a total of 3,316 patients , who were referred for coronary angiography to ludwigshafen heart center in southwest germany , were recruited between july 1997 and january 2000 . inclusion criteria were german ancestry , clinical stability except for acute coronary syndromes , and the availability of a coronary angiogram . one of the original purposes of the study also was the identification of genetic components of coronary artery disease ( cad ) . to avoid population admixture , we aimed at including caucasians only . for pragmatic reasons , we therefore only included patients the indications for angiography in individuals in clinically stable condition were chest pain and/or noninvasive test results consistent with myocardial ischemia . individuals suffering from any acute illness other than acute coronary syndromes , chronic noncardiac diseases , or malignancy within the 5 past years and those unable to understand the purpose of the study were excluded . people with known diabetes were excluded because c - peptide levels change over the course of diabetes with a high interindividual variability and are in addition altered by different antidiabetic drugs . moreover , a long duration of type 2 diabetes confers increased cardiovascular risk , thus being an additional potential confounder . moreover , subjects with missing data on fasting c - peptide were additionally ruled out , resulting in a subgroup of 2,306 ( 69.5% ) of 3,316 ludwigshafen risk and cardiovascular health ( luric ) study participants for the present analyses . these subjects were excluded when the associations of c - peptide with cardiovascular mortality were analyzed . the study was approved by the ethics committee at the rztekammer rheinland - pfalz and was conducted in accordance with the declaration of helsinki . diabetes was diagnosed according to the 2010 guidelines of the american diabetes association ( 15 ) . fasting glucose , postchallenge glucose ( performed in 1,524 of 2,096 participants with fasting glucose < 126 mg / dl ) , and glycated hemoglobin were used to categorize diabetes . hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mmhg or if there was a history of hypertension , evident through the use of antihypertensive drugs . acute myocardial infarction ( mi ) was defined as an mi that had occurred within the 4 weeks prior to enrollment . a definite st elevation mi ( stemi ) was diagnosed if typical electrocardiogram changes were present along with prolonged chest pain , refractory to sublingual nitrates , and/or enzyme or troponin t elevations ( > 0.1 g / l ) . non - stemi was diagnosed if symptoms and/or troponin t criteria , but not the electrocardiogram criteria for stemi , were met . cerebrovascular disease was defined clinically by documented history of a previous cerebrovascular disease event ( transient ischemic attack , prolonged ischemic neurologic deficit , and cerebral infarction with or without a remaining neurologic deficit ) or by documented carotid plaques ( 50% luminal obstruction ) . peripheral vascular disease was defined by a history of intermittent claudication , angiographic documentation of atherosclerotic luminal obstruction of the peripheral arteries , or a history of a peripheral arterial intervention for atherosclerotic disease ( angioplasty or surgery ) . we formed three groups : group 0 ( 0 score points ) , group 1 ( 1 score point ) , and group 2 ( 2 score points ) ( 17 ) . a questionnaire with a scoring system ranging from 1 , sedentary ( avoid walking or exertion ) , to 11 , regular heavy exercise , was used to classify the mean physical activity . the study participants were grouped into the following three categories of physical activity : below average ( scores 13 ) , average ( scores 47 ) , and above average ( scores 811 ) . there was a follow - up for all - cause and cardiovascular mortality ; the latter defined as mortality due to cardiovascular diseases ( icd-9 codes 390448 and icd-10 codes i00i79 ) . the mean (  sd ) duration of the follow - up was 7.6  2.1 years . they were blinded to any data of the study participants . in cases of a disagreement or uncertainty concerning the coding of a specific cause of death , classification was made by a principal investigator of the luric study ( w.m . ) . c - peptide was measured with an enzyme immunoassay ( aia - pack c - peptide ) on an aia 1200 analyzer ( eurogenetics , eschborn , germany ) . glucose was measured enzymatically on a hitachi 717 analyzer ( roche , mannheim , germany ) . insulin was analyzed with an immunoenzymometric assay ( aia pack iri ) on an aia 1200 analyzer ( eurogenetics ) . glycated hemoglobin was measured with an immunoassay ( hemoglobin a1c unimate 5 ; hoffmann - laroche , grenzach - whylen , germany ) . precipitation method and measured on a wako 30 r analyzer ( wako chemicals gmbh , neuss , germany ) . triglycerides were quantified with an enzymatic assay on a hitachi 717 analyzer ( roche ) . creatinine was measured with the jaff method on a hitachi 717 analyzer ( roche ) ( 18 ) . the baseline characteristics are reported as numbers and percentages in cases of categorical variables and as means with sd or medians with interquartile ranges in cases of continuous variables . comparisons among the three groups were made with the  test and with anova for categorical and continuous data , respectively . triglyceride and insulin levels ( shapiro - wilk w test ) were transformed logarithmically before being used in parametric statistical procedures . kaplan - meier curves were plotted for the relationships of c - peptide with all - cause and cardiovascular mortality . the cox proportional hazards model was used to perform multivariate analyses for the associations among the tertiles of c - peptide and mortality data . three predefined models of adjustment ( model 1 : adjusted for sex and age ; model 2 : adjusted for sex , age , bmi , hypertension , smoking , glomerular filtration rate [ gfr ] , triglycerides , ldl cholesterol , and hdl cholesterol ; and model 3 : model 2 with additional adjustment for fasting glucose , fasting insulin , hba1c , newly diagnosed diabetes , proinsulin , free fatty acids , free glycerol , as well as c - reactive protein ) were used . z - transformation was performed to investigate the increase in risk of all - cause and cardiovascular mortality conferred by sd of c - peptide levels included as a continuous variable . all statistical tests were two - sided , and p values < 0.05 were considered significant . the spss 15.0 statistical package ( spss inc . , a total of 3,316 patients , who were referred for coronary angiography to ludwigshafen heart center in southwest germany , were recruited between july 1997 and january 2000 . inclusion criteria were german ancestry , clinical stability except for acute coronary syndromes , and the availability of a coronary angiogram . one of the original purposes of the study also was the identification of genetic components of coronary artery disease ( cad ) . to avoid population admixture , we aimed at including caucasians only . for pragmatic reasons , we therefore only included patients the indications for angiography in individuals in clinically stable condition were chest pain and/or noninvasive test results consistent with myocardial ischemia . individuals suffering from any acute illness other than acute coronary syndromes , chronic noncardiac diseases , or malignancy within the 5 past years and those unable to understand the purpose of the study were excluded . people with known diabetes were excluded because c - peptide levels change over the course of diabetes with a high interindividual variability and are in addition altered by different antidiabetic drugs . moreover , a long duration of type 2 diabetes confers increased cardiovascular risk , thus being an additional potential confounder . moreover , subjects with missing data on fasting c - peptide were additionally ruled out , resulting in a subgroup of 2,306 ( 69.5% ) of 3,316 ludwigshafen risk and cardiovascular health ( luric ) study participants for the present analyses . these subjects were excluded when the associations of c - peptide with cardiovascular mortality were analyzed . the study was approved by the ethics committee at the rztekammer rheinland - pfalz and was conducted in accordance with the declaration of helsinki . diabetes was diagnosed according to the 2010 guidelines of the american diabetes association ( 15 ) . fasting glucose , postchallenge glucose ( performed in 1,524 of 2,096 participants with fasting glucose < 126 mg / dl ) , and glycated hemoglobin were used to categorize diabetes . hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mmhg or if there was a history of hypertension , evident through the use of antihypertensive drugs . acute myocardial infarction ( mi ) was defined as an mi that had occurred within the 4 weeks prior to enrollment . a definite st elevation mi ( stemi ) was diagnosed if typical electrocardiogram changes were present along with prolonged chest pain , refractory to sublingual nitrates , and/or enzyme or troponin t elevations ( > 0.1 g / l ) . non - stemi was diagnosed if symptoms and/or troponin t criteria , but not the electrocardiogram criteria for stemi , were met . cerebrovascular disease was defined clinically by documented history of a previous cerebrovascular disease event ( transient ischemic attack , prolonged ischemic neurologic deficit , and cerebral infarction with or without a remaining neurologic deficit ) or by documented carotid plaques ( 50% luminal obstruction ) . peripheral vascular disease was defined by a history of intermittent claudication , angiographic documentation of atherosclerotic luminal obstruction of the peripheral arteries , or a history of a peripheral arterial intervention for atherosclerotic disease ( angioplasty or surgery ) . we formed three