data format and content were in compliance with the health insurance portability and accountability act requirements .
approvals for this study protocol were obtained from the tulane and vha institutional review boards and the vha office of research and development .
adult patients ( age 18 years ) with a diagnosis of type 2 diabetes ( identified by icd-9-cm codes 250.xx , except for 250.x1 and 250.x3 ) in at least one inpatient record or in two outpatient records from 1 january 2004 to 1 september 2010 were included .
a new antihyperglycemic medication , after a 6-month washout period , was defined as the index treatment , with its first dispense date defined as the index date . since at least a 1-year baseline ( preindex ) period and a 2-year follow - up ( postindex ) period
were required for the analysis , the index treatments had to be initiated between 1 january 2005 and 1 september 2008 .
the hypoglycemia group was identified by a diagnosis of hypoglycemia ( icd-9-cm codes 250.8 , 251.0 , 251.1 , and 251.2 ) within the index treatment period , which was from the index date to the end of the last fill of the index treatment .
other inclusion / exclusion criteria were as follows : patients with any diagnosis of cvd ( icd-9-cm 410 , 412 , 430438 , 428 , 443.9 , 785.4 , and v43.4 ) and/or microvascular complications ( icd-9-cm 250.4250.6 ) during the 1-year preindex period were excluded .
finally , patients with the first recorded hypoglycemic episode beyond the index treatment period were excluded , as well as patients whose first recorded hypoglycemia occurred within the index treatment period but beyond 1 year after the index date .
baseline sociodemographic characteristics , illness characteristics , the charlson comorbidity index ( cci ) , tobacco use , vital signs , and hba1c levels were measured during a 1-year preindex period .
clinical events over the whole follow - up period after the index date were studied , including cvd , microvascular complications , and all - cause death .
cvd was defined as any of the following conditions diagnosed : myocardial infarction ( icd-9-cm 410 and 412 ) , stroke ( icd-9-cm 430438 ) , congestive heart failure ( icd-9-cm 428 ) , and peripheral vascular disease ( icd-9-cm 441.x , 443.9 , 785.4 , and v43.4 ) .
microvascular complications were defined as diabetes with renal , ophthalmic , or neurologic manifestations ( icd-9-cm 250.4250.6 ) .
propensity score matching using the greedy 5 to 1 method was applied to adjust for noncomparable baseline characteristics ( heterogeneity of hypoglycemia and control groups ) ( 19 ) . through a logistic regression model on group membership ,
the best set of baseline variables predicting occurrence of hypoglycemia was used to produce the propensity score to construct a 1:1 matched sample .
cox proportional hazards regression models were also used to compare time to clinical events , controlling for the covariates , including baseline demographic and illness characteristics , vital signs , prior medication use , and type of index drug .
adult patients ( age 18 years ) with a diagnosis of type 2 diabetes ( identified by icd-9-cm codes 250.xx , except for 250.x1 and 250.x3 ) in at least one inpatient record or in two outpatient records from 1 january 2004 to 1 september 2010 were included .
a new antihyperglycemic medication , after a 6-month washout period , was defined as the index treatment , with its first dispense date defined as the index date . since at least a 1-year baseline ( preindex ) period and a 2-year follow - up ( postindex ) period
were required for the analysis , the index treatments had to be initiated between 1 january 2005 and 1 september 2008 .
the hypoglycemia group was identified by a diagnosis of hypoglycemia ( icd-9-cm codes 250.8 , 251.0 , 251.1 , and 251.2 ) within the index treatment period , which was from the index date to the end of the last fill of the index treatment .
other inclusion / exclusion criteria were as follows : patients with any diagnosis of cvd ( icd-9-cm 410 , 412 , 430438 , 428 , 443.9 , 785.4 , and v43.4 ) and/or microvascular complications ( icd-9-cm 250.4250.6 ) during the 1-year preindex period were excluded .
finally , patients with the first recorded hypoglycemic episode beyond the index treatment period were excluded , as well as patients whose first recorded hypoglycemia occurred within the index treatment period but beyond 1 year after the index date .
baseline sociodemographic characteristics , illness characteristics , the charlson comorbidity index ( cci ) , tobacco use , vital signs , and hba1c levels were measured during a 1-year preindex period .
