Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus

INTRODUCTION — Heart disease, particularly coronary heart disease (CHD), is a major cause of morbidity and mortality among patients with diabetes mellitus [1]. The epidemiology of and risk factors for CHD and the frequency of silent myocardial ischemia in patients with diabetes will be reviewed here. Therapeutic issues are discussed separately. (See "Acute myocardial infarction: Patients with diabetes mellitus" and "Coronary artery revascularization in stable patients with diabetes mellitus".)

PREVALENCE AND EXTENT OF INCREASED RISK — Compared with individuals without diabetes, those with diabetes have a higher prevalence of coronary heart disease (CHD), have a greater extent of coronary ischemia, and are more likely to have a myocardial infarction (MI) and silent myocardial ischemia [2]. This elevated risk prompted the National Cholesterol Education Program report from the United States and guidelines from Europe to consider type 2 diabetes to be a CHD equivalent, thereby elevating it to the highest risk category [3,4]. However, although diabetes confers an increased risk of CHD events, subsequent data have called into question its designation as a CHD risk equivalent [5]. For example, in a meta-analysis of 13 studies representing over 45,000 patients, those with diabetes but no history of MI had a 43 percent lower risk of CHD events compared with patients without diabetes who had a history of MI (odds ratio [OR] 0.56, 95% CI 0.53-0.60) [6].

The elevated risk for CVD in type 2 diabetes is likely dependent on the aggregation of risk factors and the effectiveness of guideline-based treatment for them [7]. While patients with diabetes have a higher risk of CVD than those without diabetes, the absolute risk has decreased due to adherence to guideline-endorsed preventive measures (eg, statins) [8,9].

The importance of the association between diabetes and CHD can be illustrated by findings from the Framingham Heart Study and the Multiple Risk Factor Intervention Trial (MRFIT). In the Framingham Heart Study, the presence of diabetes doubled the age-adjusted risk for cardiovascular disease in men and tripled it in women [10]. Diabetes remained a major independent cardiovascular risk factor even when adjusting for advancing age, hypertension, smoking, hypercholesterolemia, and left ventricular hypertrophy.

Similar observations were noted in MRFIT [11]. Among 5163 men who reported taking medications for diabetes (mostly type 2), 9.7 percent died from cardiovascular disease over a 12-year period; the comparable cardiovascular death rate in the 342,815 men not taking medications for diabetes was 2.6 percent. This difference was independent of age, ethnic group, cholesterol level, systolic blood pressure, and tobacco use. However, among diabetic men, the increase in cardiovascular risk rose more steeply than in nondiabetics with the addition of each of these risk factors.

The Emerging Risk Factors Collaboration group performed a meta-analysis of 102 studies that included 530,083 patients with no history of MI, angina, or stroke at the initial study visit [12]. After adjusting for other risk factors, patients with diabetes had an overall risk of CHD twice that of patients without diabetes (hazard ratio [HR] 2.0, 95% CI 1.8-2.2), with a similarly higher risk of cardiac death (HR 2.3, 95% CI 2.1-2.6) and non-fatal MI (HR 1.8, 95% CI 1.6-2.0).

The relative risk for cardiovascular disease compared with nondiabetics of similar age is even greater in patients with type 1 diabetes [13]. In a cohort of 292 patients, CHD mortality increased rapidly after age 30, particularly in patients with kidney disease. The cumulative CHD mortality was 35 percent by age 55, compared with 8 and 4 percent in nondiabetic males and females, respectively, in the Framingham Heart Study. Similar relationships were noted for nonfatal MI and angina.

The age at which an individual transitions to a high risk for cardiovascular disease category is another way to demonstrate the powerful risk imparted by the presence of diabetes mellitus. This relationship was evaluated in a retrospective, population-based cohort of Canadians using a large provincial health claims database [14]. The transition to a high-risk category (10-year event rate risk of greater than 20 percent) occurred at a younger age for patients with type 2 diabetes than for those without diabetes (mean difference 15 years). Using a broad definition of cardiovascular disease, the age of onset of high risk was 41 and 48 years for males and females with diabetes, respectively.

