in this multicenter , prospective , open - label , randomized study , we enrolled 375 adult patients admitted to general medicine and surgery services .
we recruited patients with a known history of t2d and with a bg before randomization between 140 and 400 mg / dl , a known history of t2d for > 3 months , age between 18 and 80 years , and treatment at home with diet alone , any combination of oral antidiabetic agents , or low - dose insulin therapy at a daily dose 0.4 units / kg before admission . on admission , we stopped oral antidiabetic agents , and bg was measured before meals and at bedtime .
patients treated with low - dose insulin before admission had the same insulin regimen continued and were invited to participate if bg exceeded 140 mg / dl .
we excluded patients with an admission , patients with any bg > 400 mg / dl before randomization or with a history of hyperglycemic crises , patients with hyperglycemia without a known history of diabetes , patients admitted to or expected to require icu admission , patients undergoing cardiac surgery , patients receiving corticosteroid therapy , patients with clinically relevant hepatic disease or impaired renal function ( serum creatinine 3.0 mg / dl ) , patients with a history of diabetic ketoacidosis ( 19 ) , pregnant patients , and patients with any mental condition rendering them unable to give informed consent . patients
were randomized according a 2:2:1 ratio to one of three regimens : a basal - bolus regimen with insulin glargine given once daily and glulisine before meals plus corrective doses of glulisine by sliding scale for bg > 140 mg / dl ( lantus and apidra ; sanofi ) , a basal plus regimen with a daily dose of glargine and corrective doses of glulisine by sliding scale before meals for bg > 140 mg / dl , or ssi for bg > 140 mg / dl ( novolin r ; novo nordisk ) .
patients in the basal - bolus group were started at a total daily dose ( tdd ) of 0.5 units / kg divided with half as insulin glargine once daily and half as insulin glulisine before meals .
patients in the basal plus group received 0.25 units / kg of glargine plus corrective doses of glulisine before meals . in patients
70 years of age and those with a serum creatinine 2.0 mg / dl , the starting tdd in the basal - bolus group was reduced to 0.3 units / kg in the basal - bolus , and tdd of glargine was reduced to 0.15 units / kg in the basal plus regimen ( 10,20 ) .
the goal of insulin therapy was to maintain fasting and premeal glucose concentrations between 100 and 140 mg / dl .
the doses of insulin were adjusted daily according to protocol ( supplementary table 1 ) . during treatment ,
treatment failure was arbitrarily defined as a mean daily bg level > 240 mg / dl or two consecutive values > 240 mg / dl ( 9,10 ) . in case of treatment failure ,
patients in the basal plus and ssi groups were switched to a basal - bolus regimen starting at a tdd of 0.5 units / kg ( 9,10 ) .
this study was conducted at grady memorial hospital , emory university hospital , and the veterans administration medical center in atlanta , georgia ; medical university of south carolina medical center in charleston , south carolina ; and tulane medical center in new orleans , louisiana .
the study protocol and consent form were approved by the institutional review board at each participating institution .
a research pharmacist at each institution followed a computer - generated randomization table to coordinate the randomization and treatment assignment .
all patients were managed for medical and surgical problems by their primary care team , who received a copy of the assigned treatment protocol .
the primary outcome of the study was difference in glycemic control , as measured by mean daily bg concentration , among patients treated with basal - bolus , basal plus , and ssi regimens ( fig .
secondary outcomes included differences between treatment groups in any of the following measures : number of hypoglycemic events ( bg < 70 and < 40 mg / dl ) after the first day of treatment , number of episodes of hyperglycemia ( bg > 200 mg / dl ) after the first day of treatment , tdd of insulin , hospital stay , and hospital complications .
differences in glycemic control in medical and surgical patients with t2d treated with basal - bolus (  ) and basal plus (  ) regimens .
this noninferiority study design was based on the hypothesis that the difference in mean daily bg between basal plus and basal - bolus would be no greater than 18 mg / dl ( 1 mmol / l ) ( 9,10 ) .
a bg difference of such a magnitude has been reported as clinically insignificant and is typically smaller than the significant treatment effects detected in other superiority trials ( 9,10 ) . in light of the data from the rabbit 2 ( randomized study of basal - bolus insulin therapy in the inpatient management of patients with type 2 diabetes ) medical and surgical trials ( 9,10 ) ,
it is reasonable to assume that the sd of mean daily bg is bounded by 50 mg / dl . on the basis of two - sample t tests or wilcoxon tests ( one - sided ,  = 0.05 )
, 147 subjects were required for both the basal plus and the basal - bolus groups to ensure 80% power to reject the noninferiority hypothesis , with bonferroni correction applied to adjust for multiple comparisons across four time points .
