Raelene E. Maser

Prevalence of Complications in IDDM by Sex and Duration: Pittsburgh Epidemiology of Diabetes Complications Study II

The prevalence of and interrelationships among all four major complications of insulin-dependent diabetes mellitus (IDDM) and their risk factors are being examined in a large epidemiologic study of IDDM subjects diagnosed in childhood. This article focuses on the baseline prevalence of complications in the 657 subjects diagnosed between 1950 and 1980 and currently aged 8–48 yr, with a mean duration of 20 yr. In addition to background retinopathy being virtually universal after 20 yr of diabetes, proliferative retinopathy affects 70% of IDDM subjects after 30 yr duration. As with overt nephropathy, prevalence of proliferative retinopathy is marginally higher in females than in males at short durations; the previously reported male excess is limited to the subjects with IDDM of longer duration (≥25 yr). Somewhat different patterns of microalbuminuria are also seen by sex. Males show a threefold increase in prevalence from 10 to 25 yr duration, whereas females show a more constant prevalence across these durations. A further rise in microalbuminuria is seen in males but not females at ≥30 yr duration, giving a combined prevalence of microalbuminuria and overt nephropathy at ≥30 yr duration of 84% (males) and 59% (females). Distal symmetrical polyneuropathy shows a constant rise with duration and is only marginally higher in men. Prevalence of cardiovascular (coronary and cerebral) disease shows no sex difference, whereas peripheral vascular disease is particularly common in women after 30 yr duration (>30%) compared with men (11%) when determined by ankle/arm blood pressure ratio <0.8 at rest or after exercise. These results suggest that the natural history of IDDM complications varies considerably by sex and that the prevalence of complications (especially renal complications in males) may be higher than previously recognized.

Factors Associated With Avoidance of Severe Complications After 25 Yr of IDDM: Pittsburgh Epidemiology of Diabetes Complications Study I

To identify characteristics associated with long-term avoidance of insulin-dependent diabetes mellitus (IDDM) complications, subjects taking part in an epidemiologic natural history study of childhood-onset IDDM, with a duration of disease ≥25 yr, were studied. Nineteen percent of 175 subjects had avoided overt nephropathy, definite cardiovascular and peripheral vascular disease, clinical neuropathy, and proliferative retinopathy. Approximately half of the nonrenal complications occurred in the absence of renal disease. Subjects free of these advanced complications were characterized by a longer duration of disease (P < 0.05), better lipid profile and blood pressure (P < 0.01), and considerably lower glycosylated hemoglobin levels (P < 0.001). Health-related behaviors, including recent medical contact, regular glucose monitoring, physical activity in youth, and avoidance of cigarette smoking, did not relate to complication status, although regular (at least weekly) alcohol consumption was more prevalent (P < 0.05) in those without complications. We conclude that a lower mean glycosylated hemoglobin level is strongly related to the avoidance of all IDDM complications.

Hypertension as a Risk Factor for Diabetic Neuropathy: A Prospective Study

The pathogeneses of diabetic neuropathy is still unclear. This study prospectively investigated the risk factors for distal symmetrical polyneuropathy (DSP) in a cohort of childhood-onset IDDM patients. Subjects from the Epidemiology of Diabetes Complications (EDC) Study were clinically examined at baseline and then biennially. DSP was diagnosed by a combination of clinical criteria, symptoms and signs (Diabetes Control and Complications Trial [DCCT] exam), and quantitative sensory threshold (QST). Among the 463 (70.4%) subjects who were free of DSP at baseline, 453 (97.8%) participated in at least one biennial reexamination during the first 6 years of follow-up and were included in the current analysis. A total of 68 (15.0%) subjects developed DSP in 6 years, giving a cumulative probability of 0.29. The Cox proportional hazards model shows that longer IDDM duration, hypertension, poor glycemic control, height, and smoking were all independent predictors of the incidence of DSP (all P < 0.0001, except for smoking for which P = 0.03). Hypertension showed the greatest impact on the development of DSP for individuals with either short or long IDDM duration. This study confirms some risk factors for DSP found in crosssectional studies and suggests a strong relationship between hypertension and DSP. The results indicate that in addition to good glycemic control, avoidance of smoking and good blood pressure control may be helpful in preventing or delaying the onset of DSP in IDDM patients.

