predictors of development and progression of microvascular complications in a cohort of brazilian...

Journal of Diabetes and Its Com

Predictors of development and progression of microvascular complications

in a cohort of Brazilian type 2 diabetic patientsB

Claudia R.L. Cardoso4, Gil F. Salles

Department of Internal Medicine, University Hospital Clementino Fraga Filho, Medical School, Federal University of Rio de Janeiro

Received 4 September 2006; received in revised form 29 December 2006; accepted 2 February 2007

Abstract

Aims: Microvascular complications are associated with increased mortality in diabetes. The objective of this study was to investigate the

predictors of microvascular complication development and progression in a prospective study of Brazilian type 2 diabetic patients. Methods:

A prospective follow-up study was carried out with 471 type 2 diabetic outpatients. Primary end points were the development or progression

of retinopathy, peripheral neuropathy, and clinical nephropathy. Predictors were assessed for each individual microvascular complication and

also as a composite outcome by Kaplan–Meier estimation of survival curves and by uni- and multivariate Cox analysis. Results: During a

median follow-up of 57 months (range 2–84 months), 196 patients (41.6%) developed or had a progression in microvascular disease.

Retinopathy occurred in 22.5%, nephropathy in 19.1%, and neuropathy in 15.5% of the patients. In Cox multivariate analysis, increased

echocardiographic left ventricular mass (LVM) and longer diabetes duration were selected as predictors for all end points. Higher mean

fasting glycemia was a predictor for retinopathy and neuropathy, lower serum high-density lipoprotein (HDL) cholesterol for neuropathy, and

higher total cholesterol for nephropathy. Increased LVM [hazard ratio (HR): 1.39, 95% CI: 1.23–1.56], higher fasting glycemia (HR: 1.19,

95% CI: 1.04–1.36), and longer diabetes duration (HR: 1.28, 95% CI: 1.11–1.47) were the predictors of the composite end point.

Conclusions: Development and progression of microvascular complications in Brazilian type 2 diabetic patients are associated with worse

hypertension and metabolic control. Additional studies are necessary to show if modification of these risk factors can reduce the burden of

morbidity and mortality related to microvascular disease in type 2 diabetes.

D 2008 Elsevier Inc. All rights reserved.

Keywords: Glycaemia left ventricular mass; Microvascular complications; Risk factors; Type 2 diabetes

1. Introduction

Type 2 diabetes is associated with microvascular and

macrovascular complications that determine increased mor-

bidity and mortality in these patients (Mbanya & Sobngwi,

2003). In developed countries, diabetic retinopathy is the

1056-8727/08/$ – see front matter D 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.jdiacomp.2007.02.004

Abbreviations: ACE, angiotensin-converting enzyme; DBP, diastolic

blood pressure; Echo-LVH, echocardiographic left ventricular hypertrophy;

HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, hazard ratio;

LVM, left ventricular mass; S, serum; SBP, systolic blood pressure;

UKPDS, United Kingdom Prospective Diabetes Study.B Drs. C. Cardoso and G. Salles have research grants from the

Brazilian National Research Council (CNPq).

4 Corresponding author. Rua Croton 72, Jacarepagua, CEP: 22750-

240, Rio de Janeiro, Brasil. Tel.: +55 21 24473577; fax: +55 21 22702193.

E-mail address: [email protected] (C.R.L. Cardoso).

leading cause of acquired blindness in adults (Sanchez-

Thorin, 1998), and diabetic nephropathy is the second cause

of renal replacement therapy (Mogensen, 1998). Peripheral

neuropathy interacts with macrovascular disease and infec-

tion in pathophysiology of diabetic foot (Mbanya &

Sobngwi, 2003), increasing the risk of foot ulcers and

amputations (Boyko et al., 1999; Reiber, Pecoraro, &

Koepsell, 1992).