we compared baseline and clinical characteristics and outcomes , such as mean daily bg after day 1 , occurrence of hypoglycemia , and occurrence of complications , both among treatment groups and between medical and surgical patients .
the comparisons were made with the use of wilcoxon tests ( or kruskal - wallis tests ) for continuous variables and  tests ( or fisher exact tests ) for discrete variables .
multivariate analysis was conducted with a repeated measures linear model , which accounted for within - subject bg correlation through an autoregressive model of order 1 ( ar 1 ) correlation structure .
the data are generally presented as mean  sd for continuous variables and n ( % ) for discrete variables .
the primary outcome of the study was difference in glycemic control , as measured by mean daily bg concentration , among patients treated with basal - bolus , basal plus , and ssi regimens ( fig .
secondary outcomes included differences between treatment groups in any of the following measures : number of hypoglycemic events ( bg < 70 and < 40 mg / dl ) after the first day of treatment , number of episodes of hyperglycemia ( bg > 200 mg / dl ) after the first day of treatment , tdd of insulin , hospital stay , and hospital complications .
differences in glycemic control in medical and surgical patients with t2d treated with basal - bolus (  ) and basal plus (  ) regimens .
this noninferiority study design was based on the hypothesis that the difference in mean daily bg between basal plus and basal - bolus would be no greater than 18 mg / dl ( 1 mmol / l ) ( 9,10 ) .
a bg difference of such a magnitude has been reported as clinically insignificant and is typically smaller than the significant treatment effects detected in other superiority trials ( 9,10 ) . in light of the data from the rabbit 2 ( randomized study of basal - bolus insulin therapy in the inpatient management of patients with type 2 diabetes ) medical and surgical trials ( 9,10 ) ,
it is reasonable to assume that the sd of mean daily bg is bounded by 50 mg / dl . on the basis of two - sample t tests or wilcoxon tests ( one - sided ,  = 0.05 )
, 147 subjects were required for both the basal plus and the basal - bolus groups to ensure 80% power to reject the noninferiority hypothesis , with bonferroni correction applied to adjust for multiple comparisons across four time points . we compared baseline and clinical characteristics and outcomes , such as mean daily bg after day 1 , occurrence of hypoglycemia , and occurrence of complications , both among treatment groups and between medical and surgical patients .
the comparisons were made with the use of wilcoxon tests ( or kruskal - wallis tests ) for continuous variables and  tests ( or fisher exact tests ) for discrete variables .
multivariate analysis was conducted with a repeated measures linear model , which accounted for within - subject bg correlation through an autoregressive model of order 1 ( ar 1 ) correlation structure .
the data are generally presented as mean  sd for continuous variables and n ( % ) for discrete variables .
a total of 375 patients with t2d gave consent ( 210 medical and 165 surgical patients ) ; of them , 22 patients were excluded from further analysis because they received < 24 h of insulin treatment , were transferred to the icu , or received corticosteroid therapy .
a total of 146 patients in the basal - bolus group , 133 patients in the basal plus group , and 74 in the ssi group were included in the final analysis .
there were no significant differences among groups in mean age , racial distribution , bmi , duration of diabetes , type of treatment before admission , or mean hospital stay .
the most common admitting diagnoses in medical patients were cardiovascular ( 48% ) , infectious ( 17% ) , and pulmonary ( 14% ) disorders , while the most common types of surgery were orthopedic ( 34% ) , abdominal ( 27% ) , and urologic ( 12% ) procedures . clinical characteristics of study patients the mean admission glucose for the entire cohort was 204  84 mg / dl , and the mean hba1c was 8.4  2.4% .
the admission bg and hba1c concentrations and changes in glycemic control during the hospital stay are shown in table 2 .
all treatment regimens resulted in prompt and sustained improvement in mean daily bg concentration during the hospital stay .
treatment with basal - bolus and basal plus regimens resulted in similar improvements in daily bg after the first day of therapy ( fig .
1 ) , and both regimens resulted in better glycemic control than did treatment with ssi ( table 2 ) .
the percentages of glucose readings within the target range between 70 and 140 mg / dl were higher in the basal plus ( 42% ) and basal - bolus ( 37% ) regimens than in the ssi treatment group ( 32% ; p = 0.04 ) , and the percentages of glucose readings > 180 mg / dl were lower in the basal - bolus and basal plus groups than in the ssi group ( 27 , 32 , and 38% , respectively ) ; however , the difference was not statistically significant ( p = 0.11 ) .
in addition , ssi resulted in higher number of treatment failures than did the basal plus and basal - bolus regimens ( 19 , 2 , and 0% , respectively ; p < 0.001 ) .