Extent of coronary disease — Most [15-22] but not all [23] studies have found that the extent of the disease in the coronary arteries is greater among diabetic patients. As an example, the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial provided coronary angiographic data obtained during an acute myocardial infarction [19]. TAMI included 148 diabetic and 923 nondiabetic patients in whom cardiac catheterization was performed at 90 minutes and 7 to 10 days after thrombolytic therapy [19]. Compared with the nondiabetics, the diabetic patients had a significantly higher incidence of multivessel disease (66 versus 46 percent) and a greater number of diseased vessels.

Multivessel CHD is also common in asymptomatic patients with type 2 diabetes, particularly those with two or more coronary risk factors other than diabetes [24]. There also may be an association between the extent of coronary disease and the degree of glycemic control. (See 'Silent ischemia and infarction' below and 'Hyperglycemia' below.)

Temporal trends — The incidence of cardiovascular disease has declined substantially in adults with and without diabetes over the last 50 years. The magnitude of this effect and the persistence of greater risk in diabetic patients were illustrated in a report from the Framingham Heart Study of participants seen between 1950 and 1966 and between 1977 and 1995 [25].

The age and sex-adjusted rate of cardiovascular events (MI, CHD death, or stroke) declined from 287 to 147 per 10,000 person years in participants with diabetes (a 49 percent decline) and from 85 to 54 cardiovascular events in those without diabetes (a 35 percent decline). Diabetes was still associated with a twofold increase in risk (multivariable-adjusted HR 1.96, 95% CI 1.44-2.66). The reductions in risk were similar in males and females.

However, different findings were noted in a report from the National Health and Nutrition Examination Survey (NHANES), which evaluated the time periods of 1971 to 1975 and 1982 to 1984 [26]. There was smaller decline in cardiovascular mortality over time in diabetic men (13 versus 36 percent in nondiabetic men), while the risk declined by 23 percent in diabetic women (compared with a 27 percent decline in risk in nondiabetic women). A possible explanation for the difference in findings is that the Framingham Heart Study compared outcomes over a much longer period, beginning in the 1950s and ending in the 1990s. In addition, the diagnosis of diabetes was confirmed in the Framingham report compared with a patient-reported clinician diagnosis in NHANES.

Myocardial infarction — Diabetes is associated with an increased risk of MI. In the worldwide INTERHEART study of patients from 52 countries, diabetes accounted for 10 percent of the population-attributable risk of a first MI [27]. (See "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.)

The importance of diabetes as a risk factor for MI was demonstrated in a study that compared the seven-year incidence of MI in 1373 nondiabetics and 1059 patients with type 2 diabetes in Finland [2]. Type 2 diabetics without a prior infarction were at the same risk for MI (20 and 19 percent, respectively) and coronary mortality (15 versus 16 percent) as nondiabetics with a prior MI. The risk of infarction was greatest in diabetics with a prior MI and lowest in nondiabetics without a prior MI (45 and 4 percent, respectively). These findings were independent of other risk factors such as total cholesterol, hypertension, and smoking.

Similar findings have been noted in other studies [28,29], including a much larger series of 13,790 patients in a population-based cohort from the Atherosclerosis Risk In Communities (ARIC) study in the United States [28]. At nine years’ follow-up, there were 634 cardiac deaths or nonfatal MIs (4.6 percent). Event rates varied among patients with or without diabetes and with or without a history of MI as follows:

●No diabetes and no MI – 3.9 percent

●Diabetes and no MI – 10.8 percent

●No diabetes and prior MI – 18.9 percent

●Diabetes and prior MI – 32.2 percent

These relationships may vary based on patient sex. In another report from Finland, prior MI was a greater risk factor for CHD mortality than diabetes without a prior MI in men (HR 1.78), but diabetes without a prior MI was a greater risk factor in women (HR 1.75) [30]. (See "Overview of atherosclerotic cardiovascular risk factors in females".)

In addition to the increase in mortality, diabetic patients are also more likely to experience a complication associated with an MI, including postinfarction angina and heart failure. Possible contributory factors are that diabetic patients are more likely to have multivessel disease [24] and fewer coronary collateral vessels [31].