There are few prospective studies with type 2 diabetic

patients that assessed the risk factors for microvascular

complications. The largest and most comprehensive was

the United Kingdom Prospective Diabetes Study (UKPDS)

(Stratton et al., 2000; UKPDS Group, 1998), which

showed that improved metabolic control and tight blood

pressure control reduced the risk of microvascular

complication development.

plications 22 (2008) 164–170

C.R.L. Cardoso, G.F. Salles / Journal of Diabetes and Its Complications 22 (2008) 164–170 165

The prevalence of macrovascular and, specifically,

microvascular complications has been previously reported

in Brazil and was high among diabetic outpatients referring

to general hospitals (Cardoso, Salles, Bloch, Deccache, &

Siqueira–Filho, 2001; Scheffel et al., 2004). Identifying the

risk factors for development and progression of micro-

vascular complications is important, given the association of

microvascular disease with increased diabetes-related mor-

bidity and mortality. However, as far as we know, there is no

study in Brazil investigating the risk factors for development

of microvascular complications. Only one cross-sectional

study described the variables associated with the presence of

diabetic retinopathy (Santos, Tschiedel, Schneider, Souto, &

Roisenberg, 2005). We have previously reported the

predictive factors associated with macrovascular disease

complications (Cardoso, Salles, & Deccache, 2003), total

mortality (Salles, Bloch, & Cardoso, 2004), and infection-

related mortality (Cardoso & Salles, 2006). So, the objective

of this study was to explore the predictors for development

or progression of microvascular degenerative complications

in a large cohort study of type 2 diabetic patients with up to

7 years of follow-up.

2. Patients and methods

Study patients have been detailed elsewhere (Cardoso

et al., 2001, 2003). Briefly, all adult diabetic outpatients,

diagnosed according to the 1985 World Health Organization

criteria, who had standard electrocardiograms recorded from

July 1994 to June 1996, were consecutively enrolled in the

study. Exclusion clinical criteria were unstable angina or

recent (b4 months) acute myocardial infarction, serum (S)

potassium or calcium electrolyte abnormalities, use of any

antiarrhythmic drug, chronic renal failure undergoing

dialysis, and atrial fibrillation. After applying clinical and

electrocardiographic exclusion criteria, a total of 471 type 2

diabetic patients made up the cohort. The study protocol

complied with the 1975 Declaration of Helsinki and was

approved by the local ethics committee.

The baseline procedures and criteria for diagnosing

clinical variables have been previously described (Cardoso

et al., 2001). The diagnosis of diabetic retinopathy was

made by an ophthalmologic examination that included

fundoscopy or retinal photography and measurement of

visual acuity, performed by an ophthalmologist. Clinical

diabetic neuropathy was based on criteria used for the

Diabetic Control and Complications Trial (The Diabetes

Control and Complications Trial Research Group, 1995).

Patients were questioned about sensory, motor, and auto-

nomic symptoms, and responses were recorded. A clinical

history regarding any other concurrent etiology for neuro-

pathy was also obtained. A standard neurological examina-

tion included evaluation of knee and ankle reflex activity,

feet sensation with the Semmes–Weinstein 5.07 (10 g)

monofilament and vibration (using a 128-Hz tuning fork).

Neuropathy was defined as the presence of at least two of

the following: symptoms, reduced vibration perception,

insensitivity to monofilament at one or more of nine sites on

either feet, and absent tendon reflexes. No test of autonomic

function was performed. Clinical nephropathy diagnosis

needed at least three consecutive proteinurias N0.5 g/24 h

or decreased glomerular filtration rate (S creatinine

N175 Amol/l). No anthropometric measures were obtained.

Arterial hypertension was diagnosed if mean office systolic

(SBP) or diastolic blood pressure (DBP) were z140/

90 mmHg or if antihypertensive drugs had been prescribed.

Laboratory evaluation included fasting glycaemia,

S fructosamine, creatinine, triglycerides, total and high-

density lipoprotein (HDL) cholesterol, and 24-h proteinuria.

Mean values of all office SBP and DBP measurements and

of laboratory examinations performed during the first year

of follow-up were recorded.

Good-quality comprehensive two-dimensional echocar-

diography (Apogee, Interspec, with 3.5-MHz transducer)

was carried out within 1 month of the admission by the

same experienced observer. Measurements of septal and

posterior wall thickness and left ventricular end-diastolic

diameter were performed according to Penn convention

(Devereux & Reichek, 1977), and left ventricular mass

(LVM) was calculated by the anatomically validated cube

formula of Devereux and Reichek (Devereux & Reichek,

1977). Cutoff values for the presence of echocardiographic

left ventricular hypertrophy (Echo-LVH) were those derived

from the Framingham study (Levy et al., 1987): N198 g for

women and N294 g for men.

2.1. Follow-up and end points

The patients were evaluated regularly at least two times a

year until June 2001. Those that failed to attend to the hospital

were contacted annually to determine health status. Annual

direct ophthalmoscopy was carried out, and visual acuity was

assessed. Neuropathy was reevaluated regularly by appear-

ance of clinical signs and symptoms. Forty-three patients

(9.1%) were lost from follow-up and were considered

censored observations at the date of their last hospital visit.

