You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality
Abstract 1:
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 :


Title 2:
Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT
Abstract 2:
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


Title 3:
The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.
Abstract 3:
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


Title 4:
Effects of rosiglitazone on plasma brain natriuretic peptide levels and myocardial performance index in patients with type 2 diabetes mellitus
Abstract 4:
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


Title 5:
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
Abstract 5:
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 ] . )
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 ) .