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AIMS: To examine the association of HbA1c and glucose levels with incident diabetic retinopathy according to black African or white European ancestry. METHODS: In this retrospective cohort study of 202 500 US Veterans with diabetes (2000-2014), measures included HbA1c , outpatient random serum/plasma glucose, and incident retinopathy [conversion from negative to ≥2 positive evaluations (ICD-9 codes), without a subsequent negative]. RESULTS: At baseline, the study population had a mean age of 59.3 years, their mean BMI was 31.9 kg/m2 , HbA1c level was 57 mmol/mol (7.4%) and glucose level was 8.8 mmol/l, and 77% were of white European ancestry (white individuals) and 21% of black African ancestry (black individuals). HbA1c was 0.3% higher in black vs white individuals (P < 0.001), adjusting for baseline age, sex, BMI, estimated glomerular filtration rate (eGFR), haemoglobin, and average systolic blood pressure and glucose. Over 11 years, incident retinopathy occurred in 9% of black and 7% of white individuals, but black individuals had higher HbA1c , glucose, and systolic blood pressure (all P < 0.001); adjusted for these factors, incident retinopathy was reduced in black vs white individuals (P < 0.001). The population incidence of retinopathy (7%) was associated with higher mean baseline HbA1c in individuals with black vs white ancestry [63 mmol/mol (7.9%) vs 58 mmol/mol (7.5%); P < 0.001)], but with similar baseline glucose levels (9.0 vs 9.0 mmol/l; P = 0.660, all adjusted for baseline age, sex and BMI). CONCLUSIONS: Since retinopathy occurs at higher HbA1c levels in black people for a given level of average plasma glucose, strategies may be needed to individualize the interpretation of HbA1c measurements.

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AIMS: To determine whether HbA1c mismatches (HbA1c levels that are higher or lower than expected for the average glucose levels in different individuals) could lead to errors if diagnostic classification is based only on HbA1c levels. METHODS: In a cross-sectional study, 3106 participants without known diabetes underwent a 75-g oral glucose tolerance test (fasting glucose and 2-h glucose) and a 50-g glucose challenge test (1-h glucose) on separate days. They were classified by oral glucose tolerance test results as having: normal glucose metabolism; prediabetes; or diabetes. Predicted HbA1c was determined from the linear regression modelling the relationship between observed HbA1c and average glucose (mean of fasting glucose and 2-h glucose from the oral glucose tolerance test, and 1-h glucose from the glucose challenge test) within oral glucose tolerance test groups. The haemoglobin glycation index was calculated as [observed - predicted HbA1c ], and divided into low, intermediate and high haemoglobin glycation index mismatch tertiles. RESULTS: Those participants with higher mismatches were more likely to be black, to be men, to be older, and to have higher BMI (all P<0.001). Using oral glucose tolerance test criteria, the distribution of normal glucose metabolism, prediabetes and diabetes was similar across mismatch tertiles; however, using HbA1c criteria, the participants with low mismatches were classified as 97% normal glucose metabolism, 3% prediabetes and 0% diabetes, i.e. mostly normal, while those with high mismatches were classified as 13% normal glucose metabolism, 77% prediabetes and 10% diabetes, i.e. mostly abnormal (P<0.001). CONCLUSIONS: Measuring only HbA1c could lead to under-diagnosis in people with low mismatches and over-diagnosis in those with high mismatches. Additional oral glucose tolerance tests and/or fasting glucose testing to complement HbA1c in diagnostic classification should be performed in most individuals.

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AIM: To characterize differences between black and white people in optimal HbA1c thresholds for diagnoses of diabetes and prediabetes. METHODS: Data were included from the National Health and Nutrition Examination Survey, 2005-2014. Black and white adults (age 18-70 years) who underwent an oral glucose tolerance test and had available fasting plasma glucose, 2-h plasma glucose and HbA1c measurements were eligible for inclusion. Diabetes or prediabetes status was defined by fasting plasma glucose and 2-h plasma glucose using American Diabetes Association criteria. Classification of diabetes, prediabetes and dysglycaemia by HbA1c was evaluated for a range of HbA1c thresholds, with optimal thresholds defined as those values that maximized the sum of sensitivity and specificity (Youden's index). RESULTS: In 5324 black (32.3%) and white (67.7%) individuals, Youden's index (optimal) thresholds for HbA1c were ≥42 mmol/mol (6.0%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs non-diabetes, ≥ 44 mmol/mol (6.2%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs prediabetes (excluding normoglycaemia), ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating dysglycaemia vs normoglycaemia, and ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating prediabetes vs normoglycaemia (excluding diabetes), in black and white people, respectively. CONCLUSIONS: Consistently higher optimal HbA1c thresholds in black people than in white people suggest a need to individualize HbA1c relative to glucose levels if HbA1c is used to diagnose diabetes and prediabetes.

