kaiser permanente medical care program (  kaiser permanente  ) is a fully integrated , nonprofit , group practice health plan that provides comprehensive medical services to over 2.5 million members ( january 1995 ) throughout northern california ( including the san francisco bay and sacramento metropolitan areas ) or 2530% of the surrounding population . the kaiser permanente membership closely approximates the general population ethnically and socioeconomically except for the extreme tails of the income distribution ( 11 ) . in 1993 , kaiser permanente established the kaiser permanente northern california diabetes registry . the registry is updated annually by identifying all health plan members with diabetes from automated databases for pharmacy , laboratory , hospitalization records , and outpatient diagnoses ( 1214 ) . the registry sensitivity is estimated to be 96% based on chart review ( 15 ) . during 19941996 , all noninstitutionalized registry members 19 years or older identified as having diabetes prior to 1 january 1996 ( n = 90,302 ) were selected for participation in a health survey ( self - administered questionnaire ) or a computer - assisted telephone interview in english or spanish . eighty - three percent of eligible members participated in the survey . after removing those denying having diabetes or discontinuing membership , 70,748 respondents with diabetes remained . the survey collected information on , among other things , ethnicity , information needed to classify diabetes type ( see karter et al . for algorithm ) , family history of diabetes , education , and behavioral risk factors . survey respondents were ethnically diverse : 14% black , 12% asian , 10% latino , and 64% non - latino white . 44% were filipino , 24% were chinese , 12% were japanese , and 19% were korean , other asian , or mixed race . we compared the demographic composition ( age , sex , socioeconomic status ) of diabetes survey responders to nonresponders in a previous study ( 14 ) and found no evidence to suggest responder bias . in addition to survey - derived data , we obtained measures of neighborhood - level socioeconomic status by linking each member s address to the 1990 census block group - level average annual 1989 per capita income . we used a survey follow - up study design to evaluate the incidence density of lea and its predictors , restricting analysis to the 28,701 survey respondents who had triglyceride data within 1 year of baseline . baseline was defined as 1 january 1995 for all members surveyed in 1994 and the survey date ( january 1995 to march 1997 ) for those surveyed after that date . the duration of follow - up ( person - time ) was tabulated through membership records and ended with an event censoring due to dropping of kaiser permanente membership for any period greater than 2 months , death , or the end of the study ( 31 december 2006 ) . we excluded those with a history of prior lea events noted in hospital discharge records during the 5 years prior to baseline . prognostic , confounding , and stratifying variables ( see below ) were ascertained at or prior to baseline from automated records , the diabetes survey , and the 1990 census . in two separate validations of amputation procedures ( a. karter , personal communication , n = 109 ; and j.v . selby and d. zhang , n = 209 ) , 99% of electronic hospital discharge records were confirmed by chart review . using direct standardization with the entire diabetes cohort as the population standard , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . we included patients with any amputation of the lower extremity . in two separate validations of amputation procedures ( a. karter , personal communication , n = 109 ; and j.v . selby and d. zhang , n = 209 ) , 99% of electronic hospital discharge records were confirmed by chart review . using direct standardization with the entire diabetes cohort as the population standard , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . using direct standardization with the entire diabetes cohort as the population standard , we calculated age - adjusted sex- and ethnicity - specific rates for lea . proportional hazards regression ( cox ) models were then used to calculate adjusted hazard ratios ( hrs ) as an estimate of the relative risk of elevated triglycerides ( < 150 , 150199 , 200499 , and > 500 mg / dl ) associated with lea . after detecting no violations of the proportionality assumption , we specified a series of cox regression models , including a base demographic model ( age- , race- , and sex - adjusted plus an indicator for elevated triglycerides , ldl , and hdl ) and specified saturated models that added socioeconomic variables ( race , individual - level education , average census block level income , and proportion in working class occupations ) , health behaviors ( smoking status , alcohol intake , self - reported treatments for diabetes including diet and exercise , and frequency of self - monitoring of blood glucose ) , and clinical factors including type of diabetes , diabetes duration , type of diabetic medications , first - degree family history of diabetes , bmi ( underweight , normal , overweight , obese ) ( 18 ) , height quartiles ( 19,20 ) , hypertension ( self - reported and pharmacy records of antihypertensive medication dispensing ) , peripheral neuropathy ( self - report ) ( 17,21 ) , a1c ( < 7 , 78 , 810 , > 10 g / dl ) , ldl ( < 100 , 100129 , 130159 , > 160 mg / dl ) , hdl ( < 40 , 4059 , > 60 mg / dl ) , and use of statin or other lipid - lowering agents . patients who sustained an lea were older ( 61 years [ sd 11.2 ] vs. 59 years [ 11.2 ] ) , had a longer duration of diabetes ( 14 years [ 9.7 ] vs. 9 years [ 9.5 ] ) , and had a higher hemoglobin a1c ( 9.05 g / dl [ 2.12 ] vs. 8.36 g / dl [ 1.94 ] ) compared with those who did not sustain an lea ( table 1 ) . the age- and sex - adjusted nontraumatic lea incidence rate ( 95% ci ) was 2.3 ( 1.53.1 ) per 1,000 person - years ( table 2 ) . the sex - specific , age - adjusted rates ( 95% ci ) were 1.4 ( 1.21.7 ) per 1,000 person - years for women and 3.2 ( 1.64.8 ) for men . the age- and sex - adjusted incidence rates ( 95% ci ) for white , black , hispanic , and asians were 2.7 ( 1.54.0 ) , 2.0 ( 1.62.5 ) , 1.4 ( 1.11.8 ) , and 0.9 ( 0.51.3 ) , respectively . baseline characteristics for 28,701 members with diabetes experiencing incident nontraumatic leas compared with those without incident lea oha , oral hypoglycemic agent . incidence rates per 1,000 person - years ( 95% cis ) for lea procedures crude hrs for triglyceride , ldl , and hdl levels revealed a significant , stepwise relationship with triglycerides : 150199 mg / dl , hr 1.10 ( 95% ci 0.921.32 ) ; 200499 mg / dl , 1.27 ( 1.101.47 ) ; and > 500 mg / dl , 1.65 ( 1.302.10 ) ( reference < 150 mg / dl ) . minimally adjusted cox proportional hazards models including triglyceride , ldl , and hdl levels continued to demonstrate a stepwise association between triglycerides and lea risk : 150199 mg / dl , hr 1.07 ( 95% ci 0.891.29 ) ; 200499 mg / dl , 1.20 ( 1.031.40 ) ; and > 500 mg / dl , 1.39 ( 1.031.88 ) ( reference < 150 mg / dl ) . ldl was again not significantly associated with amputation risk , whereas hdl showed a protective effect between 4059 mg / dl ( hr 0.74 [ 95% ci 0.640.87 ] ) but not at > 60 mg / dl ( 1.21 [ 0.921.60 ] ) ( reference hdl < 40 mg / dl ) . a further - adjusted cox proportional hazards model ( model 1 in table 3 ) including triglycerides , ldl , hdl , age , sex , and race also revealed a stepwise association of triglycerides and lea risk . cox proportional hazards models with hrs ( 95% cis ) for nontraumatic lea model 1 : triglycerides , ldl , hdl , age , sex , and race . model 2 : model 1 + education , income , whether lives in working class neighborhood , smoking , alcohol use , bmi , height , adherence to guidelines for self - monitoring of blood glucose , exercise , statin medication , fibrate / niacin medication , family history of diabetes , duration of diabetes , a1c , type of diabetes and therapy , history of hypertension , neuropathy , retinopathy , esrd , stroke , and heart attack . the stepwise association between triglycerides and lea persisted despite further adjustment for socioeconomic ( individual - level education , average census block level income , and proportion in working class occupations ) , health behavioral ( smoking , bmi , drinking , adherence to guidelines for self - monitoring of blood glucose , and exercise ) , and clinical variables ( statin medication , fibrates / niacin medication , family history of diabetes , height , duration of diabetes , a1c , type of diabetes and therapy , hypertension , neuropathy , retinopathy , stroke , heart attack , and end - stage renal disease [ esrd ] ) ( model 2 in table 3 ) . as expected , duration of diabetes , a1c , height , hypertension , neuropathy , retinopathy , esrd , stroke , and heart attack were also associated with amputation . interestingly , statin medication use and fibrates / niacin medication use did not have statistically significant hrs . ldl > 160 mg / dl and hdl > 60 mg / dl were the only levels of these tests associated with an increased risk of amputation ; it appeared to be a threshold effect for ldl , but there was no consistent or stepwise relationship for hdl . additionally , the rates of elevated triglycerides did differ substantially by race ( 21 , 40 , 46 , and 46% among african americans , asians , whites , and hispanics , respectively ; p < 0.001 ) . however , we failed to detect a significant interaction between triglyceride level and race ( p = 0.83 ) , suggesting that the relationship between triglycerides and amputation risk did not differ by race . furthermore , similar results were seen with triglyceride level and amputation risk using the entire diabetes cohort and utilizing a missing indicator for those who did not have triglyceride levels at baseline . we also found that , as expected , there was a significant , inverse correlation between triglyceride and hdl levels ( correlation = 0.24 , p < 0.0001 ) . however , this modest collinearity was not considered sufficient to distort our triglyceride effect estimates from the cox regression models . in this large , multiethnic cohort of diabetic patients , we found that elevated triglyceride levels are associated with lea even after adjusting for a host of potential confounders . the consistency of the relationship between triglycerides and lea across ethnic groups was further supportive . this is in contrast to low hdl , which was not associated with increased amputation risk . the threshold of ldl levels above 160 mg / dl was also associated with increased risk of amputation . dyslipidemia has been proposed as a potential risk factor in the development of diabetes complications such as retinopathy and neuropathy based on results utilizing the dcct / edic cohort and the eurodiab study ( 7,22 ) . our results suggest that high triglyceride levels , independent of the other major lipid components , may put patients at risk for one major diabetes complication  lea . these results add to the finding in prior studies that elevated triglyceride levels may be a risk factor for complications of diabetes ( 5,7,8 ) , including lea ( 9,10 ) . however , the current study involved a larger population and found the association to be statistically significant even after adjusting the models for a multitude of variables that were not assessed in the prior studies . given the current state of the literature , the guidelines on triglyceride management do not advocate aggressive treatment . the national cholesterol education program recommends diet and exercise for patients with triglyceride levels between 150199 mg / dl , to consider treatment in high - risk patients with levels 200499 mg / dl , and to use pharmacologic treatment when levels are 500 mg / dl or greater to prevent pancreatitis , but not necessarily to prevent microvascular and macrovascular complications ( 23 ) . clearly , further studies are needed to ascertain the role of hypertriglyceridemia in these diabetic sequelae . our study gives further support to the notion that triglycerides may be one of the key modifiable risk factors in the development of amputations . if this association holds in clinical trials , then clinicians may have a target with the potential to improve important patient outcomes . one of the main limitations of this study is that a large proportion of our population did not have data on triglyceride , hdl , and ldl levels during the year prior to baseline ; at the time , these assessments were not done nearly as frequently or routinely as is common today . however , our sensitivity analysis using missing triglycerides as an indicator and evaluating the entire diabetes cohort suggests that missing data did not substantially bias our findings . also , observational cohort studies , particularly cross - sectional designs , can make erroneous assumptions between cause and effect when suggestive variables correlate . in our study , the longitudinal study design and exclusion of patients with prevalent amputations at baseline precludes time - ordering violations ( i.e. , lea preceding the triglyceride ascertainment ) . another limitation is that observational studies are vulnerable to residual confounding ; however , we were able to adjust for a wide array of confounders , which should greatly reduce this concern . the major strengths of this study are its longitudinal cohort design , validated and complete capture of lea events , and large sample size with rich array of clinical and behavioral data . additionally , our diabetes registry captures patients who are not treated with diabetes medications ( medical nutritional therapy ) through laboratory findings and outpatient diagnosis records , providing a more representative diabetic sample than pharmacy - based registries that only capture patients receiving prescriptions or studies from diabetes specialty clinics that typically include patients with more severe disease . in summary , elevated triglyceride level was associated with subsequent lea independently of the other lipid components and a wide range of potential confounders in this large , well - characterized diabetic cohort . though specific guidelines exist for cholesterol ( ldl and hdl levels ) management in this patient population , only vague guidelines exist for triglyceride management ( 23 ) . this observational study suggests that triglyceride levels are predictive of amputation risk in a stepwise fashion . despite standards of glycemic , blood pressure , and cholesterol control , patients continue to develop microvascular and macrovascular complications ( combination of neuropathy and macroangiopathy is thought to cause leas ) , and triglyceride control may be an important additional primary prevention effort . more research is necessary to define a causal role of triglyceride levels on amputation risk in diabetic patients . based on this current robust cohort study , such research should be a priority .
objectiveto determine the association between triglyceride levels and lower - extremity amputation ( lea ) risk in a large diabetic cohort.research design and methodsthis is a 10-year survey follow - up study ( from 19952006 ) of 28,701 diabetic patients with a baseline triglyceride measure . 
 all patients were fully insured members of the kaiser permanente medical care program and responded to a survey at baseline that included information on ethnicity , socioeconomic status , education , behavioral factors , and information required to determine type of diabetes . the relationship between triglycerides and time to incident nontraumatic lea , defined by primary hospitalization discharge or procedures , was evaluated using cox proportional hazards models.resultstriglyceride level was an independent , stepwise risk factor for nontraumatic leas within this large diabetic cohort : triglycerides 150199 mg / dl , hazard ratio ( hr ) 1.10 ( 95% ci 0.921.32 ) ; 200499 mg / dl , 1.27 ( 1.101.47 ) ; > 500 mg / dl , 1.65 ( 1.302.10 ) ( reference < 150 mg / dl).conclusionshypertriglyceridemia is a significant risk factor for lea in diabetic patients even after controlling for known socioeconomic , health behavioral , and clinical factors . 
 this previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk .