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Background and Aim: Fibrosis-4 (FIB-4) index is a widely used test for non-invasively assessing liver fibrosis. We aimed to investigate the association between FIB-4 index and risk of all-cause mortality in patients at high cardiovascular (CV) risk and to determine whether coexisting renal dysfunction mediates this association., Methods and Results: Single-center prospective study of 994 patients with established or suspected coronary artery disease undergoing coronary angiography, followed for a median of 44 months. Mortality data were obtained through the Italian Health Card Database. At baseline, the median FIB-4 index was greater in deceased vs. alive patients (1.71 vs. 1.38, p < 0.001) and in those with reduced eGFR than in those with normal eGFR (1.65 vs. 1.37, p < 0.001). For each unit increase in the baseline log-FIB-4 index, the risk of all-cause mortality sharply increased during the follow-up (hazard ratio [HR] 2.31, 95%CI 1.31-4.08, p = 0.004). Similarly, assuming the lowest baseline FIB-4 risk category as the reference, the risk of all-cause mortality progressively increased across the indeterminate (HR 1.82, 95%CI 1.18-2.82, p = 0.007) and the highest baseline FIB-4 risk categories (HR 2.33, 95%CI 1.37-3.97; p = 0.002). A causal mediation analysis showed that about one-third of the effect of FIB-4 index on mortality risk was mediated by reduced eGFR (32.8 %, p = 0.01)., Conclusions: Increased FIB-4 index predicts the long-term risk of all-cause mortality in patients at high CV risk, and this risk is, at least in part, mediated by reduced eGFR. Further prospective studies are needed to confirm these findings., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To estimate the incidence of psoriatic arthritis (PsA) in patients with psoriasis who had received a continuous treatment with biological disease-modifying antirheumatic drugs (bDMARDs) compared with phototherapy., Methods: A retrospective non-randomised study involving patients with moderate-to-severe plaque psoriasis, who were prescribed at least 5 years of bDMARDs or at least three narrow-band ultraviolet light B (nb-UVB) phototherapy courses, and did not have a diagnosis of PsA at enrolment. Development of PsA in each patient was assessed by a rheumatologist according to the Classification for Psoriatic Arthritis criteria. The annual and cumulative incidence rate of PsA was estimated by using an event per person-years analysis. Cox proportional hazards models were undertaken to assess the hazard risk (HR) of PsA after adjustment for confounders., Results: A total of 464 psoriatic patients (bDMARDs, n=234 and nb-UVB, n=230) were followed between January 2012 and September 2020 (corresponding to 1584 and 1478 person year of follow-up for the two groups, respectively). The annual incidence rate of PsA was 1.20 cases (95% CI 0.77 to 1.89) versus 2.17 cases (95% CI 1.53 to 3.06) per 100 patients/year in the bDMARDs versus phototherapy group, respectively (HR 0.29, 0.12-0.70; p=0.006). The variables independently associated with higher risk of PsA were older age (adjusted HR 1.04, 1.02-1.07), nail psoriasis (adjusted HR 3.15, 1.63-6.06) and psoriasis duration >10 years (adjusted HR 2.02, 1.09-3.76); notably, bDMARDs treatment was associated with a lower risk of incident PsA (adjusted HR 0.27, 0.11-0.66)., Conclusions: bDMARDs treatment may delay or reduce the risk of incident PsA in patients with moderate-to-severe chronic plaque psoriasis., Competing Interests: Competing interests: PG has been a consultant and/or speaker for Abbvie, Almirall, Amgen, Janssen, Leo-pharma, Eli Lilly, Novartis, Pierre Fabre, Sandoz, Sanofi, and UCB. LI served as consultant and/or speaker for AbbVie, Amgen, Biogen, Merck Sharp & Dohme, Eli-Lilly, Novartis, Celgene, Sandoz. GG served as consultant and/or speaker for AbbVie, Abiogen, Almirall, Amgen, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Celltrion, Eli-Lilly, Genzyme, Leo Pharma, Novartis, OM Pharma, Pfizer, Regeneron, Samsung Sanofi and UCB., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (CVD) and mortality. Many factors are implicated in the pathogenesis of CVD in patients with T2DM. Among the factors involved, chronic hyperglycemia and the cluster of CVD risk factors, such as dyslipidemia, hypertension, and obesity, play a major role. For many years, the control of hyperglycemia has been complicated by the fact that the use of many available drugs was associated with an increased risk of hypoglycemia. Paradoxically, hypoglycemia per se represents a risk factor for CVD. Recently, new drugs for the control of hyperglycemia have become available: many of them can determine a good control of hyperglycemia with minor risks of hypoglycemia. Among these new classes of drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer many advantages. In addition to a strong anti-hyperglycemic action, they possess the ability to act on body weight and other relevant risk factors for CVD. Consistently, some of the GLP-1RAs have demonstrated, in RCT designed to assess their safety, to reduce the risk of major adverse cardiovascular events. Furthermore, GLP-1RAs possess properties useful to treat additional conditions, as the capability of improving liver damage in patients with NAFLD or NASH, highly prevalent conditions in people with T2DM. In this document, written by experts of the Italian diabetes society (SID), we will focus our attention on the therapy with GLP-1RAs in patients with T2DM, particularly on the effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH and CVD prevention., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI., Methods: We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs., Results: MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide., Conclusion: About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D., (© 2021. Italian Society of Endocrinology (SIE).)

