Author + information
- Received May 11, 2000
- Revision received December 13, 2000
- Accepted January 17, 2001
- Published online May 1, 2001.
- François Ledru, MD∗,* (, )
- Pierre Ducimetière, PhD†,
- Salvatore Battaglia, MD∗,
- Dominique Courbon, MsC†,
- Fabrice Beverelli, MD∗,
- Louis Guize, MD∗,
- Jean-Léon Guermonprez, MD∗ and
- Benoı̂t Diébold, MD∗
- ↵*Reprint requests and correspondence: Dr. Francois Ledru, Département de Cardiologie, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France
The goal of this research was to study coronary atherosclerosis in patients with type 2 diabetes compared with patients without diabetes according to the new definition of diabetes advocated by the American Diabetes Association in 1997.
Patients with diabetes (fasting plasma glucose above 7.0 mM/L) have a higher risk of cardiovascular death. The correlation with the pattern and severity of their coronary atherosclerosis, especially in the new patients with “mild” diabetes (7.0 mM/L ≤ fasting plasma glucose < 7.8 mM/L), remains unclear.
A cohort of 466 patients undergoing coronary angiography but free of any previous infarction, coronary intervention and insulin therapy were prospectively recruited. Ninety-three had diabetes (fasting plasma glucose > 7.0 mM/L or hypoglycemic oral treatment). Five angiographic indexes were calculated to describe severity and extent of coronary atherosclerosis.
Overall, patients with diabetes had more diffuse coronary atherosclerosis, a greater prevalence of mild, moderate and severe stenoses and a two-fold higher occlusion rate than patients without diabetes, even after adjustment for age, gender, body mass index, hypertension, lipid parameters, smoking, family history of cardiovascular events and ischemic symptoms. Patients with “mild diabetes” had a coronary atherosclerosis pattern more similar to patients with normal fasting plasma glucose than to patients formerly defined as diabetic according to the World Health Organization criteria, except that they had a higher prevalence of <50% stenoses.
In patients with type 2 diabetes, those with 7.0 mM/L ≤ fasting plasma glucose < 7.7 mM/L have a slightly greater prevalence of mildly severe lesions that may partly explain their higher cardiovascular event rate.
Type 2 diabetes mellitus is associated with a two- to four-fold increased incidence of myocardial infarction and cardiac death (1,2). This increased risk of major cardiac events is thought to be mostly related to accelerated development of coronary atherosclerosis, although this relationship remains controversial. An association with increased severity of coronary artery disease (CAD) in patients with diabetes has been previously shown (3–5)but has been questioned in more recent angiographic (6)and histologic (7)studies and might be accounted for by other confounding risk factors that frequently affect patients with diabetes, such as dyslipidemia, hypertension and obesity. In 1997, the American Diabetes Association (ADA) Expert Group (8)lowered the threshold value for fasting plasma glucose (FPG) to define diabetes, namely ≥7.0 mM/L (126 mg/dl), in order to better fit the results of the 2-h oral glucose tolerance test, reduce the incidence of undetected diabetes and better predict the risk of microvascular complications. The ADA fasting definition may have an impact on the association between type 2 diabetes and coronary atherosclerosis.
In 466 patients with a detailed description of the coronary anatomy, we, therefore, investigated the patterns of CAD in patients with diabetes according to the ADA definition. We also analyzed the changes in patterns of coronary atherosclerosis of patients categorized across increasing degrees of hyperglycemia, from normal plasma glucose to diabetes.
Five hundred twenty-two patients referred to our institution for coronary angiography were consecutively and prospectively screened for recruitment. The selection criteria were: 1) indication for coronary angiography (9); 2) no history of coronary intervention (whether instrumental or surgical), organ transplantation or renal hemodialysis; 3) no type 1 (insulin-dependent) diabetes mellitus; and 4) no history of myocardial infarction nor any Q waves on the 12-lead electrocardiogram (ECG).
Four hundred and sixty-six patients (88%) were finally considered for analysis; 32 were excluded for incomplete clinical or biological data, and 22 were excluded because angiogram quality was unsuitable for quantification of the CAD. Clinical presentation was stable angina in 155 patients (33%), unstable angina (10)in 155 patients (33%), silent ischemia in 12 patients (3%), atypical chest pain in 48 patients (10%) and miscellaneous (preoperative assessment, dilated cardiomyopathy, valvular heart disease) in 96 patients (21%).
