Abstract
Objective The value of urinary albumin excretion in the prediction of myocardial ischemia in men and women with type 2 diabetes is not well understood. We questioned whether gender influences the albuminuria-ischemic heart disease relationship in patients with type 2 diabetes.
Methods We designed a matched case-control study of 926 patients with albuminuria (cases) and 926 age and body mass index matched patients without albuminuria (controls). Ischemic heart disease was defined as the presence of (1) history of angina pectoris or angina equivalent symptoms and critical care unit admission, (2) myocardial infarction and/or electrocardiographic evidence of Q-wave myocardial infarction, (3) coronary revascularization and/or stenting, (4) positive myocardial single-photon emission computed tomography scan, (5) ischemic ST-segment or T-wave changes, and (6) positive stress testing.
Results Patients with albuminuria had a lower glomerular filtration rate and a longer diabetes duration than patients without albuminuria. In the group of cases, there were a greater number of men with ischemic heart disease (120 of 370; 32.4%) compared to women (97 of 559; 17.4%) (P<0.001). The odds ratio of having ischemic heart disease according to the presence or absence of albuminuria was 1.25 [95% CI: 1.01–1.56] (P<0.05) in all studied populations, 0.79 [95% CI: 0.51–1.21] (P=0.14) in women, and 2.84 [95% CI: 1.68–4.79] (P<0.001) in men. We showed that diabetes duration, high-density lipoprotein, low-density lipoprotein, and hemoglobin A1c influence albuminuria in women, while diabetes duration, fasting blood sugar, and diastolic blood pressure influence albuminuria in men.
Conclusions Men with albuminuria are at increased risk of ischemic heart disease compared to women. This may be related to the role of high-density lipoprotein on the albuminuria-gender relationship.
According to the Steno hypothesis, microalbuminuria is an index of endothelial cell dysfunction.1 Abnormally elevated rates of albumin excretion reflect endothelial dysfunction or other vascular damage that is more severe in type 2 diabetes.1,2 Albuminuria in hypertensive patients is associated with altered lysosomal activity and transforming growth factor beta 1 (TGF-β1) expression.3 Studies have substantially shown an increased risk of renal damage in the presence of cardiovascular risk factors in normal subjects as well as those with type 2 diabetes.4,5 Ischemic heart disease is the major cause of morbidity and mortality in patients with type 2 diabetes, especially in those with elevated levels of urinary albumin excretion.6,7 It is known that there are gender differences in the progression of micro-albuminuria and cardiovascular mortality in patients with type 2 diabetes.8–12
In patients with type 1 diabetes, male gender, independent of age, is a significant predictor of albuminuria progression, metabolic control, duration of diabetes, and baseline albumin excretion rate.13–15 There are limited studies with conflicting reports in type 2 diabetes.10–12 The diversity of results in the different reports may be due to the confounding effect of gender on cardiovascular risk factors such as dyslipidemia and albuminuria.16,17 In this study we aimed to examine the value of albuminuria in the prediction of ischemic heart disease in men and women with type 2 diabetes.
Methods
The study was designed in a cross-sectional, matched case-control fashion to examine the importance of albuminuria in the prediction of ischemic heart disease. From the records of diabetic patients admitted to Vali Asr hospital during the period from January 2008 to December 2010, information was obtained on all patients with and without albuminuia. For each case, one control matched by age and body mass index (BMI) was randomly selected. Using this database, information from 926 cases defined as patients with albuminuria and 926 age and BMI-matched controls was obtained. Normo-, micro- and macro-albuminuria were defined as urinary albumin excretion rate <30 mg/24 h, between 30–300 mg/24 h, and >300 mg/24 h, respectively. Albuminuria was defined as the presence of micro-/macro-albuminuria. Patients were instructed in the collection of timed 24-hour urine for the measurement of urinary albumin excretion and were instructed to return on the morning after the end of the urine collection. Ischemic heart disease was defined as (1) history of angina pectoris or angina equivalent symptoms and critical care unit admission, (2) myocardial infarction and/or electrocardiographic evidence of Q-wave myocardial infarction, (3) coronary revascularization and/or stenting, (4) positive myocardial single-photon emission computed tomography scan, (5) ischemic ST-segment or T-wave changes, and (6) positive stress testing.
Diabetes was diagnosed according to the criteria of the American Diabetes Association.18 Exclusion criteria were type 1 diabetes, acute or chronic renal failure, glomerulonephritis, congestive heart failure, acute infections, pregnancy, diabetic ketoacidosis, non-ketotic hyperosmolar diabetes, thyroid disorders, complete left bundle branch block, and hospital admission during the previous three months. None of the studied women were on hormone replacement therapy. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault formula.19
Demographic and anthropometric data including age, sex, duration of diabetes, height, waist circumference, weight in light clothing, and blood pressure in sitting position were recorded. Blood pressure was measured twice after 5 minutes and then averaged. The BMI (kg/m2) was calculated according to the Quetelet formula.20 All participants gave written informed consent before participation. This research was carried out according to the principles of the declaration of Helsinki, and the local ethics review committee of Tehran University of Medical Science approved the study protocol.