Diabetic nephropathy end points were the following: (1)

for those without clinical nephropathy at baseline, the

development of increased proteinuria z0.5 g/24 h (con-

firmed by three consecutive measurements) or the appear-

ance of a S creatinine level N175Amol/l, whichever appeared

first; (2) for those with increased 24-h proteinuria but normal

S creatinine at baseline, the first appearance of a S creatinine

level N175 Amol/l; and (3) for those with abnormal

S creatinine at baseline, the beginning of dialysis.

Retinopathy end points were the following: (1) for those

without diabetic retinopathy at baseline, the first appearance

of signs of retinopathy confirmed by an ophthalmologist;

and (2) for those with retinopathy at baseline, the occurrence

of first retinal laser photocoagulation, vitreous hemorrhage,

or blindness in at least one eye.

C.R.L. Cardoso, G.F. Salles / Journal of Diabetes and Its Complications 22 (2008) 164–170166

Peripheral neuropathy end points were the following: (1)

for those without neuropathy at baseline, the appearance of

signs and symptoms with the same criteria used in the

baseline evaluation; and (2) for those with neuropathy at

baseline, the first occurrence of foot ulcers or amputation of

at least one digit.

2.2. Statistical analysis

All statistics were performed using the SPSS statistical

package version 13.0. Continuous data were described as

means and standard deviations. Survival analysis was

performed by the Kaplan–Meier product-limit method of

estimating microvascular disease-free survival curves (com-

pared by log-rank tests) and by univariate and multivariate

Cox proportional hazards models. It has been shown that

deleting subjects with a missing value on one of the predictor

variables included in the multivariate models (the so-called

complete cases analysis) commonly leads to biased results

and, surely, to loss of power (Greenland & Finkle, 1995). So,

in order to decrease bias and increase statistical efficiency, we

imputed missing data using the expectation maximization

method, which is based on the correlations between each

variable with missing values and all other variables as

estimated from the complete cases. All variables that showed,

Table 1

Baseline characteristics of all patients and those with and without microvascular

Variables

All patients

(n=471)

Clinical variables

Female gender 161 (34.2%)

Age (years) 60.5 (11.1)

Diabetes duration (years) 9.3 (7.3)

Arterial hypertension 271 (57.5%)

Cardiac disease 71 (15.1%)

Cerebrovascular disease 26 (5.5%)

Peripheral vascular disease 43 (9.1%)

Retinopathy 95 (20.2%)

Nephropathy 69 (14.6%)

Neuropathy 68 (14.4%)

SBP (mmHg) 142.8 (19.8)

DBP (mmHg) 83.3 (10.5)

Diabetes treatment

Sulphonylureas 274 (58.2%)

Insulin 130 (27.6%)

Antihypertensive treatment

h-blockers 36 (7.6%)

Calcium-channel blockers 94 (20.0%)

Diuretics 111 (23.6%)

ACE inhibitors 135 (28.7%)

Laboratory variables

Fasting glycaemia (mmol/l) 10.7 (4.0)

Fructosamine (mmol/l) 4.2 (0.9)

S triglycerides (mmol/l) 1.92 (1.12)

S total cholesterol (mmol/l) 5.38 (1.26)

HDL cholesterol (mmol/l) 1.07 (0.27)

Left ventricular mass (g) 235.5 (75.6)

Echo-LVH 218 (46.3%)

Values are presented as absolute numbers (proportions) or means (S.D.). ACE, a

in univariate analysis, a P value b.20 entered into the

multivariate Cox models. Hence, Cox multivariate models

were fitted in backward stepwise procedure for each

individual microvascular end point. Then, a multivariate

model was fitted for the composite outcome (development or

progression of any microvascular complication). Assump-

tions of the proportional hazards models and interactions

were also tested (Concato, Feinstein, Holford, 1993), and no

violation was observed. Results were presented as hazard

ratios (HRs) with 95% CI. For continuous variables, HRs

were calculated for increments of 1 S.D. A two-tailed Pb.05

was considered statistically significant.

