Item 1

The new england journal of medicine
original article
Vascular Risk Factors and Diabetic Neuropathy

Solomon Tesfaye, M.D., Nish Chaturvedi, M.D., Simon E.M. Eaton, D.M.,
John D. Ward, M.D., Christos Manes, M.D., Constantin Ionescu-Tirgoviste, M.D.,
Daniel R. Witte, Ph.D., and John H. Fuller, M.A.,
for the EURODIAB Prospective Complications Study Group*
abstract
background
Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, From the Diabetes Research Unit, Royal
identifying potentially modifiable risk factors for neuropathy is crucial. We studied Hallamshire Hospital, Sheffield, United
Kingdom (S.T., S.E.M.E., J.D.W.); the De-
risk factors for the development of distal symmetric neuropathy in 1172 patients partment of Epidemiology and Public
with type 1 diabetes mellitus from 31 centers participating in the European Diabetes Health, Faculty of Medicine, Imperial Col-
(EURODIAB) Prospective Complications Study. lege of Science, Technology and Medicine,
London (N.C.); the Department of Inter-
nal Medicine and Diabetic Center, Papa-
methods georgiou General Teaching Hospital,
Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), Thessaloniki, Greece (C.M.); the Institute
of Diabetes, Nutrition, and Metabolic Dis-
with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clini- eases, Bucharest, Romania (C.I.-T.); and
cal evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids EURODIAB, Department of Epidemiology
and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were and Public Health, Royal Free and Univer-
sity College Medical School, London
measured in a central laboratory. (D.R.W., J.H.F.). Address reprint requests
to Dr. Tesfaye at the Diabetes Research
results Unit, Royal Hallamshire Hospital, Sheffield
S10 2JF, United Kingdom, or at solomon.
At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at tesfaye@sth.nhs.uk.
baseline (23.5 percent). The cumulative incidence of neuropathy was related to the gly-
cosylated hemoglobin value and the duration of diabetes. After adjustment for these *The investigators in the European Diabe-
tes (EURODIAB) Prospective Complica-
factors, we found that higher levels of total and low-density lipoprotein cholesterol and tions Study Group are listed in the Ap-
triglycerides, a higher body-mass index, higher von Willebrand factor levels and uri- pendix.
nary albumin excretion rate, hypertension, and smoking were all significantly associat-
N Engl J Med 2005;352:341-50.
ed with the cumulative incidence of neuropathy. After adjustment for other risk factors Copyright © 2005 Massachusetts Medical Society.
and diabetic complications, we found that duration of diabetes, current glycosylated he-
moglobin value, change in glycosylated hemoglobin value during the follow-up period,
body-mass index, and smoking remained independently associated with the incidence
of neuropathy. Cardiovascular disease at baseline was associated with double the risk
of neuropathy, independent of cardiovascular risk factors.
conclusions
This prospective study indicates that, apart from glycemic control, the incidence of
neuropathy is associated with potentially modifiable cardiovascular risk factors, includ-
ing a raised triglyceride level, body-mass index, smoking, and hypertension.
n engl j med 352;4 www.nejm.org january 27, 2005 341
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density lipoprotein (HDL) cholesterol, and triglyc-
d iabetic neuropathy is a common

