***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Aims /hypothesisUsing the Echantillon Généraliste de Bénéficiaires : r and om 1/97 permanent sample of the French national healthcare insurance system data base ( EGB ) , we investigated whether , as previously suspected , the risk of cancer in  insulin glargine ( A21Gly , B31Arg , B32Arg human insulin ) users is higher than in  human insulin users . The investigation period was from 1 January 2003 to 30 June 2010 . Methods We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin , and adjusted for insulin , biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant ( ≥80 % use time ) users of insulin glargine compared with equivalent human insulin users . Results Only type 2 diabetic patients were studied . Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin , respectively , to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin , respectively . All-type cancer HRs  with insulin glargine vs human insulin ranged from 0.59 ( 95 % CI 0.28 , 1.25 ) in incident exclusive users to 0.58 ( 95 % CI 0.34 , 1.01 ) in all predominant users . Cancer risk increased with exposure to insulin or sulfonylureas in these patients . Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 ( 95 % CI 0.32 , 1.06 ) to 0.56 ( 95 % CI 0.36 , 0.87 ) . Conclusions /interpretationThere was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those  on human insulin  alone . The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin , thereby excluding a competitive risk bias Aims /hypothesisObservational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes . We extracted data for malignancies from the ADOPT ( A Diabetes Outcome Progression Trial ) and RECORD ( Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes ) r and omised controlled clinical trials , in which the efficacy and /or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone . Methods Neoplasm occurrences were collected as adverse events in these studies . We review ed and re-analysed the individual participant data in both studies for serious adverse events , malignancies reported as adverse events and related neoplasms of special interest . Results In ADOPT , 50 participants ( 3.4 % ) on  metformin  and 55 ( 3.8 % ) on each of rosiglitazone and glibenclamide ( known as glyburide in the USA and Canada ) developed serious adverse event malignancies ( excluding non-melanoma skin cancers ) . This corresponds to 1.03 , 1.12 and 1.31 per 100 person-years , giving hazard ratios for metformin of 0.92 ( 95 % CI 0.63–1.35 ) vs rosiglitazone and 0.78 ( 0.53–1.14 ) vs glibenclamide . In RECORD , on a background of sulfonylurea , 69 ( 6.1 % ) participants developed malignant neoplasms in the metformin group , compared with 56 ( 5.1 % ) in the rosiglitazone group ( HR 1.22 [ 0.86–1.74 ] ) . On a background of metformin , 74 ( 6.7 % ) participants in the sulfonylurea group developed malignant neoplasms , compared with 57 ( 5.1 % ) in the rosiglitazone group ( HR 1.33 [ 0.94–1.88 ] ) . Conclusions /interpretationThe malignancy rates in these two r and omised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone . However , they do not refute the possibility of a difference compared with sulfonylureas 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 . ) OBJECTIVE The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase ( AMPK ) . Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels . We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes . RESEARCH DESIGN AND METHODS In an observational cohort study using record-linkage data bases and based in Tayside , Scotl and , U.K. , we identified people with type 2 diabetes who were new users of metformin in 1994–2003 . We also identified a set of diabetic comparators , individually matched to the metformin users by year of diabetes diagnosis , who had never used metformin . In a survival analysis we calculated hazard ratios for diagnosis of cancer , adjusted for baseline characteristics of the two groups using Cox regression . RESULTS Cancer was diagnosed among 7.3 % of 4,085 metformin users compared with 11.6 % of 4,085 comparators  , with median times to cancer of 3.5 and 2.6 years , respectively ( P < 0.001 ) . The unadjusted hazard ratio ( 95 % CI ) for cancer was 0.46 ( 0.40–0.53 ) . After adjusting for sex , age , BMI , A1C , deprivation , smoking , and other drug use , there was still a significantly reduced risk of cancer associated with metformin : 0.63 ( 0.53–0.75 ) . CONCLUSIONS These results suggest that metformin use may be associated with a reduced risk of cancer . A r and omized trial is needed to assess whether metformin is protective in a population at high risk for cancer BACKGROUND & AIMS Hyperinsulinemia is a putative colorectal cancer ( CRC ) risk factor . Insulin resistance ( IR ) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment -insulin resistance ( HOMA-IR ) index . To date , few studies have directly examined serum insulin as an indicator of CRC risk , and none have reported associations on the basis of HOMA-IR . METHODS We performed a case-cohort study within the Alpha-Tocopherol , Beta-Carotene Cancer Prevention ( ATBC ) Study ( n=29,133 ) . Baseline exposure and fasting serum biomarker data  were available for 134 incident CRC case and 399 non-case subjects . HOMA-IR was derived as fasting insulin x fasting glucose/22.5 . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models . RESULTS Median ( interquartile range ) values for serum insulin , glucose , and HOMA-IR were 4.1 ( 2.9 - 7.2 ) mIU/L , 101 ( 94 - 108 ) mg/dL , and 0.99 ( 0.69 - 1.98 ) for case subjects and 4.1 ( 2.7 - 6.1 ) mIU/L , 99 ( 93 - 107 ) mg/dL , and 1.02 ( 0.69 - 1.53 ) for non-case subjects , respectively . On the basis of comparison of the highest versus lowest quartiles for each biomarker , insulin ( HR , 1.84 ; 95 % CI , 1.03 - 3.30 ) and HOMA-IR ( HR , 1.85 ; 95 % CI , 1.06 - 3.24 ) were significantly associated with incident CRC , whereas glucose was marginally associated with incident CRC ( HR , 1.70 ; 95 % CI , 0.92 - 3.13 ) in age-adjusted risk models . However , trends across biomarker quartiles were somewhat inconsistent ( P trend=.12 , .04 , and .12 , respectively ) , and multivariable adjustment generally attenuated the observed risk estimates . CONCLUSIONS Data from this prospect i ve study of male smokers provide limited support for hyperinsulinemia , hyperglycemia , and /or insulin resistance as CRC risk factors OBJECTIVE Controversy remains regarding the association between type 2 diabetes mellitus ( DM ) and colorectal cancer ( CRC ) risk . To clarify and extend the existing data , we prospect ively evaluated the association between  self-reported type 2 DM ( onset at > 30 years of age ) and incident CRC , overall and by anatomic subsite , among postmenopausal women in the Iowa Women 's Health Study ( n = 35,230 ) . METHODS After 14 years of follow-up , a total of 870 incident CRC cases were identified through annual linkage to the  Iowa Cancer Registry . DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up .  CRC risks were estimated using Cox proportional hazards regression models . RESULTS After adjusting for age , body mass index and other potential confounding variables , the relative risk ( RR ) for women with DM versus women without DM was modestly increased at 1.4 [ 95 % confidence interval ( 95 % CI ) , 1.1 - 1.8 ] . By anatomic subsite , the RR for proximal colon cancer was statistically significantly increased ( RR , 1.9 ; 95 % CI , 1.3 - 2.6 ) , whereas the RRs for distal colon ( RR , 1.1 ; 95 % CI , 0.6 - 1.8 ) and rectal cancer ( RR , 0.8 ; 95 % CI , 0.4 - 1.6 ) were not statistically different from unity . Analyses that included DM ascertained at baseline and follow-up yielded similar results . CONCLUSION In this large , prospect i ve study of postmenopausal women , the association 
    Output:
    
Post-hoc analysis of r and omized controlled trials did not reveal any significant association between ADM and colorectal cancer risk .
Meta- analysis of published studies supports a protective association between metformin use and colorectal cancer risk in patients with diabetes mellitus .