abstracting data from electronic medical records , we retrospectively selected a sample of adult inpatients who received insulin at boston medical center , most of whom had a diagnosis of diabetes , admitted between 1 july 2005 and 31 december 2009 .
diabetes was defined by any one of the following : 1 ) administration of an oral antidiabetes medication ( metformin , a thiazolidinedione , or a sulfonylurea ) during hospitalization ; 2 ) a diabetes icd-9 code of 250.xx ; or 3 ) an a1c > 6.5% .
patients were excluded if they were aged < 18 years , were admitted to an intensive care unit , had a primary diagnosis of hypoglycemia , had hypoglycemia ( any blood glucose < 70 mg / dl ) within 24 h of admission , or had no point - of - care ( poc ) capillary glucose values .
the sample was restricted to only the first admission per patient , and data subsequent to the first hypoglycemic event after 24 h were excluded .
only poc values were used to measure glucose because of variability among different glucose assays .
case subjects were defined by a poc glucose < 70 mg / dl after the first 24 h of admission .
the time period examined for each case was 24 h prior to the first hypoglycemic event in order to include all relevant doses of insulin .
control subjects , defined by a poc glucose 70 mg / dl , were matched one to one on the basis of the hospital day of hypoglycemia , age ( 1830 , 3164 , or 6580 years ) , sex , and bmi ( < 18.5 , 18.525 , 2530 , or > 30
kg / m ) . matching on hospital day of hypoglycemia provided a control time frame as well as controlled for variation in clinical status during hospitalization .
the exposure was defined as the total insulin dose per body weight ( units / kg ) over the 24-h study period .
insulin doses were stratified into nonoverlapping ranges , as follows : 0 , < 0.2 , 0.20.4 , 0.40.6 , 0.60.8 , and 0.8 units / kg .
the exposure was grouped by insulin regimen type as follows : 1 ) glargine plus any other insulin , 2 ) nph plus any other insulin , 3 ) lispro and/or regular insulin only , and 4 ) no insulin . for 11 patients who received both glargine and nph in 1 day ,
group assignment was on the basis of whichever insulin dose was greater . for two patients who received the same total 24-h dose of glargine and nph ,
group assignment was on the basis of the insulin given closest to the hypoglycemic event .
the following known predictors of hypoglycemia and potential confounders were examined : weight , race , serum creatinine , albumin , liver function ( aspartate aminotransferase and alanine aminotransferase ) , a1c , white blood cell count , hematocrit , use of sliding - scale insulin ( ssi ) , fasting , length of stay , service ( medical or surgical ) , and disease severity defined by the charlson comorbidity index ( 12 ) .
use of ssi was categorized as only ssi , no ssi , or ssi plus scheduled insulin .
data were collected during hospitalization , except for missing values that were substituted by the closest value up to 3 months prior to admission .
bmi values < 10 or > 100 kg / m , weight < 20 or > 400 kg , and height < 100 or > 300 cm were considered erroneous and were deleted .
for these individuals , the average height of the sample for each sex was imputed ( 174.2  9.6 cm for male subjects and 160.8  8.5 cm for female subjects ) .
admission glucose was defined as the first poc glucose value within 24 h of admission .
summaries of categorical variables included counts and percentages , whereas for continuous variables means and sds were used .
comparability between the case and control groups for categorical variables was determined using the  test for categorical variables and the two - sample t test for continuous variables .
 regression was used for length of stay because this continuous , positive variable was not normally distributed .
conditional logistic regression was used to examine the unadjusted and the adjusted association of insulin dose with hypoglycemia .
the initial adjusted model included all variables that were associated with hypoglycemia , as well an interaction term for dose by regimen to assess effect modification by insulin regimen type on the relationship between insulin dose and hypoglycemia .
we then performed backward selection with the  level to keep variables in the model set at 0.2 ( 13 ) .
all analyses were performed using sas ( version 9.2 ; sas institute , cary , nc ) .
abstracting data from electronic medical records , we retrospectively selected a sample of adult inpatients who received insulin at boston medical center , most of whom had a diagnosis of diabetes , admitted between 1 july 2005 and 31 december 2009 .
