Diabetes and progression of coronary calcium under the influence of statin therapy

Imaging and Diagnostic Testing

Diabetes and progression of coronary calcium under the influence of statin therapy Matthew J. Budoff, MD,a Dale Yu, MD,a Khurram Nasir, MD, MPH,c Rajnish Mehrotra, MD,b Lynn Chen,a Junichiro Takasu, MD, PhD,a Nisha Agrawal,a Sandy T. Liu,a and Roger S. Blumenthal, MDc Torrance, Calif, and Baltimore, Md

Background Coronary artery calcium (CAC) is a sensitive marker for the detection of coronary heart disease (CHD). Coronary artery calcification can be accurately quantified using electron beam tomography (EBT). We sought to evaluate the progression of atherosclerosis in asymptomatic persons with type 2 diabetes and measure the influence of statin therapy on CAC progression. Methods

We evaluated 163 asymptomatic patients with type 2 diabetes (120 men, 43 women). Patients were physician referred and underwent 2 consecutive EBT scans at least 1 year apart. Demographic data, risk factors for CHD, and medication use were collected. Patients with symptoms or known CHD were excluded.

Results

The mean age was 65 F 10 years. The mean CAC score at baseline was 651 F 414. Only 9 (6%) of 163 of participants had scores of 0 at baseline. The time between scans averaged 27 F 15 months. Patients not treated with statins demonstrated a median annual increase in CAC progression of 20% (4% - 44%), whereas statin-treated patients demonstrated increase of 10% (4%-25%) ( P = .0001). Hemoglobin A1c was weakly associated with CAC progression.

Conclusions Asymptomatic diabetic patients show a high prevalence of atherosclerosis based on high frequency of coronary calcification. Statin therapy induced a 50% reduction in the rate of CAC progression. As rapid CAC progression has been associated with coronary events, EBT may serve as a noninvasive method for following atherosclerosis and response to therapy. (Am Heart J 2005;149:695 - 700.)

Type 2 diabetes mellitus (DM) is a well-established risk factor for the development of coronary heart disease (CHD). Diabetic patients also have a higher mortality from CHD than patients without diabetes.1 Patients with type 2 DM are known to have elevated triglycerides and total cholesterol levels, in addition to reduced levels of high-density lipoprotein.2,3 Not surprisingly, atherosclerosis is responsible for 80% of deaths in patients with diabetes.4 Coronary artery calcium (CAC) has been shown to correlate histologically with the amount of atheromatous plaque, which has a strong association with CHD.5,6 Measurement of coronary calcium scores by electron beam tomography

From the aDivision of Cardiology, and bDepartment of Medicine, Harbor-UCLA Medical Center Research and Education Institute, Torrance, Calif, and cDepartment of Medicine, Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, Md. Submitted March 4, 2004; accepted July 20, 2004. Reprint requests: Matthew J. Budoff, MD, Harbor-UCLA Research and Education Institute, 1124 W. Carson St, RB2, Torrance, CA 90502. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.07.034

(EBT) has been validated by numerous studies, and EBT is the most sensitive, noninvasive method of detecting CHD.6,7 Patients with diabetes have been shown to have higher CAC scores, reflecting increased atherosclerotic burden, and hence, increased cardiovascular risk in these patients. A recent study by Qu et al8 demonstrated that diabetic subjects with higher CAC scores had a 4-fold increased risk of cardiac events. In addition, large studies have shown an increased risk of cardiac events in asymptomatic patients with higher CAC scores.9,10 Prior studies have shown that rates of CAC progression by EBT ranges from 22% to 52% per year, but no study has reported specific results in persons with type 2 diabetes.11 The clearly demonstrated benefits of cholesterol-lowering therapy in reducing coronary atherosclerotic disease (CAD)12,13 are thought to be related, at least in part, to the slowed progression of CAD.14,15 In addition, statin use has been shown to slow CAC progression.7,16 However, the data on CAC progression and the effects of therapy on CAC in type 2 diabetic patients are not widely known. This observational study evaluated the rate of progression of CAC in type 2 DM (Figure 1) and also examined whether other variables, such as

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Figure 1

Patient not treated with statin therapy with calcification of the left anterior descending at baseline (left image, arrow), now with significantly more calcification in the same distribution (right image, arrow), as well as new calcification in the right coronary artery (arrowhead).

the effect of lipid-lowering use or CHD risk factors, altered CAC progression.