clinical events over the whole follow - up period after the index date were studied , including cvd , microvascular complications , and all - cause death .
cvd was defined as any of the following conditions diagnosed : myocardial infarction ( icd-9-cm 410 and 412 ) , stroke ( icd-9-cm 430438 ) , congestive heart failure ( icd-9-cm 428 ) , and peripheral vascular disease ( icd-9-cm 441.x , 443.9 , 785.4 , and v43.4 ) .
microvascular complications were defined as diabetes with renal , ophthalmic , or neurologic manifestations ( icd-9-cm 250.4250.6 ) .
propensity score matching using the greedy 5 to 1 method was applied to adjust for noncomparable baseline characteristics ( heterogeneity of hypoglycemia and control groups ) ( 19 ) . through a logistic regression model on group membership ,
the best set of baseline variables predicting occurrence of hypoglycemia was used to produce the propensity score to construct a 1:1 matched sample .
cox proportional hazards regression models were also used to compare time to clinical events , controlling for the covariates , including baseline demographic and illness characteristics , vital signs , prior medication use , and type of index drug .
from the visn 16 data warehouse , 63,003 patients ( 96.5% ) who had not experienced any hypoglycemia episode during the 2-year postindex period after the index date were identified as the control group and 2,187 patients ( 3.5% ) who had experienced at least one hypoglycemic episode within the index treatment period were identified as the hypoglycemia group .
patients ( n = 20,929 ) who had preindex records of hypoglycemia , cvd , or microvascular complications were excluded .
the analytical population consisted of 44,261 patients , including 761 patients in the hypoglycemia group and 43,500 in the control group .
the matched study sample of 1,522 patients consisted of 761 patients in the hypoglycemia group and 761 patients in the control group .
mean time from the index date to the occurrence of the first hypoglycemic episode was 143 days , and the median time was 123 days .
before matching , more patients had poor glycemic control in the hypoglycemia group ( 91.4% ) compared with the patients in the control group ( 87.8% ) ( p = 0.0043 ) .
the hypoglycemia group was generally sicker than the control group in terms of higher cci ( 2.44  1.37 vs. 2.18  1.24 ) , higher percentages of patients with renal disease ( 6.2 vs. 2.5% ) , and higher percentages of mental disorder ( 25.4 vs. 17.9% ) , substance abuse ( 23.7 vs. 16.2% ) , and tobacco use ( 18.7 vs. 13.6% ) .
a significantly higher percentage of african americans ( 25.8 vs. 19.6% ) was found in the hypoglycemia group compared with the control group .
there were fewer patients in the hypoglycemia group who had been married ( 52.8 vs. 62.3% , p < 0.0001 ) .
the proportion of patients who were on antihyperglycemic agents during the 1-year preindex period was significantly higher in the hypoglycemia group ( 62.5% ) than in the control group ( 35.6% ) , with more patients on insulin at baseline in the hypoglycemia group ( 8.9% ) than in the control group ( 2.9% ) .
the mean ( sd ) age was 62.58 ( 10.99 ) years and the cci was 2.44 ( 1.37 ) in the matched sample .
the baseline hba1c was 10.69% ( 2.61% ) in the total sample , 10.70% ( 2.57% ) in the hypoglycemia group , and 10.68% ( 2.66% ) in the control group . in the total matched sample , 61.6% of patients
had been taking oral antihyperglycemic agents and 9.6% had been taking insulin before the index date . in the total sample ,
66.5% had used antihypertensive medications , including -blockers ( 27.5% ) , before the index date .
use of statins did not statistically differ across groups ( 53.9 in the control group vs. 57.2% in the hypoglycemia group , p = 0.1972 ) .
baseline characteristics of the population by group * the type of index drug used was also similar between groups after matching .
overall , 31.3% of patients were initiated with biguanides on the index date , 32.3% with sulfonylureas , 11.6% with thiazolidinediones , and 21.7% with insulin .
the corresponding percentages were 31.0 vs. 31.7% , 31.4 vs. 33.2% , and 22.1 vs. 21.3% between the hypoglycemia and control groups , respectively .
there was no significant difference in treatment between patients with one episode and those with more than one episode .
the cumulative incidence rate of cvd events was 30.65/100 patients during 3 years in the hypoglycemia group compared with 17.48/100 patients in the control group .