cause of morbidity and death among pa-
tients with diabetes, generating a huge
economic burden.1 Apart from tight glycemic con-
trol, no other evidence-based treatments are known
erides.4-6 Levels of low-density lipoprotein (LDL)
cholesterol were calculated.7 The reference range
for glycosylated hemoglobin was 2.9 to 4.8 per-
cent.8 In order to compare the results with those of
to ameliorate or prevent neuropathy. the DCCT, measured glycosylated hemoglobin val-
The duration and level of hyperglycemia are im- ues were converted as previously reported (DCCT
portant determinants of microvascular complica- glycosylated hemoglobin=[1.0289¬the glycosylat-
tions of diabetes, including neuropathy.2 The rela- ed hemoglobin measurements for this study]+
tive effect of cardiovascular risk factors specifically 1.5263).9 DCCT-converted glycosylated hemoglo-
associated with diabetes (e.g., hypertension, dys- bin values were used in all further analyses.
lipidemia, and increased weight) or not associated Glycosylated hemoglobin values, measured cen-
with diabetes (smoking) on the development of trally according to the follow-up protocol, were
neuropathy are incompletely elucidated. The Dia- available for 1119 of 1172 patients (95.5 percent).
betes Control and Complications Trial (DCCT) re- Additional glycosylated hemoglobin values, deter-
ported a 60 percent reduction in neuropathy in the mined at one to eight (median, five) routine inter-
intensively treated groups after five years,2 but the im visits (measured and standardized according to
cumulative incidence of neuropathy (15 to 21 per- center) between baseline and the final follow-up
cent) and abnormal nerve conduction (40 to 52 per- visit, were available for 794 participants (67.7 per-
cent) remained substantial. Such findings suggest cent). All available glycosylated hemoglobin mea-
that neuropathy can develop, despite intensive surements were included in estimates of the change
control of the glucose level.2 Thus, risk factors be- in glycosylated hemoglobin during follow-up. Base-
sides hyperglycemia are probably involved in the line and final follow-up glycosylated hemoglobin
evolution of neuropathy. Identifying them, partic- values were standardized for the entire group. Lin-
ularly if they are modifiable, might lead to new ear regression for each patient provided the change
risk-reduction strategies. The European Diabetes in glycosylated hemoglobin per patient per year of
(EURODIAB) Prospective Complications Study follow-up and was included in the analyses to as-
aimed to define and assess the relative importance sess a possible association with neuropathy beyond
of other, potentially modifiable factors that increase the baseline glycosylated hemoglobin value.
the risk of distal symmetric neuropathy in patients
with type 1 diabetes mellitus. assessment and definition of diabetic
complications
methods The urinary albumin excretion rate was measured
from a single 24-hour urine collection.10 A urinary
patients and baseline investigations albumin excretion rate of 20 to 200 µg per minute
The baseline examination included 3250 patients was defined as microalbuminuria; a rate greater
(1668 men and 1582 women; mean [±SD] age, than 200 µg per minute was defined as macroalbu-
32.7±10.2 years; mean duration of diabetes, 14.7± minuria.
9.3 years).3 These patients were randomly selected The presence and severity of diabetic retinopathy
in a stratified manner from 31 diabetes clinics were assessed from retinal photographs (two fields
across Europe. Selection criteria and methods have per eye) obtained with a wide-angle camera and
been described previously.3 Written informed con- scored centrally by one expert in reading changes of
sent was obtained from all patients, and the insti- retinopathy.11 Retinopathy was classified as non-
tutional review board at each center approved the proliferative (background) or proliferative.
study. Trained physicians performed all measure- Cardiovascular disease was defined as either a
ments with standardized procedures and equip- history of physician-diagnosed cardiovascular dis-
ment according to a predefined protocol. Baseline ease (e.g., previous myocardial infarction, angina,
examinations were conducted from 1989 to 1991, coronary-artery bypass grafting, or stroke) or is-
and follow-up examinations from 1997 to 1999. chemic changes detected on a 12-lead electrocar-
Baseline blood samples, obtained after an over- diogram (classified by two observers according to
night fast, if possible, were sent to central laborato- the Minnesota code).12
ries. Measurements included total cholesterol, high- To assess the role of insulin resistance, an esti-
342 n engl j med 352;4 www.nejm.org january 27 , 2005
vascular risk factors and diabetic neuropathy
mated glucose disposal rate was calculated on the the patient’s age,15 and abnormal autonomic func-
basis of the waist-to-hip ratio, the presence of hy- tion (loss of heart rate variability with an RR ratio of
pertension, and the glycosylated hemoglobin val- less than 1.04, postural hypotension with a fall in
ue.13 Fibrinogen and von Willebrand factor were systolic blood pressure of 20 mm Hg or more, or
also measured.14 both).16 “Pure” peripheral neuropathy was defined
as distal neuropathy without autonomic symptoms
assessment of distal symmetric or abnormal autonomic-function tests.
polyneuropathy The cutoff points and the definition of neuropa-
Physicians experienced in taking a neurologic his- thy were established before any examination of the
tory assessed patients for distal symmetric polyneu- outcome data. The four criteria were evaluated at
ropathy. Patients with features suggesting other the same times (the day of the baseline visit and the
forms of diabetic neuropathy or polyneuropathy due day of the follow-up visit) for each patient.
to causes other than diabetes were excluded.
symptoms and signs of neuropathy

