***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: Objective Metformin has had a ' black box ' contraindication in diabetic patients with heart failure ( HF ) , but many believe it to be the treatment of choice in this setting . Therefore , we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large r and omized controlled trial with clinical endpoints . Study Design The pilot study was a r and omized double blinded placebo controlled trial . Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton , Alberta , Canada ( population ~1 million ) . Major exclusion criteria included the current use of insulin or high dose metformin , decreased renal function , or a glycosylated hemoglobin < 7 % . Patients were to be r and omized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes , as well as clinical events . Results Fifty-eight patients were screened over a six month period and all were excluded . Because of futility with respect to enrollment , the pilot study was ab and oned . The mean age of screened patients was 77 ( SD 9 ) years and 57 % were male . The main reasons for exclusion were : use of insulin therapy ( n = 23 ; 40 % ) , glycosylated hemoglobin < 7 % ( n = 17 ; 29 % ) and current use of high dose metformin ( n = 12 ; 21 % ) . Overall , contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent ( n = 27 ; 51 % ) . On average , patients were receiving 1,706 mg ( SD 488 mg ) of metformin daily and 12 ( 44 % ) used only metformin . Conclusion Despite uncertainty in the scientific literature , there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive r and omized trial virtually impossible . Trial registration Clinical Trials.gov Identifier : Objectives Pre clinical and clinical studies suggested cardioprotective effects of metformin treatment . In the GIPS-III trial , 4 months of metformin treatment did not improve left ventricular ejection fraction in patients presenting with ST-elevation myocardial infa rct ion ( STEMI ) . Here , we report the 2-year follow-up results . Methods Between January 2011 and May 2013 , 379 STEMI patients without diabetes undergoing primary percutaneous coronary intervention were r and omized to a 4-month treatment with metformin ( 500 mg twice daily ) ( N = 191 ) or placebo ( N = 188 ) in the University Medical Center Groningen . Two-year follow-up data was collected to determine its effect on predefined secondary endpoints : the incidence of major adverse cardiac events ( MACE ) , its individual components , all-cause mortality , and new-onset diabetes . Results For all 379 patients all-cause mortality data were available . For seven patients ( 2 % ) follow-up data on MACE was limited , ranging from 129 to 577 days . All others completed the 2-year follow-up visit . Incidence of MACE was 11 ( 5.8 % ) in metformin and 6 ( 3.2 % ) in placebo treated patients [ hazard ratio ( HR ) 1.84 , confidence interval ( CI ) 0.68–4.97 , P = 0.22 ] . Three patients died in the metformin group and one in the placebo treatment group . Individual components of MACE were also comparable between both groups . New-onset diabetes mellitus was 34 ( 17.8 % ) in metformin and 32 ( 17.0 % ) in placebo treated patients ( odds ratio 1.15 , CI 0.66–1.98 , P = 0.84 ) . After multivariable adjustment the incidence of MACE was comparable between the treatment groups ( HR 1.02 , CI 0.10–10.78 , P = 0.99 ) . Conclusions Four months metformin treatment initiated at the time of hospitalization in STEMI patients without diabetes did not exert beneficial long-term effects . Trial registration clinical trials.gov Identifier : NCT01217307 OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity Thiazolidinediones ( TZD ) have become a powerful tool for lowering insulin resistance . The problem of cardiovascular adverse events including fluid retention and risk of heart failure should be well known and recognised . We aim ed to evaluate the long-term effects of rosiglitazone on cardiac function and fluid dynamics .  Forty-six type 2 diabetic patients were r and omised to treatment with rosiglitazone or metformin or to a control group . There are no significant differences between the groups in the duration of diabetes , HbA1c , plasma brain natriuretic peptide ( BNP ) levels , body mass index and myocardial performance indexes ( MPIs ) before the treatment . After three and six months all these parameters were repeated . Rosiglitazone increased plasma BNP levels and worsened MPIs 3 months after the start of treatment . Also left ventricular end-systolic volume increased and weight gain was observed . But these results were statistically non-significant ( all p>0.05 ) . When we continued rosiglitazone treatment to six months the increase in BNP levels became soft and statistically significant improvements were seen in MPIs ( p<0.01 ) . Also left ventricular end-systolic volume decreased significantly ( p=0.004 ) and weight gain was stopped . In patients with type 2 diabetes , TZD treatment might have slight adverse effects on ventricular contractility and fluid dynamics at the beginning of the therapy . However , these changes seem to stabilise in the long term BACKGROUND The efficacy of thiazolidinediones , as compared with other oral glucose-lowering medications , in maintaining long-term glycemic control in type 2 diabetes is not known . METHODS We evaluated rosiglitazone , metformin , and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind , r and omized , controlled clinical trial involving 4360 patients . The patients were treated for a median of 4.0 years . The primary outcome was the time to monotherapy failure , which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter ( 10.0 mmol per liter ) , for rosiglitazone , as compared with metformin or glyburide . Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin , insulin sensitivity , and beta-cell function . RESULTS Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15 % with rosiglitazone , 21 % with metformin , and 34 % with glyburide . This represents a risk reduction of 32 % for rosiglitazone , as compared with metformin , and 63 % , as compared with glyburide ( P<0.001 for both comparisons ) . The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin . Glyburide was associated with a lower risk of cardiovascular events ( including congestive heart failure ) than was rosiglitazone ( P<0.05 ) , and the risk associated with metformin was similar to that with rosiglitazone . Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide ( P<0.001 for all comparisons ) . CONCLUSIONS The potential risks and benefits , the profile of adverse events , and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00279045 [ Clinical Trials.gov ] . ) 
    Output:
    
Although summarized evidence showed that metformin did not affect left ventricular function , this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels , inconsistently between diabetic and nondiabetic patients .
Effective modulation of some heart failure – related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 ( C-C motif chemokine lig and 11 ) .