the kaiser permanente northern california diabetes registry ( also referred to here as the registry ) is a well - characterized population , maintained continuously since 1993 , that has been the basis for extensive epidemiological research ( 1113 ) .
registry eligibility is based on multiple sources of data , including pharmacy records , laboratory data , and outpatient , emergency room , and hospitalization diagnoses of diabetes .
kaiser clinicians are encouraged to provide diabetes care according to internal care guidelines that mirror national clinical practice guidelines ( general treatment goals : a1c < 7.0% ; ldl cholesterol < 100 mg / dl ; and blood pressure 130/80 mmhg ) .
we included type 2 diabetic subjects from the registry who were aged 60 years at baseline ( 1 january 2004 ) and who had continuous kaiser membership and pharmacy benefits for at least 12 months before baseline . from the initial eligible population of 228,740 patients
, we excluded 62,347 for noncontinuous kaiser membership or pharmacy benefits , 22,427 for type 1 diabetes or unknown diabetes ( 14 ) , and 63,790 for being aged < 60 years .
we additionally excluded individuals with evidence of end - stage renal disease before baseline ( n = 1,127 ) and no a1c test result during the year prior to baseline ( n = 7,957 ) .
person - time follow - up started on 1 january 2004 and ended with the first occurrence of any of the defined nonfatal end points , death , discontinuation of kaiser membership or pharmacy benefits ( discontinuation defined as a gap of at least 3 months in coverage ) , or the end of our 4-year observation window ( 31 december 2007 ) .
nonfatal outcomes and the date of first occurrence were identified via hospitalization records , based on established coding algorithms using primary diagnostic ( icd-9 ) or current procedural terminology ( cpt ) codes ( see the supplementary materials ) ( 12 ) .
acute metabolic events were defined as hospitalizations for diabetes with other coma , diabetes with hyperosmolarity , diabetes with ketoacidosis , and uncontrolled diabetes .
chronic microvascular events were defined as end - stage renal disease , amputation , or severe diabetic eye disease .
chronic cardiovascular events were categorized as coronary artery disease ( myocardial infarction , coronary artery bypass surgery , or angioplasty ) , congestive heart failure , cerebrovascular disease ( ischemic or hemorrhagic stroke or carotid endarterectomy ) , or peripheral vascular disease .
mortality and dates of death were captured from the california state mortality file and social security death records .
we also created two combined outcomes :  any complication  was defined as the presence of any of the three nonfatal outcomes described above .  any complication or death  was defined by the occurrence of any of the three nonfatal outcomes or death .
the main exposure of interest was the most recent a1c within 1 year prior to baseline .
northern california kaiser medical facilities send all their a1c samples to be analyzed by a single , regional laboratory .
this laboratory is licensed by the state s department of health services , inspected and accredited by the college of american pathologists , and uses the standardization of a1c implemented by the national glycohemoglobin standardization group .
we categorized a1c as < 6.0 , 6.06.9 , 7.07.9 , 8.08.9 , 9.09.9 , 10.010.9 , and 11.0% .
for stratified analyses , we collapsed a1c categories 9.0% because of the small numbers of patients at that upper distribution of a1c .
baseline covariates evaluated in this analysis were demographics ( age , sex , and race / ethnicity ) ; duration of diabetes ; systolic blood pressure ; laboratory findings within 1 year prior to baseline , including estimated glomerular filtration rate ( gfr ) and urinary albumin excretion ( microalbuminuria or proteinuria ) ; bmi ; prevalent complications and comorbidities ( history of lower - extremity amputation , photocoagulation , hospitalization for acute metabolic event , myocardial infarction , stroke , congestive heart failure , cancer , chronic lung disease , and depression ) ; smoking ; number of inpatient admissions in the previous year ; and baseline use of glucose - lowering medications .
all analyses were performed using sas version 9.1 ( sas institute , cary , nc ) , and associations were considered statistically significant at the 0.05 level .
we first calculated crude incidence densities for each outcome ( number of events per 1,000 person - years ) .
we then specified cox proportional hazards models for each outcome , generating hazard ratios ( hrs ) for baseline glycemic control ( a1c < 6.0% as reference group ) .
bivariate analyses were first performed followed by multivariate analyses , accounting for potential confounders , including age , sex , race / ethnicity , duration of diabetes , systolic blood pressure , use of glucose - lowering medications , smoking status , glucose - monitoring adherence , gfr ( chronic kidney disease stages 15 ) , microalbuminuria , and proteinuria . to address the issue of missing data , we used multiple imputations with our adjusted models ( 15 ) .
