diabetic microvascular complications—can the presence of one predict the development of another?
TRANSCRIPT
Journal of Diabetes and Its Comp
Diabetic microvascular complications—can the presence of one predict
the development of another?
Aniz Giracha,4, Louis Vignatib
aEli Lilly and Company Limited, Sunninghill Road, Windlesham, GU20 6PH Surrey, UKbEli Lilly and Company Limited, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 1 March 2006; accepted 1 March 2006
Abstract
The number of people with diabetes is increasing dramatically worldwide. The rising prevalence of obesity in childhood and adolescence
has also been linked to a startling increase in the number of diagnosed cases of type 2 diabetes in these younger age groups. Despite the
introduction of treatment strategies, diabetes remains a major cause of new-onset blindness, end-stage renal disease, and lower leg
amputation, all of which contribute to the excess morbidity and mortality in people with diabetes. Furthermore, the management of diabetes-
related complications generates substantial costs. In order that timely treatment can be given, it is essential that patients at risk for the
development of diabetic microvascular complications are identified earlier. Diabetes duration and glycemic, blood pressure, and lipid control
have consistently been shown to correlate with diabetic retinopathy, neuropathy, and nephropathy, but to date, the relationship of one diabetic
microvascular complication to another has not been clearly described. A review of the literature has raised the question that apart from other
known risk factors, there is a possible relationship among the diabetic microvascular complications themselves, and this appears to be much
stronger than the sparse published data on it would suggest. A scoring system that can predict the development of diabetic microvascular
complications may facilitate the early identification of those patients at risk and, consequently, have a positive impact on patients’ quality of
life and reduce the economic burden of diabetes and its complications.
D 2006 Elsevier Inc. All rights reserved.
Keywords: Diabetes; Microvascular; Complications; Retinopathy; Neuropathy; Nephropathy
1. Introduction
Recent epidemiological studies (Dunstan et al., 2002;
Harris, 1998; King, Aubert, & Herman, 1998; Wild, Roglic,
Green, Sicree, & King, 2004) show a significant rise in the
prevalence of diabetes (particularly type 2 diabetes) world-
wide, resulting in an increased burden on individuals and
health care systems. The total number of people with
diabetes is projected to rise from 171 million in 2000 to
366 million in 2030 (Wild et al., 2004), with the greatest
1056-8727/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jdiacomp.2006.03.001
4 Corresponding author. Eli Lilly and Company Limited, Sunninghill
Road, Windlesham, GU20 6PH Surrey, UK. Tel.: +44 1276 484154;
fax: +44 1276 483782.
E-mail address: [email protected] (A. Girach).
increase occurring in developing compared with developed
countries (King et al., 1998). Although there is increasing
awareness of and screening for diabetes, the number of
people with undiagnosed diabetes remains high (Dunstan
et al., 2002). Since type 2 diabetes is often not diagnosed
until the individual has had the disease for many years, the
microvascular complications of diabetes (retinopathy,
nephropathy, and neuropathy) may already be present
(Spijkerman et al., 2003). Historically, type 2 diabetes has
been regarded as a disorder of middle-aged and elderly
people; however, the rising prevalence of obesity in child-
hood and adolescence has been linked to a startling increase
in the number of diagnosed cases of type 2 diabetes in these
younger age groups (Hotu, Carter, Watson, Cutfield, &
Cundy, 2004; Likitmaskul et al., 2003). What is particularly
lications 20 (2006) 228–237
Table 1
Prevalence rates and risk of diabetic nephropathy according to diabetic
retinopathy status
Diabetic retinopathy status
Diabetic
nephropathy, n (%) OR (95% CI)
All patients
Present (n=206) 40 (19.4) 5.68 (3.06–10.62)
Absent (n=442) 18 (4.1)
Type 1 diabetes
Present (n=90) 23 (25.6) 13.39 (3.79–74.11)4
Absent (n=120) 3 (2.5)
Type 2 diabetes
Present (n=116) 17 (14.7) 3.51 (1.6–7.74)4
Absent (n=322) 15 (4.7)
4 Statistically significant.
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237 229
worrying is that affected adolescents are likely to suffer
from premature morbidity caused by the associated diabetic
microvascular complications (Hotu et al., 2004).
Diabetic microvascular complications may have devas-
tating consequences, including blindness, end-stage renal
disease (ESRD), and lower leg amputations, which almost
triple the annual cost of managing diabetes (Bate & Jerums,
2003). In the United States, diabetic retinopathy, nephrop-
athy, and neuropathy account for almost 50% of the total
costs of complications resulting from type 2 diabetes (Caro,
Ward, & O’Brien, 2002). The global increase in the
prevalence of diabetes will inevitably lead to increases in
the prevalence of diabetic microvascular complications and,
consequently, significantly increased health care expendi-
ture (Harris, 1998).