3250 Patients
The presence or absence of the following symp-
toms within the previous six months was ascer-
tained: “asleep” numbness or “dead feeling” in the 927 Had neuropathy
feet, a prickling sensation in the feet, deep aching at baseline
or burning pains in the legs, unusual difficulty in
climbing stairs, difficulty with bladder control, and
nocturnal diarrhea. Symptoms were evaluated care- 59 Were not assessed for
neuropathy at baseline
fully to rule out other causes. In addition, reflexes of
the ankle and knee tendons were assessed, with re-
inforcement if necessary. 437 Were at a center that
did not participate in
the follow-up
perception of vibration 8 Did not meet entry
criteria
The threshold of perception of vibration was mea-
sured by centrally calibrated biothesiometers (Bio-
medical).15 Three readings on the right big toe and 1819 Qualified for follow-up
right medial malleolus were obtained and averaged
for the analysis.
28 Died
autonomic function 508 Were lost to follow-up
Autonomic function was assessed according to two 11 Had an unknown
status of life or death
cardiovascular reflex responses after the patients
had rested in a supine position for at least five min-
utes — a change in heart rate and a change in sys-
tolic blood pressure on standing, as determined 1272 Reached follow-up
with a Hawksley random-zero sphygmomanome-
ter. The RR ratio was calculated by one observer.
The RR ratio is the ratio of the longest electrocar-
diographic RR interval between the 28th and 32nd
beats after standing to the shortest interval be-
tween the 13th and 17th beats. 100 Were not assessed 1172 Were assessed
for neuropathy for neuropathy
definition of neuropathy
Figure 1. Patients Analyzed for Progression to Neuropathy in the EURODIAB
Neuropathy was diagnosed in patients with two or Study.
more of the following four measures: the presence Initial and follow-up assessments were available for 1272 of 3250 patients.
of one or more symptoms, the absence of two or Of these patients, 100 did not have the neuropathy component assessed at
more reflexes of the ankle or knee tendons, a vibra- follow-up, yielding a final study population of 1172 patients.
tion-perception threshold that was abnormal for
Of 3250 patients examined, 927 had neuropathy Odds ratios for continuous risk factors were stan-
at baseline,17 whereas 1172 patients without neu- dardized, thus expressing the risk associated with
ropathy at baseline had neuropathy assessed at fol- a 1-SD increase in the continuous risk factors. All
low-up (Fig. 1). Baseline investigations and assess- logistic-regression models were adjusted for the
ment of neuropathy were repeated after a mean of duration of diabetes and glycosylated hemoglobin
7.3 years of follow-up. values. The relation between the change in glycosy-
lated hemoglobin values and the incidence of neu-
statistical analysis ropathy was assessed with the use of logistic regres-
Statistical analyses were performed with Stata soft- sion, with adjustments for potential confounders.
ware (version 7.0). The characteristics of patients The odds ratio for the incidence of neuropathy as-
who did and those who did not undergo assessment sociated with each increase of one quintile in the
for neuropathy were compared with the use of Stu- glycosylated hemoglobin value, as compared with
dent’s t-test or the Mann–Whitney U test where ap- the lowest quintile (the reference category), was also
propriate. The possibility of a threshold effect in the assessed.
relation between glycosylated hemoglobin values All relevant risk factors were included in a mul-
and the risk of neuropathy was evaluated by com- tivariate logistic-regression model to calculate mu-
paring the linear and exponential trend lines accord- tually adjusted, standardized odds ratios (Model 1).
ing to quintiles of glycosylated hemoglobin, as pre- In addition, complications of diabetes were added
viously reported.9,18 The relation between risk to the model (Model 2).
factors and the incidence of neuropathy was ana- We used logistic-regression models to assess the
lyzed with the use of logistic-regression models. development of neuropathy during follow-up, rath-
Odds ratios for dichotomous variables express the er than an analysis of failure time (time to diagno-
risk of neuropathy for patients with the risk factors sis of neuropathy) for current-status data, because
as compared with those without the risk factors. there was little variation in follow-up time (mean,
Table 1. Comparison of Baseline Data in 1819 Patients According to Whether There Was an Assessment for Neuropathy
at Follow-up.*
Variable Assessed for Neuropathy at Follow-up P Value