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OBJECTIVE: Familial hypercholesterolemia (FH) is a genetic disease with very high levels of circulating low density lipoprotein cholesterol (LDL-C) levels that leads to accelerated atherosclerosis. Lipoprotein apheresis is an effective treatment option for patients with FH and results in reduced cardiovascular morbidity and mortality. Circulating progenitor cells (CPCs) are markers of overall vascular health and diminished levels have been associated with decreased reparative potential and worse outcomes. We assessed the short-term change in CPC levels following a single lipoprotein apheresis session in FH patients who are already on stable lipoprotein apheresis therapy. We hypothesized that in addition to a reduction in atherogenic lipids, the cardiovascular benefit from lipoprotein apheresis therapy is mediated by enhanced vascular reparative capacity through mobilization of CPCs. METHODS: Eight FH patients (1 homozygous and 7 heterozygous) on stable lipoprotein apheresis therapy for at least three months had CPCs measured at baseline (prior to apheresis) and two hours after apheresis. Results were compared with data from age-matched hyperlipidemic (HLP) patients on statin therapy and healthy volunteers. RESULTS: FH patients had higher baseline circulating levels of CD34+/CD133+ and CD34+/CD133+/CXCR4+ cells compared to HLP and healthy subjects. There was no significant change in CPCs after apheresis in FH patients. CONCLUSIONS: FH patients had higher CPC counts at baseline compared to age-matched HLP and healthy controls, suggesting activation of reparative mechanism in this high risk population. Larger studies are needed to better characterize differences in CPC counts between FH subjects and HLP patients over time.

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AIMS: To test the hypothesis that a 50-g oral glucose challenge test with 1-h glucose measurement would have superior performance compared with other opportunistic screening methods. METHODS: In this prospective study in a Veterans Health Administration primary care clinic, the following test performances, measured by area under receiver-operating characteristic curves, were compared: 50-g oral glucose challenge test; random glucose; and HbA1c level, using a 75-g oral glucose tolerance test as the 'gold standard'. RESULTS: The study population was comprised of 1535 people (mean age 56 years, BMI 30.3 kg/m2 , 94% men, 74% black). By oral glucose tolerance test criteria, diabetes was present in 10% and high-risk prediabetes was present in 22% of participants. The plasma glucose challenge test provided area under receiver-operating characteristic curves of 0.85 (95% CI 0.78-0.91) to detect diabetes and 0.76 (95% CI 0.72-0.80) to detect high-risk dysglycaemia (diabetes or high-risk prediabetes), while area under receiver-operating characteristic curves for the capillary glucose challenge test were 0.82 (95% CI 0.75-0.89) and 0.73 (95% CI 0.69-0.77) for diabetes and high-risk dysglycaemia, respectively. Random glucose performed less well [plasma: 0.76 (95% CI 0.69-0.82) and 0.66 (95% CI 0.62-0.71), respectively; capillary: 0.72 (95% CI 0.65-0.80) and 0.64 (95% CI 0.59-0.68), respectively], and HbA1c performed even less well [0.67 (95% CI 0.57-0.76) and 0.63 (95% CI 0.58-0.68), respectively]. The cost of identifying one case of high-risk dysglycaemia with a plasma glucose challenge test would be $42 from a Veterans Health Administration perspective, and $55 from a US Medicare perspective. CONCLUSIONS: Glucose challenge test screening, followed, if abnormal, by an oral glucose tolerance test, would be convenient and more accurate than other opportunistic tests. Use of glucose challenge test screening could improve management by permitting earlier therapy.

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INTRODUCTION: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. METHODS: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. RESULTS: PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113). CONCLUSION: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.