Reported clinical data included personal medical history, risk factors, history of medications, family history of cardiovascular events and diabetes, height, weight and blood pressure recorded twice in the sitting position. The biochemical parameters were obtained after a 12-h fasting period during an overnight hospital stay and included FPG (glucose oxidize method), serum total cholesterol and its high and low density lipoprotein (HDL and LDL) subfractions and triglyceride levels. Hemoglobin A1cwas not routinely obtained and was not used in this study.
Diabetes was defined as the intake of a diabetic diet or oral hypoglycemic agents or a FPG above 7 mM/L (126 mg/dl) according to the new ADA criteria (8). Patients without diabetes were further subdivided into normal patients (FPG < 6.1 mM/L) and patients with impaired fasting glucose (6.1 mM/L ≤ FPG < 7.0 mM/L). Patients with diabetes were also subdivided into patients with newly diagnosed “mild” diabetes (7.0 mM/L ≤ FPG < 7.8 mM/L) and patients with diabetes according to the former World Health Organization (WHO) definition. Since the 75 goral glucose tolerance test was not routinely performed, by convention in this study we consider WHO-diabetes as the intake of any oral hypoglycemic agents or a FPG ≥ 7.8 mM/L (140 mg/dl) (11). Hypertension was defined as the intake of antihypertensive drugs or two measurements of the systolic/diastolic blood pressure above 160/95 mm Hg. Hypercholesterolemia was defined as the intake of a cholesterol-lowering agent or the combination of total cholesterol above 5.2 mM/L and LDL above 3.3 mM/L. Patients who currently smoked or who had quit smoking for less than two years were considered smokers. Silent ischemia was defined as evidence of ischemia without any symptom of angina, either at rest using 12-lead ECG or in daily activities using Holter ST-segment monitoring.
Quantitative coronary study
The coronary angiograms were independently analyzed by two of the same three experienced cardiologists throughout the study who were unaware of the clinical and biological data. Each of the 15 coronary segments (12)was graded according to its most severe diameter reduction as follows: grade 0, <25% stenosis; grade 1, <50% stenosis; grade 2, <75% stenosis; grade 3, ≥75% stenosis; grade 4, occlusion defined as a >95% diameter stenosis with a severely reduced or no antegrade flow (13). Segments downstream of grade 4 stenoses or less than 1-mm diameter vessels were not analyzed. Discrepancies in quantification between the observers were resolved by quantitative analysis of the disputed segment using the ARTREK software (ImageComm Systems, Santa Clara, California). Ninety-five angiograms had to be reviewed to reach a consensus (20%).
Four scores were derived to describe coronary atherosclerosis. The “coronary score” was defined by the number of coronary arteries exhibiting a stenosis greater than 75% diameter reduction (grade 3 or 4) (14). Stenosis of the left main coronary artery greater than 50% was considered a two-vessel CAD. The “extent score” was the number of segments exhibiting lesions greater than or equal to grade 1, adjusted to 15 coronary segments. The “severity score” was calculated as the average grade of the diseased coronary segments (i.e., graded 1 or more). The “atherosclerotic score” was calculated as the average severity of all analyzable segments. Interobserver variability was 2.0%, 6.0%, 10.4% and 2.4% for the “coronary score,” the “extent score,” the “severity score” and the “atherosclerotic score,” respectively. Atherosclerosis involving the left main, the proximal left anterior descending and circumflex arteries and the first three segments of the right coronary artery was considered proximal coronary atherosclerosis, while atherosclerosis involving the other coronary segments was considered distal coronary atherosclerosis.
Data were analyzed using the SAS package (SAS Institute, Cary, North Carolina). Unless otherwise stated, values are expressed as the mean ± 1 SD. Two-group comparisons were performed by the unpaired ttest. Multivariate analyses were performed by linear regression with a forward stepwise selection of explaining variables to enter into the regression, with p value ≤0.05.
Characteristics of patients with and without diabetes
The clinical and biological data are displayed in Table 1. Patients with diabetes were statistically older, had greater overweight, hypertension and familial history of diabetes than patients without diabetes, but clinical presentation was not significantly different. Among the 93 patients with diabetes, 53 (57%) had been taking at least one hypoglycemic agent for a median of six years (range 1 month to 27 years). Among the 40 patients with newly discovered diabetes, 20 had a FPG between 7 mM/L and 7.7 mM/L, and 20 had a FPG above 7.8 mM/L. In 66% of both the patients with and without diabetes, left ventricular ejection fraction was calculated by ventricular angiography. It was in the normal range and similar in the two groups.
As expected, patients with diabetes had higher triglyceride levels and lower HDL-cholesterol levels than patients without diabetes but similar total and LDL-cholesterol levels. The rate of cholesterol-lowering agents intake was similar with a median intake duration of three years (range 0 to 34 years) in both groups. Only 54% of the patients without diabetes and 65% of the patients with diabetes were taking a platelet-blocking agent, but this difference was not significant. However, duration of antiplatelet therapy was slightly longer (p = 0.014) in patients with diabetes (median 5 months [0 to 24 years]) than it was in patients without diabetes (1 month [0 to 16.5 years]). No significant clinical and biological differences were observed between patients with normal fasting glucose and impaired fasting glucose, as well as between patients with “mild” diabetes and WHO-defined diabetes (data not shown).
Impact of the new definition of diabetes on the patterns of coronary atherosclerosis
Coronary atherosclerosis scores are displayed in Table 2. Patients with diabetes had a significantly higher prevalence of multivessel disease and higher “coronary score,” “extent score” and “atherosclerotic score.” They had a higher number of diseased segments both in the proximal and the distal locations along the coronary vasculature than did the patients without diabetes. There was, however, no interaction between diabetes and proximal/distal location of diseased segments. Overall, diabetic patients had significantly less normal (grade 0) segments and more mildly (grade 1), moderately (grade 2) and severely (grade 3) diseased segments. Left main disease was identified in 5.1% of patients without diabetes and 3.2% of patients with diabetes (p = NS). Occlusion (grade 4) rate was also higher in patients with diabetes than it was in patients without diabetes, both in the proximal and distal locations. However, the difference did not reach significance for distal occlusions.
After adjustment for other well-known cardiovascular risk factors, diabetes remained associated with higher “extent score,” “atherosclerosis score” and occlusion rate (Table 3A and B). Additional adjustments for symptoms of angina (combination of chronic and unstable angina) yielded similar results (data not shown). Forward stepwise analyses were undertaken to evaluate the best predictors of the various coronary atherosclerosis scores in the tested population. The analysis displayed in Table 4included only patients not taking any cholesterol-lowering agent. The presence of diabetes affected the “extent score,” “atherosclerosis score” and occlusion rate but did not affect the mean “coronary score,” nor the mean “severity score.” However, the major predictors were age, gender and hypertension.
Impact of the new categories of hyperglycemia on the pattern of coronary atherosclerosis
Table 5shows the compared angiographic scores between patients with normal fasting glucose, impaired fasting glucose, “mild” diabetes and WHO-defined diabetes. The “coronary score,” “atherosclerosis score,” “extent score,” occlusion rate, prevalence of proximal/distal lesions and distribution of severity grade significantly increased with increasing plasma glucose categories, as opposed to the “severity score.” There was no significant difference in these indexes between patients with normal plasma glucose and patients with impaired fasting glucose. On the other hand, major and statistically significant differences in these angiographic scores were observed between patients with normal FPG and patients with WHO-defined diabetes, except for the “severity score.” The “coronary score,” “extent score,” “atherosclerotic score” and occlusion rate in patients with “mild” diabetes was intermediate between these two patients’ subgroups but overall more similar to the patients with normal plasma glucose or impaired fasting glucose than they were to the WHO-defined patients with diabetes.
Figure 1depicts the distribution of coronary segments by severity grade (normalized to 15 segments) and by increasing categories of fasting plasma glucose. It shows that the patients with “mild” diabetes had a pattern of coronary lesions very similar to the patients with a FPG below 7 mM/L and significantly fewer segments of a given severity grade than WHO-defined patients with diabetes. However, they had a number of mildly diseased coronary segments significantly greater than patients with normal FPG or impaired fasting glucose (p = 0.05) and were similar to the WHO-defined patients with diabetes.
