Umberto Valentini

Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non–Insulin-Dependent Diabetes Mellitus

Background — It is not presently known whether non–insulin-dependent diabetes mellitus (NIDDM) is associated with the presence of structural alterations in small arteries or whether the combination of hypertension and NIDDM may have an additive effect on endothelial dysfunction. Therefore, we investigated subcutaneous small arteries in 12 normotensive subjects (NT group), 18 patients with essential hypertension (EH group), 13 patients with NIDDM, and 11 patients with NIDDM and EH (NIDDM+EH group). Methods and Results — Subcutaneous small arteries were evaluated by a micromyographic technique. The internal diameter, the media-to-lumen ratio, remodeling and growth indices, and the collagen-to-elastin ratio were calculated. Concentration-response curves to acetylcholine, bradykinin, the endothelium-independent vasodilator sodium nitroprusside, and endothelin-1 were performed. The media-to-lumen ratio was higher in the EH, NIDDM, and NIDDM+EH groups compared with the NT group. EH patients showed the presence of eutrophic remodeling, whereas NIDDM and NIDDM+EH patients showed 40% to 46% cell growth. The collagen-to-elastin ratio was significantly increased in the EH and NIDDM+EH groups compared with the NT group. The vasodilatation to acetylcholine and bradykinin was similarly reduced in EH, NIDDM, and NIDDM+EH groups compared with the NT group. The contractile responses to endothelin-1 were similarly reduced in EH, NIDDM, and NIDDM+EH patients. Conclusions — Our data suggest that the effects of NIDDM and EH on small artery morphology are quantitatively similar but qualitatively different and that the presence of hypertension in diabetic patients has little additive effect on small artery morphology and none on endothelial dysfunction.

Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins.

BackgroundDespite the high cardiovascular risk, evidence of efficacy of preventive strategies in individuals with diabetes is scant. In particular, recommendations on the use of aspirin in patients with diabetes mostly reflect an extrapolation from data deriving from other high risk populations. Furthermore, the putative additive effects of aspirin and statins in diabetes remain to be investigated. This aspect is of particular interest in the light of the existing debate regarding the need of multiple interventions to reduce total cardiovascular risk, which has also led to the proposal of a polypill. Aim of the study is to evaluate the efficacy of aspirin in the primary prevention of major cardiovascular events in diabetic patients candidate for treatment with statins. These preventive strategies will be evaluated on the top of the other strategies aimed at optimizing the care of diabetic patients in terms of metabolic control and control of the other cardiovascular risk factors.Methods/DesignThe ACCEPT-D is an open-label trial assessing whether 100 mg/daily of aspirin prevent cardiovascular events in patients without clinically manifest vascular disease and treated with simvastatin (starting dose 20 mg/die). Eligible patients will be randomly assigned to receive aspirin + simvastatin or simvastatin alone. Eligibility criteria: male and female individuals aged >=50 years with diagnosis of type 1 or type 2 diabetes, already on treatment with statins or candidate to start the treatment (LDL-cholesterol >=100 mg/dL persisting after 3 months of dietary advise). The primary combined end-point will include cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospital admission for cardiovascular causes (acute coronary syndrome, transient ischemic attack, not planned revascularization procedures, peripheral vascular disease). A total of 515 first events are needed to detect a reduction in the risk of major cardiovascular events of 25% (alpha = 0.05; 1-beta = 0.90). Overall, 5170 patients will be enrolled. The study will be conducted by diabetes specialists and general practitioners.DiscussionThe study will provide important information regarding the preventive role of aspirin in diabetes when used on the top of the other strategies aimed to control cardiovascular risk factors.Trial registrationCurrent Controlled Trials ISRCTN48110081.

TSH-Lowering Effect of Metformin in Type 2 Diabetic Patients: Differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients

OBJECTIVE To assess the interplay between metformin treatment and thyroid function in type 2 diabetic patients. RESEARCH DESIGN AND METHODS The acute and long-term effects of metformin on thyroid axis hormones were assessed in diabetic patients with primary hypothyroidism who were either untreated or treated with levothyroxine (L-T4), as well as in diabetic patients with normal thyroid function. RESULTS No acute changes were found in 11 patients with treated hypothyroidism. After 1 year of metformin administration, a significant thyrotropin (TSH) decrease (P < 0.001) was observed in diabetic subjects with hypothyroidism who were either treated (n = 29; from 2.37 ± 1.17 to 1.41 ± 1.21 mIU/l) or untreated (n = 18; 4.5 ± 0.37 vs. 2.93 ± 1.48) with L-T4, but not in 54 euthyroid subjects. No significant change in free T4 (FT4) was observed in any group. CONCLUSIONS Metformin administration influences TSH without change of FT4 in patients with type 2 diabetes and concomitant hypothyroidism. The need for reevaluation of thyroid function in these patients within 6–12 months after starting metformin is indicated.