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AIMS/HYPOTHESIS: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. METHODS: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR). RESULTS: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18). CONCLUSIONS/INTERPRETATION: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

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OBJECTIVE: To clarify the differences in the baseline characteristics, prevalence and incidence of atherothrombosis in patients recruited from Asia versus non-Asian regions. DESIGN: International Prospective Cohort Study. SETTING: Region focused substudy. PATIENTS: The Reduction of Atherothrombosis for Continued Health (REACH) Registry recruited 68 236 stable outpatients with established atherothrombosis or ≥3 atherothrombotic risk factors from 44 countries. INTERVENTIONS: No intervention. MAIN OUTCOME MEASURES: Risk factors, use of medications, vascular disease bed location, and 1-year cardiovascular (CV) outcomes (CV death, myocardial infarction, stroke). RESULTS: The percentages of patients recruited with CVD (Cerebrovascular Disease) were higher in Asia (41.0%) than in non-Asian regions (25.1%) (p<0.0001). The prevalence of diabetes mellitus was higher in Asia (46.6%) than in non-Asian regions (43.3%) (p<0.0001) despite the former having a lower body mass index (BMI) (24.4±3.9 vs 28.8±5.6) (p<0.0001). The combined endpoint of CV death/myocardial infarction/stroke of patients recruited from non-Asian regions of 4.38% (95% CI 4.20 to 4.56) is equivalent to those from the Asian region excluding Japan of 4.65% (95% CI 4.04 to 5.25), but that is significantly lower in patients recruited from Japan of 3.40% (95% CI 2.76 to 4.04, p<0.05). CONCLUSIONS: There is a higher prevalence of CVD and higher prevalence of diabetus mellitus with lower body mass index in patients recruited from the Asian region as compared those recruited from non-Asian regions. The CV event rate in patients recruited from non-Asian regions is equivalent to that of patients recruited from the Asian region excluding Japan, but significantly lower in patients recruited from Japan.

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One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

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OBJECTIVE: To review published data on vascular disease- and diabetes-related outcomes related to adiposity and metabolic risk factors. DESIGN: Community cohort study with cross-sectional and prospective data. SUBJECTS: Middle-aged Caucasian adults in a suburban environment. MEASUREMENTS: Traditional risk factors for cardiovascular disease and the type 2 diabetes mellitus, as well as measures of insulin resistance, left ventricular hypertrophy and vascular calcification. RESULTS: The cardiometabolic risk factors cluster in the population and a common core that includes adiposity (both waist and body mass index), abnormal lipids (both HDL cholesterol and triglycerides), and abnormal glucose and insulin metabolism was found to be present in Framingham participants. Increased insulin resistance was also found to be associated with coronary artery calcification and left ventricular hypertrophy in women. Analyses of the metabolic syndrome risk factors showed that a greater burden of risk factors was associated with greater risk of both cardiovascular disease and diabetes mellitus. An equation to estimate risk of developing type 2 diabetes mellitus has been developed from the Framingham experience, and the risk factors included in the metabolic syndrome are key components, including increased waist girth, elevated blood pressure, low HDL cholesterol, high triglycerides and impaired fasting glucose. CONCLUSION: Cardiometabolic factors and insulin resistance are important contributors to the development of type 2 diabetes mellitus, subclinical cardiovascular disease and clinical cardiovascular disease.

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OBJECTIVE: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. METHODS: Serum 17beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. RESULTS: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (> or =125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. CONCLUSIONS: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

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Bony proliferation (exostoses) and vascular calcification are common in elderly men and women, but it is unclear whether they have a common etiology. Lateral lumbar and hand radiographs were obtained (1967-1970) in 777 men and 1,241 women (mean age 59, range 47-80 years) from the Framingham Heart Study. Each group of hand exostoses, specifically apiostoses (tufting), enthesophytes, and osteophytes, was graded on a scale of 0-3 (absent to severe) and summed across phalanges of digits 2-5. Anterior lumbar osteophytes were assessed in intervertebral spaces T12-L5 and abdominal aortic calcification (AAC) at lumbar segments L1-L4. Information on age, sex, body mass index, smoking, alcohol consumption, physical activity, systolic blood pressure, total cholesterol level, diabetes, and estrogen replacement therapy in women was obtained at the time of radiography and adjusted for in multivariate analyses. We used multivariable logistic regression models to assess the relationship between AAC (dependent variable) and exostoses for each sex. Multivariable adjusted logistic regression revealed a significant association between increased anterior lumbar osteophytes and prevalent AAC in men [odds ratio (OR) = 1.20, 95% confidence interval (CI) 1.1-1.3 per unit increase in osteophytes] and in women (OR = 1.25, 95% CI 1.1-1.4). There also was an inverse association between enthesophytes and AAC in women only (OR = 0.82, 95% CI 0.73-0.92). Apiostoses were weakly associated with AAC in men only. Hand osteophytes were not associated with AAC. In conclusion, in this cross-sectional study, anterior lumbar osteophytes and AAC occurred in the same individuals after adjustment for age and other covariates. In general, hand exostoses were not associated with aortic calcification.