groups : group 0 ( 0 score points ) , group 1 ( 1 score point ) , and group 2 ( 2 score points ) ( 17 ) . a questionnaire with a scoring system ranging from 1 , sedentary ( avoid walking or exertion ) , to 11 , regular heavy exercise , was used to classify the mean physical activity . the study participants were grouped into the following three categories of physical activity : below average ( scores 13 ) , average ( scores 47 ) , and above average ( scores 811 ) . a questionnaire with a scoring system ranging from 1 , sedentary ( avoid walking or exertion ) , to 11 , regular heavy exercise , was used to classify the mean physical activity . the study participants were grouped into the following three categories of physical activity : below average ( scores 13 ) , average ( scores 47 ) , and above average ( scores 811 ) . there was a follow - up for all - cause and cardiovascular mortality ; the latter defined as mortality due to cardiovascular diseases ( icd-9 codes 390448 and icd-10 codes i00i79 ) . the mean (  sd ) duration of the follow - up was 7.6  2.1 years . they were blinded to any data of the study participants . in cases of a disagreement or uncertainty concerning the coding of a specific cause of death , classification was made by a principal investigator of the luric study ( w.m . ) . c - peptide was measured with an enzyme immunoassay ( aia - pack c - peptide ) on an aia 1200 analyzer ( eurogenetics , eschborn , germany ) . glucose was measured enzymatically on a hitachi 717 analyzer ( roche , mannheim , germany ) . insulin was analyzed with an immunoenzymometric assay ( aia pack iri ) on an aia 1200 analyzer ( eurogenetics ) . glycated hemoglobin was measured with an immunoassay ( hemoglobin a1c unimate 5 ; hoffmann - laroche , grenzach - whylen , germany ) . lipoproteins were separated using a combined ultracentrifugation  precipitation method and measured on a wako 30 r analyzer ( wako chemicals gmbh , neuss , germany ) . triglycerides were quantified with an enzymatic assay on a hitachi 717 analyzer ( roche ) . creatinine was measured with the jaff method on a hitachi 717 analyzer ( roche ) ( 18 ) . the baseline characteristics are reported as numbers and percentages in cases of categorical variables and as means with sd or medians with interquartile ranges in cases of continuous variables . comparisons among the three groups were made with the  test and with anova for categorical and continuous data , respectively . triglyceride and insulin levels ( shapiro - wilk w test ) were transformed logarithmically before being used in parametric statistical procedures . kaplan - meier curves were plotted for the relationships of c - peptide with all - cause and cardiovascular mortality . the cox proportional hazards model was used to perform multivariate analyses for the associations among the tertiles of c - peptide and mortality data . three predefined models of adjustment ( model 1 : adjusted for sex and age ; model 2 : adjusted for sex , age , bmi , hypertension , smoking , glomerular filtration rate [ gfr ] , triglycerides , ldl cholesterol , and hdl cholesterol ; and model 3 : model 2 with additional adjustment for fasting glucose , fasting insulin , hba1c , newly diagnosed diabetes , proinsulin , free fatty acids , free glycerol , as well as c - reactive protein ) were used . z - transformation was performed to investigate the increase in risk of all - cause and cardiovascular mortality conferred by sd of c - peptide levels included as a continuous variable . all statistical tests were two - sided , and p values < 0.05 were considered significant . the spss 15.0 statistical package ( spss inc . , chicago , il ) was used . clinical and laboratory baseline characteristics according to c - peptide tertiles are shown in table 1 . in the overall population analyzed , persons in the highest c - peptide tertile had a significantly higher prevalence of cad than subjects in the lower tertiles ( 71.8 vs. 63.1 vs. 63.3% , respectively ) . in addition , persons in the highest c - peptide tertile exhibited significantly higher bmi , waist circumference , fasting glucose , fasting insulin , triglycerides , c - reactive protein , and had lower ldl cholesterol levels as well as a lower gfr . moreover , subjects in the highest tertile had more often newly diagnosed type 2 diabetes , systemic hypertension , high comorbidity , and a lower level of physical activity . the proportion of past and current smokers and the use of ace inhibitors , calcium antagonists , and diuretics were significantly higher in patients with higher c - peptide levels ( table 1 ) . baseline characteristics according to tertile of fasting c - peptide because experimental data suggest that c - peptide may be causally involved in early atherogenesis , we analyzed the association of c - peptide with biochemical markers of endothelial dysfunction and atherosclerosis . subjects in the highest c - peptide tertile