The 30-Year Natural History of Type 1 Diabetes Complications

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The 30-Year Natural History of Type 1 Diabetes Complications

http://www.medscape.com/viewarticle/531782?src=mp

Georgia Pambianco; Tina Costacou; Demetrius Ellis; Dorothy J. Becker;

Klein; Trevor J. Orchard

Diabetes. 2006;55(5):1463-1469. ©2006 American Diabetes Association, Inc.

Posted 05/11/2006

Abstract and Introduction

Abstract

Declining incidences in Europe of overt nephropathy, proliferative

retinopathy, and mortality in type 1 diabetes have recently been

reported. However, comparable data for the U.S. and trend data for

neuropathy and macrovascular complications are lacking. These issues are

addressed using the prospective observational Pittsburgh Epidemiology of

Childhood-Onset Diabetes Complications Study. Participants were

stratified into five cohorts by diagnosis year: 1950–1959, 1960–1964,

1965–1969, 1970–1974, and 1975–1980. Mortality, renal failure, and

coronary artery disease (CAD) status were determined on the complete

cohort (n = 906) at 20, 25, and 30 years. Overt nephropathy,

proliferative retinopathy, and neuropathy were assessed at 20 and 25

years on the subset of participants with a clinical examination. There

was a decreasing trend by diagnosis year for mortality, renal failure,

and neuropathy across all time intervals (P < 0.05), with the 1950–1959

cohort having a fivefold higher mortality at 25 years than the 1970s'

cohorts. Proliferative retinopathy and overt nephropathy showed

nonsignificant declines at 20 years (P < 0.16 and P < 0.13,

respectively) and no change at 25 years. CAD event rates, which were

lower than the other complications, also showed no trend. Although some

type 1 diabetes complications (mortality, renal failure, and neuropathy)

are declining, others (CAD, overt nephropathy, and proliferative

retinopathy) show less favorable changes by 30 years.

Introduction

A decreasing incidence of diabetes complications, particularly overt

nephropathy and proliferative retinopathy, has been reported in the type

1 diabetes population around the world over the past 15–20 years.[1–3]

Mortality rates have also been decreasing,[4–6] most likely reflecting

better management and the declining morbidity. Improved metabolic

control, facilitated by the advent of self-monitoring of blood glucose

and HbA1c (A1C) testing and stimulated by the results of the Diabetes

Control and Complications Trial,[7] along with better blood pressure

management[1–3,5,6] are likely to be major contributors. However,

Rossing et al. were unable to show decreasing rates for diabetic

nephropathy[8] and retinopathy[9] after 15 years in a hospital-based

cohort, whereas Brown et al.,[10] using a historical comparison of type

2 diabetic patients, demonstrated an unchanged prevalence of

proliferative diabetic retinopathy, despite improved levels of glycemia

and blood pressure. Furthermore, few data exist for neuropathy or

macrovascular complications. We therefore report the cumulative

incidence (and incidence density), up to 30 years, by diagnosis cohort

(1950–1980) of all major type 1 diabetes complications in the Pittsburgh

Epidemiology of Diabetes Complications (EDC) study.

Research Design and Methods

The EDC study is a representative[11] prospective type 1 diabetes

cohort, now entering its 18th year of follow-up. The EDC baseline

examinations were conducted between 1986 and 1988, and participants were

examined biennially thereafter. Figure 1 shows the recruitment tree for

the study. A total of 1,124 patients were eligible for the study, having

been diagnosed or seen within 1 year of diagnosis at Children's Hospital

of Pittsburgh between 1 January 1950 to 31 May 1980 and living within

100 miles or 2.5 h from Pittsburgh. Of the 1,124 eligible patients, 145

(13%) had died before baseline (1986–1988) and 191 (17%) chose not to

participate. A total of 788 (70%) participated, with 130 (16%) providing

survey information only.

Figure 1.

The Pittsburgh EDC study recruitment tree, from the Children's

Hospital of Pittsburgh Registry, 1 January 1950 to 31 May 1980.