Autonomic imbalance: prophet of doom or scope for hope?

Diabet. Med. 28, 643–651 (2011)

The progression of retinopathy over 2 years: the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study.

This study examined potential risk factors for the incidence and progression of retinopathy in a large representative cohort of childhood onset insulin-dependent diabetic patients. Participants in the Epidemiology of Diabetes Complications (EDC) Study underwent a full clinical examination at baseline and again at a 2-year follow-up. Retinopathy status was ascertained using stereo fundus photographs graded according to the modified Airlie House System. The study population is based on a large cohort of childhood-onset insulin-dependent diabetic patients, seen within 1 year of diagnosis at the Childrens Hospital of Pittsburgh between January 1950 and May 1980. A total of 657 subjects participated at baseline (1986-1988), with 80% of eligible survivors taking part in the follow-up examination. This report concerns risk factors associated with the progression of diabetic retinopathy over a 2-year period, and the interaction of these factors with the presence of nephropathy. Analyses showed that baseline diastolic blood pressure was significantly associated with the incidence of any retinopathy, while glycosylated hemoglobin, baseline severity of retinopathy, serum triglycerides, and, to a lesser extent, higher levels of low-density lipoprotein (LDL) cholesterol and fibrinogen were associated with the progression of retinopathy. Progression to proliferative retinopathy was related to higher LDL cholesterol, fibrinogen, serum triglycerides, albumin excretion rate, and glycosylated hemoglobin (GHb). Risk factors varied with the presence of nephropathy. In the absence of nephropathy, GHb was a significant predictor of progression, whilst this was not the case in the presence of nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Why does diabetic autonomic neuropathy predict IDDM mortality? An analysis from the Pittsburgh Epidemiology of Diabetes Complications Study

BACKGROUND Previous studies have suggested that IDDM subjects with diabetic autonomic neuropathy (DAN) have a greatly increased risk of mortality which may relate to a specific cardiologic etiology. OBJECTIVES To examine the predictors of DAN in IDDM and its relationship to subsequent mortality. STUDY POPULATION The Epidemiology of Diabetes Complications Study based on an incident cohort of childhood onset IDDM subjects. Data from two examinations, separated by 2 years, are utilized. METHODS Diabetic autonomic neuropathy was determined by Expiration/Inspiration (E/I ratio). A variety of baseline risk factors were related to its subsequent incidence (n = 57 out of 325 subjects free of DAN at baseline). Two-year mortality by DAN status was also determined for all 479 subjects seen at baseline. RESULTS Duration of diabetes, the cardiovascular risk profile (hypertension, elevated LDL cholesterol and triglycerides), and other complications (e.g. nephropathy) were all univariately associated with subsequent DAN (P < 0.01). Smoking status and hemoglobin A1 (HbA1) but less strongly, related (P < 0.05). Cox proportional hazards modeling showed diabetes duration and HbA1 to be significant independent predictors. Distal Symmetrical Polyneuropathy also contributed if added to the model. Mortality was increased four-fold in those with DAN (P = 0.005), although this difference no longer was significant after adjustment for baseline nephropathy (P = 0.35) or hypertension (P = 0.42). CONCLUSIONS Duration of diabetes and HbA1 are the major predictors of DAN. However, although DAN is clearly associated with increased mortality, this is largely explained by associations with complications (e.g. nephropathy) and increased cardiovascular risk factors (e.g. hypertension).