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CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

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AIMS/HYPOTHESIS: We evaluated the -174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis. METHODS: We tested for associations between the -174 IL-6 G/C promoter polymorphism and fasting plasma glucose (FPG) and type 2 diabetes in a sample of 1,428 individuals from the largest 182 families in the National Heart, Lung and Blood Institute's Framingham Heart Study population. RESULTS: A significant association was found with FPG (p=0.01) and log (FPG) (p=0.005) using a modified family-based transmission disequilibrium test, the family-based association test (FBAT). The association between IL-6 genotype and FPG (p=0.035) and log (FPG) (p=0.03) was also found in the subset of families that were informative in FBAT using a mixed-effects regression model and strengthened after adjustment for potential confounders (p=0.008 for log [FPG]). The mean glucose level estimated from models with log (FPG) as the dependent variable for the GG genotype in the informative families was significantly lower (5.20+/-0.06 mmol/l) than for the GC (5.41+/-0.06 mmol/l) and CC (5.38+/-0.06 mmol/l) genotypes (p=0.03 for contrast between GG and GC genotypes). In the subset of informative families, the risk of type 2 diabetes associated with the GG genotype was lower relative to the GC and CC genotypes combined (potential confounder-adjusted, mixed-effects odds ratio 0.35, 95% CI 0.14-0.88, p=0.026, unaffected n=391, affected n=32). CONCLUSIONS/INTERPRETATION: These results are consistent with a protective role for the -174 IL-6 G allele against type 2 diabetes and warrant further analysis of this polymorphism.

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OBJECTIVE: To evaluate the contributions of socioeconomic, lifestyle, and body weight factors to predicted risk of coronary heart disease (CHD) in the population and thus provide a focus for policies on prevention. DESIGN: Prospective study and cross-sectional population health survey. SUBJECTS: In all, 3090 men in the Framingham study and 2571 men in the 1998 Health Survey for England (HSE) aged 35-74 y with no history of cardiovascular disease participated in the study. MEASUREMENTS: Data on sex, age, systolic blood pressure and antihypertensive medication, total and high-density lipoprotein cholesterol levels, diabetes, and their association with the incidence of myocardial infarction and fatal CHD in the Framingham study population were used to derive functions for predicting individual 10-y risk of CHD. These functions were applied to the same data on participants in the HSE. High risk was defined as 10-y CHD risk > or = 15%. The proportion of high risk in the English population attributable to each of the risk factors examined was assessed. RESULTS: In all, 32% of men in England had predicted 10-y CHD risk > or =15%. Such high risk was significantly associated with body mass index (BMI, kg/m2), waist:hip ratio (WHR), smoking, and levels of physical activity, educational attainment, and income (all P < or = 0.007). In this population, 47% of high CHD risk was attributable to excess body weight--BMI > or = 25 kg/m2 and/or WHR > or = 0.95--and 31% to the sum of the four other significant factors: lack of educational qualifications, low income, smoking, and physical inactivity. CONCLUSION: Overweight and obesity now dominate the standard risk factors of CHD in men and should be the focus of national policies for prevention.