3. Results

3.1. Baseline characteristics and follow-up microvascular

end points

After a median follow-up of 57 months (range 2–

84 months), 196 patients (41.6%) developed a new or had

a progression in microvascular disease. Retinopathy out-

come occurred in 106 patients (22.5%), nephropathy in 90

(19.1%), and neuropathy in 73 patients (15.5%). Table 1

shows the baseline characteristics of all patients and of those

disease development or progression during follow-up

Patients with

microvascular disease

development (n=196)

Patients without

microvascular disease

development (n=275

79 (40.3%) 82 (29.8%)

59.7 (10.3) 61.0 (11.6)

10.2 (7.7) 8.6 (7.0)

120 (61.2%) 151 (54.9%)

35 (17.9.%) 36 (13.1%)

11 (5.6%) 15 (5.5%)

23 (11.7%) 20 (7.3%)

67 (34.2%) 28 (10.2%)

50 (25.5%) 19 (6.9%)

49 (25.0%) 19 (6.9%)

143.1 (20.0) 142.3 (19.7)

83.9 (10.7) 82.7 (10.3)

103 (52.6%) 171 (62.2%)

78 (39.8%) 52 (18.9%)

9 (4.6%) 27 (9.8%)

42 (21.4%) 52 (18.9%)

35 (17.9%) 76 (27.6%)

56 (28.6%) 79 (28.7%)

11.3 (4.3) 10.3 (3.7)

4.2 (1.0) 4.2 (0.8)

1.97 (1.19) 1.89 (1.07)

5.36 (1.20) 5.39 (1.31)

1.05 (0.30) 1.08 (0.25)

250.7 (82.1) 224.6 (68.7)

105 (53.6%) 113 (41.1%)

ngiotensin-converting enzyme.

)

Table 2

Baseline status and cumulative incidence of development and progression

of microvascular complications during up to 7 years of follow-up

Microvascular

disease

Baseline status,

no. of patients

Development

[no. of patients (%)]

Progression

[number of

patients (%)]

Retinopathy Absent, 376 65 (17.3%)

Present, 95 41 (43.2%)

Nephropathy Absent, 402 50 (12.4%)

Present, 69 40 (58.0%)

Peripheral

neuropathy

Absent, 403 48 (11.9%)

Present, 68 25 (36.8%)

Table 4

Results of Cox multivariate analysis for development or progression of each

microvascular complication and for the composite end point.

Variables S.D.a HR 95% CI P

Retinopathy (n=106)

Diabetes duration (years) 7.3 1.29 1.07–1.55 .008

Left ventricular mass (g) 75.6 1.21 1.02–1.45 .033

Fasting glycemia (mmol/l) 0.9 1.20 1.01–1.44 .044

Peripheral neuropathy (n=73)

S HDL cholesterol (mmol/l) 0.27 0.66 0.51–0.85 .001



Left ventricular mass (g) 75.6 1.24 1.02–1.51 .033

Nephropathy (n=90)

Left ventricular mass (g) 75.6 1.93 1.65–2.25 b.001

S total cholesterol (mmol/l) 1.26 1.63 1.29–2.05 b.001


Composite microvascular end point (n=196)




a For continuous variables, HRs were calculated for increments of 1 S.D.


with and without development or progression of micro-

vascular complications. Patients with microvascular com-

plication development were more frequently males and

hypertensives, had longer diabetes duration, used more

commonly insulin, and had higher mean fasting glycemia

and greater LVM. Patients without microvascular disease

development used more antihypertensive drugs, particularly

diuretics and h-blockers. Table 2 shows patients according

to the presence or absence of microvascular disease at

baseline and the cumulative incidence of microvascular

disease development and progression during follow-up.

3.2. Univariate survival analysis

On univariate Cox analyses (Table 3), male gender,

diabetes duration, arterial hypertension, presence of cardiac

disease and peripheral arterial disease at baseline, sulpho-

nylureas, insulin and diuretic usage, fasting glycemia,

S HDL cholesterol, and LVM were the variables with

strongest associations with development or progression of

microvascular complications during follow-up.

3.3. Multivariate survival analysis

Results of multivariate Cox survival analyses for each

microvascular end point are shown in Table 4. Longer

Table 3

Results of univariate Cox analysis for variables associated with the

composite end point (development or progression of any microvascular

complication)