patients in the hypoglycemia group were more likely to develop cvd than those in the control group ( p < 0.0001 ) .
the other kaplan - meier survival analyses on subcategories of cvd events found that patients in the hypoglycemia group were at higher risks of having stroke , congestive heart failure , and peripheral vascular disease ( all p < 0.05 ) .
the cumulative incidence rates during 3 years were 12.99 vs. 6.28 , 9.99 vs. 6.15 , and 13.42 vs. 5.12 per 100 patients for stroke , congestive heart failure , and peripheral vascular disease , respectively .
however , the risk of myocardial infarction was not significantly different between the hypoglycemia and control groups ( log - rank test p = 0.4612 ; cumulative incidence rate = 4.47 vs. 4.52 per 100 patients during 3 years ) . a : cumulative incidence rate of cvd events by group .
log - rank test showed significance ( both p < 0.0001 ) in risks of cvd events and microvascular complications between groups .
( a high - quality color representation of this figure is available in the online issue . ) in a similar manner , patients in the hypoglycemia group were more likely to develop microvascular complications ( p < 0.0001 ) ( fig .
the cumulative incidence rate of microvascular complications was 34.46/100 patients during 3 years in the hypoglycemia group and 22.03 in the control group .
furthermore , the cumulative incidence rate of any cvd events and microvascular complications was 50.38 during 3 years in the hypoglycemia group , which was significantly higher than the control group ( cumulative incidence rate = 36.12/100 patients in 3 years ) .
the mortality rates were not significantly different between these two groups ( p = 0.1593 ; cumulative incidence rate = 9.37 vs. 7.22 per 100 patients in 3 years ) . controlling for confounding variables , patients in the hypoglycemia group had higher risk of cvd events than patients in the control group ( hazard ratio [ hr ] 2.00 [ 95% ci 1.632.44 ] )
. increased risks of subcategories of cvd events , except myocardial infarction , also were found among the hypoglycemia group , with the hrs varying from 1.81 to 2.58 ( table 2 ) .
specifically , patients in the hypoglycemia group were 2.58 times more likely to have peripheral vascular disease ( 2.58 [ 1.813.67 ] ) and 2.25 times more likely to have a stroke ( 2.25 [ 1.623.13 ] ) than patients in the control group .
the risk of congestive heart failure was 81% higher for the hypoglycemia group than the control group ( 1.81 [ 1.272.56 ] ) .
compared with the control group , an increased risk of microvascular complications was shown in the hypoglycemia group ( 1.76 [ 1.462.11 ] ) .
patients in the hypoglycemia group were 1.73 times as likely to have a vascular event ( any cvd and microvascular complication ) as those in the control group ( 1.73 [ 1.492.02 ] ) .
it is notable that no significant effect of group membership on all - cause mortality was shown ( 1.29 [ 0.941.77 ] ) .
cox proportional hazards regression models for vascular events and mortality : hypoglycemia group vs. control group furthermore , compared with patients with only one episode of hypoglycemia , those who experienced more than one episode were more likely to have vascular events .
the adjusted hrs for vascular events in general were 1.53 ( 95% ci 1.101.66 ) ; for microvascular complications , 1.58 ( 1.242.02 ) ; and for peripheral vascular disease , 1.72 ( 1.162.56 ) .
hba1c levels during the 1-year postindex period remained similar in both the control group and the hypoglycemia group , at 10.35% ( sd 2.79% ) and 10.17% ( 2.66% ) , respectively .
postindex hba1c levels decreased from baseline in both groups ( by 0.42% in the total sample , with a decrease of 0.51 and 0.32% in the hypoglycemia and control groups , respectively ) .
in this study , we found that patients who experienced hypoglycemia during the index treatment period after the administration of a new antihyperglycemic drug were at approximately twofold risk to have cvd compared with patients in the control group .
a post hoc study using the advance data examined the association between severe hypoglycemia and the risks of macro- and microvascular events and death and found adjusted hrs of 3.45 ( 95% ci 2.345.08 ) for macrovascular events , 2.07 ( 1.323.26 ) for microvascular events , and 3.30 ( 2.314.72 ) for all - cause death ( 17 ) .