Demographic details for the follow-up cohort analyzed in this report are

listed in Table 1 (n = 906, excluding 3 predeceased with no death

certificate and 24 without follow-up for the relevant durations [total =

27]). Of the predeceased, 88% were diagnosed at or before 1964, whereas

67% of the survey-only and exam participants were diagnosed after 1964.

Predeceased were included where possible (mortality, renal failure, and

coronary artery disease [CAD]), whereas for other complications, the

analyses were limited to those diagnosed after 1964.

At the baseline examination, mean age was 28 years and diabetes duration

19 years. The current analyses are based on 906 subjects (81% of those

initially eligible [n = 1,124]) who comprise three groups: those who

died before baseline exam (predeceased, n = 145), those who provided

survey information at baseline and at the 12-year follow-up (survey

only, n = 130), and those who had a full baseline examination (exam, n =

658). Some follow-up information has been obtained on 97.1% (n =

906/933) of the total cohort (99% of those examined, 85% of survey-only

participants, while death certificates were obtained on 99% of the

predeceased).

These 906 participants with follow-up were classified into five separate

cohorts according to their year of diabetes diagnosis: 1950–1959,

1960–1964, 1965–1969, 1970–1974, and 1975–1980. Cumulative incidence was

examined at three separate time intervals: 20, 25, and 30 years of

diabetes. Follow-up was censored on 31 December 2000. Some

complications, i.e., mortality, renal failure, and coronary artery

disease, which can be determined by death certificates and surveys, were

analyzed in the total cohort (n = 906), while other complications, which

require examination, i.e., overt nephropathy and neuropathy, are

analyzed only in the examined subjects. Because of high mortality before

the baseline exam (1986–1988) in those diagnosed between 1950 and 1964

(33%), these complications are only analyzed in the examined post-1964

diagnosis cohorts (n = 319) where the survival bias is minimal

(mortality < 3%).

Mortality

For the death of an exam or survey-only participant, the next-of-kin was

contacted and a copy of the death certificate, and where appropriate the

hospital record, was requested. Death certificates for the predeceased

had been previously obtained[4]. Data were reviewed by a physician

mortality classification committee (chaired by T.J.O.), which classified

deaths according to standard procedures[12].

Renal Failure

Self-reported renal transplantation or renal dialysis defined renal

failure in the exam and survey-only participant groups. For the

predeceased cases, a mention of renal failure on the death certificate

was accepted, in which case the duration of diabetes at death was

considered the duration at the onset of renal disease.

CAD

For exam and survey-only participants, CAD status was defined as CAD

death, a history of myocardial infarction confirmed by Q-waves on

electrocardiogram (Minnesota codes 1.1 or 1.2) or hospital records, or

angiographic stenosis ≥50% confirmed by hospital records, including

revascularization. For the predeceased, mention of myocardial infarction

and/or CAD on the death certificate was accepted.

Proliferative Retinopathy

Proliferative retinopathy was based on stereoscopic fundus photographs

of fields 1, 2, and 4 with a Zeiss camera, read by the Fundus

Photography Reading Center, University of Wisconsin–Madison and

classified according to the modified Arlie House system[13]. For

individuals refusing fundus photographs or not attending any particular

exam, proliferative retinopathy was defined as receiving laser therapy

for proliferative diabetic retinopathy (n = 43). Duration was determined

from onset of diabetes to the date of the laser procedure and/or date of

fundus photography. To date, 202 EDC examination participants have been

identified as having proliferative retinopathy and self-reported laser

therapy. Of those 202 participants, 126 (62%) also had study fundus

photographs, confirming their proliferative retinopathy status.

Overt Nephropathy

Overt nephropathy was defined as an albumin excretion rate >200 µg/min

in at least two of three timed urine collections (24-h, overnight, and

post-clinic).[14,15]In the absence of urine, a serum creatinine >2 mg/dl

or renal failure was accepted.

