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

Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria

Background Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known. Methods We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20-59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm Hg diastolic, and no more than 155 mm Hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months. Findings There were no differences in baseline characteristics by treatment group; mean AER was 8.0 mu g/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 mu g/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2.0-3.27, p=0.03), adjusted for baseline AER and centre, absolute difference 2 2 mu g/min. In people with normoalbuminuria, the treatment difference was 1.0 mu g/min (12.7% [-2.9 to 26.0], p=0.1). In those with microalbuminuria, however, the treatment difference was 34.2 mu g/min (49.7% [-14.5 to 77.9], p=0.1; for interaction, p=0.04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38.5 mu g/min in those with microalbuminuria at baseline (p=0.001), and 0.23 mu g/min in those with narmoalbuminuria at baseline (p=0.6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin. Interpretation Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER greater than or equal to 20 mu g/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM

Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria.

Background Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known.Methods We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20-59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm Hg diastolic, and no more than 155 mm Hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months.Findings There were no differences in baseline characteristics by treatment group; mean AER was 8.0 mu g/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 mu g/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2.0-3.27, p=0.03), adjusted for baseline AER and centre, absolute difference 2 2 mu g/min. In people with normoalbuminuria, the treatment difference was 1.0 mu g/min (12.7% [-2.9 to 26.0], p=0.1). In those with microalbuminuria, however, the treatment difference was 34.2 mu g/min (49.7% [-14.5 to 77.9], p=0.1; for interaction, p=0.04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38.5 mu g/min in those with microalbuminuria at baseline (p=0.001), and 0.23 mu g/min in those with narmoalbuminuria at baseline (p=0.6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin.Interpretation Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER greater than or equal to 20 mu g/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study.

CONTEXT AND OBJECTIVE: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro- and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. DESIGN AND METHODS: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40±10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. RESULTS: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised β=0.07 (95% confidence interval (CI): 0.02-0.12) and β=0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro- and macroalbuminuria: odds ratio (OR)=1.24 (95% CI: 0.90-1.71) and OR=1.61 (95% CI: 1.15-2.25) respectively, P for trend=0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. CONCLUSIONS: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro- and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein