Coronary Artery Disease Associated With Low-Grade Albuminuria in Type 2 Diabetes Mellitus

Original Article

Coronary Artery Disease Associated With Low-Grade Albuminuria in Type 2 Diabetes Mellitus Paulo R. Mota,1,2 Elizabeth F. Daher,3 Geraldo B. Silva Júnior,3,4 José Wellington O. Lima,5 Alexandre B. Libório,4 Adriana C. Forti1,2 Microalbuminuria can be measured in 24-hour urine samples for early detection of patients at high risk of developing vascular complications. The present study investigated the relation between vascular disease and normal levels of urinary albumin. The prevalence of coronary artery disease (CAD) and diabetic retinopathy (DR) was investigated in 145 patients with type 2 diabetes who had normal renal function. The patients were classified according to levels of microalbuminuria (normal ≤ 14 mg/24 hr, high-normal > 14 mg/24 hr to < 30 mg/24 hr). The association between CAD and DR and various patient parameters were investigated, including sex, age, time of diagnosis, family history of diabetes, smoking habits, body mass index, abdominal circumference, high blood pressure, absence of nocturnal blood pressure fall as registered by ambulatory 24-hour monitoring, retinopathy, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and glycosylated hemoglobin. The overall prevalence of CAD was 24.0% and that of DR was 18.3% among the 142 patients. A trend was observed toward an association of CAD with age > 60 years (p = 0.08) and family history of hypertension (p = 0.058). A significant association was found between CAD and high-normal microalbuminuria (relative risk 2.79; 95% confidence interval 1.88–4.16; p < 0.001). DR was statistically associated with female sex (p = 0.028) and duration of diagnosis > 5 years (p = 0.022). DR displayed a tendency for association with an absence of nocturnal blood pressure fall (p = 0.067), but was not statistically associated with either of the two levels of microalbuminuria (p = 0.657). CAD is significantly associated with the level of microalbuminuria > 14 mg/24 hr. The presence of DR could not be statistically associated with high-normal levels of microalbuminuria. [Hong Kong J Nephrol 2011;13(1):27–32] Key words: association, coronary artery disease, diabetes mellitus, microalbuminuria, retinopathy હནΝኙ࣍ᗷ‫ݟ‬ఐ൛ृΔ۞ 24 ՛ழ‫෈ݟ‬ᗴᛀ‫נ‬ऱპၦ‫ػ‬๨‫ػ‬Δ‫܂ױ‬੡ۨጥࢤࠓ࿇఑ऱ೏‫ڂٲ‬՗ Ζ ‫ء‬ઔߒኙۨጥࢤࠓ࿇఑ፖ‫ػ‬๨‫ݟػ‬఑ऱᣂএ‫נ܂‬൶ಘ Ζ ֱऄΚઔߒԳ୉‫ א‬145 ‫ۯ‬࿽‫פ‬౨‫إ‬ൄऱรԲীᗷ‫ݟ‬ఐ൛ृ੡ኙွΔኙগण೯౧ఏఐʳ (CAD) ֗ᗷ ‫ီࢤݟ‬ጻᓂఐ᧢ (DR) ऱฐ۩෷ၞ۩อૠΔࠀ௅ᖕპၦ‫ػ‬๨‫ݟػ‬఑ऱֽؓʳ ψ ( ‫إ‬ൄω≤ʳ14 mg/24 hr, ψ‫إ‬ൄೣ೏ωˑʳ14 mg/24 hrʳˏʳ30 mg/24 hr)ʳၞ۩։ิΔൕۖኙʳCAD ֗ʳDR ፖ‫א‬Հ‫ڂ‬՗ऱᣂএ‫נ܂‬։ ࣫Κࢤܑ Ε‫ ᤿ڣ‬Ε်ឰழၴ Εᗷ‫ݟ‬ఐ୮ග‫ ׾‬Ε‫ܮ‬ᄿ฾ክ ΕBMI Εᆮ໮ Ε೏ۨᚘ Ε࡙ၴۨᚘ‫נآ‬ ෼Հ૾ʳ(24 ՛ழۨᚘ጑ྒྷʼ Εီጻᓂఐ᧢ Ε᜔ᜬࡐᔧ ΕHDL ᜬࡐᔧ ΕLDL ᜬࡐᔧ ΕԿᎨ‫ز‬ई౟ Ε ֗ᗷ֏ۨદైΖ ࿨࣠Κ‫ ڇ‬142 ‫ۯ‬ఐԳၴΔCAD ֗ʳ DR ऱฐ۩෷։ܑ੡ʳ 24%֗ʳ 18.3% ΖCAD ‫׏ۿ‬ፖࠟႈ‫ڂ‬՗‫ڶ‬ ᣂΚ‫᤿ڣ‬ʳˑʳ60ᄣʳ (pʳ= 0.08) ֗೏ۨᚘ୮ග‫( ׾‬pʳ=ʳ0.058)Δ‫᧩ࣔ׊‬ፖψ‫إ‬ൄೣ೏ωპၦ‫ػ‬๨‫ݟػ‬఑‫ڶ‬