No Yes
No. of patients 647 1172
Age (yr) 30.7±9.1 30.7±8.8 0.91
Duration of diabetes (yr) 12.7±8.5 12.4±8.1 0.45
Glycosylated hemoglobin (% of hemoglobin) 8.3±1.9 8.0±1.8 0.01
Insulin dose per kg of body weight (IU) 0.7±0.2 0.7±0.2 0.55
Systolic blood pressure (mm Hg)† 118.0 (96, 148) 117.0 (96, 142) 0.03
Diastolic blood pressure (mm Hg)† 74.0 (57, 92) 74.0 (58, 91) 0.95
Weight (kg) 66.7±10.6 66.8±10.5 0.85
Body-mass index‡ 23.3±2.7 23.4±2.7 0.58
Waist-to-hip ratio 0.8±0.1 0.8±0.1 0.64
Albumin excretion rate (µg/min) 9.5 (3.2, 148.2) 9.9 (3.3, 147.1) 0.32
Total cholesterol (mmol/liter) 5.28±1.04 5.16±1.05 0.02
Triglycerides (mmol/liter) 0.90 (0.48, 2.22) 0.86 (0.48, 2.20) 0.03
von Willebrand factor (U/ml) 1.08±(0.51, 1.95) 1.11 (0.55, 2.21) 0.07
* Plus–minus values are means ±SD. Alternatively, in cases of skewed distributions, data are medians (5th percentile, 95th
percentile). P values are derived from Student’s t-test for data normally distributed or, in cases of skewed distributions,
from a Mann–Whitney U test. To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. To convert
values for triglycerides to milligrams per deciliter, divide by 0.01129.
† The blood-pressure data exclude patients who were undergoing antihypertensive therapy.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
7.3±0.6 years); the response is therefore the cumu- baseline glycosylated hemoglobin, systolic blood
lative incidence of neuropathy during the follow- pressure, total cholesterol, and triglyceride levels.
up period. All P values are two-sided. Of the remaining 1172 patients without neuropa-
thy at baseline, neuropathy had developed in 276 at
results follow-up — a cumulative incidence of neuropathy
of 23.5 percent. There was little variation in the in-
baseline characteristics of the patients cidence of defining variables: symptoms of neurop-
without neuropathy at baseline athy developed in 24.4 percent of patients, absent
Table 1 compares baseline data among the 1819 pa- reflexes in 20.5 percent, abnormal vibration-percep-
tients without neuropathy at baseline. Those who tion threshold in 20.4 percent, and abnormal auto-
were lost to follow-up or died or in whom neurop- nomic-function results in 17.3 percent. There were
athy was not assessed (647 patients) had higher no significant differences between centers in the in-
Table 2. Baseline Characteristics of 1819 Patients According to the Incidence of Neuropathy.*
Progression No Progression
Variable to Neuropathy to Neuropathy P Value
No. of patients 276 896
Age (yr) 33.6±10.0 29.8±8.1 <0.001
Duration of diabetes (yr) 14.9±8.9 11.6±7.6 <0.001
Male sex (%) 48.6 51.1 0.46
History of smoking (%) 53.6 41.6 <0.001
Height (cm) 169±9 169±9 0.66
Weight (kg) 68.9±11.1 66.1±10.2 <0.001
Body-mass index 24.2±3.0 23.1±2.5 <0.001
Waist-to-hip ratio 0.8±0.1 0.8±0.1 0.2
Glycosylated hemoglobin (% of hemoglobin) 8.4±1.9 7.9±1.8 <0.001
Insulin dose per kg of body weight (IU) 0.7±0.2 0.7±0.2 0.8
Estimated glucose disposal rate (mg/kg/min) 8.46±0.14 9.24±0.06 <0.001
Total cholesterol (mmol/liter) 5.45±1.13 5.07±1.01 <0.001
Low-density lipoprotein cholesterol (mmol/liter) 3.44±0.99 3.15±0.91 <0.001
High-density lipoprotein cholesterol (mmol/liter) 1.48±0.42 1.52±0.43 0.12
Triglycerides (mmol/liter) 0.98 (0.54, 2.89) 0.83 (0.48, 2.08) <0.001
Fibrinogen (g/liter) 3.17±0.89 3.14±0.86 0.71
von Willebrand factor (U/ml) 1.20 (0.63, 2.28) 1.08 (0.53, 2.17) 0.004
Systolic blood pressure (mm Hg)† 118 (96, 153) 116 (96, 140) 0.48
Diastolic blood pressure (mm Hg)† 75 (56, 90) 73 (58, 92) 0.52
Albumin excretion rate (µg/min) 11.6 (3.6, 398.0) 9.5 (3.1, 78.4) <0.001
Hypertension (%) 25.1 14.9 <0.001
Macroalbuminuria (%) 7.2 2.7 0.006
Microalbuminuria or macroalbuminuria (%) 31.1 20.1 <0.001
Any retinopathy (%) 51.2 31.9 <0.001
Proliferative retinopathy (%) 6.2 2.8 0.03
History of cardiovascular disease (%) 12.8 4.7 <0.001
* Plus–minus values are means ±SD. Alternatively, in cases of skewed distributions, data are medians (5th percentile, 95th
percentile). P values are derived from Student’s t-test or, in cases of skewed distributions, from a Mann–Whitney U test.
To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. To convert values for triglycerides to mil-
ligrams per deciliter, divide by 0.01129.
† The blood-pressure data exclude patients who were undergoing antihypertensive therapy.
cidence of neuropathy. At baseline, 570 of the 927 and a lower estimated glucose disposal rate. More
subjects defined as having neuropathy (61.5 per- patients in whom neuropathy developed had base-
cent) had an abnormal measurement of the vibra- line hypertension, microalbuminuria or macroal-
tion-perception threshold. buminuria, any retinopathy, a history of cardiovas-
cular disease, and a history of smoking.
baseline characteristics according to There was no evidence of a significant threshold
the incidence of neuropathy effect of glycosylated hemoglobin at baseline and
Table 2 shows baseline characteristics of the study progression to neuropathy. An abnormal vibration-
population grouped according to whether neurop- perception threshold was present in 166 (60.1 per-
athy did or did not develop during the study. Pa- cent) of the 276 patients in whom neuropathy de-
tients in whom neuropathy developed were on av- veloped.
erage 3.8 years older, had had diabetes for 3.3 years
longer, and had poorer blood glucose control (a gly- risk factors for neuropathy
cosylated hemoglobin value 0.5 percent higher) at after adjustment for glycosylated
baseline than those in whom neuropathy did not hemoglobin and duration of diabetes
develop. Adjustment for possible confounding by the two
In unadjusted comparisons, patients in whom major known determinants of neuropathy — dura-
neuropathy developed also had higher baseline lev- tion of diabetes and glycosylated hemoglobin value
els of total and LDL cholesterol and fasting triglyc- (Table 3) — attenuated or abolished some associa-
erides, a higher body-mass index, higher von Will- tions with progression to neuropathy. The risk fac-
ebrand factor levels and albumin excretion rate, tors that remained significantly associated with the
development of neuropathy were baseline cardio-
vascular risk factors (body-mass index and levels of
Table 3. Risk Factors for Neuropathy after Adjustment for Glycosylated
total cholesterol, LDL cholesterol, and triglycerides).
Hemoglobin Values and Duration of Diabetes.*
The urinary albumin excretion rate at baseline and
Odds Ratio the von Willebrand factor level were also elevated
Variable (95% CI) P Value
in patients in whom neuropathy developed (Table
Total cholesterol (mmol/liter) 1.26 (1.10–1.45) 0.001 3), as was the insulin resistance (but the estimated
Low-density lipoprotein cholesterol (mmol/liter) 1.22 (1.03–1.45) 0.02 glucose disposal rate was lower).
Triglycerides (mmol/liter) 1.35 (1.16–1.57) <0.001 After adjustment for glycosylated hemoglobin
von Willebrand factor (U/ml)† 1.20 (1.02–1.42) 0.03 value and duration of diabetes, we found that the
Weight (kg) 1.34 (1.17–1.54) <0.001 presence of hypertension, albuminuria (either mi-
Body-mass index 1.40 (1.22–1.61) <0.001 croalbuminuria or macroalbuminuria), any retinop-
Waist-to-hip ratio 1.06 (0.93–1.22) 0.4 athy, history of cardiovascular disease, and history
Estimated glucose disposal rate (mg/kg/min) 1.37 (1.08–1.73) 0.01
of smoking at baseline were significantly associat-
Albumin excretion rate (µg/min)† 1.25 (1.10–1.43) 0.001
ed with newly diagnosed neuropathy (odds ratio for
microalbuminuria or macroalbuminuria, 1.48; and
Insulin dose per kg of body weight (IU) 1.09 (0.95–1.26) 0.2
for history of cardiovascular disease, 2.74). Both
History of smoking 1.55 (1.17–2.04) <0.001
former and current smoking at baseline were sig-
Hypertension 1.92 (1.30–2.82) <0.001
nificantly related to neuropathy when included sep-
Macroalbuminuria 2.08 (1.11–3.90) 0.02
arately, with adjustment for glycosylated hemoglo-
Microalbuminuria or macroalbuminuria 1.48 (1.07–2.04) 0.02 bin values and duration of diabetes. Since both
Proliferative retinopathy 1.54 (0.79–2.98) 0.2 smoking groups had similar risk, they are present-
Any retinopathy 1.70 (1.19–2.43) 0.003 ed jointly.
Cardiovascular disease 2.74 (1.68–4.49) <0.001
change in glycosylated hemoglobin levels
* Standardized odds ratios are expressed per SD increase in each continuous during follow-up
risk factor. Odds ratios for dichotomous variables have as a reference group
those patients without the respective risk factor. CI denotes confidence inter- An increase in glycosylated hemoglobin was asso-
val. To convert values for cholesterol to milligrams per deciliter, divide by ciated with an odds ratio of 1.45 (95 percent confi-
0.02586. To convert values for triglycerides to milligrams per deciliter, divide dence interval, 1.23 to 1.72; P<0.001), after adjust-
by 0.01129.
† Log transformation was used. ment for baseline glycosylated hemoglobin value
and duration of diabetes. Figure 2 depicts the odds
ratio for each quintile of change in the glycosylated