glycemic control , insulin therapy , and hospital complications in patients treated with basal - bolus , basal plus , and ssi regimens we conducted repeated measures analysis with a linear mixed model to investigate the treatment effect during the hospital stay adjusted for a variety of factors , including participating institutions , hospital service ( medicine vs. surgery ) , diabetes duration ( > 5 vs.  5 years ) , bg concentration at randomization (  180 vs. > 180 mg / dl ) , and admission hba1c ( 7.5% vs. > 7.5% ) . in this model , we observed that treatment with ssi versus basal bolus , a longer history of diabetes , a higher bg at randomization , and a higher hba1c were significantly associated with worse glycemic control during the hospital stay . compared with patients with glucose 180 mg / dl , those with a bg > 180 mg / dl had significant higher mean daily glucose after the first day of therapy in the three treatment groups ( all p < 0.001 ) and had a higher number of treatment failures ( p = 0.006 ) .
similarly , the admission hba1c level was found to correlate with inpatient glycemic control and response to treatment . compared with patients with
> 7.5% had significant higher mean daily glucose : basal bolus , 142  32 vs. 166  35 mg / dl ; basal plus , 147  30 vs. 181  37 mg / dl ; and ssi , 152  26 vs. 197  43 mg / dl ( all p < 0.001 ) .
in addition , treatment failures were more common in ssi - treated patients with hba1c > 7.5% ( 33% vs. 7% ; p = 0.007 ) .
the tdd of insulin was higher in the basal - bolus group ( 32.2  16 units / day ) than in the basal plus group ( 27.3  11 units / day ; p < 0.001 ) , and both were higher than in the ssi group ( 8.2  5 units / day ; p < 0.001 ) ( table 2 ) .
there was no difference in the glargine daily dose between the basal - bolus and basal plus groups ( 21.1  9 and 22.1  8 units / day , respectively ; p = 0.21 ) ; however , patients in the basal - bolus group received a higher dose of glulisine than did those in the basal plus group ( 17.1  9 vs. 9.3  6 units / day , respectively ; p < 0.01 ) .
there were no differences in the frequency of hypoglycemic events between basal - bolus and basal plus regimens .
bg values < 70 and < 60 mg / dl were reported in 16 and 13% ( p = 0.48 ) and in 8 and 5% , respectively ( p = 0.43 ) .
the frequency of hypoglycemia was lower in the ssi group ( 3% ) than in the glargine - based groups ( p = 0.009 ) ( table 2 ) .
severe hypoglycemia ( < 40 mg / dl ) was uncommon and reported in 1% in the basal - bolus group , 1% in the basal plus group , and 0% in the ssi group ( p = 0.76 ) . the frequency of hypoglycemia was higher among patients treated with insulin before admission ( 22% ) than among insulin - naive patients ( 9.9% ; p = 0.01 ) . in all cases ,
hypoglycemia was corrected with oral dextrose , and no episodes were associated with adverse outcomes .
this prospective , multicenter , randomized clinical trial compared the efficacy and safety of a daily dose of glargine plus corrective doses with glulisine before meals against a standard basal - bolus regimen and ssi in general medical and surgical patients with t2d .
we observed that treatment with basal plus and basal - bolus regimens resulted in similar improvements in glycemic control , and both regimens resulted in better glycemic control and in a lower number of treatment failures than did ssi treatment .
the association between hyperglycemia and increased risk of hospital complications is well established in both icu and non - icu patients ( 3,4,6,8,2123 ) .
recent clinical trials have also shown treatment with a basal - bolus regimen to be superior to ssi alone in the management of patients with t2d . the rabbit 2 medical trial ( 9 )
reported that a bg target of < 140 mg / dl was achieved in two - thirds of patients treated with a basal - bolus regimen , whereas only one - third of those treated with ssi achieved target glycemia .
in general surgical patients , the rabbit 2 surgical trial ( 10 ) reported improvement in glycemic control as well as a significant reduction in the frequency of hospital complications , including wound infection , pneumonia , bacteremia , and acute respiratory and renal failure ( 10 ) . in this study
, we report that the basal plus approach with a single dose of basal insulin plus corrective doses of rapid - acting insulin analogs before meals resulted in a similar improvement in mean daily bg to the basal - bolus regimen , with no difference in the number of treatment failures and similar numbers of hypoglycemic events , and both regimens had better glycemic control and fewer treatment failures than did treatment with ssi . in agreement with previous studies ( 9,10,24 )
, we show that the use of basal insulin alone or as part of a basal - bolus regimen is well tolerated with a low rate of hypoglycemia . in the rabbit 2 medical trial
, 3% of patients in the basal - bolus group had a bg < 60 mg / dl and no patients had a value < 40 mg / dl ( 9 ) .
in the rabbit 2 surgical trial , 12% of patients treated with basal - bolus regimen had a bg < 60 mg / dl and 4% had a value < 40 mg / dl ( 10 ) .