Asymptomatic CHD — In addition to the increase in cardiovascular events, patients with type 2 diabetes also have a high rate of asymptomatic coronary disease as determined by the presence of coronary artery calcification (CAC) on electron-beam computed tomography (CT) scanning and by inducible silent ischemia on stress imaging [32]. These issues, as well as possible screening for CHD in patients with diabetes, are discussed in detail separately. (See "Screening for coronary heart disease in patients with diabetes mellitus".)

In addition to an increased rate of structural disease, patients with type 2 diabetes also have reduced myocardial flow reserve, a reflection of coronary vasodilator capacity [33,34]. This abnormality is inversely related to glycemic control [33].

Silent ischemia and infarction — Some diabetic patients have a blunted appreciation of ischemic pain, which may result in atypical anginal symptoms, silent ischemia, or even silent infarction. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".)

Silent ischemia in diabetes is thought to be caused at least in part by autonomic denervation of the heart [35-38]. In support of this hypothesis is the observation that the uptake of iobenguane I-123 (diagnostic), a norepinephrine analog, is reduced in diabetic patients with silent ischemia [37]. This finding is suggestive of sympathetic denervation, which has also been seen with positron emission tomography [34,39]. Furthermore, regional heterogeneity in sympathetic innervation can predispose to myocardial electrical instability that may lead to life-threatening arrhythmias [39]. (See "Diabetic autonomic neuropathy".)

Another component of decreased perception of myocardial ischemia is that diabetic patients have a prolongation of the anginal perceptual threshold during exercise testing (ie, the time from onset of ischemic changes on the electrocardiogram to the onset of angina) [40]. The longer the threshold, the greater the exercise capacity and the more severe the ischemia.

Diabetic patients also have an increased frequency of silent ST segment depression and coronary perfusion abnormalities during stress testing. Although the supportive data are presented separately, the potential magnitude of silent CHD can be illustrated by the results of the following study (see "Screening for coronary heart disease in patients with diabetes mellitus"):

●The rate of silent ischemia was evaluated in an observational study of 1899 asymptomatic patients with type 2 diabetes age ≤60 years (mean age 53) [24]. The patients underwent stress testing with dipyridamole myocardial contrast echocardiography (MCE) and follow-up coronary angiography if the MCE were abnormal. The stress test was abnormal in 60 percent, 65 percent of whom had significant coronary disease on angiography.

●This report also evaluated the relationship between the number of risk factors and the presence of silent ischemia. Sixty percent of patients had ≥2 CHD risk factors (dyslipidemia, hypertension, smoking, a positive family history of premature CHD, or the presence of microalbuminuria).

●The two risk groups (≥2 versus 0 or 1 risk factors) had equivalent rates of an abnormal stress test (60 percent) and significant coronary disease on angiography (65 percent). However, the patients with ≥2 risk factors had more severe coronary disease with significantly higher rates of three-vessel disease (33 versus 8 percent), diffuse disease (55 versus 18 percent), and vessel occlusion (31 versus 4 percent); they also had a lower rate of single-vessel disease (46 versus 71 percent). (See "Coronary artery revascularization in stable patients with diabetes mellitus".)

Diabetes is associated with an increased frequency of unrecognized MI, as well as silent ischemia, at least in men [35,41,42]. In a report from the Framingham Heart Study, for example, the fraction of infarctions that were detected on routine electrocardiograms but unrecognized clinically was more than twice that in nondiabetic men (39 versus 18 percent) [41]. By comparison, diabetic women were less likely to have silent infarction, a finding also noted in a report from the Heart and Estrogen/Progestin Replacement Study (HERS) [43].

CHD before diabetes — Impaired glucose tolerance or overt diabetes may first be diagnosed in the setting of acute MI. This could reflect blood testing being performed during the hospitalization in patients with previously unrecognized diabetes. A second mechanism is that the stress of MI unmasks or worsens the tendency toward hyperglycemia.