discussion
hemoglobin value, as compared with the lowest
quintile of change (the reference category), with ad- During a period of seven years, the incidence of neu-
justment for the baseline glycosylated hemoglobin ropathy in the EURODIAB cohort of patients with
value and duration of diabetes. The odds ratio for type 1 diabetes was 23.5 percent, confirming the
the development of neuropathy was 2.48 (95 per- previously reported strong contributions of glyce-
cent confidence interval, 1.50 to 4.11) for patients mic control and duration of diabetes to the risk of
with the highest rate of deterioration of glycosylat- neuropathy.17,19,20 We observed that the rate of de-
ed hemoglobin (the highest quintile). terioration of glycemic control during follow-up
contributed markedly to the risk of neuropathy, in-
multivariate models dependently of the glycosylated hemoglobin value
In a multivariate logistic-regression model (Table 4, at baseline. Furthermore, cardiovascular risk fac-
Model 1) that mutually adjusted for the presence of tors, such as hypertension, smoking, obesity, and
all other risk factors, we found that duration of dia- elevated triglyceride levels, and the presence of car-
betes, glycosylated hemoglobin value, change in diovascular disease at baseline appear to be related
glycosylated hemoglobin value, triglyceride level, to newly diagnosed neuropathy.
body-mass index, history of smoking, and presence This study used a definition of neuropathy that
of hypertension at baseline remained significantly was similar to that in other protocols,2,21,22 and
associated with the incidence of neuropathy. The 28.5 percent of patients had neuropathy at base-
relation between cholesterol level and the incidence line,17 a frequency similar to that observed in other
of neuropathy in Model 1 did not reach statistical studies.22 Of the patients with neuropathy at base-
significance, and albumin excretion rate was unre- line, approximately 60 percent had an abnormal
lated to neuropathy. The strongest relation was with vibration-perception threshold. Moreover, 500 ran-
hypertension, which carried an odds ratio of 1.57. domly selected subjects within the cohort under-
Addition of the estimated glucose disposal rate to went nerve-conduction studies of the arms and legs
this model did not materially change the odds ratios at follow-up; there was a significant relationship
for the other variables, and the glucose disposal rate between the slowing of nerve conduction and the
itself was not associated with newly diagnosed neu-
ropathy (odds ratio, 0.99; 95 percent confidence in-
terval, 0.90 to 1.08; P=0.75). 4.5
When complications of diabetes were added to 4.0
the model (Table 4, Model 2), odds ratios for tri-
Odds Ratio for the Development
3.5
glycerides and hypertension were not statistically
significant. Duration of diabetes, glycosylated he- 3.0
of Neuropathy
moglobin value, change in glycosylated hemoglo- 2.5