these findings are consistent with what was observed in our study , except that we did not find a significant increased risk of all - cause mortality .
the post hoc analysis of the advance study also found higher risks of nonvascular events associated with hypoglycemia .
furthermore , no dose - response relationship was found between repeated episodes of hypoglycemia and vascular events or death .
therefore , the advance investigators concluded that hypoglycemia was likely to be a marker of vulnerability to these clinical events but argued that a direct causal relationship was still possible ( 17,18 ) . although the causal relationship between hypoglycemia and cvd events can not be established from our study ,
future large prospective trials and mechanistic studies are needed to confirm the causal link between hypoglycemia and these vascular events .
hypoglycemia induces several counterregulatory responses , including indirect changes such as inflammation , increased platelet and neutrophil activation , and epinephrine secretion ( 18 ) .
more important , it is also possible that the first hypoglycemic episode leads to further episodes that are asymptomatic ( 20 ) and associated with cardiovascular ischemic and proarrhythmic changes ( 21,22 ) .
moreover , hypoglycemia may not only precipitate ischemia but also induce changes in autonomic function that can lead to silent ischemia and arrhythmias ( 18 ) .
this may explain the observed difference in heart failure but not myocardial infarction between the groups in our study .
in addition , myocardial infarction is a single event that is likely to be multifactorial , whereas heart failure is the end stage of multiple processes , some of which may be triggered by hypoglycemia .
microvascular disease , on the other hand , has been shown to behave differently and may worsen in the short - term after improvement in glycemic control but improve in the long run ( 23,24 ) .
patients with long - standing poor antecedent control , as in our study , may be particularly susceptible .
it is difficult to determine what role hypoglycemia plays in exacerbating these mechanisms . in the bonds
et al . ( 16 ) analysis on accord data , more deaths among the patients who had experienced hypoglycemia were observed ( hr 1.41 within the intensive glucose control arm and 2.30 within the standard glucose control arm ) , whereas in our study , a significantly different all - cause mortality rate was not found in the hypoglycemia group after controlling for the covariates .
the lack of statistical significance may relate to the lack of a sufficient power of the sample .
the numerical difference observed in this study can be interpreted into the number needed to harm for one additional death , which was estimated to be 108 patients .
it is notable that some differences exist between the study populations of the clinical trials ( advance and accord ) and our retrospective study , in addition to the differences in study design .
of import , our study population was required to have no record of cvd and microvascular disease during the 1-year preindex period .
both trials targeted lower hba1c levels , while in our study , the hba1c levels were much higher at either baseline or after the index date . in this study ,
indeed , it is likely that poor glycemic control was the reason why patients were started on a new antihyperglycemic medication .
the degree of improvement is compatible with the degree of effectiveness reported in clinical antihyperglycemic interventions .
while there was a larger decrease in 1-year hba1c levels from baseline in the hypoglycemia group , the difference from the control group was not statistically significant .
although a correlation between aggressive glycemic control ( i.e. , lower hba1c levels to 6.06.5% for type 2 diabetic patients ) and higher risk of hypoglycemia has been found , hba1c itself may not be a good indicator of optimal glycemic management . in a post hoc epidemiological analysis of the accord study , a greater risk of hypoglycemia
indeed , tight glycemic control may not be the best predictor of severe hypoglycemia , with several other factors , such as glucose variability , being more important ( 28,29 ) .
moreover , responses to intensive treatment targeting euglycemia may vary across patients with the underlying illness .
two studies find increased risks of cvd and mortality among patients with either low or high hba1c ( 30,31 ) . in our study , the mean hba1c was 10% , suggesting a group of patients with poor antecedent control .
comparison of vascular outcomes among higher hba1c and lower hba1c groups is warranted for future studies .
the results of this study should be interpreted in light of the limitations of the study design and the vha population .
first , it is a retrospective study using existing vha electronic medical records data where clinical information is still limited .
we can access only the information on medical records that have been processed through the vha .
therefore , we could capture only severe episodes of hypoglycemia that were reported and recorded by the physicians or had required medical assistance from a clinical facility .
moreover , the propensity score approach can match patients from the two groups on observed variables only .