Blood samples were collected after approximately 12 hours of fasting. Serum creatinine, fasting blood sugar (FBS), total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and hemoglobin A1c (HbA1c) were measured. Glucose measurements (intra-assay coefficient of variation [CV] 2.1%, inter-assay CV 2.6%) were carried out using the glucose oxidase method. Creatinine was measured using calibrated Jaffe method (Parsazmoon, Karaj, Iran). Cholesterol, HDL, LDL, and TG were determined using direct enzymatic methods (Parsazmun, Karaj, Iran). HbA1c was estimated by high-pressure liquid chromatography (HPLC) method. Serum creatinine was measured using direct colorimetric method.
Statistical Analysis
The statistical package SPSS 16 for windows (Chicago, Illinois, USA) was used for the primary analysis of the cases and controls. Standard statistical methods were used for the analysis of matched case-control studies using STATA/SE for windows (Texas, USA). The data were individually matched. All 926 cases and controls were eligible for the analysis. Quantitative variables are presented as mean ± standard error of mean. Qualitative variables are presented as number and percent. Independent sample t test (for quantitative variables) and Chi square test (for qualitative variables) were employed to compare cases and controls. To provide a measure of association of albuminuria and the presence of ischemic heart disease, conditional logistic regression was employed. Conditional logistic regression was also used for modeling the variables influencing the albuminuria-gender relationship. A forward stepwise procedure was employed, using HbA1c, HDL, LDL, TG, cholesterol, FBS, diabetes duration, and systolic and diastolic blood pressure. Variables with P<0.2 in the primary analysis were included in the model until a final best model was achieved. The studied variables, except FBS and diabetes duration, were categorized and included in the model. The cut points for the categorization of the variables were: HDL, 40 mg/dL; LDL, 100 mg/dL; HbA1c, 7%; TG, 150 mg/dL; cholesterol, 150 mg/dL; systolic blood pressure, 130 mmHg; and diastolic blood pressure, 80 mmHg.
Results
Demographic, biochemical, and clinical characteristics of participants are illustrated in table 1. The frequency of insulin therapy was 20% (185 of 926) in patients with albuminuria and 23% (213 of 926) in patients without albuminuria. Forty-six percent (852 of 1852) of the patients were on statin therapy, and 52% (963 of 1852) were on antihypertensive treatment. Approximately 30% (556 of 1852) of all patients were on insulin therapy.
Demographic and anthropometric parameters, cardiovascular risk factors, and diabetic complications in the study groups.
Patients with albuminuria had a lower glomerular filtration rate (GFR) and longer diabetes duration than patients without albuminuria (table 1). To study the distribution of risk factors between men and women, the studied population was stratified according to gender. In patients with albuminuria, women had a lower GFR compared to men (45.9±2.1 vs. 57.4±2.1) (P<0.001). In patients without albuminuria, women had a lower GFR (61.3±1.5 vs. 66.2±1.4) (P<0.05) and higher cholesterol levels (192.04±3.50 vs. 173.13±4.92) (P<0.001) than men with albuminuria. In the group of patients with albuminuria, there were a greater number of men with ischemic heart disease (120 of 370; 32.4%) compared to women (97 of 559; 17.4%) (P<0.001). The odds ratio of having ischemic heart disease according to the presence or absence of albuminuria was 1.25 [95% CI: 1.01–1.56] (P<0.05) in all studied populations, 0.79 [95% CI: 0.51–1.21] (P=0.14) in women, and 2.84 [95% CI: 1.68–4.79] (P<0.001) in men. Table 2 presents the number of patients with ischemic heart disease according to the presence or absence of albuminuria. The predictors of albuminuria in men and women (table 3) were then studied. Results showed that while diabetes duration, HDL, LDL, and HbA1c influence albuminuria in women, diabetes duration, FBS, and diastolic blood pressure influence albuminuria in men (table 3).
Association of ischemic heart disease with presence or absence of albuminuria.
Conditional logistic regression was employed to study variables influencing albuminuria in patients with type 2 diabetes stratified according to gender.*
Discussion
The main finding of the present study was the effect of gender on the albuminuria-ischemic heart disease relationship. The odds ratio of having ischemic heart disease according to the presence or absence of albuminuria was highest in men with type 2 diabetes. Furthermore the prevalence of ischemic heart disease was significantly higher in men with albuminuria compared to men without albuminuria. The strength of this study is the large cohort of both the cases and the controls.
Rapid decline in renal function has been repeatedly shown to be more prevalent in men.21–23 There are conflicting reports concerning the effect of gender on rate of urinary albumin excretion in patients with type 2 diabetes.13–15 Hashim et al7 demonstrated that urinary albumin excretion is associated with insulin resistance and cardiovascular risk factors in patients with type 2 diabetes that is more severely pronounced in women. However, some other studies have shown male gender as an independent risk factor for the progression of albuminuria in patients with type 2 diabetes.11,12 Villar et al12 showed that elderly women have a worse outcome in the progression to end-stage renal disease and death compared to elderly men with type 2 diabetes. Hidden confounders such as lifestyle differences between men and women that have not been included in the studied variables may account for the difference as well. Non-use of angiotensin-converting enzyme inhibitors is an identified risk factor of rapid progression to albuminuria in patients with type 2 diabetes.24 Consistently, Larkin et al25 suggested that risk reducing measures, such as taking medications, are underused in women with both type 1 and type 2 diabetes. Cigarette smoking, which is five times more prevalent among Persian men compared to women,26 leads to reduced relaxant responses of the cutaneous microcirculation27 as well as to blunted basal and stimulated nitric oxide bioactivity.28
Consistent with the findings in the present study, De Cosmo et al29 showed that, in patients with type 2 diabetes, increased urinary albumin excretion is associated with cardiovascular risk factors, which is significantly higher in men than in women. In a study on healthy individuals, Verhave et al30 showed that cardiovascular risk factors and urinary albumin excretion rate are significantly correlated only in men. This is the first study demonstrating the effect of gender on the albuminuria-ischemic heart disease relationship in patients with type 2 diabetes. The odds ratio of having albuminuria was significantly higher in men with ischemic heart disease compared to women.
There are a number of theories postulated to explain the prognostic value of albuminuria in the prediction of ischemic heart disease in men with type 2 diabetes. Some believe that this may be due to the deleterious role of androgens in men or the protective role of estrogen in women. Androgens are known to activate the renin-angiotensin system and might cause endothelial cell injury.31 Testosterone causes salt and water retention, particularly in elderly men,32,33 which may contribute to edema, hypertension, and vascular injury.34 Lowered testosterone levels following orchiectomy have been shown to reduce oxidative stress and renal injury after ischemia.35 Furthermore, Chandie Shaw et al36 demonstrated that central obesity, which is more frequent in men with metabolic syndrome and type 2 diabetes, is an independent risk factor of albuminuria in healthy individuals. Interestingly, Schneider et al11 demonstrated that nitric oxide availability in the renal circulation is greater in women than in men with type 2 diabetes and is associated with reduced levels of oxidative stress in the renal circulation of women.
The current study showed that while diabetes duration, HDL, LDL, and HbA1c influence albuminuria in women, diabetes duration, FBS, and diastolic blood pressure influence albuminuria in men. Consistent with these findings, some studies have shown that duration of diabetes, poor glycemic control, high serum cholesterol, high triglycerides, low serum HDL, uncontrolled hypertension, and cigarette smoking are important risk factors for the progression to albuminuria.37–43 In a previous study, we showed that in type 2 diabetes, men have a higher mean level of urinary albumin excretion rate compared to women.10 Observations of that study demonstrated that this difference vanished after adjusting for age and HDL levels.10 We believe that HDL plays an important role in the progression to albuminuria in patients with type 2 diabetes. This may also explain the gender differences observed in albuminuria progression. Because men have lower serum HDL levels, they have a higher risk of progression to albuminuria. In the current study, we showed the protective role of serum HDL on albuminuria in women. Future prospective studies on patients with type 2 diabetes may elucidate the role of HDL, LDL, HbA1c, and diastolic blood pressure on the progression to albuminuria in men and women.
Conversely, we showed lower GFR levels in women compared to men. In a recent study, Afghahi et al44 showed that the majority of patients with type 2 diabetes and renal impairment registered at the Swedish National Diabetes Register were nonalbuminuric. They suggested that the cause-effect relationships observed in cross sectional studies may be confounded by unknown variables.44 Donahue et al45 showed that women who progress from normoglycemia to pre-diabetes have greater endothelial dysfunction, a greater degree of fibrinolysis/thrombosis, and are more hypertensive than men.45 It has been shown that women with hypertension have a higher prevalence of other concomitant cardiovascular risk factors.46,47 White et al48 suggested that the diabetic state is associated with estrogen-stimulated production of superoxide and a reduced level of nitric oxide within the vasculature. By controlling for adverse cardiac events, we may have excluded those women who are more genetically susceptible to albuminuria. It seems that urinary albumin excretion rate and the declination in the GFR are not consistent in men and women with type 2 diabetes. Considering the impact of sex steroid hormones, markers of oxidative stress, inflammation, and antioxidants like leptin, C-reactive protein, and HDL, we suggest that diabetes-induced complications may be mediated by different pathways in men and women. This is an interesting topic for future prospective studies.
The limitation of this study is its cross-sectional nature, which precludes the determination of the direction of causality; however, we took advantage of a relatively large sample size and close similarity between groups in most of the confounding variables. Patients in the case and control groups were almost similar regarding the medications they were receiving, although we did not match the cases and controls according to the diabetes, hyperlipidemic, and hypertensive treatment which may have had confounded our findings. In conclusion, we showed the value of albuminuria in the prediction of ischemic heart disease. Moreover, HDL-C, HbA1c, and systolic blood pressure influenced the gender-albuminuria relationship in patients with type 2 diabetes. This may add to the understanding of the pathogenesis of diabetes complications in men and women with type 2 diabetes.
- Received May 10, 2011.
- Revision received August 12, 2011.
- Revision received September 8, 2011.
- Accepted September 21, 2011.
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