exhibited significantly higher levels of intracellular adhesion molecule ( icam)-1 , vascular cell adhesion molecule ( vcam)-1 , p - selectin , and e - selectin , as well as lipoprotein - associated phospholipase a2 ( lppla2 ) ( table 2 ) . moreover , history of mi , peripheral vascular disease , and cerebrovascular disease were more frequent in subjects with high c - peptide levels ( table 1 ) . in accordance , the proportion of subjects with prevalent clinical and angiographic cad ( table 1 ) as well as lesion extension as assessed by the friesinger score increased in parallel with the c - peptide tertiles ( table 2 ) . furthermore , cardiac insufficiency as reflected by high new york heart association functional class was more frequent in subjects with high c - peptide levels ( table 1 ) . taken together , these data underscore the hypothesis that c - peptide could play a direct role in the development of arteriosclerosis . markers of atherosclerosis and friesinger score according to tertile of fasting c - peptide all - cause mortality and causes of death are shown in supplementary table 1 . in 14 subjects , we did not obtain sufficient information to classify their cause of death and therefore only included them in the analyses of all - cause mortality and excluded them from further analyses . among the 2,306 patients without known diabetes and available c - peptide levels , 440 deaths ( 19.1% ) occurred during a mean follow - up of 7.6 years . compared with subjects in the lowest tertile , the age- and sex - adjusted hazard ratio ( hr ) for death was 1.46 ( 95% ci 1.151.85 ; p = 0.002 ) in the highest tertile ( table 3 ) . further adjustment for bmi , hypertension , smoking , gfr , triglycerides , ldl cholesterol , and hdl cholesterol did not influence the prognostic value of c - peptide in the highest tertile , resulting in an hr of 1.49 ( 1.161.91 ; p = 0.002 ) compared with the lowest tertile ( table 3 , model 2 ) . additional adjustment for fasting glucose , fasting insulin , hba1c , newly diagnosed diabetes , proinsulin , free fatty acids , free glycerol , as well as c - reactive protein had only minor influence on the hr of 1.46 ( 1.101.93 ; p = 0.008 ) ( table 3 , model 3 ) . c - peptide levels included as continuous variable increased the risk in all - cause mortality per sd by hr 1.12 ( 1.051.20 , p = 0.001 ; model 1 ) . the association remained unchanged after adjustment for cardiovascular risk factors , hr 1.12 ( 1.041.20 ; p = 0.002 ; model 2 ) , and after full adjustment in model 3 , hr 1.13 ( 1.041.22 ; p = 0.005 ) . mortality according to tertile of fasting c - peptide among the 2,292 subjects with known causes of death , 252 ( 10.9% ) died of cardiovascular causes , 26 ( 1.1% ) of infection , 76 ( 3.3% ) of cancer , and 72 ( 3.1% ) of miscellaneous causes . compared with the lowest c - peptide tertile , the age- and sex - adjusted hr for cardiovascular death was 1.58 ( 95% ci 1.152.18 ; p = 0.005 ) ( table 3 ) . after full adjustment ( model 3 ) , the prognostic value of c - peptide in the highest compared with the lowest tertile was still significant , with an hr of 1.55 ( 1.072.24 ; p = 0.022 ) . c - peptide levels included as continuous variable increased the risk in cardiovascular mortality per sd by hr 1.16 ( 95% ci 1.071.26 ; p < 0.001 ; model 1 ) . the association remained unchanged after adjustment for cardiovascular risk factors , hr 1.15 ( 1.051.25 ; p = 0.002 ; model 2 ) , and after full adjustment in model 3 , hr 1.16 ( 1.051.28 ; p = 0.004 ) . kaplan - meier curves followed by a log - rank test showed that all - cause mortality ( fig . 1b ) significantly increased in the higher c - peptide tertiles ( p = 0.006 and p = 0.012 , respectively ) . a : kaplan - meier curves for all - cause mortality according to tertile ( 13 ) of fasting c - peptide b : kaplan - meier curves for cardiovascular mortality according to tertile ( 13 ) of fasting c - peptide . clinical and laboratory baseline characteristics according to c - peptide tertiles are shown in table 1 . in the overall population analyzed , persons in the highest c - peptide tertile had a significantly higher prevalence of cad than subjects in the lower tertiles ( 71.8 vs. 63.1 vs. 63.3% , respectively ) . in addition , persons in the highest c - peptide tertile exhibited significantly higher bmi , waist circumference , fasting glucose , fasting insulin , triglycerides , c - reactive protein , and had lower ldl cholesterol levels as well as a lower gfr . moreover , subjects in the highest tertile had more often newly diagnosed type 2 diabetes , systemic hypertension , high comorbidity , and a lower level of physical activity . the proportion of past and current smokers and the use of ace inhibitors , calcium antagonists , and diuretics were significantly higher in patients with higher c - peptide levels ( table 1 ) . because experimental data suggest that c - peptide may be causally involved in early