Confirmed Distal Symmetric Polyneuropathy

Confirmed distal symmetric polyneuropathy (CDSP) was defined by the

Diabetes Control and Complications Trial[16] clinical exam protocol

showing the presence of two or more of the following: symptoms, sensory

and/or motor signs, and/or reduced/absent tendon reflexes consistent

with distal symmetric polyneuropathy, in the presence of an abnormal

age-specific vibratory threshold (Vibratron II testor).

Symptomatic Autonomic Neuropathy

Symptomatic autonomic neuropathy was determined by abnormal heart rate

response to deep breathing (expiration/inspiration ratio [<1.1]) and at

least two autonomic symptoms[17].

Risk Factors

All participants completed a questionnaire concerning demographic and

medical history information before each exam. An ever-smoker was a

person who smoked ≥100 cigarettes over their lifetime. Blood pressure

was measured with a random zero sphygmomanometer[18]. Hypertension was

defined as ≥ 140/90 mmHg or use of antihypertensive medication.

Stable A1C was measured by ion exchange chromatography (Isolab, Akron,

OH) and subsequently by automated high-performance liquid chromatography

(Diamat; BioRad, Hercules, CA). Readings with the two methods are almost

identical (r = 0.95). Our upper limit of normal for A1C is 7.3%; thus,

values are higher than current A1C values. Total, HDL, and LDL

cholesterol and triglycerides were determined as previously

described.[19–23]

Statistical Analysis

The SPSS/PC statistical software (SPSS, Chicago, IL) was used for all

analyses. For each duration (20, 25, and 30 years), a participant was

classified as a case if he or she had experienced the event by that

duration using his or her closest examination or survey (± 2 years). If

data on an individual were not available at the duration of interest,

but that individual was later a noncase, that person was included as a

noncase at the specific duration. However, if that individual was later

identified as a case, he or she was not counted as a case until the

duration of interest included the duration at complication diagnosis.

Life-table analyses were only appropriate for mortality, since subjects

were not followed from diagnosis (mean baseline duration was 19 years),

and thus duration at complication diagnosis is unknown for baseline

prevalent cases. For mortality, Kaplan-Meier life tables (log-rank

tests) and proportional hazards modeling were used.

Cohort differences for continuous data were assessed using a one-way

ANOVA (with Bonferroni corrections for multiple comparisons) and

Student's t tests. Categorical variables were compared using a χ2

statistic. Logistic regression was also used to control for age at onset

of diabetes. Generalized linear regression models were used to test for

trends in the data. Incidence density was also calculated for the three

durations, <20 years, and 20–30 years and overall by dividing the number

of individuals developing a first event by the person-years of

observation for those at risk during the specified duration interval.

Results

The current analyses focus on the 906 subjects, with some follow-up as

shown in Table 1 where a significant trend (P < 0.01) toward increasing

age at diagnosis with later cohorts was noted. There was no difference

in the sex distribution by cohort.

Incidence densities are shown in Table 2 . As can be seen, complication

risk is highest for proliferative retinopathy in both duration strata

and >5% per year for those with 20–25 years' duration. Also evident is

the greater risk after 20 years' duration for each complication

(increase two- to threefold, in general) except for overt nephropathy,

which shares a similar rate irrespective of duration, and symptomatic

autonomic neuropathy, which occurred rarely (n = 3) in the 20- to

25-year duration interval.

Cumulative mortality at 20 years was reduced by 84%, i.e., from 22%

(1950–1959) to 3.5% (1975–1980). At 25 years, mortality declined by 80%

from 35% (1950–1959) to 7% (1970–1974), while mortality was 41% lower at

30 years, i.e., having fallen from 39% (1950–1959) to 23% (1965–1969).

Life-table analyses (Fig. 2) showed for each cohort a better survival

than seen for those diagnosed in all earlier cohorts, with two

exceptions: 1969–64 vs. 1950s (P = 0.9) and 1975–1980 vs. 1970–1974 (P =

0.8). Controlling for age at onset of diabetes did not alter these

findings. There were no inter-cohort differences in mortality rates by

sex, but males had higher rates at each time point, which was

significant in the 1970–1974 cohort at both 20 and 25 years (P < 0.05).

