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Diabetes

Not reported

aNot reported, because all persons with diabetes were not included in this survey aNot reported, because all persons with diabetes were not included in this survey

The Pittsburgh epidemiology of diabetes complications study included 363 subjects with type 1 diabetes more than 18 years of age in a defined community (Allegheny County, PA) (6-8). Two of three of the following criteria had to be satisfied to fulfill the definition of neuropathy:

1. Abnormal sensory or motor signs on clinical examination.

2. Neuropathic symptoms.

3. Abnormal tendon reflexes.

Overall neuropathy prevalence was 34% (18% in 19-29 year olds, and 58% in those 30 years of age or older) (Table 1). Higher prevalence of neuropathy was associated with longer diabetes duration, higher glycosylated hemoglobin, lower HDL-cholesterol, smoking, and presence of peripheral vascular, coronary artery, or cerebrovascular disease (Table 1). Another analysis of the Pittsburgh population explored the association between physical activity and distal symmetric polyneuropathy among 628 subjects with type 1 diabetes between 8 and 48 years of age (9). Male subjects who reported higher historical levels of leisure time physical activity (adjusted for diabetes duration, age, and current activity levels) had a significantly lower prevalence of neuropathy. No association between historical levels of physical activity and neuropathy prevalence was seen in females.

Data from the US National Health Interview Survey were used to generate neuropathy prevalence statistics on a nationwide sample of diabetic subjects with diabetes (10). A total of 2405 self-reported subjects with diabetes and 20,037 self-reported subjects without diabetes were surveyed for the presence of symptoms of neuropathy in the extremities (numbness, pain, decreased hot or cold sensation). Prevalence of symptoms was more than three times greater in subjects with diabetes vs subjects without diabetes (Table 1). Among subjects with type 2 diabetes, higher prevalence of symptoms was associated with longer diabetes duration, hypertension, and self-reported frequent high blood glucose, whereas age, gender, height, insulin treatment, and smoking were unrelated to this outcome.

A population-based survey in Western Australia included 1084 diabetic subjects with diabetes, estimated to be 70% of the total that resided in this geographical area (11). Sensory neuropathy was defined as a bilateral reduction in pinprick sensation in the feet during a sensory examination performed by endocrinologists. Neuropathy was found in 14% of subjects, and was related to greater age at diabetes diagnosis, diabetes duration, plasma creatinine, insulin dose, and orthostatic blood pressure difference (Table 1).

In a survey of 10 general practices in an English community, 1077 subjects with diabetes were identified and screened for neuropathy (12). Two of the following five criteria fulfilled the definition of neuropathy:

1. Neuropathic foot symptoms.

2. Loss of light touch sensation.

3. Impaired pinprick sensation.

4. Absent ankle jerk reflexes.

5. Vibration perception threshold greater than 97.5% of an age-standardized value.

A total of 16.8% of subjects with diabetes fulfilled these criteria, in comparison with 750 non-diabetic subjects controls drawn from the same general practices. Risk factors associated with higher neuropathy prevalence are shown in Table 1.

A survey of subjects with diabetes in a defined community in Sweden yielded 375 subjects between the ages of 15-50 with diabetes (78% type 1 diabetes) (13). A vibrameter was used to assess vibration threshold and pain sensation was evaluated with application of an electric current to the foot. Among subjects with type 1 diabetes, neuropathy presence was associated with greater age, diabetes duration, and height, although the association with height disappeared in multivariate analysis after adjustment for gender. Among subjects with type 2 diabetes, neuropathy was associated with greater height only.

A survey of subjects with type 2 diabetes in a Dutch community revealed a high prevalence of neuropathy, but also found that a substantial proportion of subjects without diabetes also tested positive for neuropathy, probably because the high median age of the population (70 years) (14). Proportion of subjects with diabetes and control subjects with abnormal results by test is as follows: temperature 63% vs 49%, vibration (128 Hz tuning fork) 53% vs 33%, and absent tendon reflexes 62% vs 21%. Analysis of risk factors for neuropathy was not performed.

