Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: The EURODIAB Prospective Complications Study

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes

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

Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes

Background Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. Methods As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-fever scale (none to proliferative). Findings The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p=0.2). Patients on lisinopril had significantly lower HbA(1c) at baseline than those on placebo (6.9% vs 7.3 p=0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p=0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p=0.06). Lisinopril also decreased progression by two or move grades (0.27 [0.07-1.00], p=0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p=0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p=0.4). Interpretation Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated

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

Do European people with type 1 diabetes consume a high atherogenic diet? 7-year follow-up of the EURODIAB Prospective Complications Study

BACKGROUND/OBJECTIVES: Individuals with type 1 diabetes have a high risk of developing cardiovascular diseases, and it has been reported that they consume a high atherogenic diet. We examined how nutrient intake and adherence to current European nutritional recommendations evolved in a large cohort of European individuals with type 1 diabetes over a period of 7 years. SUBJECTS/METHODS: We analysed data from the EURODIAB Prospective Complications Study, a European multicentre prospective cohort study. Standardized 3-day dietary records were employed in individuals with type 1 diabetes. One thousand one hundred and two patients (553 men, 549 women, baseline age 33 ± 10 years, duration 15 ± 9 years) had complete nutritional data available at baseline and after 7 years. We calculated mean differences in reported nutrients over time and adjusted these for age, gender, HbA1c and BMI with ANOVA models. RESULTS: Compared to baseline, there were minor changes in nutrients. Reported protein (-0.35% energy (en), fat (-1.07% en), saturated fat (-0.25% en) and cholesterol (-7.42 mg/1000 kcal) intakes were lower, whereas carbohydrate (+1.23% en) and fibre (+0.46 g/1000 kcal) intakes were higher at the 7-year follow-up. European recommendations for adequate nutrient intakes were followed in individuals with type 1 diabetes for protein (76% at baseline and 78% at follow-up), moderately for fat (34, 40%), carbohydrate (34, 41%) and cholesterol (39, 47%), but poorly for fibre (1.4, 2.4%) and saturated fat (11, 13%). CONCLUSION: European individuals with type 1 diabetes consume a high atherogenic diet as few patients met recommendations for dietary fibre and saturated fat. This study showed minor changes in dietary nutrients and energy intakes over a period of 7 years. Nutrition education needs particular focus on strategies to increase dietary fibre and reduce saturated fat to exploit their potential benefi

Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: The EURODIAB Prospective Complications Study

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes

Dietary saturated fat and fibre and risk of cardiovascular disease and all cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study

Low adherence to recommendations for dietary saturated fatty acid (SFA) and fibre intake in patients with type 1 diabetes mellitus may heighten their increased risk of cardiovascular disease (CVD) and mortality. We examined the relationship of SFA and total, soluble and insoluble fibre with incident CVD and all-cause mortality in type 1 diabetic patients