we found no substantive differences between results from models with complete data and models using multiple imputations .
all results presented are from models with complete data . to address the dynamic nature of a1c over time
, we also conducted sensitivity analyses using extended cox models ( time - dependent effects ) .
person - time follow - up started on 1 january 2004 and ended with the first occurrence of any of the defined nonfatal end points , death , discontinuation of kaiser membership or pharmacy benefits ( discontinuation defined as a gap of at least 3 months in coverage ) , or the end of our 4-year observation window ( 31 december 2007 ) .
nonfatal outcomes and the date of first occurrence were identified via hospitalization records , based on established coding algorithms using primary diagnostic ( icd-9 ) or current procedural terminology ( cpt ) codes ( see the supplementary materials ) ( 12 ) .
acute metabolic events were defined as hospitalizations for diabetes with other coma , diabetes with hyperosmolarity , diabetes with ketoacidosis , and uncontrolled diabetes .
chronic microvascular events were defined as end - stage renal disease , amputation , or severe diabetic eye disease .
chronic cardiovascular events were categorized as coronary artery disease ( myocardial infarction , coronary artery bypass surgery , or angioplasty ) , congestive heart failure , cerebrovascular disease ( ischemic or hemorrhagic stroke or carotid endarterectomy ) , or peripheral vascular disease .
mortality and dates of death were captured from the california state mortality file and social security death records .
we also created two combined outcomes :  any complication  was defined as the presence of any of the three nonfatal outcomes described above .  any complication or death  was defined by the occurrence of any of the three nonfatal outcomes or death .
the main exposure of interest was the most recent a1c within 1 year prior to baseline .
northern california kaiser medical facilities send all their a1c samples to be analyzed by a single , regional laboratory .
this laboratory is licensed by the state s department of health services , inspected and accredited by the college of american pathologists , and uses the standardization of a1c implemented by the national glycohemoglobin standardization group .
we categorized a1c as < 6.0 , 6.06.9 , 7.07.9 , 8.08.9 , 9.09.9 , 10.010.9 , and 11.0% .
for stratified analyses , we collapsed a1c categories 9.0% because of the small numbers of patients at that upper distribution of a1c .
baseline covariates evaluated in this analysis were demographics ( age , sex , and race / ethnicity ) ; duration of diabetes ; systolic blood pressure ; laboratory findings within 1 year prior to baseline , including estimated glomerular filtration rate ( gfr ) and urinary albumin excretion ( microalbuminuria or proteinuria ) ; bmi ; prevalent complications and comorbidities ( history of lower - extremity amputation , photocoagulation , hospitalization for acute metabolic event , myocardial infarction , stroke , congestive heart failure , cancer , chronic lung disease , and depression ) ; smoking ; number of inpatient admissions in the previous year ; and baseline use of glucose - lowering medications .
all analyses were performed using sas version 9.1 ( sas institute , cary , nc ) , and associations were considered statistically significant at the 0.05 level .
we first calculated crude incidence densities for each outcome ( number of events per 1,000 person - years ) .
we then specified cox proportional hazards models for each outcome , generating hazard ratios ( hrs ) for baseline glycemic control ( a1c < 6.0% as reference group ) .
bivariate analyses were first performed followed by multivariate analyses , accounting for potential confounders , including age , sex , race / ethnicity , duration of diabetes , systolic blood pressure , use of glucose - lowering medications , smoking status , glucose - monitoring adherence , gfr ( chronic kidney disease stages 15 ) , microalbuminuria , and proteinuria . to address the issue of missing data , we used multiple imputations with our adjusted models ( 15 ) .
we found no substantive differences between results from models with complete data and models using multiple imputations .
to address the dynamic nature of a1c over time , we also conducted sensitivity analyses using extended cox models ( time - dependent effects ) .
the mean age of the population was 71.0 years ; 14.6% were over the age of 80 years ( table 1 ) .
the population was ethnically diverse , with 45.9% of subjects composed of nonwhite racial / ethnic groups .
population description by baseline a1c categories * all complications or conditions were prevalent at baseline .
a total of 15% of the population had an a1c < 6.0% , 60% had an a1c < 7.0% , and 6.5% had an a1c 9.0% .
the most frequently prescribed medications for glucose control were sulfonylureas ( 50.6% ) , followed by metformin ( 37.7% ) , and any form of insulin ( 17.5% ) .
