Anne Sofie Astrup

Subclinical Coronary and Aortic Atherosclerosis Detected by Magnetic Resonance Imaging in Type 1 Diabetes With and Without Diabetic Nephropathy

Background— Patients with type 1 diabetes and nephropathy maintain an excess cardiovascular mortality compared with diabetic patients with normoalbuminuria. We sought to evaluate coronary and aortic atherosclerosis in a cohort of asymptomatic type 1 diabetic patients with and without diabetic nephropathy using cardiovascular magnetic resonance imaging. Methods and Results— In a cross-sectional study, 136 subjects with long-standing type 1 diabetes without symptoms or history of cardiovascular disease, including 63 patients (46%) with nephropathy and 73 patients with normoalbuminuria, underwent cardiovascular magnetic resonance imaging. All subjects underwent cardiac exercise testing and noninvasive tests for peripheral artery disease and autonomic neuropathy. Coronary artery stenoses were identified in 10% of subjects with nephropathy (versus 0% with normoalbuminuria; P=0.007). Coronary plaque burden, expressed as right coronary artery mean wall thickness (1.7±0.3 versus 1.3±0.2 mm; P<0.001) and maximum right coronary artery wall thickness (2.2±0.5 versus 1.6±0.3 mm; P<0.001), was greater in subjects with nephropathy. The prevalence of thoracic (3% versus 0%; P=0.28) and abdominal aortic plaque (22% versus 16%; P=0.7) was similar in both groups. Subjects with and without abdominal aortic plaques had similar coronary plaque burden. Conclusions— In asymptomatic type 1 diabetes, cardiovascular magnetic resonance imaging reveals greater coronary plaque burden in subjects with nephropathy compared with those with normoalbuminuria.

Markers of Endothelial Dysfunction and Inflammation in Type 1 Diabetic Patients With or Without Diabetic Nephropathy Followed for 10 Years Association with mortality and decline of glomerular filtration rate

OBJECTIVE—We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients. RESEARCH DESIGN AND METHODS—We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline. RESULTS—We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1–2.6]; P = 0.025 and 1.5 [1.1–2.2]; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0–2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = −0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient −1.38 [95% CI −2.27 to −0.50]; P = 0.002). CONCLUSIONS—Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR.

Predictors of mortality in patients with type 2 diabetes with or without diabetic nephropathy: a follow-up study

Objective To evaluate the prognostic significance of cardiovascular risk factors including 24-h ambulatory blood pressure level and rhythm for all-cause mortality in type 2 diabetic patients. Methods In a prospective observational study, 104 patients with type 2 diabetes were followed: 51 patients with diabetic nephropathy and 53 patients with persistent normoalbuminuria. At baseline, 24-h ambulatory blood pressure, left ventricular hypertrophy, glomerular filtration rate and cardiac autonomic neuropathy were measured. Blood samples were taken and patients answered a World Health Organization questionnaire. Dipping was calculated as the average nocturnal reduction in systolic and diastolic blood pressure. Results Mean follow-up was 9.2 years (range 0.5–12.9). During follow-up, 54 of 104 patients died. Sixteen patients (15%) had higher blood pressure at night than during the day (reversed pattern); 14 of these patients died (88%), compared to 40 of 88 patients (45%) with reduced dipping or normal dipping; log rank P = 0.001. In a Cox regression analysis, predictors of all-cause mortality were: age, male sex, presence of left ventricular hypertrophy, glycated haemoglobin A1c (HbA1c), daytime systolic blood pressure, cardiac autonomic neuropathy, glomerular filtration rate and dipping (1% increase; hazard ratio 0.97, 95% confidence interval 0.94–0.998, P = 0.033). Conclusion Type 2 diabetes patients with non-dipping of night blood pressure were at higher risk of death as compared to dippers, independent of known cardiovascular risk factors. Since non-dipping has a high prevalence in patients with diabetic nephropathy, 24-h ambulatory blood pressure should be used to assess a full risk profile and blood pressure-lowering therapy in these patients.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril.

Diabet. Med. 27, 1144–1150 (2010)

Effect of Adjunct Metformin Treatment in Patients with Type-1 Diabetes and Persistent Inadequate Glycaemic Control. A Randomized Study

Background Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control. Methodology/Principal Findings One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA1c (HbA1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA1c after one year of treatment. At enrolment, mean (standard deviation) HbA1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA1c, 0.13% (−0.19; 0.44), p = 0.422; Total daily insulin dose, −5.7 U/day (−8.6; −2.9), p<0.001; body weight, −1.74 kg (−3.32; −0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated. Conclusions/Significance In patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted. Trial Registration ClinicalTrials.gov NCT00118937

Tubular and glomerular injury in diabetes and the impact of ACE inhibition.