The 1999-2000 National Health and Nutrition Examination Survey (NHANES) (15) examined 2873 men and women aged >40 years, and included 419 people with diabetes. Peripheral neuropathy was assessed using self-reported symptoms and by testing foot sensation with the 5.07 gauge Semmes-Weinstein nylon monofilament. The plantar surface of the foot was tested for sensation at three sites on each foot. Peripheral neuropathy was defined as >1 insensate area(s). The overall prevalence of peripheral neuropathy was 14.8%, among whom over three-fourths were asymptomatic. Among individuals without diabetes, the prevalence of peripheral neuropathy was 13.3% (95% confidence interval [CI] 11.4-15.3), of whom only 2.3% were symptomatic. The prevalence among those with diabetes was 28.5% (95% CI 22-35.1%), among whom 10.9% were symptomatic. The prevalence of peripheral neuropathy increased steeply with age and was higher in non-Hispanic blacks, Mexican Americans, and people with diabetes.

Another community-based study that was conducted in two municipalities in Sicily will be mentioned but not discussed in detail, because only subjects who responded affirmatively to questions regarding the presence of symptoms of neuropathy were evaluated further by a neurologist (16). This method likely led to considerable underascer-tainment of neuropathy prevalence.

Although not community-based, two other cross-sectional studies are worthy of mention because of their large sample sizes and, in one case, multinational composition. The EURODIAB IDDM Complications Study examined prevalence of neuropathy, defined if two or more of the following were present: symptoms, absence of two or more ankle or knee reflexes, abnormal vibration perception threshold, and abnormal autonomic function (postural systolic blood pressure fall of 30 mmHg or more or loss of heart rate variability as demonstrated by an R-R ratio <1) (17). The factors positively correlated with neuropathy prevalence were age, diabetes duration, HbA1c, weight, current smoking, severe ketoacidosis, macroalbuminuria, and retinopathy. The UK Prospective Diabetes Study examined the association between neuropathy and potential risk factors among newly diagnosed subjects with type 2 diabetes. Neuropathy was defined as absence of both ankle reflexes or both knee reflexes, or mean biosthesiometer reading from both great toes of 25 V or greater. A cross-sectional report on 2337 subjects at the onset of the study found 5% of subjects had absent ankle or knee reflexes and 7% had abnormal bios-thesiometer readings (18). Neuropathy was significantly related to the presence of smooth or hairless skin, but unrelated to HbA1c, fasting plasma glucose, smoking, serum lipid and lipoprotein levels, and the albumin:creatinine ratio.

Of the five community-based cross-sectional studies reviewed of subjects with type 2 diabetes that presented data on risk factors for neuropathy, three reported a higher prevalence of this outcome with longer diabetes duration and higher glycosylated hemoglobin, and two found neuropathy prevalence correlated with age and height. The remaining risk factors reported were not reproduced by other investigators. The 1999-2000 NHANES study did not determine which type of diabetes the patient reported, so it is not possible to determine an association between diabetes type and risk factors. Only three community-based cross-sectional studies addressed neuropathy prevalence in subjects with type 1 diabetes in association with risk factors. Two of these investigations reported a correlation between diabetes duration and neuropathy prevalence. No other significant risk factor was reported by more than one community-based study done with subjects with type 1 diabetes. Cross-sectional research affirms the importance of intensity and duration of hyperglycemia as potential risk factors for neuropathy, but also suggests other possible etiologies, as shown in Table 1.

DISTAL SYMMETRIC POLYNEUROPATHY—INCIDENCE AND RISK FACTORS (PROSPECTIVE RESEARCH)

The most important epidemiological study performed to date is the Diabetes Control and Complications Trial (DCCT). Although designed to answer a therapeutic question, this trial provides much valuable information regarding the incidence of diabetic neuropathy

Rochester Diabetic Neuropathy Trial

Fig. 1. Cumulative incidence of neuropathy after 5 years of follow-up in intensively treated and control subjects enrolled in the diabetes control and complications trial. Definitions of neuropathy and primary and secondary cohorts are provided in the text. Intensive treatment consisted of three or more insulin injections per day or an insulin pump, in comparison with two injections of insulin daily in the control group.