Figure 2.

All-cause mortality by diagnosis cohort: the Pittsburgh EDC study.

white triangle, 1950–1959; black triangle, 1960–1964; O, 1965–1969;

white square, 1970–1974; black square, 1975–1980.

A significant improvement in renal failure rates was also noted (Fig.

3A) for individuals diagnosed after 1964. At 20 years, 4% of those

diagnosed after 1964 had developed renal failure versus 16% for those

diagnosed in the 1950s. At 30 years' duration, renal failure rates had

fallen from 31% (1950s) to 18% (1965–1969). Overall, males were more

likely to have renal failure by 30 years (33 vs. 24%, P < 0.05), with

this difference being significant within the 1950–1959 cohort (38 vs.

23%, P < 0.05).

Figure 3.

Cumulative incidence (%) by duration of diabetes: the Pittsburgh

EDC study: diagnosed between 1950 and 1980. shaded square, 1950–1959;

black square, 1960–1964;shaded square, 1965–1969; white square,

1970–1974;striped square, 1975–1980. A: Renal failure. B: Total CAD

(events and procedures). C: CAD events (myocardial infarction and CAD

deaths only). P values adjusted for age at onset of diabetes.

CAD rates of events and procedures (Fig. 3B) were similar across

diagnosis cohorts at 30 years. Because revascularization interventions

may have increased with time, analyses were repeated, with CAD limited

to myocardial infarction or CAD death (Fig. 3C). No cohort differences

were seen at either 20 or 30 years (pooled rates of 3.5 and 15%,

respectively), whereas at 25 years (overall rate was 8%), the rates were

marginally lower in the latter cohorts (P < 0.30). CAD rates were

similar by sex within each cohort.

Figure 4 shows the cumulative incidence in the exam population of

proliferative retinopathy, overt nephropathy, symptomatic autonomic

neuropathy, and CDSP at 20 and 25 years' duration. At 20 years, a

nonsignificant declining trend (P < 0.16) was evident, with rates for

proliferative retinopathy (Fig. 4A) decreasing from 38% (1965–1969) to

26.5% (1975–1980), whereas no difference was seen at 25 years when ~53%

of the participants had proliferative retinopathy.

Figure 4.

Cumulative incidence (%) by duration of diabetes: the Pittsburgh

EDC study: restricted population, examined cohort diagnosed between 1965

and 1980.striped square, 1965–1969; white square, 1970–1974;shaded

square, 1975–1980. A: Proliferative retinopathy (adjusted for age of

onset). B: Overt nephropathy (adjusted for age of onset). C: Symptomatic

autonomic neuropathy (adjusted for age at onset). D: Confirmed distal

symmetric polyneuropathy (adjusted for age at onset).

A nonsignificant decline was also seen for overt nephropathy (Fig. 4B)

at 20 years (1975–1980 cohort rates [19%] were 37% lower than the

1965–1974 cohorts). However, the cumulative incidence rates at 25 years

were similar, with a pooled incidence of 32%. To compare with previous

Steno data,[24] Fig. 5 was constructed and displays incidence by 2-year

diabetes duration intervals for the two studies. The early peak

incidence at 16 years in the Steno data are clearly absent in the later

EDC data. Symptomatic autonomic neuropathy showed a steady decline

across all cohorts (Fig. 4C) at 20 years (P < 0.05) and at 25 years (P <

0.06). CDSP (Fig. 4D), however, showed a more significant lower trend at

both 20 years (P < 0.01) and 25 years (P < 0.05).

Figure 5.

Incidence of nephropathy in the Pittsburgh EDC study (black

triangle; 1986–2000) and the Steno clinic population (black square;

1933–1984).

There were no differences in overt nephropathy, proliferative

retinopathy, symptomatic autonomic neuropathy, or CDSP rates at 20 and

25 years by sex. Because of the increasing age of onset with year of

diagnosis, all cumulative incidence results were repeated after

stratification by median age of onset (8.5 years for the total cohort;

8.9 years for the exam subjects diagnosed after 1964). Similar patterns

were seen for both strata, as reported above for the whole population

(data not shown).

