despite advances in insulin therapy , hypoglycaemia remains a significant concern and limits optimization of insulin dosing to achieve glycaemic targets.1 hypoglycaemia is associated with increased morbidity and cardiovascular risk.1 patients / caregivers may be fearful of nocturnal hypoglycaemia , which may affect sleep and wellbeing.2 
  basal insulin peglispro ( bil ) is pegylated insulin lispro and has a flat pharmacokinetic profile with a 23 day halflife.3 bil has an hepatopreferential action versus glargine as a result of a reduced peripheral action rather than an enhanced effect on the liver 4 
 . the primary objective of the bil phase iii studies was to demonstrate the noninferiority of glycated haemoglobin ( hba1c ) for bil versus glargine . the three doubleblind studies were also powered for the key secondary objective of superiority of bil versus glargine for reduction in nocturnal hypoglycaemia rate . in five phase iii imagine trials , bil treatment met the primary objective of noninferiority to glargine for hba1c.5 , 6 , 7 , 8 , 9 the five imagine trials also resulted in 0.20.5% greater hba1c reduction versus glargine over 26 , 52 and 78 weeks in patients with type 1 diabetes ( t1d ) and those with type 2 diabetes ( t2d ) , meeting the key secondary objective of statistical superiority ( with multiplicity adjustment ) , with higher basal insulin doses.5 , 6 , 7 , 8 , 9 
  the present report summarizes prespecified pooled hypoglycaemia analyses from the imagine studies with a glargine comparator . table 1 provides an overview of the five phase iii imagine studies of bil versus glargine that were included in the prespecified pooled analyses of : patients with t2d receiving basal insulin only ; patients with t2d receiving basalbolus insulin ; and patients with t1d receiving basalbolus insulin . entry criteria , study design , dosing algorithms and results , including individual study glycaemic / hypoglycaemia data , have been previously reported.5 , 6 , 7 , 8 , 9 all were treattotarget trials with the same basalbolus insulindosing algorithms applied to both treatments and with a fasting / premeal selfmonitored blood glucose ( smbg ) target of 5.6 mmol / l . overview of imagine studies , patient clinical characteristics , glycated haemoglobin and insulin dose 
 gl , insulin glargine ; ls , least squares ; oam , oral antihyperglycaemic medication ; s.d . , standard deviation ; s.e . 52 weeks for t2d basal only ; 26 weeks for t2d basalbolus ; 52 weeks for t1d . nocturnal hypoglycaemia was an event between bedtime and waking for t2d basalonly studies ( imagine 2 and 5 ) . for studies using electronic diaries ( imagine 1 , 3 and 4 ) with direct transfer of time / date stamped smbg values,10 nocturnal hypoglycaemia severe hypoglycaemia was investigatordetermined and defined as episodes accompanied by neurological impairment requiring medical assistance to administer carbohydrates , glucagon or other resuscitative actions . for the pooled analyses of patients with t2d on basal insulin only ( imagine 2 and 5 ) and patients with t1d ( imagine 1 and 3 ) , 52week data were included , as this was a consistent time point . blinded continuous glucose monitoring ( cgm ) was performed in patient subsets in the three doubleblind studies ( imagine 2 , 3 and 4 ) to assess duration ( min ) with glucose values 3.9 mmol / l from 00:00 to 06:00 hours and over 24 hours and duration of individual hypoglycaemic episodes . the medtronic cgms ipro continuous glucose recorder ( imagine 3 ) or the ipro2 professional cgm ( imagine 2 and 4 ) were used over 3 or 6 days , respectively . cgm data were centrally collected ( phase v technologies , wellesley , massachusetts ) at baseline / prespecified time points during treatment . the 52week data are presented for imagine 2 and 3 and 26week data for imagine 4 ( table s1 , appendix s1 ) . analyses ( sas 9.1 , cary , north carolina ) were conducted on the modified intentiontotreat population of all randomized patients who received 1 study insulin dose . all tests were conducted at a twosided  value = 0.05 and 95% confidence intervals ( cis ) were calculated . total / nocturnal hypoglycaemia frequencies were analysed using negative binomial regression and a modelbased rate for each treatment was estimated.11 the rate of severe hypoglycaemia was analysed using an empirical method ; hypoglycaemia incidence was assessed using a logistic regression model or cochran  mantel  haenszel test ( if < 10 patients with events ) . a total of 4927 patients randomized to bedtime bil ( n = 2949 ) or glargine ( n = 1978 ) were included . 4972% of patients with t2d and 6471% of patients with t1d were previously treated with glargine . the pooled analyses were consistent with the individual study results , with a 0.210.33% greater reduction in hba1c with bil versus glargine ( table 1 ) . basal insulin doses were 1024% higher with bil versus glargine across phase iii studies ( table 1).5 , 6 , 7 , 8 , 9 bolus insulin doses were 27% lower with bil versus glargine in t1d ( table 1 ) , but not statistically significantly different in patients with t2d receiving basalbolus insulin ( table 1).6 