Prevention of complications is the main aim of diabetes
management (Bate & Jerums, 2003). The Diabetes Control
and Complications Trial (DCCT) study (The DCCT
Research Group, 1993), and the United Kingdom Prospec-
tive Diabetes Study (UHPDS; UKPDS 33, 1998; UKPDS
38, 1998) established the benefits of intensive glycemic
control and improved blood pressure control in reducing
the incidence and progression of diabetic microvascular
complications in type 1 and type 2 diabetes. Policies to
improve control of blood glucose and blood pressure have
also been shown to be cost-effective (Gray, Clarke, Farmer,
& Holman, 2002). Nonetheless, intensive therapy cannot
completely prevent these debilitating complications. In
some cases, intensive therapy may even adversely affect
the development of certain complications such as diabetic
retinopathy (The DCCT Research Group, 1998).
In addition to the established risk factors for the
development of diabetic microvascular complications, some
authors have identified an association among the com-
plications themselves (El-Asrar, Al-Rubeaan, Al-Amro,
Moharran, & Kangave, 2002; Molitch, Steffes, Cleary, &
Nathan, 1993). Consequently, it has been suggested that
early detection of microvascular disease may be facilitated if
all three diabetic microvascular complications are consid-
ered as having similar etiological factors and, hence, are all
screened for in the same patient (Girach, Manner, & Porta,
in press). However, to date, there is very little published data
on whether the development of one diabetic microvascular
complication influences the risk of developing a second
complication. This review explores this concept further and
identifies and discusses the published data on the complex
interrelationships among the three diabetic microvascular
complications, a topic that is poorly reported in the literature
to date.
2. Methods
A systematic evidence-based review was undertaken to
establish the interrelationship between diabetic retinopathy,
diabetic nephropathy, and diabetic neuropathy and relative
risk of disease progression, together with current approaches
to scoring or grading risk. Published trials were found by
searching Medline from 1966 to 2003 and Embase from
1974 to 2004 using a comprehensive search strategy and by
searching Biosis to identify abstracts. In addition, Develop-
ment and Evaluation Committee Reports, Evidence-Based
Medicine Reviews databases, and the Cochrane Library
were searched through direct Internet access to the
appropriate site. Citations for review were checked to
identify multiple publications of the same trial data.
3. Results
3.1. The relationship between diabetic retinopathy and other
diabetic microvascular complications
Diabetic retinopathy is one of the most common micro-
vascular complications (Williams et al., 2004) and the most
frequent cause of new cases of blindness among adults aged
20–74 years (Fong et al., 2003; Stitt, Jenkins, & Cooper,
2002). Extensive research on potential risk factors for
diabetic retinopathy has established a definitive relationship
between hyperglycemia and diabetic retinopathy in both
type 1 and type 2 diabetes (DCCT, 1993; UKPDS 33, 1998).
Other risk factors such as diabetes duration and hyper-
tension have also been found to play a role (UKPDS 38,
1998; Orchard et al., 1990). More recently, studies have
shown that the presence of diabetic retinopathy itself may
reveal patients at risk of diabetic nephropathy (El-Asrar
et al., 2002; Rossing, Hougaard, & Parving, 2002; Villar,
Garcia, Goicolea, & Varquez, 1999).
El-Asrar et al. (2002) enrolled 648 patients with type 1
(32.4%) and type 2 (67.6%) diabetes in a cross-sectional
study to determine the predictive value of diabetic retinop-
athy. Univariate analyses indicated that patients with
diabetic retinopathy were 5.68, 13.39, and 3.51 times as
likely to have diabetic nephropathy when compared with
those without diabetic retinopathy in the whole study
population and in patients with type 1 and type 2 diabetes,
respectively (Table 1). The predictive value of diabetic
Table 2
Prevalence rates and risk of diabetic nephropathy according to diabetic
macular edema status
Diabetic retinopathy status
Diabetic
nephropathy, n (%) OR (95% CI)
All patients
No retinopathy
(n=442)
18 (4.1) 5.54 (2.68–11.5)4
Diabetic macular
edema (n =105)
20 (19)
Type 1 diabetes
No retinopathy
(n=120)
3 (2.5) 10.54 (2.5–61.65)4
Diabetic macular
edema (n =47)
10 (21.3)
Type 2 diabetes
No retinopathy
(n=322)
15 (4.7) 4.26 (1.67–10.8)4
Diabetic macular
edema (n =48)
10 (17.2)
4 Statistically significant.
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237230
retinopathy for diabetic nephropathy appeared stronger in
patients with type 1 diabetes than in those with type 2
diabetes. In this study, the prevalence of diabetic nephrop-
athy was found to rise with increasing severity of diabetic
retinopathy. Multivariate logistic analyses indicated that
patients with diabetic retinopathy were 4.37 times likely to
have diabetic nephropathy as those without diabetic
retinopathy. In addition, the prevalence rates of diabetic
nephropathy [odds ratio (OR)=5.54; 95% confidence
interval (CI)=2.68–11.5] were significantly higher among
patients with diabetic macular edema when compared with
those without diabetic retinopathy (Table 2).
