Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

Large-fiber dysfunction in diabetic peripheral neuropathy is predicted by cardiovascular risk factors.

OBJECTIVE: Diabetic large-nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance. RESEARCH DESIGN AND METHODS: We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean +/- SD age of 32.7 +/- 10.2 years with diabetes duration of 14.7 +/- 9.3 years and follow-up of 7.3 +/- 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient s age. RESULTS: An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P < OR = 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT. CONCLUSIONS: This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors.

Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS).

OBJECTIVE: The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up. RESULTS: There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality. CONCLUSIONS: Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors.