Microalbuminuria Accounts for the Increased Vascular Disease Risk in Diabetic Patients With Metabolic Syndrome

INTRODUCTION

There are a number of definitions of metabolic syndrome (MS),¹ an entity that nearly doubles the risk of cardiovascular disease (CVD).² Nevertheless, the utility of identifying diagnostic criteria for MS in patients who have already developed type 2 diabetes mellitus (DM2), and even MS itself, has recently been questioned.^3-5

In a previous article,⁶ we demonstrated that the simultaneous presence of all the components of MS, defined according to the World Health Organization (WHO),⁷ was related to an increase in the cardiovascular risk of patients with DM2. In the present report, we attempt to validate the utility of diagnosing MS in patients with DM2 and to determine whether all its components have the same prognostic value.

METHODS

A prospective cohort study was carried out in a previously defined population.⁶ Between June 1, 1994 and June 1, 1998, DM2 patients were selected from the out-patient endocrinology clinic of the Regional Hospital in Alcañiz, Teruel, in eastern Spain. The present study involves 317 of the 318 patients of the original cohort.⁶

The definition of MS was based on that provided by the WHO,⁷ according to which a person with diabetes has MS if he or she meets 2 or more of the following criteria: hypertension (systolic pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg, and/or receiving hypotensive agents), dyslipidemia (triglyceride levels ≥150 mg/dL and/or high-density lipoprotein level <35 mg/dL in men, or <39 mg/dL in women), obesity (body mass index >30 and/or waist-to-thigh ratio >0.9 in men, or >0.85 in women), and microalbuminuria (albumin excretion rate >30 mg/24 hours).

The follow-up of the cohort was prospective in all the patients until their death or until the end of the study, on February 14, 2005. The development of clinical events and causes of death were obtained from the hospital records or through the attending primary care physician, as described in our previous article.⁶

The numbers of events per 1000 person-years were compared using Kaplan-Meier analysis and the log-rank test. The independent contribution of MS was evaluated by means of multivariate analysis with the Cox model of proportional hazard regression. The main dependent variable analyzed was the incidence of CVD, defined as a combination of new-onset angina, fatal or nonfatal acute myocardial infarction (AMI), transient ischemic attack (TIA), fatal or nonfatal stroke, sudden death, or lower extremity amputation. The attempt was made to evaluate the contribution of the different metabolic risk factors to the prognostic significance of MS by means of their sequential inclusion. The statistical significance of the improvement in the plausibility of the models when new variables are introduced progressively is analyzed by means of the χ² test. A P value less than .05 was considered to indicate statistical significance.

RESULTS

The study included 317 patients (129 men and 188 women), with a mean age (standard deviation [SD]) of 64.6 (9) years and a duration of diabetes of 10.8 (7.7) years. The prevalence of MS was 87%.

The mean duration of follow-up in event-free patients was 7.7 years, with a total of 2151 patient-years. There were 15 new-onset anginas (4.7%), 18 nonfatal AMI (5.7%), 9 fatal AMI (2.8%), 12 TIA (3.8%), 16 nonfatal strokes (5%), 2 fatal strokes (0.6%), 5 sudden deaths (1.6%), and 4 above-knee amputations (1.3%). The incidence rates of CVD and coronary artery disease increased as the number of metabolic risk factors grew (P=.002 in a linear trend for CVD and P=.01 for coronary events; Figures 1 and 2).

Figure 1. Cardiovascular event-free survival curve according to the number of metabolic risk factors present. The difference in the incidence rates (16.4/1000 without metabolic syndrome [MS], 33.3/1000 with 2 metabolic risk factors in addition to diabetes, 42.8/1000 with 3 factors, and 80/1000 with 4 factors) was significant (P=.007).

Figure 2. Coronary event-free survival curve according to the number of metabolic risk factors present. The difference in the incidence rates (9.8/1000 without metabolic syndrome [MS], 18.7/1000 with 2 metabolic risk factors, 23.5/1000 with 3 factors, and 55.4/1000 with 4 factors) was significant (P=.014).

The univariate predictors of CVD and coronary artery disease with a P<.1 appear in Table 1.

In the multivariate analysis, with adjustments for age, sex, duration of diabetes, smoking, glycohemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and prevalent CVD, MS did not significantly increase the risk of incident CVD, (relative risk [RR]=2.5; 95% confidence interval [CI], 1-7.1; P=.07) or of coronary events (RR=2.7; 95% CI, 0.6-11; P=.18).

The significant predictors of incident CVD in the multivariate analysis were: age (RR=1.06; 95% CI, 1.02-1.1; P=.0003), prevalent CVD (RR=1.8; 95% CI, 1.1-3; P=.017), and the simultaneous existence of 4 metabolic risk factors (RR=5.8; 95%CI, 1.8-18; P=.003). For coronary artery disease, they were: LDL-C (RR=1.01; 95% CI, 1-1.02; P=.03), prevalent CVD (RR=2.3; 95% CI, 1.2-4.3; P=.01), and the simultaneous existence of four metabolic risk factors (RR=7.4; 95% CI, 1.5-36; P=.013).

In an additional analysis, according to the ATP-III definition,¹ MS was not related to an increase in total cardiovascular risk (RR=1.22; 95% CI, 0.7-2.1; P not significant) or coronary risk (RR=1.016; 95% CI, 0.49-2.28; P not significant).

DISCUSSION

In the present report, we have confirmed⁶ the fact that there is an increase in total cardiovascular risk and coronary risk in patients with DM2 who present the largest number of metabolic risk factors, and that microalbuminuria was the factor with the greatest predictive power.

Type 2 diabetes mellitus is associated with insulin resistance and a high prevalence of MS.^8,9 The advisability of performing diagnostic tests for MS in patients with DM2 is a matter of controversy,⁴ with inconsistent results reported in the medical literature with regard to its ability^8,10 or inability¹¹ to predict cardiovascular events. Other findings of these studies are that the risk increases as the number of metabolic risk factors grows^10,12 and that microalbuminuria is the component with the greatest predictive power.^8,11

In our study, MS did not significantly increase vascular risk, probably because of the limited number of subjects. Given the high prevalence of MS in DM2,¹³ in these patients, we consider it to be of greater interest to take into account the total number of metabolic risk factors than whether or not they have MS. The fact that the greatest part of the risk conferred by MS was due to the inclusion of microalbuminuria, a marker of generalized endothelial dysfunction,¹⁴ in its definition was also very interesting. In fact, when the ATP-III definition was applied, MS was related to a lesser increase in vascular risk (1.22 vs 2.5) than when the WHO definition was employed. Thus, we consider the elimination of microalbuminuria from the recent definitions of MS to be the right move.¹⁵

In conclusion, we think it is more important to consider the number of metabolic risk factors than MS in the evaluation of the vascular risk of the patient with DM2.

Given that microalbuminuria is a marker of endoth

elial dysfunction, we feel that its exclusion from the definition of MS to be the proper approach.

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Correspondence: Dr. J.A. Gimeno-Orna.
Bielsa, 27, 6.°A. 50014 Zaragoza. España.
E-mail: [e-mail]

Received December 19, 2006.
Accepted for publication May 31, 2007.