diabetes was defined by any one of the following : 1 ) administration of an oral antidiabetes medication ( metformin , a thiazolidinedione , or a sulfonylurea ) during hospitalization ; 2 ) a diabetes icd-9 code of 250.xx ; or 3 ) an a1c > 6.5% .
patients were excluded if they were aged < 18 years , were admitted to an intensive care unit , had a primary diagnosis of hypoglycemia , had hypoglycemia ( any blood glucose < 70 mg / dl ) within 24 h of admission , or had no point - of - care ( poc ) capillary glucose values .
the sample was restricted to only the first admission per patient , and data subsequent to the first hypoglycemic event after 24 h were excluded .
only poc values were used to measure glucose because of variability among different glucose assays .
case subjects were defined by a poc glucose < 70 mg / dl after the first 24 h of admission .
the time period examined for each case was 24 h prior to the first hypoglycemic event in order to include all relevant doses of insulin .
control subjects , defined by a poc glucose 70 mg / dl , were matched one to one on the basis of the hospital day of hypoglycemia , age ( 1830 , 3164 , or 6580 years ) , sex , and bmi ( < 18.5 , 18.525 , 2530 , or > 30
kg / m ) . matching on hospital day of hypoglycemia provided a control time frame as well as controlled for variation in clinical status during hospitalization .
the exposure was defined as the total insulin dose per body weight ( units / kg ) over the 24-h study period . insulin doses were stratified into nonoverlapping ranges , as follows : 0 , < 0.2 , 0.20.4 , 0.40.6 , 0.60.8 , and 0.8 units / kg .
the exposure was grouped by insulin regimen type as follows : 1 ) glargine plus any other insulin , 2 ) nph plus any other insulin , 3 ) lispro and/or regular insulin only , and 4 ) no insulin . for 11 patients who received both glargine and nph in 1 day ,
group assignment was on the basis of whichever insulin dose was greater . for two patients who received the same total 24-h dose of glargine and nph ,
group assignment was on the basis of the insulin given closest to the hypoglycemic event .
the following known predictors of hypoglycemia and potential confounders were examined : weight , race , serum creatinine , albumin , liver function ( aspartate aminotransferase and alanine aminotransferase ) , a1c , white blood cell count , hematocrit , use of sliding - scale insulin ( ssi ) , fasting , length of stay , service ( medical or surgical ) , and disease severity defined by the charlson comorbidity index ( 12 ) .
use of ssi was categorized as only ssi , no ssi , or ssi plus scheduled insulin .
data were collected during hospitalization , except for missing values that were substituted by the closest value up to 3 months prior to admission .
bmi values < 10 or > 100 kg / m , weight < 20 or > 400 kg , and height < 100 or > 300 cm were considered erroneous and were deleted .
for these individuals , the average height of the sample for each sex was imputed ( 174.2  9.6 cm for male subjects and 160.8  8.5 cm for female subjects ) .
admission glucose was defined as the first poc glucose value within 24 h of admission .
summaries of categorical variables included counts and percentages , whereas for continuous variables means and sds were used .
comparability between the case and control groups for categorical variables was determined using the  test for categorical variables and the two - sample t test for continuous variables .
 regression was used for length of stay because this continuous , positive variable was not normally distributed .
conditional logistic regression was used to examine the unadjusted and the adjusted association of insulin dose with hypoglycemia .
the initial adjusted model included all variables that were associated with hypoglycemia , as well an interaction term for dose by regimen to assess effect modification by insulin regimen type on the relationship between insulin dose and hypoglycemia .
we then performed backward selection with the  level to keep variables in the model set at 0.2 ( 13 ) .
all analyses were performed using sas ( version 9.2 ; sas institute , cary , nc ) .
of 6,376 eligible patients abstracted from hospital records , 1,012 ( 15.8% ) had hypoglycemia . after matching , 995 case subjects ( 98.3% ) and 995 nonhypoglycemic control subjects remained ( supplementary table 1 ) . compared with 4,386 unmatched patients , the matched control sample was older ( aged 63.3 vs. 60.6 years , p < 0.001 ) , had lower weights ( 86.1 vs. 91.4 kg , p < 0.001 ) , were less obese ( bmi 31.2 vs. 33 kg / m , p < 0.001 ) , had a higher proportion of african americans ( 39.4 vs. 36.6% , p = 0.04 for race ) , and a had lower proportion of hispanics ( 12.7 vs. 16.1% ) .