Evidence for a particular pattern of coronary atherosclerosis in patients with diabetes
More than a decade ago, large cross-sectional studies from Lemp et al. (3)and Freedman et al. (4)reported a comorbid association between type 2 diabetes and angiographic severity of CAD. Changing the definition of diabetes according to the recommendations of the ADA Expert committee published in 1997 (8)does not change the strength of this association. However, the angiographic scores that were used to defined CAD in these pioneering studies only considered severe lesions: presence of at least one >70% stenosis (3), number of diseased vessels (≥75% stenoses) and summed obstruction score (4), presence of at least one >50% stenosis (5). This could have biased the true evaluation of coronary atherosclerosis and minimized the prognostic importance of “nonhemodynamically significant” obstructive lesions although these nonsevere lesions could become unstable and affect outcome by leading to myocardial infarction and death (15–17). More thorough analysis of the compared coronary anatomy in this study, including nonstenotic atheromatous plaques, shows that ADA-defined patients with diabetes have not only a greater number of diseased coronary segments (on average +1.6 out of 15 segments) but also a proportional increased prevalence of mild (>25%), moderate (>50%) and severe (>75%) stenoses and a higher prevalence of total or subtotal vessel occlusion (odds ratio: 1.8 overall, 2.3 for proximal and 1.5 for distal occlusions), although none of these patients had any history of infarction or Q waves on the ECG. Besides, presence of diabetes affects the extent of mild to severe coronary atherosclerosis, both in the proximal and distal epicardial arteries. Using quantitative coronary angiography, Pajunen et al. (6)also found similar average percent diameter stenosis and atheroma burden (ratio of the plaque area to the segment length) between 55 type 2 patients with diabetes and 55 patients without diabetes who were matched for age, gender and body mass index. As opposed to our findings, however, the “extent score,” that was defined by the ratio of the stenosis length to the segment length, was not significantly different between patients with and without diabetes. This discrepancy might be due to differences in population sample and selection and in quantification methodologies. In few studies, intravascular ultrasound has been used to provide insights into the respective role of vascular remodeling and plaque accumulation on lumen compromise in nonstenotic coronary vessels (18)and stenotic lesions before angioplasty (19). Limited vessel wall remodeling was observed in both studies but seemed to be confined to patients with type 1 diabetes, whereas patients with type 2 diabetes had very similar plaque burden and vascular remodeling to subjects without diabetes, at least in obstructive (>50% stenotic) lesions (19). Further studies of the vessel wall will help us better understand the underlying mechanisms of this diffuse compromise of the coronary arteries in patients with type 2 diabetes.
Interestingly, however, the presence of diabetes did not seem to affect the average degree of stenosis and plaque growth since the “severity score” that computes the average grade of the diseased segments was similar in patients with and without diabetes. The increased prevalence of total or subtotal vessel occlusion in patients with diabetes might, thus, be explained by an intrinsic susceptibility to subacute arterial thrombosis of moderate stenoses that combines endothelium dysfunction (20), platelet hyperaggregability and impaired fibrinolytic activity (21,22).
This association between type 2 diabetes and coronary atherosclerosis persists after adjustment for other well-known cardiovascular risk factors, as well as for the presence of ischemic symptoms, confirming previous findings (3)but in contradiction with other data based on a different methodology (histologic analysis of coronary specimens) and a smaller nondiabetic population (7). Altogether, our angiographic data further document the independent contribution of hyperglycemia to the initiation or development of coronary atherosclerosis. However, stepwise analyses showed that type 2 diabetes was less determinant in coronary atherosclerosis development than age, gender, LDL-cholesterol or hypertension (Table 4). These findings may partly explain why vigorous control of blood pressure and cholesterol levels have a much more beneficial impact on cardiovascular prognosis than the strict control of glycemia in patients with diabetes (23,24).