Cardiovascular autonomic neuropathy (expiration and inspiration ratio) in type 1 diabetes: Incidence and predictors

The pathogenesis of diabetic neuropathy is poorly understood. In this prospective study, we investigated the incidence rate and potential predictors for cardiovascular autonomic neuropathy (CAN) in a cohort of childhood-onset type 1 diabetic patients. Subjects from the Epidemiology of Diabetes Complications Study were examined at baseline and then biennially. CAN was diagnosed by abnormal (</=1. 1) expiration/inspiration ratio during deep breathing. During the 4. 7-year mean follow-up period, CAN developed in 104 patients from the 373 subjects who were free of CAN at baseline and provided follow-up data, an incidence-density of 5.9 cases/100 person-years. Cox proportional hazard modeling showed age (relative risk [RR]=2.15, p=0.0001), HbA1 (RR=1.50, p=0.0002) and nephropathy (albumin excretion >200 ug/min) (RR=2.46, p=0.0001) to be significant independent predictors. Hypertension was, however, predictive if nephropathy was not included in the model. We conclude that beyond age and poor glycemic control, nephropathy is a significant risk factor for CAN and this association may explain some of the increased mortality seen in CAN.

Lipoprotein(a) Concentration Shows Little Relationship to IDDM Complications in the Pittsburgh Epidemiology of Diabetes Complications Study Cohort

OBJECTIVE To examine the potential associations of lipoprotein(a) and the complications of IDDM and their risk factors. RESEARCH DESIGN AND METHODS This report focuses on 186 individuals with IDDM (mean age = 34 yr) participating in a 10-yr prospective study examining various complications. Lp(a) concentrations were evaluated for those with and without complications. RESULTS A weak correlation was seen between Lp(a) and HbAj (r = 0.16, P < 0.05). Lp(a) concentrations were not significantly different for those with or without proliferative retinopathy, overt nephropathy, peripheral vascular disease, or definite myocardial infarction or angina. However, an inverse association (P < 0.05) was seen with distal symmetric polyneuropathy. These results were also confirmed by categorical analyses (i.e., Lp(a) levels <30 vs. >30 mg/dl). CONCLUSIONS These results suggest that any association of Lp(a) concentration with IDDM complications is likely to be weak or nonexistent. However, prospective studies are needed before its full role can be determined.

Neuropathy: The Crystal Ball for Cardiovascular Disease?

Cardiovascular disease (CVD) is a major cause of death in patients with type 2 diabetes. Unclear, however, is the effect of intensive therapy in reducing the development of cardiovascular complications. The UK Prospective Diabetes Study (UKPDS), involving patients with newly diagnosed disease, showed a nonsignificant trend in the reduction of rates for myocardial infarction (MI) (1). However, data 10 years after cessation of the trial showed a 15% reduction in the risk of MI for those in the original intensive therapy group (2). This benefit from early intensive therapy persisted despite the fact that the within-trial differences for A1C between the intensive and conventional therapy groups were lost within 1 year of completion of the trial. The sustained benefit from early aggressive treatment is referred to as the legacy effect or metabolic memory. The question of more intensive therapy and reduction in cardiovascular complications was addressed for people with type 2 diabetes of long duration in three other studies (i.e., the Action to Control Cardiovascular Risk in Diabetes [ACCORD] [3], the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] [4], the Veterans Affairs Diabetes Trial [VADT] [5]). Although the three studies utilized different patient cohorts, with varying durations of diabetes (ACCORD, 10 years; VADT, 11.5 years; and ADVANCE, 8 years) and had different treatment regimens, the results of these trials indicated that intensive glucose control did not reduce CVD events. In fact, the ACCORD trial was terminated early because an increased rate of mortality was found to be associated with intensive control of hyperglycemia (6). A higher rate of mortality for those on intensive treatment was not, however, found in ADVANCE and VADT. Recent articles from the ACCORD trial, by Pop-Busui et al. (7) and Calles Escandon et …

Cardiovascular autonomic neuropathy: The clinical significance of its determination

Cardiovascular autonomic neuropathy (CAN), a frequent complication of diabetes mellitus, may be one of the most overlooked of all serious complications of diabetes. Reduced heart rate variability is the earliest indicator of CAN. Using commercially manufactured noninvasive bedside instrumentation, C