Fig. 1. Cumulative incidence of neuropathy after 5 years of follow-up in intensively treated and control subjects enrolled in the diabetes control and complications trial. Definitions of neuropathy and primary and secondary cohorts are provided in the text. Intensive treatment consisted of three or more insulin injections per day or an insulin pump, in comparison with two injections of insulin daily in the control group.

and its relation to glycemic control. This clinical trial included 1161 subjects with type 1 diabetes who were followed for 5 years for the development and progression of neuropathy. Subjects were randomized to intensive or control treatment groups, after being initially divided into a primary (diabetes for 5 years or less, no microalbuminuria, no retinopathy) or secondary prevention (diabetes for 15 years or less, moderate or less nonproliferative retinopathy, urinary albumin excretion less than 200 mg per 24 hour) subgroups, depending on the presence of end point complications at baseline. Clinical neuropathy was defined as two of the three following conditions: (1) neuropathic symptoms; (2) sensory deficit to light touch, position, temperature, or pinprick; and (3) abnormal deep tendon reflexes. Confirmed clinical neuropathy was defined as an abnormal clinical exam plus either abnormal nerve conduction in two or more nerves or abnormal response to autonomic testing. After 5 years of follow-up, the cumulative incidence of clinical neuropathy, confirmed clinical neuropathy, and abnormal nerve conduction was lower in the intensively treated vs control groups, irrespective of presence of complications at baseline (Fig. 1). Among controls, the cumulative incidence of clinical neuropathy was 15-21%, depending on presence of baseline complications. Cumulative incidence of abnormal nerve conduction was very high among controls (40-52%). These data demonstrate the crucial role of hyperglycemia in the development of distal symmetric polyneuropathy, but also suggest that neuropathy will continue to develop even in intensively treated subjects exposed to milder degrees of hyperglycemia.

The UK Prospective Diabetes Study (UKPDS) (19), a randomized intervention trial of intensive vs conventional diabetes treatment, enrolled 3867 subjects with newly diagnosed type 2 diabetes, with a median follow-up of 10 years. Neuropathy was defined as loss of both ankle or both knee reflexes or vibration sensation measured with a bios-thesiometer having a mean reading from both great toes of 25 V or more. At baseline 11.8% of subjects assigned intensive therapy, and 11.4% of subject's assigned conventional therapy had an abnormal biosthesiometer reading. After 12 years follow-up, on average, there was no difference in the proportion of subjects with peripheral neuropathy between the intensive and conventional treatment arms. Absent ankle reflexes were found in 35% of subjects in the intensive treatment group and in 37% in the conventional group (p = 0.60). Absent knee reflexes were found in 11% of subjects in the intensive treatment group and 12% in the conventional treatment arm (p = 0.42). Biosthesiometer readings were abnormal in 30.2% of the intensive treatment group and 32.8% in the conventional treatment group (p = 0.42).