The potential frequency with which this might occur was demonstrated in a prospective study of 181 patients with an acute MI and no previous diagnosis of diabetes in whom the fasting blood glucose and two-hour blood glucose after a standard load were serially measured [44]. Impaired glucose tolerance was present in 35 percent at hospital discharge and in 40 percent three months later. The respective values for previously undiagnosed diabetes were 31 and 25 percent using oral glucose tolerance test criteria and 10 and 13 percent when only the fasting blood glucose was used.

The hemoglobin A1C concentration on admission was an independent predictor for abnormal glucose tolerance at three months, indicating that the metabolic abnormality preceded the infarction and that the hyperglycemia could not be entirely attributed to stress.

These findings strongly suggest that the fasting plasma glucose concentration and hemoglobin A1c should be measured during hospitalization in nondiabetic patients with an acute MI and that elevated values be repeated after discharge to identify those at increased risk. Whether an oral glucose test should be part of the standard evaluation remains uncertain.

An increase in risk before the diagnosis of diabetes was also noted in a report from the Nurses' Health Study in which approximately 5 percent of over 115,000 initially nondiabetic women developed type 2 diabetes at 20-year follow-up [45]. These women had a multivariate adjusted relative risk for MI before the diagnosis of diabetes of 3.17 (95% CI 2.61-3.85).

There appears to be a graded rise in cardiovascular risk with increasing degrees of glucose intolerance below the definition of overt diabetes [46-52].

●In a meta-analysis of 20 studies that included almost 100,000 people, there was a curvilinear increase in the risk for a cardiovascular event with increasing glucose intolerance. As an example, when compared with patients with a fasting glucose of 75 mg/dL (4.2 mmol/L), the risk of an event was higher in patients with a fasting glucose of 110 mg/dL (6.1 mmol/L) or a two-hour glucose of 140 mg/dL (7.8 mmol/L) (relative risk [RR] 1.33 and 1.58, respectively) [46].

●Among survivors in the Framingham Heart Study, the HbA1c concentration was significantly related to prevalent cardiovascular disease in women but not men [48]. For each 1 percent increase in HbA1c (eg, from 5 to 6 percent), the relative odds of cardiovascular disease was 1.39 (95% CI 1.06-1.83).

●In a review of over 10,000 adults, a 1 percentage point increase in HbA1c was associated with a relative risk for all-cause mortality of 1.24 (95% CI 1.14-1.34) in men and 1.28 (95% CI 1.06-1.32) in women [51]. The relative risk was not changed (1.26) when patients with known diabetes or cardiovascular disease or an HbA1c ≥7 percent were excluded. The increase in risk was also independent of other major cardiovascular risk factors. The rates of cardiovascular disease and mortality were lowest at HbA1c values less than 5 percent, a finding that has also been noted in another study [53].

It has been suggested that the two-hour glucose has greater predictive value than the fasting glucose [44,49]. Similar findings have been noted in other studies in which higher glucose levels two hours after an oral glucose tolerance test were also more closely associated than fasting glucose levels with cardiovascular risk factors [54,55].

Among patients with diabetes, the impact of glycemic control on cardiovascular risk is discussed below. (See 'Effect of glycemic control' below.)

CHD RISK FACTORS AND DIABETES — Patients with diabetes have a greater burden of atherogenic risk factors than nondiabetics, including hypertension, obesity, lipid abnormalities, and elevated plasma fibrinogen [1,56,57]. Many of these risk factors are also present in the prediabetic state prior to conversion to overt type 2 diabetes [58].

Patients with the constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia are considered to have metabolic syndrome (also called insulin resistance syndrome or syndrome X), which is associated with increased cardiovascular risk. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

The coronary heart disease (CHD) risk in patients with diabetes varies widely with the intensity of these risk factors. The evidence is strongest for hypertension, elevated low-density lipoprotein (LDL), smoking, metabolic syndrome, hyperglycemia, and microalbuminuria. The following discussion is limited to the unique aspects of coronary risk factors in patients with diabetes.

Hypertension — The general role of hypertension as a risk factor for cardiovascular disease and its importance in patients with diabetes are discussed in detail elsewhere. (See "Cardiovascular risks of hypertension" and "Treatment of hypertension in patients with diabetes mellitus".)