the matched and unmatched control subjects were similar in terms of sex distribution and mean a1c .
the median time from admission to the first hypoglycemic event in case subjects was 2.7 days ( range 1.033.7 ) . during the index 24-h period ,
glargine was the most frequently administered insulin ( 31.7% ) , followed by short - acting insulin ( 28.4% ) , no insulin ( 24.0% ) , and nph insulin ( 15.9% ) ( table 1 ) .
ssi only was less common than ssi plus scheduled insulin and no ssi at all ( 25.3 , 37.0 , and 37.7% ) .
approximately 50% of the patients were given metformin , 33% were given a sulfonylurea , and 13% were given a thiazolidinedione .
the sample was racially diverse : 40.6% were african american , 34.1% were white , 13.9% were hispanic , and 11.4% were of other race / ethnicity .
the mean a1c was 8.1  2.2% , and mean serum creatinine was 1.5  1.7 mg / dl .
of the 1,990-patient sample , 1,418 ( 71.3% ) were not on insulin as an outpatient .
sample characteristics of unmatched factors by case status data are n ( % ) , percentages , or means  sd . * p values for categorical variables were generated by  tests .
hypoglycemia prevalence among patients who received lispro was similar to that among patients given regular insulin ( 31.8 vs. 36.1% ) .
hypoglycemic patients were more likely to be given glargine or nph and less likely to be given only ssi or no insulin than control subjects ( p < 0.001 ) .
ssi plus scheduled insulin was more common , whereas ssi without scheduled insulin was less common , among case subjects than control subjects ( p < 0.001 ) .
hypoglycemic patients had a lower albumin and hematocrit and higher creatinine and length of stay than nonhypoglycemic patients ( p < 0.001 for each comparison ) .
case subjects also had higher comorbidity index scores than control subjects ( p < 0.001 ) .
there was no difference in mean a1c ( 8.0  2.1 vs. 8.1  2.3% , p = 0.44 ) or admission glucose ( 199.8  109.5 vs. 193.6  96.9 mg / dl , p = 0.20 ) between case and control subjects .
higher insulin doses were associated with progressively higher blood glucose levels ( supplementary table 2 ) . within each dose range , the mean glucose levels of case subjects were lower than the mean glucose levels of control subjects .
relative to insulin doses < 0.2 units / kg , the unadjusted odds of hypoglycemia increased with increasing insulin dose ( table 2 ) .
adjusted for insulin regimen , ssi use , and albumin , creatinine , and hematocrit levels , the higher odds of hypoglycemia with increasing insulin doses remained ( table 3 and fig .
1 ) . patients who received insulin doses of 0.6 units / kg were at increased odds of hypoglycemia .
in contrast , the adjusted odds of hypoglycemia were not higher in patients who received 0.20.6 units / kg .
the association of insulin dose with hypoglycemia did not vary by regimen type , as indicated by a statistically nonsignificant interaction term in the multivariate model ( p = 0.524 ) .
distribution of insulin dose by case status data are n ( % ) or percentages .
predictors of hypoglycemia in the multivariate conditional logistic regression model multivariate - adjusted odds of hypoglycemia at different insulin doses in 995 case subjects vs. 995 matched control subjects .
error bars represent 95% cis . or , odds ratio . * p < 0.05 by conditional logistic regression .
in addition to insulin dose , there were several significant predictors of hypoglycemia , including creatinine and hematocrit .
the odds of hypoglycemia were threefold greater among those who did not receive ssi relative to those who did .
patients who received ssi plus scheduled insulin or ssi alone had higher blood glucose levels than patients who did not receive ssi ( 203  64 , 185  52 , and 128  33 mg / dl , p < 0.001 ) .
there was a trend toward higher odds of hypoglycemia among patients who received nph compared with patients given glargine or short - acting insulin . to investigate whether the risk of hypoglycemia depends on the ratio of basal insulin ( nph or glargine ) relative to the total daily dose , a post hoc analysis revealed that basal ratios < 0.4 confer lower odds of hypoglycemia than 0.40.6 ( odds ratio 0.50 [ 95% ci 0.250.97 ] , p = 0.040 ) .