1

Postgraduate Program in Public Health, Department of Community Health, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil, 2Diabetes and Hypertension Care Center, Ceará State Secretary of Health, Fortaleza, Ceará, Brazil, 3 Department of Internal Medicine, Division of Nephrology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil, 4School of Medicine, Health Sciences Center, University of Fortaleza, Fortaleza, Ceará, Brazil, and 5Department of Public Health, School of Medicine, State University of Ceará, Fortaleza, Ceará, Brazil. Correspondence to: Professor Elizabeth De Francesco Daher, Rua Vicente Linhares, 1198, Fortaleza, CE, Brasil CEP 60135-270. E-mail: [email protected] Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

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P.R. Mota, et al

ᣂʳ(RRʳ=ʳ2.79; 95% CI, 1.88–4.16; p <ʳ0.001) ΖDRʳঞࣔ᧩ፖՖࢤࢤܑ (pʳ=ʳ0.028) ်֗ឰழၴʳˑʳ5 ‫ڶڣ‬ ᣂ (pʳ=ʳ0.022)Δٍ‫ױ‬౨ፖ࡙ၴۨᚘ‫נآ‬෼Հ૾‫ڶ‬ᣂ (pʳ=ʳ0.067)Δ‫܀‬ፖპၦ‫ػ‬๨‫ݟػ‬఑ֽؓऱᣂএঞ ‫آ‬ሒอૠᖂრᆠʳ(pʳ=ʳ0.657)Ζ ࿨ᓵΚCAD ऱ‫ڇژ‬ፖპၦ‫ػ‬๨‫ݟػ‬఑ʳˑʳ14 mg/24 hr ࣔ᧩‫ڶ‬ᣂΙ‫܀‬ʳDRʳऱ‫ڇژ‬ፖპၦ‫ػ‬๨‫ݟػ‬఑հ ၴऱᣂএঞ‫آ‬ሒอૠᖂრᆠΖ

Coronary artery disease (CAD) is the main cause of death in patients with diabetes mellitus (DM) [1–3]. Diabetic retinopathy is frequently associated with microvasculopathy in DM, and is the main cause of blindness among adults 20–74 years of age in the United States [4]. An association between diabetic retinopathy (DR) and mortality has been demonstrated in past studies [5,6]. Clinical and experimental studies have demonstrated that the presence of microalbuminuria is a marker for diabetic nephropathy and cardiovascular disease [7–11]. Microalbuminuria is also an independent risk factor for cardiovascular mortality in DM [9,12]. The presence of normal levels of albumin in the urine is suggestive of being at low risk for developing renal disease, but some studies have demonstrated that some of these patients have well-established renal lesions [13]. Microalbuminuria in 24-hour urine samples may be measured for early detection of patients at high risk for developing vascular complications. It is known that reducing microalbuminuria during treatment translates to a reduction in cardiovascular events [14]. The traditional upper limit of normal daily albumin excretion has been 30 mg/24 hr, but more recent data suggest that levels in the general population are actually much lower. Within this range of low-grade albuminuria, increasing excretion rates are associated with increasing risk of cardiovascular disease [15]. Higher levels of albumin excretion within the normal range are associated with cardiovascular disease in high-risk individuals [16]. The present study was performed to investigate the relation between vascular disease and “normal” levels of albuminuria (low-grade albuminuria). For this purpose, we evaluated the association between macrovascular complications (CAD) and microvascular complications (DR) and two levels of albuminuria.

high-normal > 14 mg/24 hr but < 30 mg/24 hr). Patients were included who met the inclusion criteria: normal level of microalbuminuria (< 30 mg/24 hr), assessed during the last 12 months on at least two occasions, normal renal function (glomerular filtration rate > 90 mL/min), and regular use of oral hypoglycemic drugs or insulin. Among the 170 patients initially selected, 24 were excluded after a new laboratory evaluation, because they had microalbuminuria > 30 mg/day, and 1 patient had a psychiatric disorder. The Ethics Committee of the Federal University of Ceará, Brazil approved the study.