Table 3 shows risk factor characteristics at 25 years' duration for exam

participants diagnosed after 1964 by cohort. Only A1C levels showed a

significant difference, being lower in the 1970–1974 cohort than the

1965–1969 cohort.

Discussion

These data suggest the natural history of type 1 diabetes complications

is improving, with major declines in total mortality and renal failure

rates in individuals diagnosed after the mid-1960s and for neuropathy in

those diagnosed in the 1970s. However, declines are not so impressive

for overt nephropathy and proliferative retinopathy, and any favorable

patterns seen at 20 years have largely disappeared by 25 years'

duration. Although CAD event rates are low, no difference in cumulative

incidence at 30 years was seen (P < 0.84). Event rates are high for

individuals having a diabetes duration of 20–30 years (and thus aged in

their early 30s at the time of the event), having a 1.5% annual risk of

mortality and a 1% annual risk of a major CAD event ( Table 2 ). As the

incidence of angina and ischemia exceeds that of hard CAD in these

cohorts,[25] the total CAD annual risk rate is ~2% or more for

individuals with 20 years' duration. Two recent reports from Steno,

Denmark,[1] and Linkoping, Sweden,[2] show a decline in overt

nephropathy and proliferative retinopathy at 20 and 25 years' duration

(for those diagnosed between 1960 and 1975) but provide no data on total

mortality, CAD, or neuropathy. The current report thus compliments these

European data and expands both the breadth of complications studied and

length of follow-up.

The dramatic decrease over time in the cumulative incidence of mortality

and renal failure is consistent with two reports from our Allegheny

County registry: a community-based population of childhood-onset type 1

diabetes[5,6] and an Israeli mortality study[26]. The explanation for

the improved mortality is likely to be multifaceted, but because our

data show only a modest decrease in the underlying complications that

lead to death (overt nephropathy and CAD), improved management of

complications, as well as decreased incidence, are likely to contribute.

Despite the declining rate, however, a major excess mortality still

exists in the type 1 diabetes population compared with nondiabetic

populations[27].

The true decline in renal failure may be greater than we have shown in

this article, since the onset of renal failure for the predeceased rate

was established at the date of death, whereas the exact onset may have

appeared earlier. Because overt nephropathy demonstrated only a small

decline in incidence at 20 years and no difference at 25 years, it is

likely that much of the improved renal failure rates reflect better

management rather than prevention of the nephropathic state. This is

consistent with the Allegheny County end-stage renal disease (ESRD)

survival data[5] and an increase in ACE inhibitor use, as we have

documented[28]. Although our overt nephropathy rates are higher than

those reported from Linkoping,[2,3] they are very consistent with recent

Steno data[1]. As shown in Fig. 5, a major shift in the incidence

pattern of overt nephropathy has likely occurred compared with the

earlier Steno data[24]. With loss of the " 16-year peak, " it is important

to note that incidence is only being delayed until the later years.

After 20 years' duration, the incidence is in fact higher in the more

recent EDC data than the earlier Steno data. The explanation for the

much lower Linkoping rates is undetermined but may relate to

methodological differences in follow-up, as well as reflecting a truly

lower level of complications and better glycemic control.[2,3]

Like Rossing et al.,[9] we do not demonstrate a significant decrease in

proliferative retinopathy with increasing calendar year of diagnosis,

although at 20 years, a nonsignificant trend was evident (P < 0.16). Our

rates, although slightly higher, are again comparable to the later

report from Steno[1] at 20 years. Similarly, early results from

Linkoping showed little change in proliferative retinopathy rates by

diagnosis cohort,[29] whereas a later report[2] demonstrated a marked

decrease. In this report, a decline of >50% was reported for

proliferative retinopathy. Again, why the more recent rates of

proliferative retinopathy are much lower in Linkoping than Pittsburgh or

Steno is unclear. The nonsignificant change in overt nephropathy and

proliferative retinopathy at 25 years may be reflective of the sample

size. However, because we do have 80% power to detect a 17% (overt

nephropathy) and 20% (proliferative retinopathy) difference between the

two diagnosis cohorts, we feel fairly confident declines much greater

than this have not occurred.