in contrast , there was no difference in the odds of hypoglycemia between basal ratios > 0.6 or 0 and 0.40.6 .
hypoglycemia was not more common among patients given insulin with an oral diabetes medication compared with those on insulin alone ( 49.4 vs. 54.6% , p = 0.13 ) .
however , of the 201 patients who did not receive insulin but did receive an oral agent , sulfonylureas were more common among hypoglycemic patients than in control subjects ( 27.4 vs. 16.4% , p < 0.001 ) .
patients who received only ssi were more likely to be given an oral agent than those on ssi plus scheduled insulin and those not given ssi ( 54.5 , 28.1 , and 38.3% , p < 0.001 ) .
although hypoglycemia was proportionately more common on medical services than on surgical services ( table 1 , p = 0.008 ) , this variable was not significant in the multivariate model .
there was no difference in mean blood glucose in medical versus surgical patients ( 173  62 vs. 168  59 , p = 0.12 ) .
however , medical patients received more insulin than surgical patients ( 0.35  0.88 vs. 0.26  0.38 units / kg , p = 0.013 ) .
in addition , ssi only was less common among medical patients ( 20.9 vs. 36.0% , p < 0.001 ) .
the sample included 77 patients ( 3.9% ) without a diagnosis of diabetes who had an inpatient a1c > 6.5% . a sensitivity analysis excluding these patients yielded similar results .
this retrospective , matched , case - control study of 1,990 hospital - ward patients with diagnosed or probable diabetes shows that higher weight - based insulin doses are associated with greater odds of hypoglycemia , independent of the types of insulin used .
adjusted for insulin regimen , ssi use , and albumin , creatinine , and hematocrit levels , patients given at least 0.8 units / kg within a 24-h period are at threefold - higher odds of hypoglycemia than patients who receive < 0.2 units / kg .
however , 0.6 units / kg seems to be a threshold below which the odds of hypoglycemia are relatively low .
in addition , patients who do not receive ssi are at threefold - greater odds of hypoglycemia than patients who receive ssi with or without scheduled insulin . because ssi typically is administered in response to a glucose value above a predetermined threshold , patients given ssi are hyperglycemic by design .
patients who did not receive ssi may have been given excessive scheduled insulin , resulting in more frequent hypoglycemia .
together , these data suggest that the insulin program with the lowest risk of hypoglycemia consists of scheduled insulin plus ssi at total daily doses < 0.6 units / kg . our findings are broadly consistent with other studies of insulin use in non  intensive care unit inpatients that show that insulin is a risk factor for hypoglycemia ( 14,15 ) .
these studies , however , did not examine how the risk of hypoglycemia varies by insulin dose or type .
the lack of a clear difference in the odds of hypoglycemia between glargine and nph is similar to data from a randomized trial comparing weight - based analog insulins with nph and regular insulins that found no difference in hypoglycemia rates between the treatment groups ( 11 ) .
also consistent with other studies are our findings that high creatinine and low hematocrit levels are independently associated with hypoglycemia ( 16,17 ) .
the frequent use of oral agents was surprising given that our medication guideline for hospitalized patients with diabetes encourages the discontinuation of oral agents .
however , we support the judicious use of oral diabetes medications in patients who are eating regularly , who are no longer acutely ill , and/or who preparing for discharge , consistent with some expert opinions ( 1,18 ) .
our data provide evidence for the safety of this approach in terms of hypoglycemia . a number of limitations must be acknowledged .
also , bias can not be completely accounted for by matching and multivariate analysis of retrospective data .
the use of poc glucose values at the exclusion of serum glucose values may underestimate the occurrence of hypoglycemia .
this effect , however , is likely to be small because almost all inpatients with diabetes are ordered poc testing four times daily , and a poc glucose is more likely to be checked on a patient with hypoglycemic symptoms than a serum glucose .
another limitation is that a case - control design precludes the calculation of hypoglycemia rates ; however , the odds ratio provides a reasonable estimate of relative risk .