Summarized briefly, hypertension is present at diagnosis in many patients with type 2 diabetes but generally does not occur until after the onset of kidney disease in patients with type 1 diabetes [59]. The most compelling evidence for the importance of hypertension in diabetes comes from the United Kingdom Prospective Diabetes Study (UKPDS) [60]. The following findings were noted at nine-year follow-up:

●Each 10 mmHg reduction in updated mean systolic pressure was associated with a 12 percent risk reduction in any complication related to diabetes (including cardiovascular disease); the lowest risk occurred at a systolic pressure below 120 mmHg.

●A similar relationship was noted with fatal or nonfatal MI as the incidence fell from 33.1 per 1000 patient years at an updated mean systolic pressure ≥160 mmHg to 18.4 per 1000 patient years at an updated mean systolic pressure below 120 mmHg.

Based upon these and other observations, antihypertensive therapy is warranted in all hypertensive patients with diabetes [61]. The optimal goal blood pressure and choice of antihypertensive drugs in such patients are discussed in detail separately.

Dyslipidemia — There are a number of differences in the lipid profile between diabetics and nondiabetics that may contribute to the increase in atherosclerosis [62,63]. The serum lipid abnormalities differ somewhat in patients with type 1 and type 2 diabetes [63]. These abnormalities are discussed in detail elsewhere but will be briefly reviewed here.

●The lipid pattern in patients with type 1 diabetes is largely related to glycemic control. The Diabetes Control and Complications Trial (DCCT) found that patients with type 1 diabetes (mean HbA1c 8.8 percent) had similar serum lipid values as nondiabetic individuals in the Lipid Research Clinics (LRC) prevalence study except for young women, who had somewhat higher serum total cholesterol and lower high-density lipoprotein (HDL) cholesterol concentrations [64]. By comparison, worse glycemic control is characteristically associated with hypertriglyceridemia and low HDL cholesterol concentrations [62,65].

●Among patients with type 2 diabetes, insulin resistance, relative insulin deficiency, and obesity are associated with hypertriglyceridemia, low serum HDL cholesterol concentrations, and occasionally high serum LDL cholesterol and lipoprotein(a) values [62,63]. This pattern of lipid abnormalities can be detected before the onset of overt hyperglycemia and is thought to be due in part to hyperinsulinemia and/or insulin resistance [66].

For any serum lipoprotein concentration, diabetic patients have more coronary disease than nondiabetic patients. This increase in risk may be due in part to qualitative differences in the lipoprotein fractions or to the presence of other proatherosclerotic metabolic changes. Among these changes are high serum concentrations of small dense LDL particles, enhanced oxidative modification of LDL, and elevations in serum lipoprotein(a) [63].

The association of elevated LDL cholesterol with cardiovascular risk in many epidemiologic studies has been reinforced by randomized clinical trials showing that statin therapy improves outcomes in diabetics, including those without clinical evidence of CHD and those with values below 116 mg/dL (3 mmol/L) [67,68]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

Non-HDL cholesterol (total cholesterol minus HDL cholesterol, which includes all cholesterol present in lipoprotein particles considered to be atherogenic; LDL, lipoprotein(a), intermediate-density lipoprotein, and very low-density lipoprotein [VLDL]), appears to be a particularly strong predictor of CHD in both males and females with diabetes [69]. Elevated triglycerides carry significant CHD risk, which is not reduced by LDL treatment and improves with targeted therapy [70]. (See "Hypertriglyceridemia in adults: Management", section on 'Moderate hypertriglyceridemia'.)

Smoking — As in nondiabetics, smoking in patients with diabetes increases cardiovascular morbidity and mortality, raises serum LDL cholesterol, and can impair glycemic control [71]. This increase in risk is gradually reduced with smoking cessation.

Hyperglycemia — There is a graded rise in cardiovascular risk with increasing hyperglycemia in patients with overt diabetes. The magnitude of this effect was illustrated in a meta-analysis of 13 prospective cohort studies (10 in type 2 diabetes, including the UKPDS) [72]. For every one percentage point increase in glycosylated hemoglobin (HbA1c), the relative risk for any cardiovascular event was 1.18 (95% CI 1.10-1.26).