Table I. Baseline demographics of the study population Total study population (N = 163)

Methods Study population Type 2 diabetic subjects without evidence of CAD were evaluated in a cross-sectional study. Type 2 diabetes was defined as adult-onset hyperglycemia, with a fasting blood glucose N126 mg/dL or use of hypoglycemic medications (insulin or oral hypoglycemics). We evaluated 163 serial asymptomatic persons with type 2 diabetes referred to our center for assessment of cardiovascular risk. The population consisted of 120 men and 43 women, with a mean age 65 F 10 years (range 41-90 years), who underwent previous EBT calcium score testing at Harbor-UCLA before enrollment (Table I). The interscan period was 27 F 15 months (range 12-80 months). All patients were asymptomatic and referred by their primary physician to evaluate the presence and amount of coronary calcification. Patients were excluded with cardiac symptoms or known CAD (including revascularization), stroke, or peripheral vascular disease. Information on the presence or absence of traditional cardiovascular risk factors, including hypertension, family history of premature CAD, hyperlipidemia, smoking, DM, and statin use, was obtained before the initial and follow-up EBT scans. We elicited personal history such as medication use, family and smoking history, and repeated their EBT. The presence and number of risk factors for a participant were calculated based on the National Cholesterol Education Program guidelines.17 Risk factors included: males age N45 years, females N age 55 years, current cigarette smoking, history of premature coronary disease in first-degree relative, hypertension, and hypercholesterolemia. Current cigarette smoking was defined as use of N10 cigarettes per day. Hypertension was defined by current use of antihypertensive medication or known and untreated hypertension. Hypercholesterolemia was defined as use of cholesterol-lowering medication or, in the absence of cholesterol-lowering

Male sex High cholesterol Family history Tobacco use Age (y) Range Baseline score

120 (74%) 105 88 20 65 F 10 41-90 y 651 F 414

medication use, as having a total serum cholesterol N240 mg/dL. Serum hemoglobin A1c ( HbA1c ) values were obtained from chart review, when available, if obtained within 3 months of the EBT scan. Eighty-five patients had HbA1c available for analysis. The institutional review board of the Harbor-UCLA Research and Education Institute approved the study protocol and patients gave written informed consent.

Electron beam tomography methodology Electron beam tomography studies (both at baseline and follow-up) were performed with an Imatron C-150XL Ultrafast computed tomographic scanner (Imatron, South San Francisco, Calif) in the high-resolution volume mode using a 100-millisecond exposure time. Electrocardiographic triggering was used so that each image was obtained at the same point in diastole, corresponding to 40% of the R-R interval. Coronary artery visualization was obtained without contrast medium injection, and at least 30 consecutive images were obtained at 3-mm intervals beginning 1 cm below the carina and progressing caudally to include the entire coronary artery tree.18 Using a field-of-view of 30 cm2 (pixel size 0.586 mm), a calcified focus was defined as a minimum of 3 pixels with a density of z130 Hu within the border of the coronary arteries. Total radiation exposure using this technique was b0.01 Gy per participant.

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Table II. Demographics of Statin versus No statin Groups

Age (y) Baseline score Hypertension Tobacco Family history Follow-up score Interscan interval (mo) Mean change per year Percent change per year

Statin

No statin

P

64 F 10 796 F 1205 42 (52%) 11 (14%) 55 (69%) 934 F 1238 30 F 16 63 F 103 18 F 31

67 F 10 511 F 829 39 (47%) 9 (11%) 33 (40%) 723 F 1154 25 F 14 143 F 420 32 F 51

NS .04 NS NS .002 NS NS .04 .02

Figure 2

Table III. Multivariate analyses of demographic and treatment variables with median annualized change in coronary calcium scores in 163 patients Variable Statin use Male sex Hypertension Hypercholesterolemia Family history Age (y) Baseline score Tobacco use