atherogenesis , we analyzed the association of c - peptide with biochemical markers of endothelial dysfunction and atherosclerosis . subjects in the highest c - peptide tertile exhibited significantly higher levels of intracellular adhesion molecule ( icam)-1 , vascular cell adhesion molecule ( vcam)-1 , p - selectin , and e - selectin , as well as lipoprotein - associated phospholipase a2 ( lppla2 ) ( table 2 ) . moreover , history of mi , peripheral vascular disease , and cerebrovascular disease were more frequent in subjects with high c - peptide levels ( table 1 ) . in accordance , the proportion of subjects with prevalent clinical and angiographic cad ( table 1 ) as well as lesion extension as assessed by the friesinger score increased in parallel with the c - peptide tertiles ( table 2 ) . furthermore , cardiac insufficiency as reflected by high new york heart association functional class was more frequent in subjects with high c - peptide levels ( table 1 ) . taken together , these data underscore the hypothesis that c - peptide could play a direct role in the development of arteriosclerosis . all - cause mortality and causes of death are shown in supplementary table 1 . in 14 subjects , we did not obtain sufficient information to classify their cause of death and therefore only included them in the analyses of all - cause mortality and excluded them from further analyses . among the 2,306 patients without known diabetes and available c - peptide levels , 440 deaths ( 19.1% ) occurred during a mean follow - up of 7.6 years . compared with subjects in the lowest tertile , the age- and sex - adjusted hazard ratio ( hr ) for death was 1.46 ( 95% ci 1.151.85 ; p = 0.002 ) in the highest tertile ( table 3 ) . further adjustment for bmi , hypertension , smoking , gfr , triglycerides , ldl cholesterol , and hdl cholesterol did not influence the prognostic value of c - peptide in the highest tertile , resulting in an hr of 1.49 ( 1.161.91 ; p = 0.002 ) compared with the lowest tertile ( table 3 , model 2 ) . additional adjustment for fasting glucose , fasting insulin , hba1c , newly diagnosed diabetes , proinsulin , free fatty acids , free glycerol , as well as c - reactive protein had only minor influence on the hr of 1.46 ( 1.101.93 ; p = 0.008 ) ( table 3 , model 3 ) . c - peptide levels included as continuous variable increased the risk in all - cause mortality per sd by hr 1.12 ( 1.051.20 , p = 0.001 ; model 1 ) . the association remained unchanged after adjustment for cardiovascular risk factors , hr 1.12 ( 1.041.20 ; p = 0.002 ; model 2 ) , and after full adjustment in model 3 , hr 1.13 ( 1.041.22 ; p = 0.005 ) . among the 2,292 subjects with known causes of death , 252 ( 10.9% ) died of cardiovascular causes , 26 ( 1.1% ) of infection , 76 ( 3.3% ) of cancer , and 72 ( 3.1% ) of miscellaneous causes . compared with the lowest c - peptide tertile , the age- and sex - adjusted hr for cardiovascular death was 1.58 ( 95% ci 1.152.18 ; p = 0.005 ) ( table 3 ) . after full adjustment ( model 3 ) , the prognostic value of c - peptide in the highest compared with the lowest tertile was still significant , with an hr of 1.55 ( 1.072.24 ; p = 0.022 ) . c - peptide levels included as continuous variable increased the risk in cardiovascular mortality per sd by hr 1.16 ( 95% ci 1.071.26 ; p < 0.001 ; model 1 ) . the association remained unchanged after adjustment for cardiovascular risk factors , hr 1.15 ( 1.051.25 ; p = 0.002 ; model 2 ) , and after full adjustment in model 3 , hr 1.16 ( 1.051.28 ; p = 0.004 ) . kaplan - meier curves followed by a log - rank test showed that all - cause mortality ( fig . 1b ) significantly increased in the higher c - peptide tertiles ( p = 0.006 and p = 0.012 , respectively ) . a : kaplan - meier curves for all - cause mortality according to tertile ( 13 ) of fasting c - peptide . b : kaplan - meier curves for cardiovascular mortality according to tertile ( 13 ) of fasting c - peptide . the current study demonstrates that levels of the proinsulin cleavage product c - peptide are independently associated with all - cause mortality and cardiovascular mortality in a large cohort of patients referred to coronary angiography . moreover , c - peptide was associated with prevalent cad , and the severity of angiographic changes increased with c - peptide levels . the association of c - peptide with mortality as well as cardiovascular mortality remained significant even after full adjustment including bmi , fasting glucose , fasting insulin , hba1c , proinsulin , free fatty acids , free glycerol , high - sensitivity c - reactive protein , and gfr , as well as newly diagnosed diabetes . elevated levels of the proinsulin cleavage product c - peptide have been found in patients with insulin resistance , early type 2 diabetes , as well as those with chronic kidney disease . measurement of c - peptide levels has been used as a surrogate for insulin secretion ( e.g. , in obese patients with insulin resistance ) ( 19 ) . in this context , the association of c - peptide with cardiovascular mortality could simply reflect the increased risk of patients with insulin resistance and early type 2 diabetes in our population . indeed , subjects in the highest tertile of c - peptide had higher fasting glucose , higher fasting insulin , a higher bmi , as well as a higher prevalence of newly diagnosed diabetes . however , adjustment for all of these factors did basically not change the hr for cardiovascular mortality as well as overall mortality , suggesting that c - peptide is an independent risk factor in our study population . to the best of our knowledge , this is the first study to demonstrate that c - peptide is associated with mortality and cardiovascular mortality in patients without previously known diabetes . various studies have shown that elevated c - peptide levels are associated with mortality as well as cardiovascular mortality in patients with diabetes and nondiabetic cancer patients , most likely serving as an indirect marker for obesity , insulin resistance , and undiagnosed diabetes ( 12,13 ) . various data from in vitro as well as animal models have shown proatherogenic effects of c - peptide ( 1,7,20 ) . our data , demonstrating an association of c - peptide levels with markers of endothelial activation such as icam-1 , vcam-1 , and e - selectin , as well as a highly significant association with levels of lppla2 , a novel marker of arteriosclerosis , raise the question if c - peptide could potentially also directly influence atherogenesis in humans , but our data can not prove a causal relationship . furthermore , patients in the highest tertile of c - peptide had the highest incidence of cad and the most severe lesion extension as assessed by the friesinger score , underscoring the hypothesis that c - peptide may play a role in the pathophysiology of cad . still , our study can not prove causality , and further research is warranted to address this question . of note , therapeutic application of c - peptide in patients with type 1 diabetes , lacking endogenous c - peptide , exhibits beneficial effects on microvascular complications such as neuropathy ( 4 ) , suggesting different mechanisms of action of exogenous c - peptide in c - peptide  deprived patients and those with elevated endogenous c - peptide levels . our study has some limitations : the results obtained in this study apply only to a highly selected caucasian patient population undergoing coronary angiography without other major noncardiac diseases or malignancies . therefore , the results may not be generalizable to other populations with younger age , other ethnicity , or other underlying diseases . moreover , each of the study participants coronary angiography was clinically indicated , which may have produced referral bias . finally , despite the fact that we adjusted our results for multiple potential confounders , we can not rule out additional factors . taken together , our study suggests that elevated levels of c - peptide are predictive of both all - cause as well as cardiovascular mortality in patients undergoing coronary angiography and raises the hypothesis that c - peptide could potentially play a causal role in atherogenesis in humans . however , future research has to prove causality and examine the underlying mechanism for the findings of this study .
objectivec - peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin , and elevated levels of c - peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus . 
 recent data suggest that c - peptide could play a causal role in the pathophysiology of vascular disease , but nothing is known about the prognostic value of c - peptide concentrations in the circulation.research design and methodswe examined whether c - peptide is associated with cardiovascular and total mortality in 2,306 patients from the ludwigshafen risk and cardiovascular health study who underwent coronary angiography at baseline ( 19972000).resultsduring a mean follow - up of 7.6 years , 440 deaths ( 19.1% ) occurred , 252 ( 10.9% ) of which were due to cardiovascular causes . 
 age- and sex - adjusted hazard ratios ( hrs ) in the third compared with the first tertile of c - peptide were 1.46 ( 95% ci 1.151.85 ; p = 0.002 ) for all cause and 1.58 ( 1.152.18 ; p = 0.005 ) for cardiovascular mortality . 
 after further adjustment for common risk factors as well as markers of glucose metabolism , these hrs remained significant at 1.46 ( 1.101.93 ; p = 0.008 ) and 1.55 ( 1.072.24 ; p = 0.022 ) , respectively . 
 moreover , patients in higher tertiles of c - peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions.conclusionsin patients undergoing coronary angiography , c - peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease . 
 further studies are needed to examine a potential causal role of c - peptide in atherogenesis in humans .