across a1c categories , patients with lower baseline a1c values tended to be older and more likely to be non - hispanic white .
patients with lower a1c values also were more likely to have a shorter duration of diabetes , better cholesterol control , and lower gfr , but less evidence of other microvascular complications ( e.g. , microalbuminuria , laser photocoagulation ) .
patients with lower a1c levels also were much less likely to be treated with insulin .
chronic cardiovascular events had the highest incidence ( 47.2 per 1,000 person - years ) , followed by mortality ( 40.4 per 1,000 person - years ) , chronic microvascular events ( 26.7 per 1,000 person - years ) , and acute metabolic events ( 1.2 per 1,000 person - years ) ( table 2 ) .
baseline a1c , complications , and mortality : overall population results * * cox proportional hazards models adjusted for age ; sex ; race / ethnicity ; duration of diabetes ; systolic blood pressure ; use of insulin , sulfonylurea , or thiazolidinedione ; smoking status ; glucose - monitoring adherence ; gfr ( chronic kidney disease stages 15 ) ; microalbuminuria ; and proteinuria .
the risk of acute metabolic events , based on point estimates , increased steeply with each unit change in a1c above 6.0% ; this increased risk became statistically significant above the a1c of 7.0% .
the adjusted hr for an a1c of 7.07.9% was 2.35 ( 95% ci 1.314.23 ) and increased to 11.52 ( 5.16623.47 ) at an a1c 11.0% ( reference : a1c < 6.0% ) .
adjusted hrs were somewhat attenuated compared with unadjusted hrs , but the steep , monotonic pattern persisted .
there was a similar , stepwise relationship between baseline a1c and chronic microvascular events . in the unadjusted model ,
the increased risk associated with higher glucose levels was significantly different than the reference ( a1c < 6.0% ) , starting at a1c 6.06.9% ( hr 1.56 [ 95% ci 1.411.72 ] ) .
the a1c  microvascular event relationship was attenuated in the adjusted model but still suggested an increased risk beginning at a1c 6.0% ( 1.11 [ 0.991.25 ] ) .
the risk became significantly higher than the reference for a1c levels 7.0% ( 1.25 [ 1.111.41 ] ) for a1c 7.07.9% .
for chronic cardiovascular events , a1c levels 6.0% also were associated with a significantly increased risk in both unadjusted and adjusted models .
the risk increased continuously without a clear threshold level , although the risk increase was less steep than that observed for acute metabolic or chronic microvascular events . unlike the nonfatal complications , mortality had a u - shaped relationship with baseline a1c . in unadjusted models ,
the risk of mortality was significantly lower for a1c levels between 6.0 and 8.9% relative to a1c levels < 6.0% .
after adjustment , this general pattern of lower risk in the midrange of a1c still was observed , although the lower risk for a1c levels between 8.0 and 8.9% was no longer statistically significant .
the mortality risk did not differ statistically between reference group ( a1c < 6.0% ) and a1c 9.0% in the unadjusted model , although the point estimates for a1c 10.0% indicated a somewhat higher risk . in adjusted models
only , mortality risk became significantly higher once a1c levels exceeded 10.0% ( hr 1.21 [ 95% ci 1.011.45 ] ) . when evaluating  any complication ,  we found that the risk rose steadily with each incremental rise in baseline a1c without a clear threshold , although the steepness of the relationship was attenuated in adjusted models . after adding death to this combined end point ( i.e. ,  any complication or death  ) , the risk increased significantly at a1c 6.0% in the unadjusted model .
however , after adjustment , the risk increase was not significant until a1c was 8.0% .
the epidemiologic patterns observed in the overall population were similar across the three age - groups ( 6069 , 7079 , and 80 years ) , with some notable exceptions ( table 3 ) .
all three age - groups had u - shaped mortality curves with the highest risk of death among patients with a1c levels at the extremes ( a1c < 6.0 and 9.0% ) . for patients aged 6069 years
, the lowest point estimate for mortality risk was observed with a1c levels between 7.0 and 7.9% . for patients aged 70 years
, the mortality risk was statistically lower across a broader range of a1c categories ( e.g. , a1c 6.07.9% for the aged 80 years group ) compared with the reference group . for the  any complication  outcome , patients aged 6069 years had a continuous , positive relationship between a1c and complications with no clear threshold . for older patients ,
the increased risk ( relative to the reference ) of any complications was significantly higher at the threshold of a1c 7.0% .
for the  any complication or death  outcome , there was an increased risk in the outcome for all age - groups when a1c exceeded 8.0% , although for patients aged > 80 years , this was statistically significant only for a1c 9.0% .
age - stratified results : adjusted analyses * * models adjusted for sex ; race / ethnicity ; duration of diabetes ; systolic blood pressure ; use of insulin , sulfonylurea , or thiazolidinedione ; smoking status ; glucose - monitoring adherence ; gfr ( chronic kidney disease stages 15 ) ; microalbuminuria ; and proteinuria . in analyses of effect modification , the relationships between a1c and mortality or the combined outcomes were not significantly different for those with differing durations of diabetes ( data not shown ) . in a sensitivity analysis using extended cox models that accounted for the time - varying nature of a1c , the overall forms of the relationships between a1c and complications did not change from the baseline analyses , although the strengths of the associations weakened , particularly for chronic complication events ( data not shown ) . for extended cox models of the  any complication  outcome , a1c was significantly associated with a higher risk of events at a1c 8.0% , instead of a1c 6.0% , whereas for the  any complication or death  outcome , a1c became significantly associated with higher risk at a1c 10% , instead of a1c 8.0% .
the clinical uncertainty surrounding the care of older diabetic patients can be lessened with more in - depth study of this important subpopulation ( 16 ) . with our large , contemporary , geriatric cohort
, we found a u - shaped relationship between a1c and mortality for the overall cohort and for each age category .
this u - shaped relationship was not commonly reported in older epidemiological studies but has been found in more recent studies . using datasets from the 1990s , blaum et al .
( 17 ) found a linear relationship between a1c and mortality , whereas nelson et al .
( 18 ) found that an a1c 8.0% was significantly associated with an increased risk of mortality .
general population of diabetic patients and found a u - shaped association , with the risk of mortality elevated at low glucose levels ( a1c 6.16.6% ) and at high glucose levels ( a1c 10.111.2% ) . likewise , post hoc analyses of the accord trial results have revealed a u - shaped a1c - mortality relationship in the control arm ( 19 ) .
in contrast , analyses of the intensive arm have revealed a linear a1c - mortality association .
the accord findings suggest that glucose - lowering treatments may alter the relationship between glucose levels and mortality . considering all of these studies in total ,
the differences between the older and more recent studies are likely attributed to secular changes in glycemic control levels , greater use of combination therapies , and the arrival of newer therapeutic classes . in our cohort ,
sulfonylureas were the most frequently used oral agents , with heavy use of tolazamide and glyburide .
it remains to be seen whether observations of an elevated risk of mortality at low a1c levels represent an actual effect of glucose control or are a result of other factors associated with low a1c levels .
older patients with lower a1c levels may suffer from poor nutritional status , frailty , or sarcopenia , each of which may contribute to an elevated mortality risk ( 20 ) .
the possibility that factors other than glucose control may explain the a1c - mortality relationship is reinforced by the observation of a u - shaped mortality curve in a nondiabetic population ( 21 ) .
the relationship between low a1c and mortality clearly deserves additional study , especially in the elderly .
our findings regarding a1c and the incidence of chronic complications are consistent with previous literature , primarily conducted in younger patients , demonstrating a continuous relationship between glycemic control and microvascular and cardiovascular complications ( 7,22 ) .
importantly , our analyses of these outcomes indicate that these continuous relationships also exist among the oldest patients , conditioned on survival . for the overall study population ,
for patients aged > 70 years , a statistically significant higher risk was evident above a 7.0% threshold .
the most important results from our study concern the distinctions between the risk of  any complication  versus the most inclusive outcome ,  any complication or death .  unlike the risk of  any complication ,  the risk of  any complication or death  significantly increased relative to the reference group after a1c levels exceeded 8.0% .
this outcome integrates the u - shaped curve associated with mortality and the continuous curve associated with complications .
findings for this outcome identify glycemic thresholds that minimize mortality while enhancing quality of life through the prevention of complications . the relationship between baseline a1c and the  any complication or mortality  outcome differed modestly by age - group , suggesting the impact of competing mortality . within each a1c strata above the reference level , the hr attenuated with increasing age .
thus , although the general pattern was similar , the slopes became less steep and less statistically significant with advancing age .
the a1c 8.0% threshold appeared to demarcate a risk increase for patients aged 6079 years .
