Apolipoprotein B (apoB) and non–high-density lipoprotein cholesterol (non-HDL-C) are cardiovascular disease risk markers, although data in adults with type 1 diabetes mellitus (DM) are limited. We hypothesized that elevated apoB and non-HDL-C would be associated with greater odds of coronary artery calcification progression (CACp), a measure of coronary atherosclerosis, than either category alone in adults with type 1 DM. We grouped subjects with type 1 DM (n = 652) into 4 groups: elevated apoB (≥90 mg/dl) and elevated non-HDL-C (≥130 mg/dl), elevated non-HDL-C alone, elevated apoB alone, and normal apoB and non-HDL-C. We used logistic regression to examine the associations between the groups and CACp for a period of 6 years. We performed sensitivity analyses with elevated apoB and non-HDL-C redefined as at or more than the cohort means (91.4 and 119.0 mg/dl, respectively). Subjects with elevated apoB and non-HDL-C had greater odds of CACp compared with those with normal apoB and non-HDL-C (odds ratio 1.90, 95% confidence interval 1.15 to 3.15) and compared with subjects with elevated apoB alone (odds ratio 2.86, 95% confidence interval 1.43 to 5.74) adjusting for age, gender, duration, hemoglobin A1c, and statins. Similar results were obtained with elevated apoB and non-HDL-C defined as at or more than the cohort means. In conclusion, elevated apoB and non-HDL-C carry a greater risk of atherosclerosis than elevated apoB in the absence of elevated non-HDL-C in adults with type 1 DM. These data suggest that apoB and non-HDL-C should be viewed as complementary rather than competitive indexes of cardiovascular disease risk in type 1 DM.
Apolipoprotein B (apoB) and non–high-density lipoprotein cholesterol (non-HDL-C) have been proposed to be superior indicators of cardiovascular (CV) risk than total cholesterol and/or low-density lipoprotein cholesterol (LDL-C). Some investigators argue that although non-HDL-C and apoB correlate, they are not interchangeable and may provide unique information about CV risk. There are insufficient data on the concordance between apoB and non-HDL-C in adults with type 1 diabetes mellitus (DM) across a wide range of risk factors for atherosclerosis including triglycerides (TGs) and body mass indexes (BMIs). Moreover, it remains unclear whether elevated apoB (≥90 mg/dl) or elevated non-HDL-C (≥130 mg/dl) independently carries the same risk for atherosclerosis as elevation of both lipid indexes in type 1 DM. When comparing 2 tests, the clinical consequences of the tests are best understood through their agreement and disagreement. In cases where elevated apoB or elevated non-HDL-C are individually associated with the same risk for atherosclerosis as elevation of both lipid indexes, risk may be equally served by either test. This is clinically important as measurement of apoB incurs an additional cost. Accordingly in this study, we sought to examine the correlation of non-HDL-C and apoB across a wide range of lipid, metabolic, and CV profiles in adults with type 1 DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. Second, we sought to examine whether adults with elevated measures of apoB (≥90 mg/dl) and non-HDL-C (≥130 mg/dl) had greater odds of coronary artery calcification progression (CACp) compared with adults with elevated apoB alone or elevated non-HDL-C alone and compared with adults with normal measures of both apoB and non-HDL-C.
Methods
The CACTI Study enrolled 1,416 subjects 19 to 56 years old, 652 with type 1 DM and 764 without diabetes, who were asymptomatic for cardiovascular disease (CVD) at the baseline visit in 2000 to 2002 and then were re-examined 6 years later. The study was approved by the Colorado Multiple Institutional Review Board, and all participants provided informed consent.
We measured height and weight and calculated BMI in kilograms per square meter. Systolic blood pressure (SBP) at test and fifth-phase diastolic blood pressure were measured 3 times while the patient was seated, and the second and third measurements were averaged. After an overnight fast, blood was collected, centrifuged, and separated. Plasma was stored at 4°C until assayed. High-performance liquid chromatography was used to measure HbA1c (high-performance liquid chromatography; Bio-Rad, Hercules, California variant). Total plasma cholesterol and TG levels were measured using standard enzymatic methods, HDL-C was separated using dextran sulfate, and LDL-C was calculated using the Friedewald formula. Non-HDL-C was calculated by subtracting HDL-C from total cholesterol, and the ratio of TG to HDL-C was calculated by dividing TG by HDL-C. ApoB was measured by Beckman Array Nephelometer (Beckman Coulter Inc., Brea, California). Elevated apoB was defined as ≥90 mg/dl and elevated non-HDL-C as ≥130 mg/dl per consensus report from the American Diabetes Association (ADA) and the American College of Cardiology (ACC) Foundation.
CAC measurements were obtained in duplicate using an ultrafast Imatron C-150XLP electron beam computed tomography scanner (Imatron, San Francisco, California), and the 2 scores were averaged. The average of the 2 scores was used as the CAC score for that visit. Scans were repeated on follow-up, an average of 6.2 ± 0.6 years after the baseline examination. Presence of CAC was defined as a CAC score >0. Progression of CAC was defined as an increase in volume of CAC of ≥2.5 square root–transformed units.
Differences between men and women were assessed using the chi-square test for categorical variables and t test for continuous variables. To examine the relations between apoB and non-HDL-C, we used Pearson’s correlation and scatter plots. We explored the relation in entire cohort and also stratified the analyses by tertiles of TG (low: <67, mid: 67 to 95, and high: ≥95 mg/dl), BMI (low: <24.1, mid: 24.1 to 27.3, and high: ≥27.3 kg/m 2 ), statin use, and the presence/absence of CACp, respectively. The agreement between elevated apoB (≥90 mg/dl) and elevated non-HDL-C (≥130 mg/dl) were tested with the chi-square and Kappa test with Kappa coefficient <0 indicating no agreement, <0.40 as poor, 0.40 to 0.60 as moderate, >0.61 to 0.80 as good, and >0.81 as excellent. We stratified subjects into 4 groups: those with elevated apoB and elevated non-HDL-C (n = 196), those with elevated apoB and normal non-HDL-C (n = 116), those with normal apoB and elevated non-HDL-C (n = 10), and those with normal apoB and normal non-HDL-C (n = 330). Because of the limited number of subjects with normal apoB and elevated non-HDL-C (n = 10), we also grouped subjects by mean apoB (91.4 mg/dl) and mean non-HDL-C (119.0 mg/dl): those with apoB and non-HDL-C at or more than the cohort means (n = 247), those with only non-HDL-C at or more than the cohort mean (n = 41), those with only apoB at or more than the cohort mean (n = 39), and those with apoB and non-HDL-C less than the cohort means (n = 325). Multivariable logistic regression models were applied to examine the odds of CAC progression among the groups: unadjusted and adjusted for gender, age, HbA1c, SBP, and statin use. Gender was evaluated for effect modification of the 4-level categorical apoB/non-HDL-C variables by adding the gender by apoB/non-HDL-C variable interaction term in the logistic regression models. The interaction terms were not significant, and gender was considered a confounder. We also performed C-statistics and examined the area under the receiver-operating characteristics (ROC) curves for CACp by elevated apoB and elevated non-HDL-C, elevated apoB and normal non-HDL-C, and normal apoB and elevated non-HDL-C. The C-statistic has been criticized for insensitivities to changes in clinical decisions yielded for information gained. Therefore, we also integrated discrimination index (IDI), which uses probability differences to examine prediction performance. All analyses were performed in SAS (version 9.3 for Windows; SAS Institute, Cary, North Carolina). A value of p <0.05 was considered statistically significant.
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