Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 ± 9.0%, 37.6 ± 8.9%, and 38.1 ± 9.1%, p <0.001) and total atheroma volume (198.3 ± 85.9, 190.7 ± 85.0, and 186.3 ± 79.1 mm 3 , p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 ± 174.3 vs 484.4 ± 160.7 mm 3 , p = 0.02), whereas DM was associated with lumen constriction (290.6 ± 111.7 vs 298.1 ± 105.5 mm 3 , p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 ± 0.3, +0.3 ± 0.2, and +0.1 ± 0.2%, p <0.0001) and total atheroma volume (−1.0 ± 1.8, −3.3 ± 1.8, and −4.0 ± 1.8 mm 3 , p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.
Intravascular ultrasound generates high-resolution imaging of the full thickness of the artery wall. Serial intravascular ultrasound imaging in an anatomically matched arterial segment permits evaluation of the impact of clinical characteristics and pharmacologic therapies on the progression of coronary atherosclerosis. In patients with established coronary artery disease, previous studies have reported that the presence of diabetes mellitus (DM) and metabolic syndrome (MS) is associated with greater progression of atherosclerosis. The objective of the present analysis was to determine whether the burden of coronary atherosclerosis, its progression, and associated arterial wall remodeling differ in patients with DM or MS compared to those patients who have neither disease.
Methods
The present analysis included individual patient data pooled from 7 clinical trials involving 3,459 patients that employed serial intravascular ultrasound imaging to evaluate the effects of medical therapies on atheroma progression in patients with established coronary artery disease. All patients were required to have coronary artery disease, defined as having ≥1 lumen narrowing >20% in a major epicardial coronary artery on a diagnostic coronary angiogram performed for a clinical indication. The acquisition and analysis of ultrasonic images have been described in detail previously. After anticoagulation and administration of intracoronary nitroglycerin, an imaging catheter containing a high-frequency ultrasound transducer (30 to 40 MHz) was inserted within the distal coronary artery. The target vessel for imaging was required to contain no lumen narrowing >50%, had not undergone previous revascularization, and was not considered the culprit vessel for a previous myocardial infarction. Continuous ultrasonic imaging was acquired during withdrawal of the catheter through the artery at a constant rate of 0.5 mm/s.
Images were digitized for analysis by personnel in a single core laboratory at the Cleveland Clinic (Cleveland, Ohio) who were blinded to the clinical characteristics and treatment status of patients. Arterial segments at different time points were matched by the anatomic location of side branches. Images spaced precisely 1-mm apart were selected for analysis. The leading edge of the lumen and the external elastic membrane (EEM) were defined by manual planimetry. Plaque area was defined as the difference in area occupied by the lumen and EEM borders. Total atheroma volume (TAV) was calculated by summation of the plaque area in each measured image and subsequently normalized to account for differences in segment length between subjects: TAVnormalized = ([Σ{EEMarea – EEMlumen}]/images in pullback) × median images in cohort. Percent atheroma volume (PAV) was calculated as the proportion of vessel wall volume occupied by atherosclerotic plaque: PAV = ([Σ{EEMarea – lumenarea}]/Σ[EEMarea]) × 100.
Volumes occupied by the lumen and EEM were similarly calculated by summation of their respective areas in each measured image and subsequently normalized to account for differences in segment length between subjects.
Subjects were stratified according to presence or absence of MS and DM at baseline. DM was recorded by the investigator by patient history, increased glucose (fasting level ≥126 mg/dl or nonfasting level ≥200 mg/dl), or concomitant use of antidiabetic therapies. MS was defined as by National Cholesterol Education Program Adult Treatment Panel III criteria, substituting a body mass index ≥30 kg/m 2 for waist circumference, if they fulfilled ≥3 of the following criteria: body mass index ≥30 kg/m 2 , triglyceride level ≥150 mg/dl, low levels of high-density lipoprotein cholesterol (<40 mg/dl in men and <50 mg/dl in women), impaired fasting glucose (100 to 125 mg/dl), and high systolic or diastolic blood pressure (≥130/85 mm Hg or current antihypertensive medication). Patients who met the definition for MS and DM were classified in the DM group for the present analysis. Patients classified as having DM, MS, or neither diagnosis were compared with regard to clinical characteristics, extent of coronary atherosclerosis at baseline, and serial changes.