The European Diabetes Prospective Complications Study identified risk factors for the development of distal symmetric polyneuropathy in 1172 subjects with type 1 DM in 31 centers throughout Europe (20). The subjects were assessed for neuropathy at baseline and again an average of 7.3 years later. Neuropathy was defined if the patient had two or more of the four measures: the presence of one or more symptoms such as numbness or burning in the feet, the absence of two or more reflexes of the ankle or knee tendons, a vibration-perception threshold measured by biothesiometer that was abnormal for the patient's age, and abnormal autonomic function (loss of heart rate variability with an R-R ratio of less than 1.04, postural hypotension with a fall in systolic blood pressure of 20 mmHg or more, or both). "Pure" peripheral neuropathy was defined as distal neuropathy without autonomic symptoms or abnormal autonomic-function tests. At follow-up, 23.5% of the subjects had developed neuropathy. After adjusting for complications of diabetes, which included urinary albumin excretion rate, retinopathy and cardiovascular disease, the risk factors for incident diabetic neuropathy were duration of diabetes in years (Odds ratio [OR] 1.25, 95% CI 1.03-1.51), current glycosylated hemoglobin per % of hemoglobin (OR 1.64, 95% CI 1.33-2.03), change in glycosylated hemoglobin value during follow-up period (OR 1.44, 95% CI 1.17-1.77), body-mass index (OR 1.20, 95% CI 1.01-1.43), and smoking (OR 1.68, 95% CI 1.20-2.36). The presence of cardiovascular disease at baseline was independently associated with a higher incidence of neuropathy (OR 2.12, 95% CI 1.16-3.86).

The Epidemiology of Diabetes Complications (21) Study followed 453 subjects with type 1 diabetes who were free of neuropathy at baseline, for an average of 5.3 years. Diabetic peripheral neuropathy was defined as the presence of two or more of the following: sensory, motor or autonomic symptoms, sensory and/or motor signs, and/or absent tendon reflexes. A total of 68 subjects (15%) developed diabetic peripheral neuropathy by the end of follow-up, giving an incidence rate of 2.8 per 100 person-years. Risk factors identified at baseline for incident symmetric polyneuropathy in a Cox proportional hazards model included (Hazard Ratio, 95% CI): type 1 diabetes duration, per 1 SD

increase 1.82 (1.41-2.33); height, per 1 SD increase 2.04 (1.57-2.66); glycohemoglo-bin, per 1 SD increase 1.64 (1.27-2.11); smoking, yes or no 1.73 (1.06-2.82); and hypertension, yes or no 4.10 (2.33-7.24).

Several other prospective studies were designed to specifically define the incidence of and risk factors for diabetic neuropathy. Of 288 veterans with diabetes but no neuropathy, 20% developed neuropathy after 2 years of follow-up (22). Neuropathy was defined as insensitivity to the 5.07 monofilament at one or more of nine sites on either foot. Risk factors for incident neuropathy in multivariate logistic regression analysis included (OR, 95%CI): height, 2.5 cm increase 1.2 (1.1-1.4); previous foot ulcer 2.1 (1-4.1); age, 1 year increase 1.04 (1-1.08); glycohemoglobin, 1% increase 1.2 (1-1.3); CAGE alcohol score (23), four questions answered positively vs none 7 (1.7-29); current smoking 0.2 (0.1-0.7); and serum albumin level adjusted for serum creatinine, 1 mg per dL increase 0.3 (0.1-0.8).

The Rochester Diabetic Neuropathy Study (24) invited all the subjects with diabetes that lived within the geographical confines of Rochester, Minnesota to participate. The study reported on 264 subjects, 97 with type 1 diabetes and 149 with type 2 diabetes, who were followed for a mean of 6.9 years. Although this study is prospective, incidence of neuropathy was not evaluated. Severity of neuropathy was the outcome studied. Neuropathy was defined using the neuropathy impairment score of lower limbs plus 7 tests. These tests included vibration testing at the toes, heart rate variation with deep breathing, and nerve conduction studies of the lower extremity motor and sensory nerves. There was a 36.4% prevalence of at least one nerve conduction abnormality in two or more nerves. Only 9.5% of these subjects were symptomatic. Higher mean gly-cohemoglobin, duration of diabetes, and type 1 vs type 2 diabetes were associated with the severity of diabetic peripheral neuropathy. However, the authors did not adjust for baseline severity of neuropathy.