Villar et al. (1999) also demonstrated that diabetic
retinopathy was one of the most important risk factors
responsible for the development of incipient nephropathy in
normoalbuminuric, normotensive patients with either type 1
or type 2 diabetes. This prospective, observational study
enrolled 340 normotensive patients with type 1 diabetes and
258 normotensive patients with type 2 diabetes to evaluate
progression to diabetic nephropathy. After the 24-month
observation period, 34 (5.7%) patients developed persistent
microalbuminuria and 2 (0.3%) patients developed macro-
albuminuria (or proteinuria). Diabetic retinopathy was
Table 3
Prevalence of proteinuria in different diabetic groups in relation to the
degree of diabetic retinopathy
Degree of diabetic
retinopathy
Type 1 diabetes Type 2 diabetes
Total n
Percentage
with
proteinuria Total n
Percentage
with
proteinuria
Absent 113 8.8 265 12.8
Nonproliferative 61 18.0 126 23.8
Preproliferative 46 21.7 120 37.5
Proliferative 18 44.4 23 39.1
Total 238 16.3 534 22.1
present in 9 (56%) patients with type 1 diabetes with
incipient/overt nephropathy and in 17 (85%) patients with
type 2 diabetes with incipient/overt nephropathy.
Further evidence that diabetic retinopathy may predict
the development of microalbuminuria comes from Rossing
et al. (2002), who conducted a 10-year prospective,
observational study in 537 normoalbuminuric adult patients
with type 1 diabetes. During follow-up, persistent micro-
albuminuria developed in 134 (25%) patients. Macro-
albuminuria developed in 34 of these patients (6% of all
patients). Several potentially modifiable risk factors were
identified by means of Cox multiple regression analysis,
including the presence of any diabetic retinopathy (relative
risk, 1.90; 95% CI=1.26–2.88; Pb.01).
A similar association between diabetic retinopathy and
diabetic nephropathy has been reported in the EURODIAB
Complications Study (Stephenson et al., 1995). Results from
this study suggest that diabetic retinopathy, in association
with increased blood pressure, is an important independent
risk factor for the progression of diabetic nephropathy. In this
study, which enrolled 3250 patients with type 1 diabetes, a
positive association was found between the degree of
diabetic retinopathy and the level of albuminuria. Interest-
ingly, macroalbuminuria without diabetic retinopathy was
rare (1.6%). In contrast, diabetic retinopathy without diabetic
nephropathy was common since in the patients who had
normal albumin excretion rate, more than a third (37.8%) had
proliferative diabetic retinopathy.
It has also been shown that the prevalence of proteinuria
increases in relation to the severity of diabetic retinopathy
(Schmechel & Heinrich, 1993). Schmechel and Heinrich
(1993) conducted a study of 772 patients with insulin-
treated diabetes to analyze the prevalence of clinical retinal
and renal microangiopathies over a period of 1 year. More
than half of the patients in each study group were diagnosed
with diabetic retinopathy (52.5% of patients with type 1
diabetes; 50.3% of insulin-treated patients with type 2
diabetes). Clinical diabetic nephropathy was also diagnosed
in 16.3% of patients with type 1 diabetes and in 22.1% of
patients with insulin-treated type 2 diabetes. Individuals
with diabetic retinopathy exhibited proteinuria more fre-
quently than did those without diabetic retinopathy. In
addition, the prevalence of proteinuria increased relative
to the severity of diabetic retinopathy in both diabetic
groups (Table 3).
Table 4
Risk of diabetic retinopathy and blindness in patients with increased
albuminuria relative to those with normoalbuminuria
OR of diabetic retinopathy
Blindness
No
retinopathy
Simple
retinopathy
Proliferative
retinopathy
Normoalbuminuria 1.00 1.00 1.00 1.00
Microalbuminuria 0.44 1.04 2.33 4.00
Macroalbuminuria 0.03 0.73 4.83 7.19
Fig. 1. Prevalence of albuminuria and associated diabetic retinopathy in patients with type 1 diabetes.
