly increased weight . ( Funded by Sanofi ; ORIGIN Clinical Trials.gov number , NCT00069784 . ) Abstract Aims /hypothesis . To further investigate the association of  cancer occurrence with the use of insulin glargine . Methods . We followed 114 838 individuals using insulin between 1 July and 31 December 2005 . From 1 January 2006 to 31 December 2008 , we noted the occurrence of malignancies ( cohort I ) .  Insulin users between 1 July and 31 December 2006 were followed for the occurrence of malignancies in 2007 and 2008 ( cohort II ) . Users of insulin  during three consecutive six-month periods from 1 July 2005 to 31 December 2006 were followed for the occurrence of malignancies in 2007 and 2008 ( cohort III ) . The Prescribed Drug Register , the Cancer Register , and the Causes of Death Register were used to obtain information on targeted person-time and outcome . We retrieved variables reflecting potential confounding factors from the Swedish National Diabetes Register , the Prescribed Drug Register , the Patient Register , the Medical Birth Register and the National Education Register . With Poisson regression we evaluated the association between insulin use and malignancy outcome with adjustment for confounders . Results . The adjusted incidence rate ratio ( and 95 % confidence interval ) for women who used insulin glargine alone compared with those who used other types of insulin , was 1.60 ( 1.10–2.32 ) for breast cancer but included 1.0 for malignancy outcomes other than breast cancer for men and women when analyzing cohort I with follow-up in 2006–2008 . For cohort II and III the corresponding incidence rate ratios were 1.38 ( 0.87–2.18 ) , and 0.87 ( 0.41–1.85 ) , respectively . Conclusion /interpretation . We do not see an increased risk during 2008 for breast cancer in the  insulin  glargine group . We need data for additional years before we can state with reasonable certainty that the increase in breast cancer incidence that we observed in Sweden in 2006 and 2007 was due to a r and om fluctuation or whether there is an association with the use of insulin glargine Summary Objective : It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin . This study examined the primary metabolic degradation products of insulin glargine ( LANTUS * ) in humans . Design : In this single dose , open-label study , insulin glargine was administered subcutaneously at a dose of 0.6IU/kg ; placebo was administered to one control subject . Patients : Four healthy male subjects , plus one control subject , aged 18–50 years were enrolled in this study . Measurements : Following insulin glargine administration , blood glucose levels were clamped at the subjects ' fasting concentration for 6 h and the amount of 20 % glucose infused to maintain this baseline concentration was recorded . Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay ( RIA ) . Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels . The primary pharmacodynamic measure was the glucose infusion rate ( GIR ) . Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject . Results : Metabolic profiling revealed a clear pattern : insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain , to yield products M1 and M2 , which are both structurally similar to human insulin . These degradation products are present both at the injection site and in plasma . Conclusion : Thus , during treatment with a subcutaneous injection of insulin glargine , metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system Aims /hypothesisRecent publications of data extracted from population registries have suggested a possible relationship between treatment with insulin glargine and increased incidence of cancer/breast cancer .  The aim of the present study was investigate this possible relationship using data from the manufacturer ’s ( sanofi-aventis ) pharmacovigilance data base . Methods We analysed the manufacturer ’s ( sanofi-aventis ) pharm 
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Conclusion There is no compelling evidence that any clinical ly available insulin analogue ( Aspart , Determir , Glargine , Glulisine or Lispro ) , nor human insulin  increases breast cancer risk .
Overall , the data suggests that insulin treatment is not involved in breast tumour initiation , but might induce breast tumour progression by up regulating mitogenic signalling pathways