bin value, body-mass index, and history of smoking
2.0
remained significantly related to the incidence of
neuropathy. In addition, the presence of cardiovas- 1.5
cular disease at baseline was independently related 1.0

to the incidence of neuropathy (odds ratio, 2.12). 0.5
The relation between any retinopathy and neuropa-
thy was insignificant (P=0.06) when change in the 0.0
1 2 3 4 5
glycosylated hemoglobin value was included in the (¡1.96 (¡0.58) (0.18) (0.84) (1.90)
[reference])
model but reached significance (P=0.04) when
change in the glycosylated hemoglobin value was Quintile of Change and Median Change in Glycosylated Hemoglobin
excluded.
Figure 2. Odds Ratios for the Development of Neuropathy per Quintile
Models 1 and 2 were repeated without autonom- of Change in Glycosylated Hemoglobin.
ic symptoms and the results of autonomic-function The odds ratios have been adjusted for glycosylated hemoglobin at baseline
tests. The only major difference in the results was and for duration of diabetes. Quintile 1 served as the reference category. Ver-
that the relationship between hypertension and tical bars represent 95 percent confidence intervals. The P value for trend
“pure” peripheral neuropathy was no longer statis- across quintiles is 0.009.
tically significant.
disease.23,24 Previous cross-sectional studies have