in the current study , a bg < 60 mg / dl was seen in 8 and 5% of patients treated with basal - bolus or basal plus regimens , and only 1% had a bg < 40 mg / dl . as previously reported , treatment with ssi resulted in a significantly lower rate of hypoglycemia ( 9,10 ) . minimizing hypoglycemic events is of major importance in hospitalized patients because it has been shown to be an independent risk factor of poor outcome ( 2527 ) .
the results of multivariate analysis indicate that the four more important factors associated with better glycemic control were the use of basal insulin versus ssi , duration of diabetes 5 years , a randomization bg 180 mg / dl , and an admission hba1c 7.5% .
patients with bg > 180 mg / dl and hba1c > 7.5% at admission had significant higher mean daily bg and experienced more treatment failures during therapy .
this observation has important implications in clinical practice and indicates that t2d patients admitted with poor glycemic control ( bg > 180 mg / dl or
hba1c > 7.5% ) should be treated with basal - bolus or basal plus regimens , and the use of ssi alone should be avoided because a third of all patients will continue to have significant hyperglycemia , which may increase the risk of hospital complications ( 10 ) .
we excluded patients admitted to the icu , those with clinically relevant hepatic disease or with serum creatinine 3.0 mg / dl , patients with severe hyperglycemia , and those receiving a total dose of insulin > 0.4 units / kg / day before admission .
for such patients , higher insulin doses or a standard basal - bolus approach may be the preferred approach in achieving glycemic control .
in addition , our study was not powered to determine differences in hospital complications across groups .
the recent rabbit 2 surgical trial , which included a larger number of general surgical patients , reported a significant reduction in the frequency of hospital complications in patients treated with a basal - bolus regimen compared with ssi treatment ( 10 ) .
finally , in this study we observed a lower rate of bg within target range compared with previous randomized inpatient trials , in which we observed 55% of bg within goal in patients treated with a basal - bolus regimen ( 9,10 ) . in this trial , we followed a similar starting insulin dose and escalation protocol , increasing insulin dose by 10% if bg was between 140 and 180 mg / dl and by 20% if bg was > 200 mg / dl .
it is possible that increasing the starting insulin dose and increasing insulin titration will result in better glycemic control ; however , it may also increase the risk of hypoglycemic events ( 28 ) . in summary , most general medical and surgical patients with t2d treated with diet , oral antidiabetic agents , or low - dose insulin ( 0.4 units / day ) can be managed with a single daily dose of basal insulin with supplemental ( corrective ) doses of rapid - acting insulin analogs before meals .
this basal plus regimen resulted in improvements in glycemic control and frequency of hypoglycemic events similar to those seen with a standard basal - bolus insulin regimen , and both regimens resulted in better glycemic control and in fewer treatment failures than did the use of ssi alone .
these results indicate that basal insulin is necessary for stable glucose control in the hospital and that the basal plus approach is an effective alternative to the basal - bolus regimen for the initial management of hyperglycemia in general medical and surgical patients with t2d .
 objectiveeffective and easily implemented insulin regimens are needed to facilitate hospital glycemic control in general medical and surgical patients with type 2 diabetes ( t2d).research design and methodsthis multicenter trial randomized 375 patients with t2d treated with diet , oral antidiabetic agents , or low - dose insulin ( 0.4 units / kg / day ) to receive a basal - bolus regimen with glargine once daily and glulisine before meals , a basal plus regimen with glargine once daily and supplemental doses of glulisine , and sliding scale regular insulin ( ssi).resultsimprovement in mean daily blood glucose ( bg ) after the first day of therapy was similar between basal - bolus and basal plus groups ( p = 0.16 ) , and both regimens resulted in a lower mean daily bg than did ssi ( p = 0.04 ) . 
 in addition , treatment with basal - bolus and basal plus regimens resulted in less treatment failure ( defined as > 2 consecutive bg > 240 mg / dl or a mean daily bg > 240 mg / dl ) than did treatment with ssi ( 0 vs. 2 vs. 19% , respectively ; p < 0.001 ) . 
 a bg < 70 mg / dl occurred in 16% of patients in the basal - bolus group , 13% in the basal plus group , and 3% in the ssi group ( p = 0.02 ) . 
 there was no difference among the groups in the frequency of severe hypoglycemia ( < 40 mg / dl ; p = 0.76).conclusionsthe use of a basal plus regimen with glargine once daily plus corrective doses with glulisine insulin before meals resulted in glycemic control similar to a standard basal - bolus regimen . 
 the basal plus approach is an effective alternative to the use of a basal - bolus regimen in general medical and surgical patients with t2d . 
RESEARCH DESIGN AND METHODS
Outcome measures
Statistical analysis
RESULTS
CONCLUSIONS