Autonomic neuropathy showed a significant temporal decline at 20 years

and a smaller (nonsignificant) reduction at 25 years. Whether this

reduction in autonomic neuropathy rates relates to the reduction in

renal disease is difficult to resolve at this stage[30]. CDSP, on the

other hand, showed a greater decline at both durations (20 and 25

years). We have previously shown hypertension to be a strong independent

predictor of distal symmetric polyneuropathy,[31] along with glycemic

control and duration. Tesfaye et al.[32] have also found that

cardiovascular disease risk factors predict neuropathy. Thus, ACE

inhibitor therapy and better cardiovascular disease risk factor

management in the later cohorts (1970s' cohort) may help explain this

decline, in addition to better improvement of blood glucose.

Although low, CAD rates did not differ across diagnosis cohorts, even

after excluding revascularization procedures. Only a suggestion of a

decline at 25 years emerged, which was completely lost by 30 years. The

failure to show a major decline in CAD may reflect a somewhat weaker

relationship to glycemia than is seen for other complications,[25,33–35]

although recent data from the Diabetes Control and Complications

Trial/Epidemiology of Diabetes Interventions and Complications

(DCCT/EDIC) study follow-up show a strong benefit of intensive therapy

on cardiovascular disease outcomes[36]. Of particular relevance is the

observation of no improvement in blood pressure or lipid profiles at 25

years, according to diagnosis cohort, despite a significant fall in A1C

( Table 3 ). Unfortunately, as participants were not followed from

diagnosis, we cannot fully compare risk factor exposure for the

different year of onset cohorts. These results, however, underscore the

importance of controlling blood pressure and lipids in type 1 diabetes,

which we have recently shown to be particularly poor in this cohort[37].

Another explanation for our failure to show a significant temporal

effect for CAD may be lack of power due to the low disease rate and

small sample size. However, we had 80% power to show the same

proportionate decrease as demonstrated in renal failure at 25 years

(1950–1959 vs. 1975–1980).

The particular strengths of these analyses are the representativeness of

the original incident cohort,[11] the inclusion of maximum data while

minimizing survivor bias, and the careful and standard ascertainment of

complications overtime. The major limitations are the small number of

cases after stratification by diagnosis cohort, especially for CAD, and

the lack of risk factor data from diagnosis onwards.

A further limitation is the possibility that self-reported laser therapy

may have been performed for an ophthalmic complication other than

proliferative retinopathy (e.g., macular edema), thus inflating our

proliferative retinopathy rate. This seems unlikely to be a major

limitation; of the 126 subjects with both laser history and photographs,

only 2.4% had focal scars alone, suggesting macular edema is relatively

rare in this cohort as the sole reason for laser therapy. Furthermore,

63% of the examination participants with laser history but no concurrent

photographs had prior photographs showing advanced background changes,

indicating they were close to the proliferative stage.

A potential confounder of our results is the age at diabetes onset,

which increased with calendar year of diagnosis. However, even though

age at onset may relate to complications,[38,39] controlling for age at

onset does not appear to negate the improved mortality (Fig. 1) and

complication rates.

In conclusion, while these results show encouraging trends in

complication rates, some of the improvements appear to be lost with

longer follow-up, suggesting the major change has been delay not

prevention. As recently noted,[40] whereas the role of hyperglycemia in

the development of complications is critical, other factors play a role.

For CAD, which shows the least favorable change over time, these results

suggest the need for a focus on its other risk factors, e.g., blood

pressure and lipids, which are poorly controlled[37].