Table 4. Odds Ratios for Associations between Key Risk Factors
and the Incidence of Diabetic Neuropathy with the Use of Two Logistic-
reported associations between neuropathy and
Regression Models.* height,25 cigarette smoking,26 low levels of HDL
cholesterol,19 and hypertension19,27 in addition to
Odds Ratio
Variable (95% CI) P Value
established risk factors, level of glycemia, and du-
ration of diabetes. Hypertension was observed to be
Model 1† a strong risk factor for neuropathy in 463 young
Duration of diabetes (yr) 1.40 (1.21–1.63) <0.001 patients with type 1 diabetes.21 A follow-up of sub-
Glycosylated hemoglobin (% of hemoglobin) 1.48 (1.23–1.79) <0.001 jects with either type 1 or type 2 diabetes suggested
Change in glycosylated hemoglobin 1.36 (1.14–1.62) 0.001 that both type 1 and type 2 diabetes and markers of
(% of hemoglobin) microvascular disease were associated with the se-
Triglycerides (mmol/liter) 1.21 (1.02–1.44) 0.03 verity of neuropathy.28
Total cholesterol (mmol/liter) 1.15 (0.98–1.35) 0.08 The baseline cross-sectional data in the present
Body-mass index 1.27 (1.09–1.47) <0.001 study17 are evidence of a strong association between
History of smoking 1.38 (1.03–1.85) 0.03 neuropathy and other microvascular complications,
Hypertension 1.57 (1.03–2.39) 0.03 suggesting a common pathogenic mechanism.29-31
Albumin excretion rate (µg/min) 1.01 (0.88–1.14) 0.93 We excluded all patients with neuropathy at base-
Model 2‡ line in order to identify new cases, resulting in a less
Duration of diabetes (yr) 1.25 (1.03–1.51) 0.02
robust but still significant association.
Several of the risk factors associated with neu-
Glycosylated hemoglobin (% of hemoglobin) 1.64 (1.33–2.03) <0.001
ropathy in this study are markers of insulin resis-
Change in glycosylated hemoglobin 1.44 (1.17–1.77) 0.001
(% of hemoglobin) tance. Both an elevated triglyceride level and obesity
Triglycerides (mmol/liter) 1.17 (0.97–1.41) 0.10
are strong predictors of microalbuminuria and ret-
inopathy in type 1 diabetes.9,18 Insulin resistance,
Total cholesterol (mmol/liter) 1.11 (0.93–1.34) 0.25
present in type 1 diabetes,32 may be involved in the
Body-mass index 1.20 (1.01–1.43) 0.04
development of both microvascular and macrovas-
History of smoking 1.68 (1.20–2.36) 0.003
cular complications.33,34 A potential link between
Hypertension 1.54 (0.96–2.47) 0.07 insulin resistance and microvascular complications
Cardiovascular disease 2.12 (1.16–3.86) 0.01 including neuropathy is their association with en-
Any retinopathy 1.45 (0.98–2.13) 0.06 dothelial dysfunction.35 Other complications of di-
Albumin excretion rate (µg/min) 1.02 (0.89–1.18) 0.76 abetes linked to endothelial dysfunction may also
predict the risk of microalbuminuria,18 retinopa-
* CI denotes confidence interval. To convert values for cholesterol to milligrams thy,9 and neuropathy. The patients in whom neu-
per deciliter, divide by 0.02586. To convert values for triglycerides to milli-
grams per deciliter, divide by 0.01129. ropathy developed had a lower estimated glucose
† Model 1 represents 1101 observations with urinary albumin excretion rate but disposal rate at baseline (higher insulin resistance).
without retinopathy and cardiovascular disease. However, multivariate analysis indicates that obe-
‡ Model 2 represents 932 observations with urinary albumin excretion rate and
complications of diabetes (retinopathy and cardiovascular disease). sity, glycemic control, and the level of triglycerides
were more predictive individually as compared with
the combined summary measure.
When autonomic symptoms and results of au-
number of abnormal criteria used to define neu- tonomic-function tests were excluded from the def-
ropathy. inition of neuropathy, the effect of hypertension on
Assessing neuropathy involves measures that are the incidence of neuropathy lost statistical signifi-
prone to varying degrees of subjectivity or observer cance. This is consistent with our previous report
bias. However, these measurement errors are likely that systolic blood pressure was a risk factor for the
only to underestimate the statistical significance of development of cardiac autonomic neuropathy.36
the association between risk factors and disease. Apart from the use of medication to induce glu-
Elucidating the risk factors for neuropathy is im- cose values approaching normoglycemia, no other
portant, given the association between the risk fac- treatments currently exist to reduce the progression
tors and increased diabetes-related morbidity and to neuropathy.29 Aggressive treatment of hyperten-
mortality.23 Mortality in patients with neuropathy is sion is now standard clinical practice in the man-
high, and the cause of death is often coronary heart agement of nephropathy and retinopathy, and the
results of the present study make a case for clinical The EURODIAB Prospective Complications Study was supported