Variables S.D.a HR 95% CI P

Male gender 1.58 1.18–2.10 .002


Arterial hypertension 1.30 0.98–1.72 .066

Cardiac disease 1.49 1.03–2.14 .034

Peripheral arterial disease 2.32 1.50–3.60 b.001

Sulphonylurea treatment 0.67 0.51–0.89 .005

Insulin treatment 2.09 1.57–2.79 b.001

Diuretic treatment 0.69 0.48–0.99 .046


S HDL cholesterol (mmol/l) 0.27 0.83 0.71–0.96 .012


Echo-LVH 1.66 1.25–2.20 b.001

a For continuous variables HRs were calculated for increments of

1 S.D.

diabetes duration and greater echocardiographic LVM were

predictors for all individual end points. Higher fasting

glycemia was selected as a predictor for retinopathy and

neuropathy. Higher S HDL cholesterol was a protective

factor for neuropathy and total cholesterol a predictor for

nephropathy. For the composite end point (Table 4),

increased LVM was the strongest predictor of microvascular

disease; increments in 1 S.D. (75.6 g) augmented 39% the

risk of microvascular complication occurrence or progres-

sion. Longer diabetes duration and higher mean fasting

glycemia were the other predictive variables for the

composite microvascular complication end point. Kaplan–

Meier analysis (Fig. 1) showed that the subgroup of

patients with higher (z8.9 mmol/l) mean fasting glycemia,

longer (z10 years) diabetes duration, and Echo-LVH

had a significantly worse prognosis in relation to develop-

ment and progression of microvascular disease during

up to 7 years of follow-up. This worse prognosis became

apparent after the second year of follow-up for the

glycemic control variable and after the first year for the

other two variables.

4. Discussion

The main finding of this prospective study with up to

7 years of follow-up is that poor metabolic control, both

glycemic and lipidic, and poor hypertension control,

reflected by increased left ventricular mass and hypertrophy,

are the most important independent predictive factors for

future development and progression of microvascular

disease in Brazilian type 2 diabetic patients. Diabetes

duration is also independently associated with microvascu-

lar complications. To the best of our knowledge, this is the

only prospective Brazilian study investigating factors

associated with microvascular disease development.

Fig. 1. Kaplan–Meier estimation of cumulative microvascular disease

development and progression curves in patients grouped according to

higher (z8.9 mmol/l) mean fasting glycemia (top), to longer (z10 years)

diabetes duration (middle) and to the presence of Echo-LVH (bottom).


The importance of glycemic status to development of

microvascular disease complications has been established in

various previous studies, either for the composite end point

of any microvascular complication (Stratton et al., 2000;

UK Prospective Diabetes Study (UKPDS) group, 1998) as

well as isolatedly for retinopathy (Nazimek-Siewniak,

Moczulski, & Grzesczak, 2002; Tudor, Hamman, Baron,

Johnson, & Shetterly, 1998; Tung et al., 2005; van Leiden

et al., 2002), nephropathy (Gall, Hougaard, Borch-Johnsen,

& Parving, 1997; Nazimek-Siewniak et al., 2002), and

peripheral neuropathy (Adler et al., 1997; Forrest, Maser,

Pambianco, Becker, & Orchard, 1997; Tesfaye et al., 2005).

In the present investigation, we demonstrated that mean

fasting glycemia obtained during the first year of follow-up

predicted future occurrence or progression of any micro-

vascular disease (composite end point) and, also specifi-

cally, of retinopathy and peripheral neuropathy but not of

clinical nephropathy. Some possible explanations for this

negative finding should be raised. First, for the demonstra-

tion of the association with nephropathy development,

maybe a stricter parameter of metabolic control might be

needed, such as hemoglobin A1c (HbA1c) measurement,

which was unavailable in this study. Second, a longer period

of follow-up might be necessary to demonstrate the effects

of poor glycemic control on appearance and progression of

diabetic nephropathy than for retinopathy or neuropathy. Of

note, different from the other two predictors (diabetes

duration and Echo-LVH), the effect of glycemic status only

became apparent after the second year of follow-up for the

composite outcome (Fig. 1).

The importance of arterial hypertension and blood

pressure levels to development of diabetic microvascular

disease has also been demonstrated in previous studies for

the composite end point (UKPDS Group, 1998; Adler et al.,

2000) and for retinopathy (Nazimek-Siewniak et al., 2002;

Tung et al., 2005; van Leiden et al., 2002), nephropathy

(Nazimek-Siewniak et al., 2002), and peripheral neuropathy

(Forrest et al., 1997; Tesfaye et al., 2005). In this study, we

demonstrated that an increased LVM is a strong predictor of

development or progression of any diabetic microvascular

disease, either aggregated or in isolation. Increased LVM or

hypertrophy, as a hypertension-related target-organ damage,

are well-known surrogate markers of long-term poor blood

pressure control, as well as markers of worse cardiovascular

prognosis (Schillaci et al., 2000). Thus, it was not

unexpected that it substituted hypertension and blood

pressure levels as a predictive factor for microvascular

complication development. This finding does not diminish

but emphasizes the importance of intensive blood pressure

treatment to achieve reduction in diabetic microvascular

disease occurrence and progression (UKPDS Group, 1998).