Background and Aim: The association between non-alcoholic fatty liver (NAFL) and the variant rs641738 within the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene is currently uncertain, especially in the paediatric population. We examined whether there is an association between this genetic variant and NAFL in a large multicentre, hospital-based cohort of Italian overweight/obese children., Methods and Results: We studied 1760 overweight or obese children [mean age (SD): 11.1(2.9) years, z-body mass index (zBMI) 3.2(0.9)], who underwent ultrasonography for the diagnosis of NAFL. A subgroup of these children (n = 182) also underwent liver biopsy. Genotyping of the MBOAT7 rs641738 polymorphism was performed by TaqMan-Based RT-PCR system in each subject. Overall, 1131 (64.3%) children had ultrasound-detected NAFL; 528 (30%) had rs641738 CC genotype, 849 (48.2%) had rs641738 CT genotype, and 383 (21.8%) had rs641738 TT genotype, respectively. In the whole cohort, the interaction of MBOAT7 genotypes with zBMI was not associated with NAFL after adjustment for age, sex, serum triglycerides, serum alanine aminotransferase levels and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genotype (adjusted-odds ratio 1.02 [95% CI 0.98-1.06]). Similarly, no association was found between MBOAT7 genotypes and NAFL after stratification by obesity status. MBOAT7 genotypes were not associated with the presence of non-alcoholic steatohepatitis or the stage of liver fibrosis in a subgroup of 182 children with biopsy-proven NAFLD., Conclusions: The results of this study did not show any significant contribution of MBOAT7 rs641738 polymorphism to the risk of having either NAFL on ultrasonography or NASH on histology in a large hospital-based cohort of Italian overweight/obese children., Competing Interests: Declaration of competing interest The Authors have no potential conflicts of interest to disclose., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

All vitamin D tests carried out for outpatients aged 18 years or older during the last 3 years at an Italian University Hospital was reviewed. The serum vitamin D concentrations measured since the Italian coronavirus diseases 2019 (COVID-19) lockdown to present did not significantly differ from the previous 2 years (78 vs. 77 nmol/l; P = 0.277), whilst the prevalence of vitamin D deficiency was found to be even marginally lower in 2020 (16.0% vs. 17.9%; P = 0.003). These results suggest that vitamin D deficiency in our province has not increased during the Italian COVID-19 outbreak or in correspondence with the nationwide lockdown., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD., Aims: We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors., Methods: We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system., Results: The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75-0.88] vs. 0.77 [0.70-0.84] without SNPs; p = 0.047)., Conclusions: NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Purpose: Increased arterial stiffness is an early sign of endothelial dysfunction. Nevertheless, measures of the elastic properties of the aortic root in patients with type 1 diabetes are still lacking. The aim of this study was to compare aortic root stiffness index in type 1 diabetes and healthy controls., Methods: Ninety-three patients with type 1 diabetes without cardiovascular diseases were recruited and compared to 33 healthy controls. Aortic root elastic properties were estimated by measuring the systolic and diastolic diameters on M-mode acquisition., Results: None of the subjects showed alterations of either systolic or diastolic echocardiographic parameters. Patients with type 1 diabetes had a very low prevalence of chronic complications and their metabolic control was good. Significantly increased aortic stiffness index was found in type 1 diabetes compared to controls, and the same different pattern was found in men and women. The presence of type 1 diabetes and increased pulse pressure was significantly associated with aortic stiffness index in a multivariate linear analysis., Conclusion: This study strongly suggests that patients with type 1 diabetes develop aortic root stiffness in the absence of cardiovascular diseases. This alteration may be part of a more generalized arterial dysfunction in type 1 diabetes.