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237 231
Aside from being a predictor of diabetic nephropathy,
El-Asrar et al. (2002) also showed that patients with mild to
moderate nonproliferative diabetic retinopathy or prolifer-
ative diabetic retinopathy are at an increased risk of having
diabetic neuropathy. Results from univariate analysis
showed that the presence of diabetic retinopathy was
associated with an increased risk of having diabetic neuro-
pathy (OR=2.23; 95% CI=1.56–3.18). Multivariate logistic
regression analyses did not reveal a similar association that
was statistically significant. In addition, in the whole study
Fig. 2. Prevalence of albuminuria and associated diab
group, the prevalence rate of diabetic neuropathy (OR=2.7;
95% CI=1.71–4.27; Pb.001) was significantly higher
among patients with diabetic macular edema than among
those without diabetic retinopathy.
Further evidence comes from Coppini et al. (2001), who
evaluated the long-term progression of diabetic peripheral
neuropathy in 985 patients with diabetes using vibration
perception threshold as a validated measure. It was
suggested that a combination of log-transformed vibration
perception threshold values and thermal thresholds could
etic retinopathy in patients with type 2 diabetes.
Table 5
Urinary albumin excretion
At baseline Mean UAE (mg/g)
No diabetic retinopathy (n=37) 56.01F26.87
Nonproliferative diabetic retinopathy (n=22) 126.27F334.98
Proliferative diabetic retinopathy (n=9) 332.83F188.92
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237232
identify diabetic patients at risk of developing diabetic
peripheral neuropathy. In addition, patients with diabetic
retinopathy at baseline were at an increased risk of
developing diabetic peripheral neuropathy. In this study,
78 (19.9%) patients developed diabetic peripheral neuro-
pathy over a mean 12-year period, 18 (23%) of whom had
diabetic retinopathy at baseline.
3.2. The relationship between diabetic nephropathy and
other diabetic microvascular complications
Diabetic nephropathy is one of the most serious
complications of diabetes and is the most frequent cause
of ESRD in Western countries (Squadrito & Cucinotta,
1991). The risk of developing diabetic nephropathy has
been shown to be similar in type 1 and type 2 diabetes
(Hasslacher, Ritz, Wahl, & Michael, 1989). Microalbumi-
nuria is an established surrogate marker of subsequent overt
nephropathy (Orchard et al., 1990). Approximately half
of all patients who develop microalbuminuria do so within
19 years from diagnosis of diabetes (Adler et al., 2003).
Studies have shown that microalbuminuria is also charac-
terized by an increased prevalence in proliferative diabetic
retinopathy and blindness (Parving et al., 1988). In a cross-
sectional study of 957 adult patients with type 1 diabetes,
Parving et al. (1988) demonstrated that patients with
macroalbuminuria were almost five times more likely to
develop proliferative diabetic retinopathy, as compared with
patients with normoalbuminuria. Similarly, these patients
were seven times more likely to develop blindness (Table 4).
In a review of the late complications of diabetes,
Squadrito and Cucinotta (1991) reported that the prevalence
of diabetic retinopathy increases with the severity of
diabetic nephropathy in type 1 and type 2 diabetes.
Microalbuminuria was observed in 26% of patients with
type 1 diabetes and in 39% of patients with type 2 diabetes.
In both diabetic groups, microalbuminuria increased with
diabetes duration and was frequently associated with
diabetic retinopathy and higher blood pressure, as compared
with normoalbuminuric patients (Figs. 1 and 2).
Even very early in the development of diabetic nephrop
athy and diabetic retinopathy, studies have established that
there is a relationship between them and with the level of
metabolic control (Molitch et al., 1993). In the DCCT
(Molitch et al., 1993), 10% of the secondary intervention
cohort (n=715), who had evidence of minimal diabetic
retinopathy at baseline, had elevated urinary albumin
excretion (UAE) rate levels. Within this group, there was
also a strong relationship between elevated UAE rate levels
and more advanced degrees of diabetic retinopathy. Other
studies (Billaut & Passa, 1991; Micozkadioglu, Okan, &
Gungor, 2001; Trevisan et al., 2002) have also demonstrated
that such a relationship is an important risk factor for the
development and progression of diabetic retinopathy. In a
retrospective study of 68 patients with type 2 diabetes,
Micozkadioglu et al. (2001) demonstrated that UAE
rises with the severity of diabetic retinopathy, reaching
nephropathic levels in patients with nonproliferative dia-
betic retinopathy (Table 5). Results from this study
suggest that UAE reveals diabetic retinopathy and is
also predictive of diabetic retinopathy in patients with
type 2 diabetes.