Another investigation followed 231 subjects with type 2 diabetes, who were free from distal symmetric neuropathy at baseline, for a mean follow-up period of 4.7 years to assess risk factors and incidence of this outcome (25). Distal symmetric neuropathy was defined as described previously for the San Luis Valley cross-sectional study. Incidence of this outcome was 6.1 per 100 person-years (95% CI 4.7-7.8). In a logistic regression model that included age, duration of type 2 diabetes, insulin treatment, glycohemoglo-bin, smoking, Hispanic ethnicity, gender, history of myocardial infarction, and angina, the following factors were independently related to neuropathy incidence: Duration of type 2 diabetes (5 year increase) (OR 1.3, 95% CI 1-1.6); current smoking (OR 2.2,95% CI 1-4.7), and history of myocardial infarction (OR 3.5, 95% CI 1.2-9.7). Insulin treatment (OR 2, 95% CI 0.9-4.4) and female gender (OR 1.7, 95% CI 0.9-3.3) were associated with neuropathy incidence at borderline statistical significance.

Data from a cohort of subjects with type 1 diabetes seen within 1 year of diagnosis at Children's Hospital of Pittsburgh were analyzed after four years of follow-up to assess the incidence of neuropathy in relation to baseline glycemic control, defined as poor (glycosylated hemoglobin 11% or greater, n = 220) or fair (less than 11%, n = 438) (26). Distal symmetric polyneuropathy was defined as presence of two of three criteria: neuropathic symptoms, decreased or absent tendon reflexes, or signs of sensory loss. Four year cumulative incidence of this outcome in this cohort of subjects with a mean age of 28 years, all of whom were diagnosed before age 17, was 13%, with an approx threefold higher risk in poor vs fair control groups (RR 3.2, p < 0.001).

Finnish subjects with newly diagnosed type 2 diabetes (n = 133) were followed for 10 years for the development of peripheral neuropathy defined on the basis of nerve conduction velocity and clinical symptoms (27). At baseline, 4.5% of subjects had polyneuropathy, whereas after 10 years of follow-up this proportion increased to 20.9%. Higher cumulative incidence of neuropathy was related to higher baseline fasting plasma glucose, lower fasting serum insulin, and lower serum insulin one and two hours following a 75 g oral glucose load. Baseline age, smoking, alcohol use, serum lipid values, urinary albumin excretion, and use of antihypertensive medication were unrelated to incidence of polyneuropathy after 10 years.

A sample of 444 younger onset (diagnosed with diabetes before 30 years of age and taking insulin) and 406 older onset diabetic subjects without neuropathy from an 11 county area in Wisconsin were followed for up to 10 years for the development of self-reported loss of tactile sensation or temperature sensitivity (28). Higher glycosylated hemoglobin was related to higher incidence of symptomatic neuropathy, even after adjustment for age, duration of diabetes, and gender in a multivariate model.

The only other prospective study of risk factors for diabetic neuropathy that enrolled more than 100 subjects compared baseline measures of HbA1c, age, diabetes duration, and height in relation to change in thermal, vibration, and monofilament perception of the feet more than two years of follow-up in 201 medical clinic subjects with type 2 diabetes (30% African-American, 67% Hispanic) (29). Subjects were divided into an upper fiftieth percentile change for all sensory tests vs those with change less than the fiftieth percentile for all tests. The comparisons of baseline measures by this classification did not show significant differences for any potential risk factor.

Four other small prospective studies have been performed on risk factors for diabetic neuropathy. A cohort of subjects with type 1 diabetes (n = 96) enrolled in a randomized control trial of intensive glucose control was followed for development of neuropathy defined as two or more abnormal lower extremity nerve conduction velocities or abnormal vibration or thermal sensation (30). No association was found between baseline HbA1c and incidence of neuropathy over 5 years of follow-up, although higher HbA1c during follow-up was significantly related to this outcome, except for change in vibration sensation, which was related to diabetes duration only. In another cohort of subjects with type 1 diabetes, 77 subjects ages 25-34 years without clinical neuropathy at baseline were followed for 2 years for the development of clinically overt neuropathy (as previously defined for the Pittsburgh Epidemiology of Diabetes Complications Study) (31). Nephropathy (defined as an albumin excretion rate greater than 200 ^g per min on at least 2 of 3 occasions) and higher vibration perception threshold at baseline independently predicted the development of neuropathy, which occurred in 9% of subjects. Change in vibration sensation was measured over five years in a cohort of 71 newly diagnosed subjects with type 2 diabetes (32). Mean fasting blood glucose over the 5-year period, male gender, age, and body mass index positively correlated with change in vibration sensation threshold. A study of 32 newly diagnosed subjects with type 1 diabetes followed for 5 years found poorer glucose control (HbA1c of 8.3% or greater)