OBJECTIVE We studied tubular and glomerular damage in type 1 diabetic patients by measuring urinary–liver fatty acid binding protein (U-LFABP) and albuminuria. Subsequently, we evaluated the effect of ACE inhibition on U-LFABP in patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS We studied Caucasians with type 1 diabetes: 58 with normoalbuminuria (urinary albumin <30 mg/24 h), 45 with persistent microalbuminuria (30–300 mg/24 h), and 45 with persistent macroalbuminuria (≥300 mg/24 h). A control group consisted of 57 healthy individuals. The groups were matched by sex and duration of diabetes. In addition, U-LFABP was measured in 48 type 1 diabetic patients with diabetic nephropathy in a randomized crossover trial consisting of 2 months of treatment with 20, 40, and 60 mg lisinopril once daily in random order. RESULTS In the cross-sectional study, levels of U-LFABP were significantly higher in normoalbuminuric patients versus those in the control group (median 2.6 [interquartile range 1.3–4.1] vs. 19 [0.8–3.0] μg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8–8.3] μg/g creatinine and nephropathy group 71.2 [8.1–123.4], P < 0.05 for all comparisons). U-LFABP correlates with the urinary albumin-to-creatinine ratio (R2 = 0.54, P < 0.001). In the intervention study, all doses of lisinopril significantly reduced urinary albumin excretion rate and U-LFABP from baseline. The reductions in U-LFABP were 43, 46, and 40% with increasing doses of lisinopril (NS). CONCLUSIONS An early and progressive increase in tubulointerstitial damage as reflected by increased U-LFABP levels occurs in type 1 diabetic patients and is associated with albuminuria. Furthermore, ACE inhibition reduces the tubular and glomerular damage and dysfunction.

Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes

Background: In addition to its glucose‐lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1‐year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control.

Plasma α-Defensin Is Associated with Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients

CONTEXT alpha-Defensins are antimicrobial peptides of the innate immune system. In addition, experimental evidence suggests that alpha-defensins are proatherogenic. OBJECTIVE The objective of the study was to examine the predictive value of plasma alpha-defensin as a clinical marker of cardiovascular disease (CVD) in patients with type 1 diabetes. METHODS In an observational, prospective design, 389 patients with long-lasting type 1 diabetes were examined for CVD at study start (1993; baseline) and followed up through the Danish National Register for a median of 10.1 yr (range 0.2-10.4 yr). Plasma was collected in 1993 and stored at -80 C until analysis of plasma alpha-defensin using an in-house RIA. RESULTS At baseline, plasma alpha-defensin was significantly higher in patients with than without nephropathy [median and interquartile ranges: 305 (205-321) vs. 223 (182-263) mug/liter; P < 0.0001]. During follow-up, 98 patients reached the primary end point (fatal and nonfatal events of CVD). Prospectively a baseline alpha-defensin within the upper vs. the lower tertile significantly increased the covariate-adjusted risk for CVD-related morbidity and mortality to a hazard ratio of 2.8 (1.3-5.9) (median and 95% confidence intervals, P = 0.006). CONCLUSION This study suggests that plasma alpha-defensin may serve as a clinical risk marker for CVD-related morbidity and mortality in type 1 diabetes. However, future studies are needed to clarify whether plasma alpha-defensin is causally linked to the development of CVD or an innocent bystander.

Elevated placental growth factor (PlGF) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

Background and Aim. Placental growth factor (PlGF) is up‐regulated in early and advanced atherosclerotic lesions, acts as a primary inflammatory instigator of atherosclerotic plaque instability, and may be an independent biomarker of adverse outcome in patients with acute coronary syndromes. In diabetic nephropathy the relative cardiovascular mortality and morbidity is increased and therefore, this study investigated the prognostic value of PlGF in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. Research Design and Methods. In a prospective, observational follow‐up study 190 type 1 diabetic patients with overt diabetic nephropathy (116 men, age (mean (SD)) 41±10 years, duration of diabetes 28±8 years, glomerular filtration rate (GFR) 76±33 mL/min/1.73 m2) and a matched control group of 174 patients with normoalbuminuria (104 men, age 43±10 years, duration of diabetes 27±9) were followed for 10 years (range: 0–10.3). The primary endpoint was a composite endpoint of cardiovascular death, hospitalization for myocardial infarction or stroke, coronary artery bypass grafting or percutanous coronary intervention, ischaemic amputation or peripheral bypass‐surgery. Plasma PlGF was determined by an enzyme linked immunosorbent assay at baseline. Results. During 10 years of follow‐up 74 patients (39%) with diabetic nephropathy reached the primary endpoint versus only 18 (10%) of normoalbuminuric patients, log rank test; p<0.001. During follow‐up 16 (25%) patients in the lowest, 24 (39%) in the middle and 34 (52%) patients in the upper tertile reached the primary cardiovascular endpoint, p=0.007. Hazard ratios in the second and third tertile as compared with the first tertile were 1.76 (0.92–3.38) and 2.64 (1.41–4.91) (p=0.009). Cox regression analyses including PlGF concentration as a continuous variable revealed an unadjusted hazard ratio of the primary endpoint for each 1 ng/L increase in PlGF of 1.10 (1.03–1.16), p=0.002; covariate adjusted hazard ratio 1.07 (1.00–1.14), p=0.03. Conclusions Increased PlGF is a new independent predictor of cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

Pregnancy-associated plasma protein A in a large cohort of Type 1 diabetic patients with and without diabetic nephropathy—a prospective follow-up study

Aim  Pregnancy‐associated plasma protein A (PAPP‐A) has been implicated in the aetiology of acute coronary syndromes and carotid and peripheral artherosclerosis. Diabetic nephropathy is characterized by increased cardiovascular risk. We investigated the prognostic value of PAPP‐A in a large cohort of Type 1 diabetic patients.