Evidence to support the close relationship between the
presence of diabetic retinopathy and abnormal increases in
UAE also comes from a study by Trevisan et al. (2002). In
this prospective cohort study of 65 patients (aged b75 years)
with type 2 diabetes and evidence of persistent proteinuria
(38 with diabetic retinopathy; 27 without diabetic retinop-
athy), the rate of progression of renal disease in those
patients with diabetic retinopathy was faster than that
observed in those without diabetic retinopathy. The rate of
decline of the glomerular filtration rate was higher in
patients with type 2 diabetes with diabetic retinopathy
(�6.5F4.4 ml/year) than in those without diabetic retinop-
athy (�1.8F4.8 ml/year; Pb.0001).
In a previous study, Billaut and Passa (1991) demon-
strated that diabetic nephropathy is a strong predictor of
diabetic retinopathy. In this study of 157 patients with type 1
diabetes, 50% had diabetic retinopathy, 32% had diabetic
neuropathy, and 29% had diabetic nephropathy. Of those
patients with diabetic nephropathy, 69% also had diabetic
retinopathy. On the other hand, only 39% of patients with
diabetic retinopathy had diabetic nephropathy. In this
study, it was suggested that individuals with elevated
UAE were most likely to have all three diabetic micro-
vascular complications.
Even in children, early microvascular disease can occur
simultaneously in the eye and kidney. Verotti et al. (1994)
enrolled 55 retinopathic children and adolescents with
diabetes to evaluate the relationship between diabetic
retinopathy and diabetic nephropathy. Findings from
this study show that the grade of diabetic retinopathy
was clearly related to persistent microalbuminuria and
suggest that patients with persistent microalbuminuria
have already developed or are at risk of developing a
retinal microangiopathy.
The degree of diabetic nephropathy also appears to have
an effect on the prevalence of diabetic neuropathy, as doc-
umented by Parving et al. (1988). In this study, which found a
high prevalence (22%) of microalbuminuria in 982 adult
patients who had had type 1 diabetes for 5 years or more, the
prevalence of diabetic peripheral neuropathy was found to be
higher in patients with microalbuminuria, as compared with
patients with normoalbuminuria (31% vs. 21%, respectively).
However, only patients with macroalbuminuria showed a
Table 6
Relative odds for the presence of nonproliferative and proliferative diabetic
retinopathy according to cardiovascular autonomic dysfunction in patients
with type 2 diabetes
Degree of diabetic
retinopathy
Without
cardiovascular
autonomic
neuropathy
(n =17)
With
cardiovascular
autonomic
neuropathy
(n =18)
OR
(95% CI)
None 13 3 1.0
Nonproliferative 3 7 10.11 (1.60–64.0)
Proliferative 1 8 34.67 (3.06–393.2)
Table 7
Relative odds for the presence of diabetic nephropathy according to
cardiovascular autonomic dysfunction in patients with type 2 diabetes
Degree of diabetic
nephropathy
Without
cardiovascular
autonomic
neuropathy
(n=17)
With
cardiovascular
autonomic
neuropathy
(n=18)
OR
(95% CI)
None 16 9 1.0
Overt proteinuria 1 9 16.0 (1.73–147.2)
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237 233
significant increase in the prevalence of diabetic peripheral
neuropathy (Pb.02).
Diabetic autonomic neuropathy, which is among the
least-recognized and least-understood diabetic complication,
frequently coexists with other peripheral neuropathies and
other diabetic complications (Vinik, Maser, Mitchell, &
Freeman, 2003). Cardiovascular autonomic neuropathy is
the most-studied and most clinically important form of
diabetic autonomic neuropathy (Vinik et al., 2003). There is
evidence that the presence of diabetic nephropathy is
associated with the risk of cardiovascular autonomic neuro-
pathy in patients with type 2 diabetes (Viswanathan, Prasad,
Chamukuttan, & Ramachandran, 2000). Viswanathan et al.
(2000) enrolled 70 patients in a cross-sectional study to
evaluate the adverse effects of diabetic nephropathy on
cardiac autonomic neuropathy. Twenty-five patients had
type 2 diabetes with diabetic nephropathy; 25 patients had
type 2 diabetes without diabetic nephropathy and 20 were
nondiabetic, nonhypertensive patients. It was found that
individuals with diabetic nephropathy developed cardiac
autonomic neuropathy earlier than did patients without
diabetic nephropathy. In addition, peripheral neuropathy
was found to be more prevalent among patients with
diabetic nephropathy, independent of the presence of cardiac
autonomic neuropathy.