important factors related to hypoglycemia and health outcomes may be unobserved , unavailable , or inadequately captured in the data and , therefore , are not subject to control in the analysis . for example , duration of diabetes , duration and dose of insulin use , and timely self - monitored glucose levels were not available in the data warehouse .
second , vha patients ( predominantly male and elderly ) are not representative of the u.s . population , nor does the vha system operate like other health care delivery systems . from this retrospective cohort study with an average follow - up period of 4 years
, we identified a high - risk group of veterans with type 2 diabetes who developed hypoglycemia after the initiation of a new antihyperglycemic medication and were found to be at higher risks of cvd events and microvascular complications .
physicians and patients in clinical practices should work together to prevent hypoglycemia after new medication initiation .
identification of patients who develop hypoglycemia in such a clinical situation may help us develop strategies to prevent cvd events in such patients .
in this study , we found that patients who experienced hypoglycemia during the index treatment period after the administration of a new antihyperglycemic drug were at approximately twofold risk to have cvd compared with patients in the control group .
a post hoc study using the advance data examined the association between severe hypoglycemia and the risks of macro- and microvascular events and death and found adjusted hrs of 3.45 ( 95% ci 2.345.08 ) for macrovascular events , 2.07 ( 1.323.26 ) for microvascular events , and 3.30 ( 2.314.72 ) for all - cause death ( 17 ) .
these findings are consistent with what was observed in our study , except that we did not find a significant increased risk of all - cause mortality .
the post hoc analysis of the advance study also found higher risks of nonvascular events associated with hypoglycemia .
furthermore , no dose - response relationship was found between repeated episodes of hypoglycemia and vascular events or death .
therefore , the advance investigators concluded that hypoglycemia was likely to be a marker of vulnerability to these clinical events but argued that a direct causal relationship was still possible ( 17,18 ) . although the causal relationship between hypoglycemia and cvd events can not be established from our study ,
future large prospective trials and mechanistic studies are needed to confirm the causal link between hypoglycemia and these vascular events .
hypoglycemia induces several counterregulatory responses , including indirect changes such as inflammation , increased platelet and neutrophil activation , and epinephrine secretion ( 18 ) .
more important , it is also possible that the first hypoglycemic episode leads to further episodes that are asymptomatic ( 20 ) and associated with cardiovascular ischemic and proarrhythmic changes ( 21,22 ) .
moreover , hypoglycemia may not only precipitate ischemia but also induce changes in autonomic function that can lead to silent ischemia and arrhythmias ( 18 ) .
this may explain the observed difference in heart failure but not myocardial infarction between the groups in our study .
in addition , myocardial infarction is a single event that is likely to be multifactorial , whereas heart failure is the end stage of multiple processes , some of which may be triggered by hypoglycemia .
microvascular disease , on the other hand , has been shown to behave differently and may worsen in the short - term after improvement in glycemic control but improve in the long run ( 23,24 ) .
patients with long - standing poor antecedent control , as in our study , may be particularly susceptible .
it is difficult to determine what role hypoglycemia plays in exacerbating these mechanisms . in the bonds
et al . ( 16 ) analysis on accord data , more deaths among the patients who had experienced hypoglycemia were observed ( hr 1.41 within the intensive glucose control arm and 2.30 within the standard glucose control arm ) , whereas in our study , a significantly different all - cause mortality rate was not found in the hypoglycemia group after controlling for the covariates .
the lack of statistical significance may relate to the lack of a sufficient power of the sample .
the numerical difference observed in this study can be interpreted into the number needed to harm for one additional death , which was estimated to be 108 patients .
it is notable that some differences exist between the study populations of the clinical trials ( advance and accord ) and our retrospective study , in addition to the differences in study design .
of import , our study population was required to have no record of cvd and microvascular disease during the 1-year preindex period .
both trials targeted lower hba1c levels , while in our study , the hba1c levels were much higher at either baseline or after the index date .
indeed , it is likely that poor glycemic control was the reason why patients were started on a new antihyperglycemic medication .
the degree of improvement is compatible with the degree of effectiveness reported in clinical antihyperglycemic interventions .
while there was a larger decrease in 1-year hba1c levels from baseline in the hypoglycemia group , the difference from the control group was not statistically significant .