for patients aged > 80 years , the point estimate for a1c 8.08.9% indicated an increased risk , but this result was not statistically different from the reference ; instead , there was a 9.0% threshold for these oldest patients .
the differences in results for those aged 80 years versus those aged 6079 years may be attributed to mortality becoming an increasingly random event ( with respect to diabetes ) as age increases ( 23 ) .
given the limitations of observational research and our short follow - up time , we can not assume that our findings have a purely causal basis , and , thus , relationships described in this article should be subjected to additional research .
residual confounding or reverse causality might explain an apparent short - term increase of complications or increased mortality .
we also based our primary conclusions on the relationship between baseline a1c and time to event , consistent with the approach used in most previous studies .
we find that when we account for the time - varying nature of a1c , the relationship between a1c and chronic complications actually weakens , whereas the relationship with acute metabolic events actually strengthens .
these differences were anticipated , given that a time - dependent exposure analyzed with the extended cox model is more sensitive to short - term effects , whereas a fixed baseline risk factor analyzed with the standard cox model is more sensitive to long - term effects ( 24 ) .
in addition , our conclusions regarding a1c thresholds might have differed with the use of even more granular increments of a1c ( e.g. , half - point increments ) .
numerous results revealed point estimates that indicated a positive association but with cis bracketing unity .
although we evaluated multiple outcomes , we did not evaluate the risk of hypoglycemia , which is another important clinical consideration .
our cohort was limited to patients enrolled in an integrated , managed - care system , where diabetes care may differ somewhat from that provided in other settings .
previous comparisons of diabetes care in kaiser with that of other managed - care settings have found that the quality of kaiser s care is representative of typical care across the u.s .
this cohort had relatively good glycemic control on average but did include sufficient numbers of individuals with very high a1c levels to evaluate outcomes across the spectrum of a1c levels . with respect to prevention of complications , our results indicate that older people have a graded relationship between a1c and complications . on the other hand , we observed a distinct u - shaped relationship between a1c and mortality .
our results suggest that a1c in older patients should be maintained below 8.0% to prevent both complications and mortality , with the caution that a1c levels < 6% were associated with an increased mortality risk .
additional research is needed to identify the mechanisms that underlie the increased mortality among those with very low a1c . in addition , ongoing research on care individualization in the elderly suggests that life expectancy ( 2 ) , comorbid conditions ( 3 ) , and patient preferences ( 25 ) may be important considerations in setting glycemic goals below 8.0% .
although we await the findings from this important research , the observational data presented here provide additional guidance for caring for the rapidly growing population of older diabetic patients .
 objectiveto identify the range of glycemic levels associated with the lowest rates of complications and mortality in older diabetic patients.research design and methodswe conducted a retrospective cohort study ( 20042008 ) of 71,092 patients with type 2 diabetes , aged 60 years , enrolled in kaiser permanente northern california . 
 we specified cox proportional hazards models to evaluate the relationships between baseline glycated hemoglobin ( a1c ) and subsequent outcomes ( nonfatal complications [ acute metabolic , microvascular , and cardiovascular events ] and mortality).resultsthe cohort ( aged 71.0  7.4 years [ means  sd ] ) had a mean a1c of 7.0  1.2% . 
 the risk of any nonfatal complication rose monotonically for levels of a1c > 6.0% ( e.g. , adjusted hazard ratio 1.09 [ 95% ci 1.021.16 ] for a1c 6.06.9% and 1.86 [ 1.632.13 ] for a1c 11.0% ) . 
 mortality had a u - shaped relationship with a1c . compared with the risk with a1c < 
 6.0% , mortality risk was lower for a1c levels between 6.0 and 9.0% ( e.g. , 0.83 [ 0.760.90 ] for a1c 7.07.9% ) and higher at a1c 11.0% ( 1.31 [ 1.091.57 ] ) . 
 risk of any end point ( complication or death ) became significantly higher at a1c 8.0% . 
 patterns generally were consistent across age - groups ( 6069 , 7079 , and 80 years).conclusionsobserved relationships between a1c and combined end points support setting a target of a1c < 8.0% for older patients , with the caution that a1cs < 6.0% were associated with increased mortality risk . 
 additional research is needed to evaluate the low a1c  mortality relationship , as well as protocols for individualizing diabetes care . 
RESEARCH DESIGN AND METHODS
Time frame for analysis
Outcomes
A1C
Assessment of covariates
Statistical analysis
RESULTS
CONCLUSIONS
Supplementary Material