Endothelial dysfunction in small resistance arteries of patients with non-insulin-dependent diabetes mellitus

Objective Arterial hypertension is frequently associated with the presence of endothelial dysfunction in human subcutaneous small resistance arteries, as evaluated by responses to acetylcholine or bradykinin; however it is not known whether patients with diabetes mellitus show similar alterations. Therefore, we have investigated endothelial function in subcutaneous arteries of normotensive subjects (NT), of patients with essential hypertension (EH), of patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as of patients with both essential hypertension and non-insulin-dependent diabetes mellitus (NIDDM + EH). Patients and methods All subjects were submitted to a biopsy of the subcutaneous fat. Small arteries were dissected and mounted on a micromyograph. The media to lumen ratio (M/L) was calculated. A concentration-response curve to acetylcholine, to bradykinin as well as to the endothelium-independent vasodilator sodium nitroprusside were performed. We also evaluated the contractile response to endothelin-1. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) plasma levels were also measured. Results The vasodilatation to acetylcholine and bradykinin (but not to sodium nitroprusside) was significantly and similarly reduced in EH, in NIDDM, and in NIDDM + EH compared with NT. The contractile response to endothelin-1 was similarly reduced in EH, in NIDDM and in NIDDM + EH. Plasma ICAM-1 and VCAM-1 concentrations were higher in EH, NIDDM and NIDDM + EH than in NT. Conclusions An evident endothelial dysfunction was detected in patients with NIDDM, and the simultaneous presence of EH did not seem to exert an additive effect. The contractile responses to endothelin-1 were reduced possibly as a consequence of ETA receptor down-regulation.

Baseline quality of care data from a quality improvement program implemented by a network of diabetes outpatient clinics

OBJECTIVE—To describe patterns of diabetes care and implement benchmarking activities at the national level. RESEARCH DESIGN AND METHODS—A total of 86 clinics participated, all using electronic medical records. Quality indicators were identified, and software was developed, enabling the extraction of the information needed for quality-of-care profiling. RESULTS—Overall, 114,249 patients with type 2 diabetes were seen during 2004. A1C was measured at least once in 88.0% of the patients, lipid profile in 64.6%, blood pressure in 77.2%, and microalbuminuria in 48.1%. Overall, 43.1% of individuals had A1C ≤7.0%, 36.6% had blood pressure ≤130/85 mmHg, and 29.8% had LDL cholesterol <100 mg/dl. Only 5.5% of the patients had achieved all the favorable outcomes. Wide between-center variation was documented for all indicators. CONCLUSIONS—This study is the first step of a nationwide quality-improvement effort and documents the possibility of obtaining standardized information to be used for diabetes care profiling and benchmarking activities.

THYREOTROPIN LEVELS IN DIABETIC PATIENTS ON METFORMIN TREATMENT

OBJECTIVE A retrospective study to evaluate the changes in TSH concentrations in diabetic patients treated or not treated with metformin and/or L-thyroxine (L-T(4)). METHODS Three hundred and ninety three euthyroid diabetic patients were divided into three groups on the basis of metformin and/or L-T(4) treatment: Group (M-/L-), 119 subjects never treated with metformin and L-T(4); Group (M+/L-), 203 subjects who started metformin treatment at recruitment; and Group (M+/L+), 71 patients on L-T(4) who started metformin recruitment. RESULTS The effect of metformin on serum TSH concentrations was analyzed in relation to the basal value of TSH (below 2.5 mIU/L (Q1) or between 2.51 and 4.5 mIU/L (Q2)). In patients of group M+/L+, TSH significantly decreased independently from the basal level (Q1, from 1.450.53 to 1.011.12 mU/L (P=0.037); Q2, from 3.600.53 to 1.910.89 mU/L (P<0.0001)). In M+/L group, the decrease in TSH was significant only in those patients with a basal high-normal serum TSH (Q2: from 3.24±0.51 to 2.27±1.28 mU/l (P=0.004)); in M-/L- patients, no significant changes in TSH levels were observed. In patients of group M+/L showing high-normal basal TSH levels, a significant decrease in TSH was observed independently from the presence or absence of thyroid peroxidase antibodies (ABTPO; Q2 ABTPO +: from 3.38±0.48 to 1.87±1.08 mU/l (P<0.001); Q2 AbTPO -: from 3.21±0.52 to 2.34±1.31 mU/l (P<0.001)). CONCLUSIONS These data strengthen the known TSH-lowering effect of metformin in diabetic patients on L-T(4) treatment and shows a significant reduction of TSH also in euthyroid patients with higher baseline TSH levels independently from the presence of AbTPO.