related to diminished nerve conduction and decreased thermal (but not vibration) sensation (33).

One large cohort study is worthy of mention for historical purposes. Pirart followed 4400 subjects with diabetes in a Belgian clinic for the development of complications between 1947 and 1973 (34). The cumulative incidence of neuropathy was 50% after 25 years of follow-up, and was found to occur more frequently in subjects with poorer glucose control by urine and blood testing. Although the sample size of this study is impressive, its methodology is compromised by a vague definition of neuropathy and outdated methods for measurement of glycemic control.

Prospective research on the risk of distal symmetric polyneuropathy confirms its relationship to poorer glycemic control as reflected by fasting plasma glucose or HbA1c at baseline, as reported by nine of the eleven largest (more than 100 subjects) and two smaller (less than 100 subjects) cohort studies. Four prospective studies reported duration of diabetes as a risk factor for neuropathy, three reported smoking as a risk factor, two reported age, and two reported baseline coronary artery disease as risk factors for neuropathy. The following potential risk factors were reported in one prospective study: male gender, height, increase in body-mass index, nephropathy, high CAGE alcohol use score, low serum albumin level, insulin treatment, nonsmoking, and fasting and stimulated serum insulin levels. However, another prospective study produced contradictory results by finding female gender and current smoking associated with neuropathy (25). Whether these discrepant results arise from differences in neuropathy definition, dissimilar patient populations, or both, cannot be determined at the current time.

PREVALENCE, INCIDENCE, AND RISK OF AUTONOMIC NEUROPATHY

Diabetic autonomic neuropathy has been the subject of fewer research investigations in comparison with distal symmetric polyneuropathy. The Framingham Heart Study performed a cross-sectional evaluation of the 1919 people from the Framingham Offspring Study who had ambulatory electrocardiographic recordings available (35). Subjects were categorized according to normal fasting blood glucose (<110 mg per dL), impaired fasting blood glucose (>110 and <126 mg per dL), or DM (fasting blood glucose >126 mg per dL and/or the use of insulin or an oral hypoglycemic agent). Autonomic neuropathy was defined by a time domain variable, the standard deviation of normal RR intervals, and three frequency domain variables (low frequency [LF 0.04-0.15 Hz], high frequency [HF 0.15-0.40 Hz] and the LF:HF ratio). The authors adjusted for age, sex, body-mass index, heart rate, systolic and diastolic blood pressure, hypertension treatment, cardiac medications, cigarette smoking, and coffee and alcohol consumption in multivariable regression analysis. It was found heart rate variability was decreased in subjects with diabetes, in comparison with subjects with normal fasting glucose. The subjects with impaired fasting glucose had decreased heart rate variability intermediate between those with diabetes and those with normal fasting glucose. In a community-based cross-sectional study of 168 subjects with type 1 diabetes, abnormal autonomic function, as measured by the expiratory:inspiratory (E:I) ratio and the mean circular resultant, was associated with female gender, high LDL-cholesterol, and hypertension (36). In addition, abnormal E:I ratio was related to low HDL-cholesterol, whereas abnormal mean circular resultant was associated with higher serum triglycerides. Definitions for abnormal E:I ratio or mean circular resultant were not provided in this publication.