Regression coefficient 135 29 38 68 22 0.22 0.08 15

P .006 .9 .2 .1 .5 .8 b.0001 .7

95% CIs 231 16.4 21 29 41 2 0.05 113

39 1.27 98 167 86 3 0.12 83

first scan (annualized percent change). m2 Analysis with Fisher exact test was used for differences in distribution of qualitative variables between groups. The distribution of the annualized change as well-annualized percent change was not normally distributed as evaluated by Kolmogorow-Sminrow test. As a result, to statistically analyze the differences between the first and the second scan according to treatment, the Wilcoxon matched-pairs signed rank test was used, whereas median regression was used for multivariable analysis, adjusting for traditional risk factors (derived from the interview and measured factors), including age, race, sex, elevated total cholesterol; hypertension; current cigarette smoking; and family history of premature heart disease. The statistical analyses were carried out using the STATA V8 statistical package (Stata Corp, College Station, Tex). All statistical tests were 2-tailed, with significance defined as b.05.

bDefiniteQ CAC progression Changes between baseline and follow-up EBT mean and median scores in patients treated with lipid-lowering therapy or no treatment.

The lesion score was calculated by multiplying the lesion area by a density factor derived from the maximal Hounsfield unit within this area, as described by Agatston et al.19 The density factor was assigned in the following manner: 1 for lesions whose maximal density were 130 to 199 Hu, 2 for lesions 200 to 299 Hu, 3 for lesions 300 to 399 Hu, and 4 for lesions N400 Hu. A total calcium score was determined by summing individual lesion scores from each of 4 anatomic sites (left main, left anterior descending, circumflex, and right coronary arteries). A single investigator (JT), blinded to the clinical status of the participant and temporal relationship of the scans, interpreted all studies.

Statistical analysis Continuous variables are presented as medians or means F SD. The changes in the amount of coronary calcification were assessed by subtracting the values measured in the first EBT scan from those measured in the second EBT scan, dividing the difference by the actual number of days that passed between scan 1 and scan 2 and multiplying this fraction by 365 (annualized change). The percent change was obtained by dividing the annualized absolute change by the amount of the

Patients were classified as having bdefinite progressionQ if their Agatston CAC score change was z24%, which represents 3 times the published median interscan variabilities.11,20

Results We evaluated 163 asymptomatic patients with type 2 diabetes (120 men, 43 women). The mean age was 65 F 10 years. The mean (median: interquartile range) CAC score at baseline was 636 F 1023 (252: 55-756). Only 9 (6%) of 163 participants had scores of 0 at baseline. Table I demonstrates the baseline demographics of the patient population. Mean (FSD) body mass index was 29.1 F 3.3 and HbA1c was 7.8% F 1.1%. The mean follow-up was 2.3 F 1.3 years. The average increase in CAC score was 25% per year (median 12% per year). One hundred five (64%) patients had high cholesterol and 80 patients (49%) received statin therapy. Table II demonstrates the baseline variables in individuals receiving statin therapy or not. Patients treated with statins demonstrated a mean increase in CAC progression of 18% per year whereas untreated patients progressed at 32% per year ( P = .02) (Figure 2). The median relative annual increase was 20% (4%-44%) without treatment and 10% (4%-25%) in patients taking statin therapy ( P = .0001). The median annualized absolute increase (inter-

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Figure 3

Relationship of HbA1c at follow-up and annualized progression of coronary calcium.

quartile range) in calcified score was 43 (range 3-164) without treatment compared with 38 (range 7-76) in patients taking statin therapy ( P = .18). In multiple logistic regression, CAC progression was associated with the baseline CAC score ( P b .001), and statin use ( P = .006), as shown in Table III. Hemoglobin A1c was weakly associated with CAC progression ( P = .05) (Figure 3). The mean HbA1c for the cohort was 7.8% F 1.1%.

Definite progression The prevalence of definite progression (at least 24% annual progression rate) among the no statin group was 41% (33 of 80), whereas only 26% (21 of 81) of statin patients had definite progression ( P = .03).