by grants from the Wellcome Trust, the European Union, and Diabe-
trials to confirm the efficacy of antihypertensive tes UK.
agents and possibly other strategies for cardiovas- Dr. Tesfaye reports having received consulting and lecture fees
cular risk reduction in slowing the progression of from Eli Lilly, consulting fees from AstraZeneca and Pfizer, and lec-
ture fees from Takeda and GlaxoSmithKline.
neuropathy.
ap p e n d i x
In addition to the authors, the following investigators participated in the EURODIAB Prospective Complications Study: Greece — B. Kara-
manos, A. Kofinis, K. Petrou (Hippokration Hospital, Athens); N. Papazoglou, C. Manes (General Hospital Papageorgiou of Thessaloniki,
Thessaloniki); Italy — F. Giorgino, G. Picca, A. Angarano, G. De Pergola, L. Laviola, R. Giorgino (Endocrinologia e Malattie Metaboliche,
DETO, Università Degli Studi di Bari, Bari); M. Songini, A. Casu, M. Pedron, S. Pintus, M. Fossarello (Ospedale San Michele, Cagliari); G.
Pozza, R. Mangili, V. Asnaghi (Ospedale San Raffaele, Milan); F. Santeusanio, G. Rosi, V. D’Alessandro, C. Cagini, P. Bottini, G.P. Reboldi
(Istituto di Patologia Medica, Policlinico, Perugia); R. Navalesi, G. Penno, S. Bandinelli, R. Miccoli, M. Nannipieri (Dipartimento di Endo-
crinologia e Metabolismo, Pisa); G. Ghirlanda, C. Saponara, P. Cotroneo, A. Manto, A. Minnella (Universita Cattolica del Sacro Cuore,
Rome); M. Borra, P. Cavallo Perin, S. Giunti, G. Grassi, G.F. Pagano, M. Porta, R. Sivieri, F. Vitelli, D. Ferrari, M. Veglio (Dipartimento di Me-
dicina Interna, Università di Torino and ASO CTO/CRF/Maria Adelaide, Turin); M. Muggeo, M. Iagulli (V Cattedra di Malattie del Metabo-
lismo, Verona); Ireland — J.B. Ferriss, G. Grealy, D.O. Keefe (Cork Regional Hospital, Cork); Germany — M. Toeller, C. Arden (Diabetes Re-
search Institute, Heinrich Heine University, Dusseldorf ); E. Standl, B. Schaffler, H. Brand, A. Harms (City Hospital Schwabing, Munich);
Belgium — R. Rottiers, C. Tuyttens, H. Priem (University Hospital of Ghent, Ghent); Finland — P. Ebeling, M. Kylliäinen, V.A. Koivisto (Uni-
versity Hospital of Helsinki, Helsinki); Poland — B. Idzior-Walus, J. Sieradzki, K. Cyganek, B. Solnica (Jagiellonian University, Krakow); the
Netherlands — H.H.P.J. Lemkes, J.C. Lemkes-Stuffken (Leiden University Medical Center, Leiden); Portugal — J. Nunes-Correa, M.C. Rogado,
L. Gardete-Correia, M.C. Cardoso, A. Silva, J. Boavida, M. Machado Sa Marques (Portuguese Diabetic Association, Lisbon); Luxembourg —
G. Michel, R. Wirion, S. Cardillo (Centre Hospitalier, Luxembourg City); France — B. Soussan, O. Verier-Mine, P. Fallas, M.C. Fallas (Centre
Hospitalier de Valenciennes, Valenciennes); G. Cathelineau, A. Bouallouche, B. Villatte Cathelineau (Hospital Saint-Louis, Paris); United
Kingdom — J.H. Fuller, J. Holloway, L. Asbury, D.J. Betteridge (University College London, London); J.D. Ward, S. Tesfaye, S. Eaton, C. Mody
(Royal Hallamshire Hospital, Sheffield); S. Walford, J. Sinclair, S. Hughes, V. McLelland, J. Ward (New Cross Hospital, Wolverhampton);
Austria — K. Irsigler, H. Abrahamian (Hospital Vienna-Lainz, Vienna); Croatia — G. Roglic, Z. Metelko, Z.R. Pepeonik (Vuk Vrhovac Insti-
tute for Diabetes, Zagreb); Romania — C. Ionescu-Tirgoviste, A. Coszma, C. Guja (Clinic of Diabetes, Nutrition & Metabolic Diseases, Bu-
charest); Coordinating center — J.H. Fuller, N. Chaturvedi, J. Holloway, D. Webb, L. Asbury, M. Shipley, S.J. Livingstone (University College
London, London); Central laboratories — G.-C. Viberti, R. Swaminathan, P. Lumb, A. Collins, S. Sankaralingham (Guy’s and St. Thomas’
Hospital, London).
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The new england journal of medicine

Vascular Risk Factors and Diabetic Neuropathy

n engl j med 352;4 www.nejm.org january 27, 2005 341

density lipoprotein (HDL) cholesterol, and triglyc-

d iabetic neuropathy is a common

342 n engl j med 352;4 www.nejm.org january 27 , 2005

symptoms and signs of neuropathy

n engl j med 352;4 www.nejm.org january 27, 2005 343

Variable Assessed for Neuropathy at Follow-up P Value

344 n engl j med 352;4 www.nejm.org january 27 , 2005

Table 2. Baseline Characteristics of 1819 Patients According to the Incidence of Neuropathy.*

n engl j med 352;4 www.nejm.org january 27, 2005 345

346 n engl j med 352;4 www.nejm.org january 27 , 2005

ratio for each quintile of change in the glycosylated

moglobin value, change in glycosylated hemoglo- 2.5

cular disease at baseline was independently related 1.0

n engl j med 352;4 www.nejm.org january 27, 2005 347

disease.23,24 Previous cross-sectional studies have

348 n engl j med 352;4 www.nejm.org january 27 , 2005

n engl j med 352;4 www.nejm.org january 27, 2005 349

electronic access to the journal’s cumulative index

350 n engl j med 352;4 www.nejm.org january 27, 2005

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