There may also be an association between HbA1c and the extent of coronary disease. This was suggested in a review of 315 patients with diabetes who underwent coronary angiography because of chest pain [73]. The mean HbA1c increased progressively in patients with zero-, one, two-, or three- to four-vessel disease (6.7, 8.0, 8.8, and 10.4, respectively, a trend that was highly significant). There was no significant difference among the four groups in the duration of diabetes or the prevalence of smoking, hypertension, or dyslipidemia.

As noted above, there is also a graded rise in cardiovascular risk with increasing degrees of glucose intolerance below the definition of overt diabetes [46-50]. (See 'CHD before diabetes' above.)

Effect of glycemic control — Strict glycemic control is recommended in both type 1 and type 2 diabetes because of demonstrated benefits in terms of microvascular disease. Protection against macrovascular disease is established only in type 1 diabetes. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Macrovascular disease'.)

Protection against macrovascular disease with strict glycemic control has not been established in type 2 diabetes. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Strict glycemic control appears to be important in patients with an acute myocardial infarction (MI). The data addressing this issue are presented separately.

Female sex — The increase in CHD risk in patients with diabetes is greater in women than in men [47,74]. The magnitude of this effect was illustrated in a meta-analysis of 37 studies of almost 450,000 patients with type 2 diabetes: the summary relative risk for fatal CHD in patients with diabetes was 3.5 in women and 2.1 in men [74]. The excess risk is at least in part due to diabetes being more commonly accompanied by other cardiovascular risk factors in women.

Microalbuminuria — Microalbuminuria is the earliest clinical manifestation of diabetic nephropathy and is associated with an increased risk of cardiovascular disease in both diabetic and nondiabetic patients. These relationships are discussed in detail elsewhere. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

The magnitude of the predictive value of microalbuminuria was illustrated in a review of over 9000 participants in the Heart Outcomes Prevention Evaluation (HOPE) trial [75]. The presence of microalbuminuria was associated with an increased relative risk of the primary aggregate endpoint (MI, stroke, or cardiovascular death) in those with and without diabetes (1.97 and 1.61, respectively) [75]. The risk of an adverse cardiovascular event increased progressively with increased absolute levels of microalbuminuria.

A similar impact of microalbuminuria was found among participants in the LIFE trial [76]. The urine albumin-to-creatinine ratio was measured in 7143 nondiabetic subjects (median value 1.16 mg/mmol [10.2 mg/g]) and 1063 subjects with diabetes (median value 3.05 mg/mmol [26.9 mg/g]). For every 10-fold increase in the albumin-to-creatinine ratio, the risk of cardiovascular death, MI, or stroke increased by 39 percent, and the risk of cardiovascular death increased by 47 percent among diabetics. The respective increases in risk for nondiabetics were 57 and 98 percent.

Annual cardiovascular death rates also increase with worsening diabetic nephropathy. This was illustrated in an analysis of 5097 subjects in the UKPDS [77]. Annual cardiovascular death rates for no nephropathy, microalbuminuria, macroalbuminuria, and elevated plasma creatinine concentration or kidney replacement therapy were 0.7, 2.0, 3.5, and 12.1 percent, respectively [77].

One observational study found that increased urinary albumin excretion and reduced estimated glomerular filtration rate are independent risk factors [78].

Exercise — Regular exercise is associated with a lower risk of both CHD and cardiac death for both primary and secondary prevention. However, most of the evidence comes from long-term observational studies in which those who exercise regularly have significantly less CHD. Unfortunately, this type of evidence is subject to bias, since the decision to exercise is only one of the many choices made in adopting a healthy lifestyle (eg, cessation of smoking). Thus, attribution of exercise as a prevention of CHD is confounded by other favorable reductions in risk characteristics. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Similar observational studies have been performed in patients with diabetes:

●In a prospective cohort study of 2896 diabetic adults, those who walked for at least two hours per week had lower cardiovascular mortality rates when compared with inactive individuals (hazard ratio [HR] 0.66, 95% CI 0.45-0.96; 1.4 versus 2.1 percent per year, respectively) [79].