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The incidence of cardiovascular disease (CVD) is very high in patients with chronic kidney (CKD) disease and in kidney transplant recipients. Indeed, available evidence for these patients suggests that the 10-year cumulative risk of coronary heart disease is at least 20%, or roughly equivalent to the risk seen in patients with previous CVD. Recently, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) published guidelines for the diagnosis and treatment of dyslipidemias in patients with CKD, including transplant patients. It was the conclusion of this Work Group that the National Cholesterol Education Program Guidelines are generally applicable to patients with CKD, but that there are significant differences in the approach and treatment of dyslipidemias in patients with CKD compared with the general population. In the present document we present the guidelines generated by this workgroup as they apply to kidney transplant recipients. Evidence from the general population indicates that treatment of dyslipidemias reduces CVD, and evidence in kidney transplant patients suggests that judicious treatment can be safe and effective in improving dyslipidemias. Dyslipidemias are very common in CKD and in transplant patients. However, until recently there have been no adequately powered, randomized, controlled trials examining the effects of dyslipidemia treatment on CVD in patients with CKD. Since completion of the K/DOQI guidelines on dyslipidemia in CKD, the results of the Assessment of Lescol in Renal Transplantation (ALERT) Study have been presented and published. Based on information from randomized trials conducted in the general population and the single study conducted in kidney transplant patients, these guidelines, which are a modified version of the K/DOQI dyslipidemia guidelines, were developed to aid clinicians in the management of dyslipidemias in kidney transplant patients. These guidelines are divided into four sections. The first section (Introduction) provides the rationale for the guidelines, and describes the target population, scope, intended users, and methods. The second section presents guidelines on the assessment of dyslipidemias (guidelines 1-3), while the third section offers guidelines for the treatment of dyslipidemias (guidelines 4-5). The key guideline statements are supported mainly by data from studies in the general population, but there is an urgent need for additional studies in CKD and in transplant patients. Therefore, the last section outlines recommendations for research.

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AIMS/HYPOTHESIS: Hyperinsulinaemia and insulin resistance usually precede clinical hyperglycaemia and Type 2 diabetes. Thus, plasma insulin concentrations and insulin resistance are important quantitative traits associated with risk of Type 2 diabetes, and represent key measures for genetic analysis of the syndrome. METHODS: We carried out a genome-wide search for loci related to plasma insulin concentrations and insulin resistance in 330 extended, community-based pedigrees from the Framingham Heart Study. Normalized deviates of the standardized residuals of plasma insulin concentrations in the fasting state, 2 h after oral glucose challenge and as a measure of insulin resistance were used in linkage analysis with the variance components model implemented in the computer program SOLAR. RESULTS: The results suggest susceptibility loci influencing plasma concentrations of fasting insulin and insulin resistance on chromosomes 11 (LOD 2.43 at 85 cM close to D11S2002) and 17 (LOD 1.8 at 60 cM, close to D17S784); and susceptibility loci influencing 2-h plasma insulin concentrations on chromosomes 9 (LOD 2.8 at 80 cM, close to D9S922) and 19 (LOD 1.8 at 66 cM, close to D19S245). The results of the analysis of 1000 simulations of the trait and an unlinked marker suggest that in a genome scan of 401 markers fewer than one LOD score over 1 would be due to Type 1 error, and be a false positive. CONCLUSION/INTERPRETATION: We conclude that these suggestive regions for quantitative pre-diabetic insulin traits could contain major loci in the pathogenesis of Type 2 diabetes.

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Insulin-like growth factor-1 (IGF-I) plays a central role in the maintenance of bone mass. To test whether two major IGF-I binding proteins, IGFBP-4 and IGFBP-5, are related to bone mineral density (BMD), we studied a sample of the Framingham Offspring Cohort participants (99 men and 101 women, ages 60-87). Serum levels of IGF-I, IGFBP-4, and IGFBP-5 were measured by previously validated radioimmunoassays (CVs approximately 10%). BMDs of the proximal femur and lumbar spine were measured using a Lunar DPX-L densitometer. In males, but not females, IGF-I and IGFBP-5 were inversely associated with age (r = 0.34 and r = -0.28, respectively; P <0.01), while IGFBP-4 levels were positively associated with age (P <0.01). Multivariate means for BMD (adjusted for age, body mass index, height, smoking, and in women, estrogen use) were computed across quartiles of IGFBP-4 and IGFBP-5 and IGFBP-4/IGFBP-5 ratio. In women, but not men, IGFBP-5 was positively associated with femoral neck BMD (P = 0.03), however, after statistical adjustment for IGF-I, this association was no longer significant. No other associations were observed for BMD at any other site. Further study is necessary for elucidation of the gender differences in the possible influence of IGF system components on bone mass.

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