***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: Abstract Objective : To evaluate the efficacy of pioglitazone for the prevention of macrovascular outcomes in Japanese patients with type 2 diabetes , without a recent history of macrovascular morbidity . Research design and methods : This 2.5–4 year , prospect i ve , r and omized , open-label , blinded-endpoint study was conducted in 20 Japanese centers . Patients received pioglitazone ± other oral glucose-lowering drugs ( excluding another thiazolidinedione ) [ n = 293 ] or oral glucose-lowering drugs excluding thiazolidinediones ( n = 294 ) . Treatment was adjusted to achieve HbA1c < 6.5 % . The primary endpoint was the time to onset of a macrovascular event . Results : Pioglitazone delayed the time to onset of macrovascular events and was associated with a lower cumulative incidence of such events ( 3.56 % vs. 4.49 % for controls ) . Neither finding achieved statistical significance . This was likely because of the type of patient included in the study ( i.e. no recent history of cardiovascular events ) and the high use of concomitant anti-diabetic agents . Reductions in HbA1c , fasting blood glucose and fasting blood insulin levels , and an increase in HDL-C were significantly greater with pioglitazone throughout most of the study ( p < 0.05 ) . Fewer patients in the pioglitazone group commenced permanent treatment with insulin ( 3.3 % vs. 13.7 % in the control group ) . Adverse events were reported by 97.6 % of the pioglitazone group and 96.9 % of the control group ( serious adverse events , including deaths , were 20.1 vs. 22.2 % , respectively ) . The only notable difference between the two groups was a higher incidence of edema in the pioglitazone group . The main limitation of this study was that too few patients were included to identify statistically significant differences in the primary endpoint . Conclusions : Pioglitazone produced good glycemic control in Japanese patients with type 2 diabetes , and significantly fewer patients treated with pioglitazone needed long-term insulin therapy . These changes were associated with a trend towards delayed onset of macrovascular events . Clinical trial registration : UMIN000001363 CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes ( NCT01243424 ) is an ongoing , r and omized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride .  Eligible patients were sulphonylurea-naïve with HbA1c 6.5%–8.5 % or previously exposed to sulphonylurea ( in monotherapy or in a combination regimen < 5 years ) with HbA1c 6.5%–7.5 % . Primary outcome is time to first occurrence of cardiovascular death , non-fatal myocardial infa rct ion , non-fatal stroke or hospitalization for unstable angina .  A total of 631 patients with primary outcome events will be required to provide 91 % power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95 % confidence interval as being below 1.3 for a given hazard ratio . Hierarchical testing for superiority will follow , and the trial has 80 % power to demonstrate a 20 % relative cardiovascular risk reduction . A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years , 40.0 % female , mean HbA1c 7.2 % , 66 % on 1 and 24 % on 2 glucose-lowering agents and 34.5 % had previous cardiovascular complications . The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes BACKGROUND The cardiovascular effects of adding once‐weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown . METHODS We r and omly assigned patients with type 2 diabetes , with or without previous cardiovascular disease , to receive subcutaneous injections of extended‐release exenatide at a dose of 2 mg or matching placebo once weekly . The primary composite outcome was the first occurrence of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . The co primary hypotheses were that exenatide , administered once weekly , would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy . RESULTS In all , 14,752 patients ( of whom 10,782 [ 73.1 % ] had previous cardiovascular disease ) were followed for a median of 3.2 years ( interquartile range , 2.2 to 4.4 ) . A primary composite outcome event occurred in 839 of 7356 patients ( 11.4 % ; 3.7 events per 100 person‐years ) in the exenatide group and in 905 of 7396 patients ( 12.2 % ; 4.0 events per 100 person‐years ) in the placebo group ( hazard ratio , 0.91 ; 95 % confidence interval [ CI ] , 0.83 to 1.00 ) , with the intention‐to‐treat analysis indicating that exenatide , administered once weekly , was noninferior to placebo with respect to safety ( P<0.001 for noninferiority ) but was not superior to placebo with respect to efficacy ( P=0.06 for superiority ) . The rates of death from cardiovascular causes , fatal or nonfatal myocardial infa rct ion , fatal or nonfatal stroke , hospitalization for heart failure , and hospitalization for acute coronary syndrome , and the incidence of acute pancreatitis , pancreatic cancer , medullary thyroid carcinoma , and serious adverse events did not differ significantly between the two groups . CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease , the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo . ( Funded by Amylin Pharmaceuticals ; EXSCEL Clinical Trials.gov number , NCT01144338 . Inhibitors of the sodium-glucose co-transporter-2 ( SGLT-2 ) are a novel class of glucose-lowering agents that show promising results . However , the use of canagliflozin has been associated with an increased risk of lower-limb amputation . Whether this risk concerns other SGLT-2 inhibitors is unclear , and our objective was to address this issue . We performed a disproportionality analysis using the WHO global data base of individual case safety reports ( VigiBase ) . Among the 8 293 886 reports available between January 2013 and December 2017 , we identified 79 reports of lower-limb amputation that were associated with SGLT-2 inhibitors .  Among all blood glucose lowering drugs , the proportional reporting ratio ( PRR ) was increased only for SGLT-2 inhibitors ( 5.55 [ 4.23 , 7.29 ] ) . While we observed an expected signal for canagliflozin ( 7.09 [ 5.25 , 9.57 ] ) , the PRR was also high for empagliflozin ( 4.96 [ 2.89 , 8.50 ] ) and , for toe amputations only , for dapagliflozin ( 2.62 [ 1.33 , 5.14 ] ) . In conclusion , our results reveal a positive disproportionality signal for canagliflozin  , and also for empagliflozin , and , for toe amputations only , for dapagliflozin . However , our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies . Further prospect i ve data are therefore needed to better characterize the risk of amputations with different SGLT-2 inhibitors ABSTRACT Review of : Neal B , Perkovic V , Mahaffey K , et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes . N Engl J Med . 2017;377:644–657 . The report combines the data from two trials , CANVAS and CANVAS-Renal , which were design ed to evaluate the safety and effect of canagliflozin , an SGLT-2 inhibitor , on the appearance of cardiovascular and renal events in patients with type 2 diabetes . Enrollees were patients with type 2 diabetes of at least 30 years of age , with a glycated hemoglobin of > or equal to 7.0 % and < or equal to 10.5 % . Patients either had to have preexisting cardiovascular disease or to be at elevated risk for cardiovascular disease , and to have an estimated glomerular filtration rate ( eGFR ) of > 30 ml/min . Patients were r and omized to canagliflozin at doses of either 100 mg or 300 mg or matching placebo in CANVAS , and to canagliflozin 100 mg with a possible increase to 300 mg , or placebo , in CANVAS-Renal . Physicians were instructed to continue appropriate diabetic management and other therapies in accordance with the best practice s in their community . There was a significant 14 % reduction in the combined endpoint of cardiovascular events of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke in the canagliflozin treated patients . There was also a pattern of improvement in markers of renal disease , including the change in the level and nature of albuminuria , a 40 % decrease in the glomerular filtration rate , the need for renal replacement therapy , or death from renal causes . This study exp and s the scope of SGLT-2 inhibitor therapy to prevent cardiovascular disease in diabetic patients beyond those with preexisting cardiovascular disease studied in the previous empagliflozin study , raising the question as to whether SGLT-2 inhibitor therapy should be considered appropriate for most , if not all , type 2 diabetes patients , not only to control hyperglycemia but also to reduce cardiovascular and renal events 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 
    Output:
    
Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia .
CONCLUSIONS SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects , especially in T2D patients with previous CV diseases .