Laboratory procedures The main clinical and laboratory parameters studied were defined as follows: smoking (the patient was smoking at the time of the medical visit or had a history of smoking), obesity [body mass index (BMI) > 30 kg/m2], hypertension (blood pressure > 140/90 mmHg assessed by ambulatory 24-hour monitoring or taking antihypertensive drugs), dyslipidemia [total cholesterol > 200 mg/dL, low density lipoprotein (LDL) > 100 mg/dL or high density lipoprotein (HDL) < 40 mg/dL for men and < 50 mg/dL for women, or triglycerides > 150 mg/dL], DR (presence of microaneurysms, venous dilation, hemorrhage, and exudates characteristic of nonproliferative retinopathy; or neovascularization, fibrous proliferation, preretinal hemorrhage, and vitreal hemorrhage characteristic of proliferative retinopathy), CAD (history of acute myocardial infarction, history of myocardial revascularization, angiography positive for coronary disease), normal fasting blood glucose (70–110 mg/dL), glycosylated hemoglobin (normal < 6.4%), serum creatinine (normal < 1.2 mg/dL), normal microalbuminuria (urinary albumin excretion < 30 mg/24 hr).

Statistical analysis

METHODS This cross-sectional study was conducted on patients with diabetes mellitus type 2 who were being followed in a specialized center in Fortaleza, Brazil between March 2002 and April 2003. A total of 170 patients were randomly selected, and an investigation was established to determine the prevalence of CAD and DR in regard to two levels of microalbuminuria (normal ≤ 14 mg/24 hr, 28

The association between independent variables and outcomes (CAD and DR) was analyzed by the χ2 test or Fisher’s exact test when appropriate. A multivariate analysis was performed. Results were expressed as the mean ± standard deviation in the cases of quantitative variables. The descriptive values below 5% (p < 0.05) were considered statistically significant. Statistical analysis was performed with Stata 10 software (Data Analysis Statistical Software; StataCorp LP, College Station, TX, USA). Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

Albuminuria and coronary disease in diabetes

RESULTS A total of 145 diabetic patients were included. All patients had normal microalbuminuria, as expected. The clinical and laboratory parameters are summarized in Table 1. Among these patients, 53% were > 60 years and 57% were female. The prevalence of CAD was 24.1%. DR was found in 18.3% of cases, 14.5% being nonproliferative. Hypertension was seen in 69% of patients, of whom 93% were taking antihypertensive drugs (including an angiotensinconverting enzyme inhibitor). The mean fasting blood glucose was 193.1 ± 79.4 mg/dL, and the mean glycosylated hemoglobin was 7.8 ± 1.9%. The mean 24-hour urinary albumin level was 11.9 ± 7.0 mg, with 51 (35.2%) patients presenting with albuminuria > 14 mg. The mean total cholesterol level was 208.7 ± 44.1 mg/dL, and 54.5% of patients had a level > 200 mg/dL. Table 1. Clinical and laboratory parameters of 145 patients with type 2 diabetes with normal urinary microalbumin testsa Parameter

Mean ± SD or %

Age (yr)

60.8 ± 11.5

Sex (%) Male Female

42.1 57.9

Duration of diabetes (yr) 2

Body mass index (kg/m )

8.1 ± 6.5 27.5 ± 4.7

Coronary artery disease (%)

24.1

Hypertension (%)

69.0

Diabetic retinopathy (%)

18.3

Family history of diabetes (%)

69.7

Family history of hypertension (%)

80.7

Abdominal circumference (cm) Men Women Smoking (%) Creatinine (mg/dL)

99.4 ± 11.3 98.9 ± 11.4 10.3 0.9 ± 0.2

Total cholesterol (mg/dL)

208.7 ± 44.1

HDL (mg/dL)

42.6 ± 11.2

LDL (mg/dL)

127.6 ± 35.9

Triglycerides (mg/dL)

208.7 ± 199.3

Fasting blood glucose (mg/dL)

193.1 ± 79.4

Glycosylated hemoglobin (%)

7.8 ± 1.9

Microalbuminuria (mg/24 hr)

11.9 ± 7.0

Use of antihypertensive drugs (%)

64.1

Use of oral hypoglycemic drugs (%)

85.5

Use of insulin (%)

32.4

Continuous data are expressed as mean ± standard deviation and nominal data are expressed as a percentage. a

Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

The mean BMI was 27.5 ± 4.7 kg/m2. Obesity was found in 24.1% of patients. The mean abdominal circumference was 99.4 ± 11.3 cm in men and 98.9 ± 11.4 cm in women. The prevalence of CAD and DR according to the two levels of albuminuria are shown in Table 2. In the group with higher levels of albuminuria the prevalence of CAD was 47.1% (higher than in the group with lower levels, p < 0.001). The prevalence of DR was similar in the two groups (p = 0.65). The prevalence of other risk factors for cardiovascular disease among patients with microalbuminuria > 14 mg/24 hr and ≤ 14 mg/24 hr is summarized in Table 3. There was a tendency for an association between CAD and age > 60 years (p = 0.086). There was no significant association between CAD and total cholesterol, HDL, LDL, triglycerides, or glycosylated hemoglobin. There was a significant association of DR with the patient’s sex (p = 0.028) and duration of diagnosis > 5 years (p = 0.022). There was no association of DR with total cholesterol, HDL, LDL, triglycerides, or glycosylated hemoglobin. There was no association between microalbuminuria and sex, age, time of diagnosis, family history of diabetes, smoking, BMI, obesity, and DR. There was also no association between microalbuminuria and total cholesterol, HDL, LDL, triglycerides, or glycosylated hemoglobin.

DISCUSSION An investigation regarding an association between CAD and DR with two levels of microalbuminuria (both considered normal) was conducted. CAD was found in an important percentage of patients (24%). The prevalence of CAD among diabetic patients varies between 25% and 50%, depending on the diagnostic criteria [17]. Microalbuminuria was initially recognized as a predictor of renal disease [18,19], and it was then considered as a risk factor for cardiovascular disease, being associated with other traditional risk factors, such as age, hypertension, smoking, left ventricular hypertrophy, obesity, and hyperglycemia [20]. There is evidence

Table 2. Prevalence of coronary artery disease among 145 patients with type 2 diabetes according to microalbuminuria test results

Pathology

CAD Diabetic retinopathy

Microalbuminuria ≤ 14 mg/24 hr

Microalbuminuria > 14 mg/24 hr

n (%)

n (%)

11 (11.7) 18 (19.4)

24 (47.1) 8 (16.3)

p

< 0.001 0.657

Significance is at p < 0.05. CAD = coronary artery disease. 29

P.R. Mota, et al

Table 3. Prevalence of risk factors for cardiovascular disease among 145 patients with type 2 diabetes according to microalbuminuria test results Microalbuminuria ≤ 14 mg/24 hr (n = 94)

Microalbuminuria > 14 mg/24 hr (n = 51)

n (%)

n (%)

Sex Male Female

38 (40.0) 56 (60.0)

23 (45.0) 28 (55.0)

0.60

Age > 60 yr

50 (53.0)

27 (53.0)

1.00

Duration of diagnosis > 5 yr

50 (53.0)

28 (54.9)

0.86

Glycosylated hemoglobin > 7.3%

52 (55.3)

30 (58.8)

0.72

Hypertension (mmHg)

63 (67.0)

37 (72.5)

0.57

Risk factor

p

BMI > 30 (kg/m2)

24 (25.5)

11 (21.5)

0.68

Abdominal circumference (cm) > 102 (men) or > 88 (women)

60 (63.8)

31 (60.7)

0.72

8 (8.5)

7 (13.7)

0.39

Smoking Total cholesterol > 200 mg/dL

53 (56.3)

26 (51.0)

0.60

HDL (mg/dL) < 40 (men) or < 50 (women)

62 (66.0)

27 (53.0)

0.15

LDL > 100 mg/dL

67 (71.2)

36 (70.5)

1.00

Triglycerides > 150 mg/dL

56 (60.0)

23 (45.0)

0.11

Diabetic retinopathy

18 (19.1)

8 (15.6)

0.65

Significance is at p < 0.05. BMI = body mass index; HDL = high density lipoprotein; LDL = low density lipoprotein.

that renal dysfunction is a common and powerful cardiovascular risk factor, and that treatment strategies intervening in the renin-angiotensin-aldosterone system can be used to target microalbuminuria and reduce cardiovascular and renal risk [21]. In a study that included 2,600 patients with cardiovascular disease, the combination of a decreased glomerular filtration rate with albuminuria was associated with vascular events, vascular mortality, and overall mortality [22]. Another study showed that macroalbuminuria is associated with a high risk of congestive heart failure (odds ratio, 4.3; 95% confidence interval, 1.5–11.7) [23]. Jassal et al [24] in a study comparing the risk of cardiovascular disease between men and women found a twofold higher risk among women with microalbuminuria and metabolic syndrome. Around 70% of the population have increased albumin urinary excretion, and consequently increased cardiovascular risk [25]. Renal disease associated with hypertension and microalbuminuria is also associated with a high mortality rate [26]. Our findings show that the prevalence of CAD was higher among patients with high-normal levels of microalbuminuria (> 14 mg/24 hr). Gerstein et al [27] studied 9,034 diabetic and nondiabetic patients > 55 years of age and concluded that microalbuminuria lower than the normal cutoff is associated with increased risk for cardiovascular disease. MacLeod et al [28], in a study with 153 diabetic patients, compared three groups of albuminuria—microalbuminuria (30.0–149.9 μg/min), 30