Table 1. Composition (n) and Demographic Characteristics of Diagnosis

Onset Cohort: The Pittsburgh EDC Study

1950–1959 cohort 1960–1964 cohort 1965–1969 cohort 1970–1974

cohort 1975–1980 cohort Total

n 235 153 172 167 179 906

Predeceased (n) 93 35 14 1 — 143

Exam (n) 122 102 136 143 149 652

Survey only (n) 20 16 22 23 30 111

Age at onset (mean ± SD)* 7.8 ± 3.9 8.1 ± 3.8 8.1 ± 4.3 8.6 ± 3.9

9.1 ± 3.8 8.3 ± 3.9

Sex (% male) 54 54 49 51 44 50.4

* P < 0.01, significant trend.

Table 2. Incidence Density per 100 Person-Years for Type 1 Diabetes

Complications by Diabetes Duration: The Pittsburgh EDC Study (12-Year

Follow-up Data)

Number of events Duration

<20 years 20–30 years Overall

Mortality 183 0.56 (0.46–0.69) 1.59 (1.27–1.97) 0.79 (0.67–0.91)

Renal failure 128 0.43 (0.33–0.54) 1.34 (1.02–1.72) 0.63 (0.52–0.74)

CAD including revascularization 76 0.17 (0.11–0.25) 0.98

(0.72–1.30) 0.36 (0.28–0.45)

CAD (fatal) and myocardial infarction 55 0.12 (0.07–0.18) 0.76

(0.53–1.04) 0.26 (0.19–0.34)

<20 years 20–25 years Overall

Overt nephropathy 114 1.4 (1.1–1.6) 1.23 (0.59–2.26) 1.33 (1.10–1.60)

Distal symmetric polyneuropathy 124 1.2 (0.98–1.5) 3.83

(2.64–5.37) 1.48 (1.23–1.76)

Symptomatic autonomic neuropathy 57 0.83 (0.62–1.1) 0.36

(0.07–1.1) 0.78 (0.59–1.0)

Proliferative retinopathy 182 1.59 (1.34–1.88) 5.40 (4.00–7.12)

1.95 (1.66–2.23)

Data in parentheses are 95% CIs.

Table 3. Risk Factor Profiles by Diagnosis Cohort at the 25-Year

Duration Examination: The Pittsburgh EDC Study (n = 201)

1965–1969 cohort 1970–1974 cohort

n 98 103

A1C (%)* 10.9 ± 1.9 10.3 ± 1.8

HDL cholesterol (mg/dl) 50.8 ± 12.9 53.9 ± 13.9

LDL cholesterol (mg/dl) 116.3 ± 28.7 119.1 ± 40.3

Non-HDL cholesterol (mg/dl) 136.1 ± 34.7 139.3 ± 45.2

Triglycerides (mg/dl)† 97.2 ± 71.9 104.9 ± 61.9

Systolic blood pressure (mmHg) 118.5 ± 18.1 115.8 ± 12.4

Diastolic blood pressure (mmHg) 74.6 ± 10.1 73.5 ± 9.1

Smoking (%) 31 33

Hypertension (%) 29 28

Data are means ± SD unless otherwise indicated.

*P < 0.05.

† Log transformed before statistical testing.

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Acknowledgements

We thank all study participants who volunteered their time and the EDC

staff.

Funding Information

This research was supported by National Institutes of Health Grant DK34818.

Abbreviation Notes

CAD = coronary artery disease; CDSP = confirmed distal symmetric

polyneuropathy; EDC = Epidemiology of Diabetes Complications

Reprint Address

Georgia Pambianco, Department of Epidemiology, Graduate School of Public

Health, University of Pittsburgh, Diabetes & Lipid Research Building,

3512 Fifth Ave., Pittsburgh, PA 15213. E-mail: glp@...

Georgia Pambianco,1 Tina Costacou,1 Demetrius Ellis,2 Dorothy J.

Becker,2 Klein,3 and Trevor J. Orchard1

1Department of Epidemiology, Graduate School of Public Health,

University of Pittsburgh, Pittsburgh, Pennsylvania; 2 Division of

Nephrology and Endocrinology, Children's Hospital of Pittsburgh,

Pittsburgh, Pennsylvania; 3 Department of Ophthalmology and Visual

Sciences, University of Wisconsin Medical School, Madison, Wisconsin

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