Impact of the new hyperglycemia categories on pattern of CAD and prognostic implications
From data collected in the Paris Prospective Study that recruited 6,557 middle-aged men free of any clinical cardiovascular disease and followed them for up to 23 years, Charles et al. (25)recently showed that the risk of death from coronary heart disease increased with increasing fasting plasma glucose. The age-adjusted death rate per 1,000 person-years was 2.1, 2.8, 5.4 and 6.3 for men having a fasting plasma glucose categorized closely according to the revised criteria advocated by the ADA, namely below 5.8 mM/L, between 5.8 mM/L and 6.9 mM/L, between 6.9 mM/L and 7.8 mM/L and above 7.8 mM/L, respectively. The risk of coronary death was almost doubled for a fasting plasma glucose above 6.9 mM/L with a limited additional risk above 7.8 mM/L, substantiating the choice of 7.0 mM/L as the new threshold to define diabetes and provide rigorous care. This increased risk of major cardiac events is usually thought to be attributable to accelerated or earlier development of coronary atherosclerosis. However, although WHO-defined patients with diabetes clearly have greater atherosclerosis indexes than patients without diabetes that may explain their increased risk of coronary death, the 20 patients with “mild” diabetes (7.0 to 7.7 mM/L FPG) have a coronary atherosclerosis pattern very similar to the patients without diabetes and a less severe pattern than the WHO-defined patients with diabetes. Only mildly severe (25% to 49% diameter stenosis) lesions were significantly more prevalent in patients with “mild” diabetes than they were in patients with normal plasma glucose and were as prevalent as in the WHO-defined patients with diabetes (Fig. 1). Young and soft atheromatous plaques are known to be the most prone to rupture and thrombosis (26–28), even before they become flow-limiting. Indeed, these atheromatous plaques of less than 50%-diameter stenosis have been previously shown to represent more than 60% of the ruptured and thrombotic plaques causing acute myocardial infarction and sudden death (15–17). Taken together, these findings suggest that part of the increased risk of cardiovascular death in “mild” diabetes (25)might be accounted for by a greater number of mildly severe, young and vulnerable coronary stenoses, even in asymptomatic subjects.
In such a study design, selection of the population may introduce important biases in the findings. Two-thirds of our patients had ischemic symptoms (whether chronic or unstable angina) requiring coronary evaluation and do not represent a standard diabetic population. By comparison with the United Kingdom Prospective Diabetes Study (UKPDS) (29), from which patients with significant ischemic heart disease were excluded, our patients with diabetes were, on average, 10 years older and more often men (76.3% vs. 61%), had higher cholesterol levels (mean total-cholesterol 5.72 mM/L vs. 5.4 mM/L) and took platelet-blocking (60.2% vs. 1.6%), antihypertensive (52.7% vs. 12%) and lipid-lowering (35.9% vs. 0.3%) medications more frequently. Although adjustment on symptoms of myocardial ischemia did not change the association between coronary atherosclerosis indexes and diabetes in our study, these findings should not be extended to the whole diabetic population, especially to younger patients.
Coronary angiography has its own limitations in the study of coronary atherosclerosis. It may underestimate the early development of atheroma (30)since compensatory enlargement of the vessel wall may initially accommodate young atheromatous plaques with limited lumen deformation. On the other hand, infiltrating and diffuse atheroma may also be underestimated since there may not be normal coronary segments to be taken as the reference lumen. Differences in atherosclerosis indexes between patients without diabetes and patients with type 2 diabetes who are more prone to diffuse atheroma might be even greater than found in this study. The use of intravascular ultrasound might overcome this limitation, but it allows the study of a limited number of coronary plaques in a given patient as mentioned above.
Plasma glucose was measured once, after an overnight fasting period. Categorization of a few patients using the ADA criteria might have been misleading due to intraindividual variations of FPG levels.
This angiographic study shows that patients with type 2 diabetes (FPG ≥ 7 mM/L) have a more diffuse coronary atherosclerosis, a greater prevalence of stenoses of any grade and a two-fold higher occlusion rate than patients without diabetes, even after adjustment for the other clinical and biological cardiovascular risk factors. Patients with 7 mM/L to 7.7 mM/L FPG, who are now considered to be diabetic, have an atherosclerotic pattern more similar to patients without diabetes than to the former WHO-defined patients with diabetes, except for a greater prevalence of <50% stenoses. This excess in potentially vulnerable coronary lesions may explain the increased cardiac mortality observed in this subset of patients and substantiate the need for specific cardiovascular and metabolic care in these patients.
- American Diabetes Association
- coronary artery disease
- fasting plasma glucose
- high density lipoprotein
- low density lipoprotein
- World Health Organization
- Received May 11, 2000.
- Revision received December 13, 2000.
- Accepted January 17, 2001.
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