All analyses were conducted using SAS 8.2 (SAS Institute, Cary, North Carolina). Results are expressed as mean ± SD for continuous variables with a normal distribution and median or interquartile range for non-normally distributed continuous variables and percentage for categorical variables. Baseline medical history, laboratory markers, and measurements of atheroma burden were compared using chi-square test for categorical variables and analysis of variance for continuous variables with status (DM, MS without DM or neither) as the factor variable. All 3 possible pairwise comparisons were evaluated at an alpha level of 0.017 (adjusted for multiplicity). Evaluation of serial changes in atheroma burden or vascular dimensions (PAV, TAV, EEM, and lumen) was evaluated using a separate random effects mixed model to account for possible heterogeneity across the 7 trials. Corresponding baseline measurements were controlled for in each model and adjusted changes were expressed as least square mean ± SEM. All 3 possible pairwise comparisons were conducted and evaluated at an alpha level of 0.017 to maintain an error rate at 0.05. Changes in measurements of disease burden were also compared after controlling for clinical characteristics (age, gender, hypertension, dyslipidemia) and medication use (statins, β blockers, aspirin).
Results
Clinical characteristics are presented in Table 1 . Thirty-two percent of patients were classified as having MS and 31% as having DM. Eighty-one percent of patients with DM also met the diagnostic criteria for MS. Patients with MS had the largest number of individual cardiovascular risk factors. Higher rates of hyperlipidemia and hypertension were observed in patients with DM or MS. Patients with MS were younger and most likely to be treated with a β blocker. Patients with DM were less likely to be treated with statins and more likely to receive an angiotensin-converting enzyme inhibitor. Degree of risk factor control during the studies is presented in Table 2 . Patients with DM had the highest level of glycated hemoglobin and lower low-density lipoprotein cholesterol levels. MS was associated with higher non–high-density lipoprotein cholesterol and triglyceride levels and lower high-density lipoprotein cholesterol. The 2 groups demonstrated higher systolic blood pressure and C-reactive protein compared to patients with neither diagnosis.
| Characteristic | Neither (n = 1,261) | MS (n = 1,119) | DM (n = 1,079) | p Value |
|---|---|---|---|---|
| Age (years) | 58.1 ± 9.6 | 56.5 ± 9.5 | 58.8 ± 9.02 | <0.001 |
| Women | 25.4% | 30.1% | 32.8% | <0.001 |
| Hypertension | 65.9% | 85.1% | 88.4% | <0.001 |
| Hyperlipidemia | 67.8% | 75.5% | 84.4% | <0.001 |
| Previous myocardial infarction | 30.8% | 30.9% | 28.1% | 0.26 |
| Previous bypass | 2.9% | 4.0% | 2.6% | 0.15 |
| Previous percutaneous coronary intervention | 43.2% | 44.7% | 44.4% | 0.75 |
| Statin use | 96.7% | 94.4% | 92.2% | <0.001 |
| β-blocker use | 73.3% | 80.0% | 76.6% | 0.001 |
| Angiotensin-converting enzyme inhibitor use | 42.3% | 56.6% | 67.9% | <0.001 |
| Aspirin use | 94.6% | 94.7% | 93.3% | 0.29 |
| Parameter | Neither (n = 1,261) | MS (n = 1,119) | DM (n = 1,079) | p Value |
|---|---|---|---|---|
| Triglycerides (mg/dl) | ||||
| Baseline | 125.9 ± 64.7 | 194.9 ± 95.5 | 176.5 ± 100.3 | <0.001 |
| Percent change | 4.6 ± 41.9 | −5.6 ± 39.9 | −0.6 ± 41.6 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | ||||
| Baseline | 106.0 ± 36.4 | 107.4 ± 37.7 | 96.3 ± 34.4 | <0.001 |