an additional limitation is our inability to classify the sample by diabetes type because of unavailable data .
however , at least 90% of the sample is estimated to have type 2 diabetes , in keeping with national estimates ( 19 ) .
finally , the focus of our study was hypoglycemia , and we did not examine the association of insulin dose with hyperglycemia . although lower - dose insulin regimens may confer a lower risk of hypoglycemia , they may be associated with a higher risk of hyperglycemia .
these data , however , suggest that 0.40.6 units / kg , a dose range tested in randomized controlled trials and recommended by the american diabetes association ( 5,9,11 ) , may be the highest dose at which the risk of hypoglycemia remains low . to determine a starting dose of insulin within this range for a specific patient , clinicians must balance the presence of hypoglycemia risk factors with the benefits of achieving glycemic control . despite these limitations , strengths of our study include a large sample size spanning 4.5 years . because the case and control subjects had similar admission glucose values and because we adjusted for numerous potential confounders , it is likely that we have isolated the effect of inpatient insulin dose on hypoglycemia . matching case subjects on the basis of hospital day , age , sex , and bmi
furthermore , no published study has investigated the association of weight - based insulin with inpatient hypoglycemia across a range of doses and insulin types .
one is whether the risk of hypoglycemia depends on the ratio of basal insulin relative to the total daily dose , which is an important component of insulin protocols ( 911 ) .
post hoc analysis of our data revealed that basal ratios < 0.4 confer a lower odds of hypoglycemia than basal ratios of 0.40.6 .
this may reflect a higher proportion of patients who received ssi , who are by definition hyperglycemic as discussed above .
prospective studies are necessary to determine the effect of basal ratio in scheduled insulin doses across heterogeneous inpatient populations .
another question is whether higher insulin doses cause hypoglycemia more quickly than lower insulin doses . in conclusion , we found that higher weight - based insulin doses are associated with greater odds of hypoglycemia , and this association does not differ by the type of insulin used .
insulin doses < 0.6 units / kg confer a lower odds of hypoglycemia , whereas doses > 0.6 units / kg are associated with higher odds of hypoglycemia .
given that insulin is recommended for most hospitalized patients with diabetes ( 4 ) , and hypoglycemia is associated with increased length of stay and mortality ( 15 ) , strategies to reduce hypoglycemia are of critical importance .
our findings provide additional information to help clinicians dose insulin more safely for inpatients with diabetes .
 objectiveto determine the association of weight - based insulin dose with hypoglycemia in noncritically ill inpatients with diabetes.research design and methodswe performed a retrospective , case - control study of 1,990 diabetic patients admitted to hospital wards . 
 patients with glucose levels < 70 mg / dl ( case subjects ) were matched one to one with nonhypoglycemic control subjects on the basis of the hospital day of hypoglycemia , age , sex , and bmi.resultsrelative to 24-h insulin doses < 0.2 units / kg , the unadjusted odds of hypoglycemia increased with increasing insulin dose . 
 adjusted for insulin type , sliding - scale insulin use , and albumin , creatinine , and hematocrit levels , the higher odds of hypoglycemia with increasing insulin doses remained ( 0.60.8 units / kg : odds ratio 2.10 [ 95% ci 1.084.09 ] , p = 0.028 ; > 0.8 units / kg : 2.95 [ 1.545.65 ] , p = 0.001 ) . 
 the adjusted odds of hypoglycemia were not greater in patients who received 0.20.4 units / kg ( 1.08 [ 0.641.81 ] , p = 0.78 ) or 0.40.6 units / kg ( 1.60 [ 0.902.86 ] , p = 0.11 ) . 
 although the relationship between insulin dose and hypoglycemia did not vary by insulin type , patients who received nph trended toward greater odds of hypoglycemia compared with those given other insulins.conclusionshigher weight - based insulin doses are associated with greater odds of hypoglycemia independent of insulin type . 
 however , 0.6 units / kg seems to be a threshold below which the odds of hypoglycemia are relatively low . 
 these findings may help clinicians use insulin more safely . 
RESEARCH DESIGN AND METHODS
Study sample
Variable definitions
Statistical analysis
RESULTS
CONCLUSIONS
Supplementary Material