although a correlation between aggressive glycemic control ( i.e. , lower hba1c levels to 6.06.5% for type 2 diabetic patients ) and higher risk of hypoglycemia has been found , hba1c itself may not be a good indicator of optimal glycemic management . in a post hoc epidemiological analysis of the accord study , a greater risk of hypoglycemia
indeed , tight glycemic control may not be the best predictor of severe hypoglycemia , with several other factors , such as glucose variability , being more important ( 28,29 ) .
moreover , responses to intensive treatment targeting euglycemia may vary across patients with the underlying illness .
two studies find increased risks of cvd and mortality among patients with either low or high hba1c ( 30,31 ) . in our study , the mean hba1c was 10% , suggesting a group of patients with poor antecedent control .
comparison of vascular outcomes among higher hba1c and lower hba1c groups is warranted for future studies .
the results of this study should be interpreted in light of the limitations of the study design and the vha population .
first , it is a retrospective study using existing vha electronic medical records data where clinical information is still limited .
we can access only the information on medical records that have been processed through the vha .
therefore , we could capture only severe episodes of hypoglycemia that were reported and recorded by the physicians or had required medical assistance from a clinical facility .
moreover , the propensity score approach can match patients from the two groups on observed variables only .
important factors related to hypoglycemia and health outcomes may be unobserved , unavailable , or inadequately captured in the data and , therefore , are not subject to control in the analysis . for example , duration of diabetes , duration and dose of insulin use , and timely self - monitored glucose levels were not available in the data warehouse
. other limitations of this study include a lack of formal diagnostic testing for hypoglycemia .
second , vha patients ( predominantly male and elderly ) are not representative of the u.s . population , nor does the vha system operate like other health care delivery systems . from this retrospective cohort study with an average follow - up period of 4 years , we identified a high - risk group of veterans with type 2 diabetes who developed hypoglycemia after the initiation of a new antihyperglycemic medication and were found to be at higher risks of cvd events and microvascular complications .
physicians and patients in clinical practices should work together to prevent hypoglycemia after new medication initiation .
identification of patients who develop hypoglycemia in such a clinical situation may help us develop strategies to prevent cvd events in such patients .
 objectivehypoglycemia is associated with failure to show cardiovascular benefit and increased mortality of intensive glycemic control in randomized clinical trials . 
 this retrospective cohort study aimed to examine the impact of hypoglycemia on vascular events in clinical practice.research design and methodspatients with type 2 diabetes were identified by icd-9-cm codes ( 250.xx except for 250.x1 and 250.x3 ) between 1 
 january 2004 and 1 september 2010 from the veterans integrated service network 16 . 
 index date was defined as the first date of new antihyperglycemic medications ( index treatment ) . 
 patients with 1-year preindex records of hypoglycemia , cardiovascular , and microvascular diseases were excluded . 
 the hypoglycemia group was identified by icd-9-cm codes ( 250.8 , 251.0 , 251.1 , and 251.2 ) within the index treatment period . a propensity score  
 matched group was used as control subjects . 
 cardiovascular events , microvascular complications , and all - cause death were compared using kaplan - meier analysis and cox proportional hazards regression model.resultsamong the unmatched sample ( n = 44,261 ) , the hypoglycemia incidence rate was 3.57/100 patient - years . the matched sample ( hypoglycemia group : n = 761 ; control group : n = 761 ) had a median follow - up of 3.93 years , mean age of 62.6  11.0 years , and preindex hba1c of 10.69  2.61% . 
 the 1-year change in hba1c was similar ( hypoglycemia group 0.51 vs. control group 0.32% , p = 0.7244 ) . 
 the hypoglycemia group had significantly higher risks of cardiovascular events ( hazard ratio 2.00 [ 95% ci 1.632.44 ] ) and microvascular complications ( 1.76 [ 1.462.11 ] ) but no statistical mortality difference . 
 patients with at least two hypoglycemic episodes were at higher risks of vascular events than those with one episode ( 1.53 [ 1.101.66]).conclusionshypoglycemia is associated with higher risks of incident vascular events . 
 patients with hypoglycemia should be monitored closely for vascular events . 
RESEARCH DESIGN AND METHODS
Sample selection
Measurements
Propensity score matching
Statistical analyses
RESULTS
CONCLUSIONS
Vascular risk of hypoglycemia
Glycemic control and hypoglycemia
Limitations