| Percent change | −13.4 ± 30.2 | −11.1 ± 32.1 | −2.2 ± 32.6 | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) | ||||
| Baseline | 47.6 ± 12.3 | 38.1 ± 9.1 | 40.8 ± 11.3 | <0.001 |
| Percent change | 15.4 ± 27.1 | 15.8 ± 26.0 | 12.4 ± 40.0 | 0.003 |
| Non–high-density lipoprotein cholesterol (mg/dl) | ||||
| Baseline | 133.4 ± 41.2 | 153.00 ± 34.2 | 118.3 ± 34.7 | <0.001 |
| Percent change | −13.4 ± 26.1 | −16.5 ± 25.4 | −5.2 ± 28.8 | <0.001 |
| Systolic blood pressure (mm Hg) | ||||
| Baseline | 124.3 ± 15.3 | 129.2 ± 16.4 | 129.4 ± 17.1 | <0.001 |
| Percent change | 2.9 ± 11.1 | 1.6 ± 11.6 | 2.0 ± 11.3 | 0.03 |
| Diastolic blood pressure (mm Hg) | ||||
| Baseline | 74.6 ± 8.7 | 77.3 ± 9.7 | 75.5 ± 9.7 | <0.001 |
| Percent change | 2.2 ± 11.3 | 1.5 ± 12.4 | 1.0 ± 12.1 | 0.01 |
| Glycated hemoglobin (%) | ||||
| Baseline | 5.4 ± 0.5 | 5.4 ± 0.7 | 7.2 ± 1.2 | <0.001 |
| Percent change | 6.7 ± 10.7 | 7.2 ± 12.3 | −0.2 ± 17.4 | <0.001 |
| C-reactive protein (mg/L) | ||||
| Baseline | 1.9 | 3.2 | 3.0 | <0.001 |
| Percent change | −16.7 | −20.3 | −18.5 | 0.32 |
Measurements of atheroma burden at baseline are listed in Table 3 . A most extensive burden of disease was observed in patients with DM compared to those with MS alone and those with neither diagnosis. Despite the presence of a substantial number of cardiovascular risk factors, burden of atherosclerosis in patients with MS was not greater than that observed in patients with neither diagnosis. Vascular dimensions were further explored in the 3 groups. Patients with MS demonstrated larger EEM and lumen volumes in the presence of similar PAV and TAV compared to patients with neither diagnosis. In contrast, comparison to the MS group revealed that patients with DM had smaller EEM and lumen volumes despite having the most extensive burden of atherosclerosis. Although patients with DM had a similar EEM volume as those with neither diagnosis, the lumen volume was smaller. This suggests that the pattern of arterial remodeling may differ in patients with DM and MS.
| Characteristic | Neither (n = 1,261) | MS (n = 1,119) | p Value (neither vs MS) | DM (n = 1,079) | p Value | |
|---|---|---|---|---|---|---|
| Neither vs DM | MS vs DM | |||||
| Percent atheroma volume | 38.1 ± 9.1 | 37.6 ± 8.9 | 0.13 | 40.32 ± 9.0 | <0.001 | <0.001 |
| Total atheroma volume (mm 3 ) | 186.3 ± 79.1 | 190.7 ± 85.0 | 0.30 | 198.3 ± 85.9 | 0.002 | 0.05 |
| External elastic membrane volume (mm 3 ) | 484.4 ± 160.7 | 501.3 ± 174.3 | 0.02 | 488.9 ± 174.6 | 1.00 | 0.04 |
| Lumen volume (mm 3 ) | 298.1 ± 105.5 | 310.6 ± 112.2 | 0.009 | 290.6 ± 111.7 | 0.024 | <0.001 |
Changes in atheroma burden and vessel wall dimensions during serial evaluation are presented in Table 4 . The greatest progression of PAV and TAV was observed in patients with DM compared to those with MS and those with neither diagnosis. In contrast, progression rate in patients with MS did not differ from patients with neither diagnosis. A similar relation was observed after adjusting for clinical characteristics and medication use. Patients with DM and those with MS were more likely to undergo substantial atheroma progression (≥5% relative increase in PAV) and patients with DM were less likely to undergo substantial atheroma regression (≥5% relative decrease in PAV). Patients with MS alone were just as likely to achieve substantial regression as patients with neither diagnosis. No significant differences were observed between groups with regard to changes in vascular dimensions.