  nocturnal hypoglycaemia rates were reduced by 36% in patients with t2d on basal insulin only , 45% in patients with t2d on basalbolus insulin , and 43% in patients with t1d with bil versus glargine ( figure 1a ) . nocturnal hypoglycaemia incidence was statistically significantly lower with bil versus glargine in all patient populations ( figure 1b ) . the nocturnal hypoglycaemia rate and incidence sensitivity analyses were consistent with the primary results including : prespecified analyses of the alternative nocturnal hypoglycaemia definition for basal only and basalbolus ediary studies and post hoc analyses including events between 00:01 and 05:59 hours ( figure s1 , appendix s1 ) . nocturnal , total , daytime and severe hypoglycaemia . a , nocturnal hypoglycaemia rate per patientyear  standard error ( s.e . ) . values are aggregated rate , calculated using the total number of severe hypoglycaemia episodes divided by the cumulative days on treatment from all patients within that treatment , then times 36 525 days ( for rate per 100 years ) . weeks of study data included : t2d basal only ( 052 weeks ) , t2d basalbolus ( 026 weeks ) , t1d ( 052 weeks ) . b , basal only ; bb , basalbolus ; gl , insulin glargine ; rr , relative rate . * the total hypoglycaemia rate was not significantly different in patients with t2d on basal insulin only , there was a 10% higher trend in patients with t2d on basalbolus insulin ( p = .053 ) , and the rate was 15% higher in patients with t1d ( p < .001 ) with bil versus glargine ( figure 1c ) . the total hypoglycaemia incidence was not different between treatments in any population ( figure 1d ) . in patients with t1d or t2d on basalbolus insulin , daytime hypoglycaemia was significantly higher with bil versus glargine ( figure 1e ) from 0 to 52 and 0 to 26 weeks , respectively . in t1d patients , during the maintenance period of 2652 weeks , the total hypoglycaemia relative rate ( bil / glargine ) was 1.07 ( 95% ci 1.00 , 1.14 ; p = .062 ; figure s2 , appendix s1 ) . there were no significant differences in the rate or incidence of severe hypoglycaemia between treatments in all three patient populations ( figure 1f and g ) . in the three doubleblind studies , cgm was performed in patient subsets ( bil , n = 313 , glargine , n = 215 ) . in patients with t1d or t2d , there were no significant treatment differences in duration with glucose level 3.9 mmol / l ( 00:0006:00 hours or over 24 hours ) or in the average duration of individual hypoglycaemic episodes with bil versus glargine ( table s1 , appendix s1 ) . the present analyses provide a summary of prespecified and pooled hypoglycaemia analyses from the five imagine studies with glargine comparator . bil treatment resulted in a 3645% reduction in nocturnal hypoglycaemia rate versus glargine , despite greater reduction in hba1c and higher basal insulin dosing . there was a 15% increase in total hypoglycaemia in t1d with an associated increase in daytime hypoglycaemia with basalbolus therapy in t1d and t2d . cgm in patient subsets showed no evidence of prolongation or shortening of hypoglycaemic episodes with bil versus glargine . nocturnal hypoglycaemia was also reduced with morning dosing of bil versus glargine in t1d and t2d phase ii studies12 , 13 and nocturnal / total hypoglycaemia were similar with bedtime versus 840hours variabletime dosing of bil in a t1d phase iii study.14 
  the significant reduction in nocturnal hypoglycaemia was achieved simultaneously with greater improvements in hba1c with bil versus glargine . in contrast , significant reductions in nocturnal hypoglycaemia rates were reported in clinical studies of insulin degludec15 and glargine u30016 versus glargine u100 , but with noninferiority of hba1c . this may reflect the hepatopreferential action of bil as well as longer duration of action , lower peaktotrough ratio , and reduced glucose variability versus glargine u100 seen across the bil phase iii trials.5 , 6 , 7 , 8 , 9 a study in the conscious dog has shown that peripheral insulin delivery increased hypoglycaemia risk versus portal vein insulin delivery , suggesting that hepatopreferential insulin analogues may be associated with a lower risk of hypoglycaemia.17 glucose variability has also been independently associated with the risk of hypoglycaemia.18 , 19 