This seems to be particularly relevant for nephropathy

development. An increment in 1 S.D. (75 g) in LVM nearly

doubles the risk of nephropathy, whereas increases 20% to

25% the risk of neuropathy and retinopathy (Table 4). Also

significant, the patients without microvascular complica-


tions were more intensively treated (Table 1), although a

protective effect of diuretic use was not confirmed on

multivariate analysis.

The relevance of the interaction between these two

main risk factors, hyperglycaemia and uncontrolled hyper-

tension, for the development of complications in type 2

diabetes, has been emphasized by a recent report from the

UKPDS investigators (Stratton et al., 2006). They showed

that the subgroup of subjects in the highest category of

both HbA1c and SBP had a 16-fold increased risk of

developing microvascular disease in comparison with the

subgroup in the lowest category. Clearly, this question

should be further addressed.

The relationships between S lipid levels and development

of diabetic microvascular disease are more controversial.

Our finding of total cholesterol level as an independent

predictive factor for clinical nephropathy development is

supported by previous studies (Gall et al., 1997; Ravid,

Neumann, & Lishner, 1995). We were unable to demon-

strate any association between lipid profile and risk of

retinopathy development or progression, as shown by some

investigations (Nazimek-Siewniak et al., 2002; Tung et al.,

2005; van Leiden et al., 2002), but not by others (Kohner

et al., 1998; Tudor et al., 1998). The finding of a protective

effect of S HDL cholesterol level on peripheral neuropathy

development probably reflects the interactions with the

presence of peripheral arterial disease in determining

progression of peripheral neuropathy, since a low HDL

cholesterol is a well-known risk factor for diffuse athero-

sclerotic disease. This finding is supported by a recent report

in type 1 diabetic patients (Tesfaye et al., 2005).

Longer duration of diabetes as a risk factor for development

and progression of microvascular complications is a nearly

universal finding in previous studies (Adler et al., 1997;

Forrest et al., 1997; Tesfaye et al., 2005; Tung et al., 2005;

van Leiden et al., 2002), as in the present one, suggesting

that diabetes duration may be a surrogate marker for clinical

course deterioration in type 2 diabetes (Tung et al., 2005).

Some important limitations of this study must be pointed

out. Some potentially relevant variables for prediction of

microvascular disease development were missing, such as

smoking status, HbA1c, and microalbuminuria. The relation-

ships between smoking and diabetic microvascular compli-

cations are controversial, with some studies showing

positive associations (Forrest et al., 1997; Ravid et al.,

1995; Tesfaye et al., 2005); others, no association (Kohner

et al., 1998; Nazimek-Siewniak et al., 2002), and even an

implausible protective effect for neuropathy has been

reported (Adler et al., 1997). As discussed previously,

HbA1c measurement unavailability may have been a reason

for not finding association between glycemic metabolic

control and nephropathy development, although it could be

demonstrated by mean fasting glycemia for the other

microvascular end points. Also, as no anthropometric

measurements were performed, the reported association

between height and risk of peripheral neuropathy (Adler

et al., 1997; Forrest et al., 1997) could not be evaluated.

Finally, it should be mentioned that the type 2 diabetic

patients enrolled into this cohort study came from a tertiary-

care university hospital outpatient clinic. So, they possibly

may not be representative of the general type 2 diabetic

population being followed-up in primary-care centers in

Brazil, although the cumulative incidence of microvascular

disease development and progression found here (Table 2) is

comparable to that reported in other population-based

studies (Adler et al., 1997; Tudor et al., 1998; Tesfaye

et al., 2005; Tung et al., 2005).

In conclusion, this prospective study with up to 7 years

of follow-up provides evidence that the main risk markers

for the development and progression of microvascular

disease complications in Brazilian type 2 diabetic patients

are related to poor glycemic and hypertension control and to

longer diabetes duration. Lipid fraction abnormalities are

associated with peripheral neuropathy and clinical nephr-

opathy development. Additional prospective studies with

multifactorial intervention are needed to verify if better

control of these risk factors can reduce the burden of

morbidity and mortality associated with microvascular

complications in type 2 diabetes, in a manner similar to

that demonstrated in a recent multiple risk factor interven-

tion trial (Gaede et al., 2003) for cardiovascular disease.

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