●In a similar study in 3316 Finnish patients with diabetes, both occupational and leisure time physical activity were associated with a significant reduction in cardiovascular mortality (HR 0.69 for both) and total mortality (HR 0.67 and 0.72, respectively) [80].

Lack of moderate alcohol intake — The consumption of a moderate amount of alcohol may have health benefits, particularly with regard to coronary disease. (See "Cardiovascular benefits and risks of moderate alcohol consumption".)

The effect of light to moderate alcohol consumption in diabetic patients was evaluated in the Physicians' Health Study of 87,938 subjects who were free of MI, cancer, or liver disease at baseline; 2790 had diabetes [81]. After a 5.5-year follow-up, diabetic patients who consumed alcohol on a weekly or daily basis had a significantly lower risk of death from CHD than those who rarely or never consumed alcohol (adjusted relative risk 0.67 and 0.42). The risk reduction was similar to that seen in nondiabetics.

Similar benefits of moderate alcohol consumption were noted in diabetic women in the Nurses' Health Study, which evaluated 5103 women with a diagnosis of diabetes at ≥30 years of age who were free of CHD, stroke, or cancer at baseline [82]. Compared with diabetic women reporting no alcohol intake, the adjusted relative risk for nonfatal or fatal CHD for diabetic women reporting a daily intake of 0.1 to 4.9 g of alcohol (<0.5 drinks) or ≥5 g (≥0.5 drinks) was 0.72 and 0.45, respectively.

Hyperhomocysteinemia — An elevated serum concentration of homocysteine is a known risk factor for atherosclerosis and is associated with an increased risk of MI and death. The risk appears to be greater in patients with diabetes as illustrated in a review of 2484 adults aged 50 to 75 years [83]. After adjusting for major cardiovascular risk factors, the odds ratio for five-year mortality for hyperhomocysteinemia was 2.51 for diabetics compared with 1.34 for nondiabetics. For each 5 micromol/L increment in serum homocysteine concentrations, the odds ratio for diabetics and nondiabetics was 1.60 and 1.17, respectively. (See "Overview of homocysteine".)

MECHANISMS OF INCREASED RISK — A variety of mechanisms may contribute to the increase in coronary heart disease (CHD) risk in patients with diabetes in addition to the effects on blood pressure and lipid metabolism. A complete review is beyond the scope of this discussion [84].

Endothelial dysfunction — Endothelial dysfunction has been documented in diabetic patients who have normal coronary arteries and no other risk factors for coronary disease [84-89]. The degree of impairment is related to the duration of diabetes, but a defect can occur acutely in patients who develop postprandial hyperglycemia despite having a normal fasting plasma glucose [90].

The presence of insulin resistance alone may be associated with coronary endothelial dysfunction [91,92]. In a study of 50 insulin-resistant and 22 insulin-sensitive Mexican-American participants without glucose intolerance, CHD, hypertension, cigarette use, or dyslipidemia, endothelium-dependent coronary vasomotor function was abnormal (as assessed by myocardial blood flow response to a cold pressor test) in the insulin-resistant compared with the insulin-sensitive group [91].

After three months of thiazolidinedione therapy, insulin sensitivity and coronary vasomotor function improved in the insulin-resistant subjects [91]. Endothelial function can also be improved by metformin in patients with type 2 diabetes and atorvastatin and vitamin E in patients with type 1 diabetes [93-95]. Whether the improvement in endothelial function leads to better outcomes is not known.

Platelet activation — Diabetes has a number of effects on platelet function that may predispose to coronary thrombosis. These include increased primary and secondary platelet aggregation [96-98]; increased platelet activation [99] with release of the contents of alpha-granules, including thromboglobulin and platelet factor 4 [100]; and enhanced binding of fibrinogen to the glycoprotein IIb/IIIa complex, located on the platelet surface, an effect which may be due in part to an increase in the number of glycoprotein IIb/IIIa receptors on the platelet surface.

The altered platelet function in diabetics may be mediated in part by elevated blood glucose. In one study of 42 patients with stable coronary artery disease, the fasting blood glucose was an independent predictor of platelet-dependent thrombosis [101]. This relationship was continuous and graded and was even evident in a range of glucose levels considered to be normal. Plasma insulin levels were not associated with platelet-mediated thrombosis.