“on the edge” albuminuria (10.6–29.9 μg/min), normal albuminuria (< 10.69 μg/min)—and concluded that patients with high-normal levels of microalbuminuria had more cardiovascular disease. It suggested that cardiovascular risk is increased even before the development of microalbuminuria (> 30 μg/min). Kramer et al [29], in a population-based study with 6,814 individuals, found that geometric mean coronary artery calcification scores were higher among participants with high-normal urinary albumin excretion (8.8; p = 0.07), microalbuminuria (9.9; p = 0.002), and macroalbuminuria (13.1; p = 0.02) compared with normal urinary albumin excretion (7.4), but only microalbuminuria reached statistical significance. The mean left ventricular mass was significantly higher in participants with high-normal albuminuria (37.0; p = 0.001), microalbuminuria (38.3; p ≤ 0.0001), and macroalbuminuria (42.3; p ≤ 0.0001) compared with those with normal albuminuria (36.0). They concluded that levels of excreted urinary albumin below the level of microalbuminuria may reflect the presence of subclinical cardiovascular disease in patients with diabetes. The lipid profiles for the patients revealed high cholesterol levels in more than 50% of the studied cases. In patients with type 2 diabetes mellitus, low HDL levels and high triglyceride levels are frequent [30], as observed in our study as well. Hypertension was found in 69% of patients in the present study, which is compatible with data in the literature. The prevalence of hypertension is around 40–60% in diabetic people aged Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

Albuminuria and coronary disease in diabetes

45–75 years [31]. In the present study, there was no association between hypertension and CAD (p = 0.10). These data are not in accord with those in the literature, which indicate that hypertension is one of the most important risk factors for cardiovascular disease, and its prevalence is almost twofold higher in diabetic patients [32]. We believe that this lack of association in our data is due to the number of patients enrolled, although there was a trend to significance. Other studies have shown that the treatment of hypertension decreases coronary events [33,34]. One study showed that hyperglycemia is a risk factor for the incidence of hypertension in patients with type 1 diabetes, and intensive insulin therapy reduces the long-term risk of developing hypertension [35]. In the present study, there was also no association between DR and CAD (p = 0.592). This is also not accord with data in the literature, where DR is considered a risk factor for cardiovascular disease. The Framingham Study found an association between DR and cardiovascular disease in patients aged 65–74 years and a negative association in patients aged 75–85 years [36]. There was no association between CAD and the parameters used to assess metabolic control (cholesterol, glycosylated hemoglobin, hypertension). This fact can be attributed to the homogeneous distribution of these variables among the studied population. The analysis of microalbuminuria at the higher level (high normal) found a positive association with CAD. Diabetic retinopathy was the other outcome studied here. It is the clinical expression of microvascular disease in diabetes, and was found in 18.3% of the studied patients. The prevalence of DR in the literature varies widely. There was no association between DR and the levels of albuminuria in the present study (p = 0.65). Torffvit et al [37], in a study with 476 patients with diabetes type 1, found no association of DR with various levels of albuminuria. Wirta et al [38] in a study of 174 patients with type 2 diabetes showed that the presence of microalbuminuria was associated with DR when compared with normoalbuminuria. The absence of a significant association between DR and albuminuria demonstrates the possibility of kidney abnormalities even without retinopathy, demonstrating the importance of a macrovascular disorder in the absence of significant microvascular disease. There was also no association between microalbuminuria and sex, age, duration of diagnosis, family history of diabetes, smoking, BMI, obesity, DR, total cholesterol, HDL, LDL, triglycerides, or glycosylated hemoglobin.

CONCLUSION Coronary artery disease is significantly associated with levels of albuminuria > 14 mg/24 h (which is still normal). Hong Kong J Nephrol • April 2011 • Vol 13 • No 1

The presence of DR cannot be statistically associated with high-normal levels of albuminuria. The absence of association between CAD and the clinical and laboratory parameters analyzed here suggests that there is no confounding factor for the association between CAD and albuminuria. The definition of normal albuminuria should be revised, at least with regard to macrovascular complications.

ACKNOWLEDGMENTS Dr Elizabeth De Francesco Daher received a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq (Brazilian Research council), PQ2.

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