3.3. The relationship between diabetic neuropathy and other
diabetic microvascular complications
Diabetic neuropathy is a very varied, multifocal disease
and is a major cause of morbidity (Stitt et al., 2002). Clinical
symptoms are related to the site of major involvement,
specifically the somatic or autonomic systems (Squadrito &
Cucinotta, 1991). The risk factors for diabetic peripheral
neuropathy are largely unknown, although available evi-
dence implicates, among others, the level of hyperglycemia
and diabetes duration (Tesfaye et al., 1996). A number
of studies have also noted that diabetic neuropathy
is associated with diabetic retinopathy (Cohen, Jeffers,
Faldut, Marcoux, & Schrier, 1998; Khandekar, Lawatii,
Mohammed, & Al Raisi, 2003; Maser et al., 1989;
O’Hare, Abuaisha, & Geoghegan, 1994; Tesfaye et al.,
1996). In the EURODIAB IDDM Complications Study
(Tesfaye et al., 1996), significant correlations were observed
between the presence of diabetic peripheral neuropathy and
the presence of background or proliferative diabetic
retinopathy (Pb.01). The authors also observed a significant
(Pb.01) trend in the increase in the relative risk for the
presence of diabetic neuropathy with an increase in the
progression of both diabetic retinopathy and albumin
excretion. An earlier epidemiological study (Maser et al.,
1989) also reported a univariate association of diabetic
neuropathy with diabetic retinopathy and diabetic nephrop-
athy. Further evidence of an association between various
forms of diabetic neuropathy and diabetic retinopathy comes
from a study by O’Hare et al. (1994). In this prospective
study, diabetic retinopathy (proliferative retinopathy, mac-
ulopathy, or preproliferative retinopathy serious enough to
require laser photocoagulation therapy) was significantly
(Pb.001) associated with diabetic neuropathy in type 1
diabetes and was predictive of diabetic neuropathy in
patients with type 2 diabetes.
The Appropriate Blood Pressure Control in Diabetes
study (Cohen et al., 1998) found that both diabetic
retinopathy and diabetic nephropathy were significantly
associated with diabetic neuropathy in patients with type 2
diabetes. In this study, 949 and 869 patients with type 2
diabetes were evaluated to identify the risk factors for the
development of diabetic sensorimotor peripheral neuropathy
and diabetic autonomic neuropathy, respectively. Diabetic
retinopathy was found to be independently associated with
these two forms of diabetic neuropathy; however, it was
more strongly associated with diabetic peripheral neuro-
pathy, with an OR of 2.3 compared with 1.8 in autonomic
neuropathy. Spallone, Maiello, Cicconetti, and Menzinger
(1997) reported a similar association between autonomic
neuropathy and diabetic retinopathy in an earlier study in
type 1 and type 2 diabetes. Although no significant
association was found between autonomic neuropathy and
diabetic nephropathy in both groups of patients with
diabetes, results from this study indicate a relation between
the degree of albumin excretion and severity of autonomic
damage in individuals with type 1 diabetes.
Krolewski et al. (1992) demonstrated that the risk of
early-onset proliferative diabetic retinopathy is associated
with cardiovascular autonomic neuropathy in type 1
diabetes. Similarly, the presence of cardiovascular auto-
nomic neuropathy has been found to be strongly associated
with proliferative diabetic retinopathy in patients with
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237234
type 2 diabetes (Schmid, Schaan, Cecconello, Maestri, &
Neumann, 1995). Schmid et al. (1995) investigated the
presence of proliferative diabetic retinopathy in an inception
cohort of patients with type 2 diabetes, 18 of whom had
cardiovascular autonomic neuropathy and 17 of whom were
without cardiovascular autonomic neuropathy. Both non-
proliferative and proliferative diabetic retinopathy were
found to be related to autonomic dysfunction. Relative
odds for nonproliferative diabetic retinopathy and prolifer-
ative diabetic retinopathy were 10.1 and 34.7, respectively
(Table 6). However, only proliferative diabetic retinopathy
was significantly associated when ORs were adjusted for the
presence of diabetic nephropathy, hypertension, and nonpro-
liferative and proliferative diabetic retinopathy (OR=7.1).
Schmid et al. also found that the presence of diabetic
nephropathy, both microalbuminuria and overt proteinuria,
was significantly related to the presence of cardiovascular
autonomic dysfunction (Table 7).