Discussion Important findings from this study are that long-term lipid-lowering therapy with statin therapy resulted in significant slowing of atherosclerosis progression. The mean progression of CAC scores (25% per year) in this population was consistent with the average progression (22%-52% per year) seen in prior studies.7,11,16 A significant 50% reduction ( P = .0001) in median CAC progression was seen in diabetic patients on statin therapy. This is similar to the findings of Callister et al,16 which demonstrated a statin-induced, 45% decrease of CAC progression ( P b .05) in asymptomatic patients without a history of CHD. This is the first study, to our knowledge, documenting the progression of CAC by EBT in asymptomatic patients with type 2 diabetes and the effects of statin use in these patients. Lipid-lowering therapy is critical to the management of patients with diabetes. These patients have more

extensive CHD, with higher prevalence of depressed myocardial function and more left main and triple vessel disease as compared with patients without diabetes.21 Multiple studies have shown substantial reductions of CHD events in diabetic patients on lipid-lowering therapy.3,22 Recently, the diabetic subpopulation of the Heart Protection Study was reported, demonstrating a 24% reduction in cardiac events for patients taking statin therapy.23 Furthermore, the benefit of lipidlowering therapy has been confirmed by angiographic data from the Diabetes Atherosclerosis Intervention Study, which demonstrated a 40% decrease in progression of atherosclerosis in diabetic patients on fenofibrate.24 The Diabetes Atherosclerosis Intervention Study data are consistent with the statin-induced, 50% reduction of CAC progression seen in our study. There is only one published study of outcomes related to CAC progression. This study demonstrated, in 817 persons, that EBT-measured progression was the strongest predictor of cardiac events.25 This observational study suggests that continued accumulation of CAC in asymptomatic individuals is associated with increased risk of MI in asymptomatic individuals. Overall, our results not only confirm the benefit of statin use in persons with diabetes, but also demonstrate how EBT serves as an accurate noninvasive method for monitoring response to therapy. The association of statin use as a significant predictor of higher baseline CAC scores has been shown in 2 prior studies in persons with diabetes.26,27 This may represent a treatment bias, whereas patients with higher risk profiles are more likely to be treated with statin agents. Patients with higher scores are at higher risk for CHD events, thus warranting more aggressive treatment.8-10

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Nonetheless, treatment with statin therapy still invoked a favorable slowing in the calcium progression, despite higher baseline scores (Figure 1). Coronary artery calcium variability is associated with baseline score, with higher scores having a lower variability. Our criteria for definite progression were based on previous studies of reproducibility. With higher baseline scores, the variability will be less, so use of a 24% change may be even more conservative than anticipated. The association in this study between HbA1c and CAC progression suggests that diabetes control confers a slight benefit in slowing calcium progression. This is consistent with the findings of Snell-Bergeon et al 28 who showed that a HbA1c N7.5% was the most important predictor for CAC progression in patients with type I diabetes. This study has several limitations, including the observational nature of the study. This is evident by the very high prevalence of CAC in the study population (94%). We have previously demonstrated a high prevalence of CAC in type 2 diabetic patients (72% in asymptomatic persons, 89% in symptomatic patients with DM).6 This increased prevalence most likely represents a selection bias, whereby patients with higher scores and positive studies were more likely to return for follow-up. We cannot exclude that more aggressive lifestyle and nonstatin therapies also played a role in the slowing of CAC progression in the statin-treated group. These patients may have received other therapies that contributed to the statin effect seen here and other studies.7,16 There was considerable overlap in the confidence intervals of the median progression in the treatment and non-statin group; however, the differences remained highly statistically significant ( P = .0001). Electron beam tomography serves as a sensitive, noninvasive method for tracking atherosclerosis in these patients, and thus, can track progression of disease and efficacy of therapy.29 Increasing CAC scores may imply suboptimal therapy and a need for more aggressive riskreducing treatment. In addition, individuals with CAC are more likely to be compliant with diet, medications, and lifestyle modifications.30 There are large ongoing observational National Institutes of Health studies underway to evaluate the use and predictive power of CAC in diabetic patients (EDIC).

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