Several prospective studies of autonomic neuropathy risk have been reported. The DCCT found mixed results regarding the association between intensive glucose control and 5 years cumulative incidence of autonomic neuropathy defined as R-R variation with breathing less than 15 per minute, Valsalva ratio less than 15 with R-R variation with breathing less than 20 per minute, or orthostatic blood pressure drop of 10 mmHg or more with a blunted catecholamine response (Fig. 1) (37). Greater R-R variation with breathing was seen with intensive treatment in the primary prevention cohort only at the end of follow-up, whereas Valsalva ratio did not differ by intensive treatment in either cohort. A Finnish cohort of 133 newly diagnosed subjects with type 2 diabetes was followed for 10 years for the development of parasympathetic neuropathy defined as an E:I ratio of 1.10 or lower, and sympathetic neuropathy, defined as an orthostatic systolic blood pressure decline of 30 mmHg or more (38). At baseline, 4.9% of subjects with type 2 diabetes had parasympathetic neuropathy, although apparently none had sympathetic neuropathy. After 10 years of follow-up, rates of these neuropathies were 65 and 24.4%, respectively. In a stepwise logistic regression model that considered as independent variables age, gender, body mass index, systolic blood pressure, fasting plasma insulin and glucose, and ischemic ECG changes, only fasting plasma insulin (OR 3.1, 95% CI 1.3-7.6) and female gender (OR 3.4, 95% CI 1.2-9.8) were independently and significantly related to cumulative incidence of parasympathetic neuropathy. In a similar logistic model for sympathetic neuropathy cumulative incidence that considered all these factors plus use of diuretic medication, only diuretic use entered the model at p < 0.05 (OR 2.9, 95% CI 1-8.2). The previously mentioned Stockholm clinical trial followed 96 subjects with type 2 diabetes for changes in autonomic function as measured by respiratory sinus arrhythmia, Valsalva maneuver, and orthostatic blood pressure fall (30). Baseline HbA1c was unrelated to change in autonomic function, but HbA1c during 5 years of follow-up was significantly related to this outcome. The remaining prospective study was small in size (n = 32 subjects with type 1 diabetes), and found poorer glucose control (HbA1c > 8.3%) related to diminished heart rate variability at rest and during deep breathing over five years of follow-up (33).

The UK Prospective Diabetes Study evaluated the heart-rate response to deep breathing as one of the surrogate end points (19). There was no difference between the intensive and conventional diabetes treatment groups after 12 years of follow-up. However, the median basal heart rate was 69.8 beats per minute (IQR 62.5-78.9) in the intensively treated group in comparison with 74.4 beats per minute (IQR 65.2-83.3) in the conventional group (p < 0.001).

The Steno-2 Study (39) randomized 160 subjects with type 2 diabetes with microalbuminuria to conventional treatment or to intensive, multifactorial treatment which provided a stepwise implementation of behavior modification and pharmacological therapy that targeted hyperglycemia, hypertension dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. Subjects were followed for a mean of 7.8 years. Autonomic neuropathy was defined as heart rate variation on deep breathing. R-R variation higher than 6 beats per minute was considered normal, 4-6 was considered impaired, and less than 4 to have absent variation. Orthostatic hypotension was defined as a drop in systolic blood pressure of 25 mmHg or more. At baseline, 27% of these subjects with microalbuminuria had autonomic neuropathy. Autonomic neuropathy progressed in 43 subjects (53%) in the conventional treatment group and in 24 subjects (30%) in the intensive-therapy group. The hazard ratio was 0.37 (95% CI 0.18-0.79).

The literature on risk factors for diabetic autonomic neuropathy can be characterized as smaller in size and less consistent in comparison with that available for distal symmetric polyneuropathy. The only risk factor reported in more than one study was female gender, found to be associated with higher risk by two authors. The absence of a consistent relationship between glucose control and autonomic neuropathy risk raises the possibility that the course of this complication is set soon after diabetes develops and is not amenable to change thereafter, or that available research, including the DCCT, may have been statistically underpowered for the detection of this association.

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