4. Discussion
The prevalence of diabetes remains high and is reaching
epidemic proportions. Individuals with diabetes are at risk
for diabetic microvascular complications such as retinop-
athy, neuropathy, and nephropathy compared with individ-
uals without diabetes (American Diabetes Association,
2003). According to recent estimates, the costs associated
with diabetes in terms of medical expenditure and lost
productivity may be as high as US$132 billion in the United
States; however, this figure may rise even further if the
prevalence of diabetes continues to grow (American
Diabetes Association, 2003). The management of diabetes-
related complications generates substantial costs, not just in
the year that the event occurs but also in each subsequent
year (Caro et al., 2002; Clarke, Gray, Legood, Briggs, &
Holman, 2003). In 2002, direct medical expenditure for
chronic complications attributable to diabetes in the United
States was estimated at US$24.6 billion (American Diabetes
Association, 2003).
Susceptibility to diabetic microvascular complications,
however, varies greatly from one individual to another
(Ebeling & Koivisto, 1997). In a study of 10,079 patients
with diabetes, Morgan et al. (2000) found evidence to show
that although not all people with diabetes developed
complications, multiple complications occur in almost one
fifth of individuals. In addition, the frequency of individual
and multiple complications increases with both age and
duration of diabetes. Interestingly, although more than 30%
of individuals with diabetic nephropathy also had diabetic
retinopathy, only 4% of individuals with diabetic retinop-
athy had concomitant diabetic nephropathy.
It has been established that prolonged hyperglycemia is a
primary predictor of the development and progression of
diabetic microvascular complications (Stitt et al., 2002).
Consequently, a number of approaches for the prevention of
adverse effects of hyperglycemia have been studied, in
particular the role of protein kinase C (PKC) inhibitors
(Aiello, 2002; Campochiaro and The C99-PKC412-003
Study Group, 2004) and advanced glycation end (AGE)
products (Chiarelli et al., 1999; Sugiyama et al., 1996). It is
known that hyperglycemia leads to generation of diacylgly-
cerol, which activates PKC, leading to effects on the retinal,
renal, cardiac, and nerve vasculature (Bloomgarden, 2002).
Clinical trials are currently underway, looking at several
different ways to prevent or reduce the adverse effects of
hyperglycemia. PKC activation is one of the sequelae of
hyperglycemia and is thought to play a pivotal role in
the development of diabetic microvascular complications
(Curtis & Scholfield, 2004). PKC inhibitors are currently
being studied as a potential treatment for multiple diabetic
microvascular complications, including diabetic retinopathy,
diabetic macular edema, and diabetic peripheral neuropathy.
Similarly, increased serum AGE levels may be associated
with early microvascular complications (Chiarelli et al.,
1999), and this has been the focus of many groups in
trying to find a suitable treatment. Unfortunately, most of
the AGE inhibitors studied either have not yielded positive
results or have necessitated discontinuation due to their side-
effect profiles.
However, in order that timely treatment can be given, it is
essential that patients at risk for the development of diabetic
microvascular complications are identified earlier, and in
order to do this, the clinician needs to be aware of the
interrelationships between the microvascular complications
themselves as well as the risk factors involved (Girach et al.,
in press). It is also prudent that the clinician screen for all
other microvascular complications when faced with a
patient with diabetes, irrespective of which complication
may have been the cause of attendance.
It can be postulated that all the three microvascular
complications begin their course at the same time, at
some time point after developing diabetes, and that the
appearance of diabetic retinopathy before diabetic nephro-
pathy and diabetic neuropathy may in fact be an indication
of the relative ease of diagnosis of the ocular complication,
as compared with the other two. However, reports in the
literature tend to indicate a more definitive chronological
order of development of the microvascular complications
(Ebeling & Koivisto, 1997). Two further studies, Billaut and
Passa (1991) and the EURODIAB IDDM Complications
Study (Stephenson et al., 1995), may also indicate that
diabetic retinopathy develops prior to the development of
diabetic nephropathy, with diabetic neuropathy, with its
inherent diagnostic challenges, occurring at the same time or
later than diabetic nephropathy. This chronological order, if
real, may prove to be a valuable tool for the clinician in
helping to manage the patient with more than one apparent
microvascular complication.