  increased daytime hypoglycaemia with bil versus glargine in basalbolus therapy may also reflect the hepatopreferential action and longer duration of action of bil . in t1d , the adjustment of basalbolus dosing occurred gradually during the titration period and resulted in significantly reduced bolus insulin requirements with bil compared with glargine . during the maintenance period of 2652 weeks and after basalbolus dose adjustment and stabilization , total hypoglycaemia decreased in t1d and was not significantly different between groups ( figure s2 , appendix s1 ) . the strengths of the present pooled analyses of five bil phase iii studies include the doubleblind design of three trials , which were also powered to detect differences in nocturnal hypoglycaemia , the large sample size of > 4900 patients , as well as the global nature of the studies . the use of an ediary in three basalbolus studies10 allowed wireless , direct capture of smbg values and hypoglycaemic events . limitations include the ability to translate the findings outside of a clinical trial setting and exclusion of patients with t1d with > 1 and patients with t2d with 1 severe hypoglycaemic episode within 6 months of screening . in addition , it is unknown from these studies if other basalbolus insulindosing algorithms , including algorithms different from those used with conventional basal insulins , could more rapidly optimize bolus insulin dosing with bil . in conclusion , across five phase iii trials , bil treatment resulted in greater hba1c reduction with less nocturnal hypoglycaemia in all patient populations compared with glargine despite higher basal insulin doses . basalbolus treatment with bil versus glargine resulted in higher daytime hypoglycaemia in t1d and t2d , with an associated increase in total hypoglycaemia in patients with t1d . as assessed by continuous glucose monitoring ( cgm ) in three doubleblind imagine studies . 
 figure s1 . sensitivity analyses for nocturnal hypoglycemia between 00:00 and 05:59 hours . a , nocturnal hypoglycemia rate per patient year  se . weeks of study data included : t2d basal only ( 052 weeks ) , t2d basalbolus ( 026 weeks ) , t1d ( 052 weeks ) . abbreviations : b , basal only ; bb , basalbolus ; bil , basal insulin peglispro ; ci , confidence interval ; gl , insulin glargine ; pt , patient ; rr , relative rate ; se , standard error ; t1d , type 1 diabetes ; t2d , type 2 diabetes ; yr , year . * p < .05 for between treatment group comparisons . 
 figure s2 . abbreviations : bil , basal insulin peglispro ; gl , insulin glargine ; se , standard error ; t1d , type 1 diabetes . * p < .05 for between treatment group comparisons . click here for additional data file . j. r. has served on scientific advisory boards and received honoraria or consulting fees from eli lilly , novo nordisk , sanofi , merck , daiichi sankyo , janssen , boehringer ingelheim , astrazeneca and intarcia . he has received grants / research support from merck , pfizer , sanofi , novo nordisk , bristolmyers squibb , eli lilly , glaxosmithkline , takeda , astrazeneca , hanmi , janssen , daiichi sankyo , asahi , mannkind , boehringer ingelheim , intarcia and lexicon . m. m. has served on advisory boards for abbott , intarcia , merck sharpe & dohme , novo nordisk , sanofi and servier , has received honoraria or speaking fees from abbott , eli lilly and company , merck sharpe & dohme , novo nordisk , sanofi and servier and has received research grants from merck sharpe & dohme , novartis , novo nordisk , sanofi and servier . e. j. b. was an employee of eli lilly and company during these clinical trials and is currently a consultant to viacyte , inc . , san diego , california . y. q. , s. z. and a. m. c. are employees and shareholders of eli lilly and company . j. r. and m. m. participated as trial investigators and in the discussion / interpretation of the research , and reviewed / edited the manuscript . e. j. b. and m. j. p. participated in study design , the conduct of the studies , the data analysis / interpretation of the research , and reviewed / edited the manuscript . y. q. and s. z. contributed to the study design , designed and conducted the statistical analyses , and participated in the interpretation of the research and reviewed / edited the manuscript . a. m. c. contributed to the study design , the conduct of the studies , the data analysis / interpretation of the research and in writing the manuscript .