Coagulation abnormalities — In addition to platelet activation, diabetes also predisposes individuals to abnormalities in various pathways involved in coagulation, hemostasis, and fibrinolysis [102]. The following are among the abnormalities that have been described.

●Diabetes is associated with an increase in plasma fibrinogen, which is a cardiovascular risk factor [103-105]. Elevated plasma fibrinogen is also associated with other cardiovascular risk factors including older age, increased body mass, smoking, total cholesterol, and triglycerides [105].

●Fibrinolytic activity is reduced [106,107]. Although circulating tissue-type plasminogen activator (tPA) levels are normal or increased in the plasma of diabetics, tPA activity is decreased because of increased plasma concentrations of and enhanced binding to its inhibitor, plasminogen activator inhibitor (PAI-1) [108,109]. Elevations in PAI-1, presumably due to increased synthesis, are also found in atheromata obtained from type 2 diabetic patients undergoing atherectomy, probably reflecting increased levels in the vessel wall [110].

Hyperglycemia may contribute to impaired fibrinolysis via nonenzymatic glycosylation of certain proteins. Low-density lipoprotein (LDL) normally stimulates the production of PAI-1 and reduces the generation of tPA; these effects are enhanced by glycosylated LDL [111]. In addition, precursors of insulin such as proinsulin, the plasma concentrations of which are increased in patients with type 2 diabetes, also can contribute to the increase in PAI-1 synthesis [112].

●Both tissue factor and blood thrombogenicity are increased in patients with poorly controlled diabetes and return toward normal with improved glycemic control [113].

Plaque composition — Plaque composition may differ in diabetics and affect coronary risk. In a histologic study of atherectomy specimens from patients with and without diabetes, coronary tissue from diabetics contained a greater amount of lipid-rich atheroma, more macrophage infiltration (both of which are associated with a greater risk for plaque rupture), and a higher incidence of thrombosis [114]. Even in patients with prediabetes (defined as impaired glucose tolerance or insulin resistance in the absence of glucose intolerance) may have the phenotype of a coronary plaque with a pathobiology with a higher future risk of disruption and superimposed thrombosis [115]. However, plaques from younger patients with type 1 diabetes at autopsy were characterized by dense fibrous tissue and few foam cells, which should enhance plaque stability [116]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)

MULTIFACTORIAL RISK FACTOR REDUCTION — Risk factor reduction is effective for the secondary prevention of cardiovascular disease. This is relevant to patients with diabetes since, as mentioned above, the National Cholesterol Education Program report considered diabetes to be a coronary heart disease (CHD) equivalent [3]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

The different components and efficacy of risk factor reduction in diabetic patients, including the importance of glycemic control, are discussed separately. (See "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Treatment of hypertension in patients with diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Prevalence and extent of risk – Compared with individuals without diabetes mellitus, those with diabetes have a higher prevalence of coronary heart disease (CHD), have a greater extent of coronary ischemia, and are more likely to have a myocardial infarction (MI) and silent myocardial ischemia. The National Cholesterol Education Program report from the United States and guidelines from Europe consider type 2 diabetes to be a CHD equivalent, thereby elevating it to the highest risk category. (See 'Prevalence and extent of increased risk' above.)

●Coronary heart disease risk factors – Patients with diabetes have a greater burden of atherogenic risk factors than nondiabetics, including hypertension, obesity, and lipid abnormalities. The CHD risk in patients with diabetes varies widely with the intensity of these risk factors, with the strongest evidence seen with hypertension, elevated low-density lipoprotein (LDL), smoking, metabolic syndrome, hyperglycemia, and microalbuminuria. (See 'CHD risk factors and diabetes' above.)

●Mechanisms of increased risk – A variety of mechanisms may contribute to the increase in CHD risk in patients with diabetes, including endothelial dysfunction, platelet activation, coagulation abnormalities, and atherosclerotic plaque composition. (See 'Mechanisms of increased risk' above.)

●Risk factor reduction – This is effective for the secondary prevention of cardiovascular disease. This is particularly relevant to patients with diabetes since diabetes is considered to be a CHD equivalent. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)