A review of the literature has shown that, among other
known risk factors, there is a possible relationship among
the diabetic microvascular complications themselves, and
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237 235
this appears to be much stronger than the sparse published
data available that examine these relationships would
suggest. A number of studies provide evidence that diabetic
retinopathy may independently predict the development of
microalbuminuria and hence be a powerful predictor of the
progression of renal damage in diabetic patients with
proteinuria (Rossing et al., 2002; Stephenson et al., 1995;
Trevisan et al., 2002). Further support of the close relation-
ship between renal and retinal complications comes from
other studies (Billaut & Passa, 1991; Molitch et al., 1993)
that show that diabetic nephropathy is a strong predictor of
diabetic retinopathy and that there is a strong relationship
between elevated UAE rate levels and more advanced
degrees of diabetic retinopathy. The prevalence of diabetic
retinopathy also increases with the severity of diabetic
nephropathy (Squadrito & Cucinotta, 1991). Consequently,
some authors suggest that individuals with macroalbumi-
nuria should be regarded as a high-risk group not only for
their increased risk of progression but also for their
increased risk of developing diabetic retinopathy (Squadrito
& Cucinotta, 1991). In contrast, other authors have found no
evidence to suggest that the incidence of diabetic retino-
pathy is associated with clinical signs of diabetic nephrop-
athy (Lovestam-Adrian, Agardh, & Agardh, 1999). It has
been reported that microvascular complications in the retina
and kidney can occur in isolation, which suggests that there
are fundamental differences in some aspects of the patho-
genesis of diabetic retinopathy and diabetic nephropathy
(Kanauchi, Kawano, Uyama, Shiiki, & Dohi, 1998).
Data from a number of studies, however, provide clear
evidence to suggest that the presence of diabetic peripheral
neuropathy is closely associated with the presence of
background or proliferative diabetic retinopathy. In addition,
cardiovascular autonomic neuropathy, which has been
linked to an increased risk of mortality (Maser, Mitchell,
Vinik, & Freeman, 2003), may also play a role in the deve-
lopment of proliferative diabetic retinopathy (Krolewski
et al., 1992). In another study (Viswanathan et al., 2000), the
prevalence of cardiovascular autonomic neuropathy was
found to be twofold higher in patients with type 2 diabetes
with diabetic nephropathy than in those without diabetic
nephropathy, thus emphasizing the need for an early
screening for cardiovascular autonomic neuropathy, partic-
ularly in this group of patients. The associations between
diabetic nephropathy and diabetic peripheral neuropathy,
however, are not so strong. Although the EURODIAB
IDDM Complications Study (Tesfaye et al., 1996) observed
a significant association between the presence of diabetic
peripheral neuropathy and the presence of albuminuria,
Shaw, Gokal, Hollis, and Boulton (1998) found that a
significant number of patients with diabetic nephropathy did
not have diabetic peripheral neuropathy.
A number of scoring systems have recently been
developed to identify individuals at high risk for undiag-
nosed type 2 diabetes (Lindstrom & Tuomilehto, 2003), to
predict undiagnosed hyperglycemia in ethnic minority
groups (Spijkerman et al., 2004), and to diagnose distal
polyneuropathy (Meijer et al., 2002). Since understanding
and identifying early predictors of diabetic microvascular
complications may also facilitate the prevention and man-
agement of these complications, a scoring system is
currently being developed, which will enable physicians to
make an accurate assessment of a patient’s overall risk of
worsening diabetic microvascular complications and assess
their management requirements. The scoring system will
identify patients at greatest risk of developing diabetic
microvascular complications so that appropriate measures
can be put into place for the optimal management of their
diabetes and the ensuing microvascular complications.
5. Conclusion
Despite the introduction of treatment strategies, diabetic
microvascular complications remain a major cause of
morbidity and mortality in diabetes. Diabetes duration and
glycemic, blood pressure, and lipid control have consis-
tently been shown to correlate with diabetic retinopathy,
diabetic neuropathy, and diabetic nephropathy, but to date,
the relationship of one diabetic microvascular complication
to another has not been clearly described. The data suggest
that the presence of a preexisting complication (diabetic
retinopathy, diabetic nephropathy, or diabetic neuropathy)
contributes to the development of another. Overall, the
association between diabetic retinopathy and diabetic
nephropathy seems to be much stronger according to the
published data, followed by the associations between
diabetic retinopathy and diabetic peripheral neuropathy, as
compared with the association between diabetic nephro-
pathy and diabetic peripheral neuropathy.
This review article describes the interrelationships and
associations among the three microvascular complications
as described in the published literature. The published data
seem to highlight the importance of screening for other
diabetic microvascular complications when a patient has
developed one already and the need for better and effective
communication between the different health care profes-
sionals involved in order to optimize the management of
the patient with diabetes. Further research on the timing and
progression rate of the diabetic complications relative to one
another is also required to further refine the risks posed to
each patient. In addition, a scoring system that can predict
the development of diabetic microvascular complications
may facilitate the early identification of those patients at risk
and, consequently, have a positive impact on patients’
quality of life and reduce the economic burden of diabetes
and its complications.
Acknowledgments
The authors would like to acknowledge Strategen Ltd.
for its help in the evidence-based review.
A. Girach, L. Vignati / Journal of Diabetes and Its Complications 20 (2006) 228–237236
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