Four‐year impact of a continuous quality improvement effort implemented by a network of diabetes outpatient clinics: the AMD‐Annals initiative

Diabet. Med. 27, 1041–1048 (2010)

Predicting the risk of diabetic retinopathy in type 2 diabetic patients.

AIMS Diabetic retinopathy (DR) is often asymptomatic even in its more advanced stages. Timely and repeated screening for DR avoids a late diagnosis of DR, but the high number of diabetic patients precludes a frequent screening; thus, the need for a method to identify patients at higher risk for DR becomes crucial. METHODS A prospective analysis of 5034 type 2 diabetic patients followed from 1996 to 2007 and not affected by retinopathy at the time of the recruitment was performed. Patients were randomly divided (ratio 2:1) into two groups: the train data set and the test set (3327 and 1707 patients, respectively). Factors associated with the occurrence of DR were assessed by the Coxs proportional hazard model. RESULTS Duration of diabetes, glycosylated hemoglobin, systolic blood Pressure, male gender, albuminuria and diabetes therapy other than diet were all significantly associated with the occurrence of DR. CONCLUSIONS The nomogram could help in ranking the type 2 diabetic patients at higher risk to develop DR and thus with a need for more frequent ophthalmologic checks, without enhancing neither the time nor the costs.

Quality of diabetes care predicts the development of cardiovascular events: results of the AMD-QUASAR study.

OBJECTIVE The QUASAR (Quality Assessment Score and Cardiovascular Outcomes in Italian Diabetes Patients) study aimed to assess whether a quality-of-care summary score predicted the development of cardiovascular (CV) events in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In 67 diabetes clinics, data on randomly selected patients were extracted from electronic medical records. The score was calculated using process and outcome indicators based on monitoring, targets, and treatment of A1C, blood pressure, LDL cholesterol, and microalbuminuria. The score ranged from 0 to 40. RESULTS Overall, 5,181 patients were analyzed; 477 (9.2%) patients developed a CV event after a median follow-up of 28 months. The incidence rate (per 1,000 person-years) of CV events was 62.4 in patients with a score of <15, 41.0 in those with a score between 20 and 25 and 36.7 in those with a score of >25. Multilevel analysis, adjusted for clustering and case-mix, showed that the risk to develop a new CV event was 84% higher in patients with a score of <15 (incidence rate ratio [IRR] = 1.84; 95% confidence interval [CI] 1.29–2.62) and 17% higher in those with a score between 15 and 25 (IRR = 1.17; 95% CI 0.93–1.49) compared with those with a score of >25. Mean quality score varied across centers from 16.5 ± 7.5 to 29.1 ± 6.3. When the score was tested as the dependent variable, it emerged that 18% of the variance in the score could be attributed to setting characteristics. CONCLUSIONS Our study documented a close relationship between quality of diabetes care and long-term outcomes. A simple score can be used to monitor quality of care and compare the performance of different centers/physicians.

Obesity and changes in urine albumin/creatinine ratio in patients with type 2 diabetes: The DEMAND Study

BACKGROUND AND AIMS Obesity is a potential risk factor for renal disease in non-diabetic subjects. It remains unclear whether this also applies to diabetic patients. We investigated whether obesity predicted changes in albumin excretion rate in individuals with type 2 diabetes. METHODS AND RESULTS Fifty Italian diabetes outpatient clinics enrolled a random sample of 1289 patients. A morning spot urine sample was collected to determine urinary albumin/creatinine ratio (ACR) at baseline and after 1 year from the study initiation. Progression of albumin excretion was defined as a doubling in ACR, while regression was defined as a 50% reduction. Multivariate logistic regression analyses were used to evaluate correlates of these outcomes. Data are expressed as odds ratios (OR) with 95% confidence intervals (CI). The risk of progression increased by 7% (OR=1.07; 95%CI 1.00-1.15) for every 5-cm increase in waist circumference measured at baseline, and by 17% (OR=1.17; 95%CI 1.03-1.33) for every one-unit increase in BMI during follow-up. The likelihood of regression was not independently associated with any of the variables investigated. The effect of obesity on progression of ACR was independent of metabolic control, blood pressure, treatment, and baseline level of albumin excretion. CONCLUSIONS We found a tight link between obesity and changes in albumin excretion in diabetic subjects, suggesting potential benefits of interventions on body weight on end-organ renal damage.