Objective: To compare different methods assessing the burden of cardiovascular mortality in diabetes mellitus, which is usually underestimated by standard mortality statistics based on the underlying cause of death., Patients and Methods: All residents in the Veneto Region (Italy) aged 30-89 years with co-payment exemption for diabetes in January 2010 (n=185,341) were identified and linked with mortality records (2010-2015). The underlying causes of death, as well as all the diseases mentioned in the death certificate (multiple causes), were extracted. The standardized mortality ratios (SMR) were computed with regional rates as a reference., Results: After grouping diabetes and circulatory diseases as the underlying cause of death, the mortality rates were highly increased, especially among patients aged 30-54 years: SMR 4.24 (95% confidence interval 3.57-5.00) and 9.84 (7.47-12.72) in males and females, respectively. After re-assignment of the underlying cause in deaths from diabetes, the percentage of overall mortality caused by circulatory diseases increased from 33.8% to 41.7%. Based on multiple causes, the risk of death was increased for several cardiovascular diseases, including causes rarely emerging from standard mortality statistics such as atrial fibrillation/flutter., Conclusions: The re-assignment of the underlying cause and the analyses of the multiple causes of death allowed to estimate the whole burden of mortality associated with cardiovascular diseases.

Background: The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure (HF) has been investigated in observational registries and clinical trials, but the results have been often inconclusive. We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial., Clinical Trial Registration: CLINICALTRIALS., Gov Identifier: NCT00336336., Methods: We assessed the rates of all-cause death, cardiovascular death, cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF., Results: Patients in the 3rd serum uric acid tertile (>7.2 mg/dl) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death, and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile (<5.7 mg/dl). Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly. The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors, HF etiology, left ventricular ejection fraction, medication use and other potential confounders, with an adjusted hazard ratio of 1.37 (95% CI 1.22-1.55) for all-cause death, 1.48 (1.29-1.69) for cardiovascular death, 1.19 (1.09-1.30) for cardiovascular hospitalization and 1.21 (1.11-1.31) for the composite endpoint, respectively., Conclusions: Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aims: To investigate the risk of mortality from infections by comparing the underlying causes of death versus the multiple causes of death in known diabetic subjects living in the Veneto region of Northern Italy., Methods and Results: A total of 185,341 subjects with diabetes aged 30-89 years were identified in the year 2010, and causes of death were assessed from 2010 to 2015. Standardized Mortality Ratios (SMRs) with 95% confidence intervals (CIs) were computed with regional mortality rates as reference. The underlying causes of death and all the diseases reported in the death certificates were scrutinized. At the end of the follow-up, 36,382 subjects had deceased. We observed an increased risk of death from infection-related causes in subjects with diabetes with a SMR of 1.83 (95% CI, 1.71-1.94). The SMR for death from septicemia was 1.91 (95% CI, 1.76-2.06) and from pneumonia was 1.47 (95% CI, 1.36-1.59). The use of the multiple causes of death approach emphasized the association of infectious diseases with mortality., Conclusion: The results of the present study demonstrate an excess mortality due to infection-related diseases in patients with diabetes; more interestingly, by routine mortality analyses, the results show a possible underestimation of the effect of these diseases on mortality., (Copyright © 2017. Published by Elsevier B.V.)

Aims: Several studies have reported that moderately elevated serum uric acid levels are associated with an increased risk of tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus (T2DM). It is currently unknown whether an association also exists between elevated serum uric acid levels and cardiac conduction defects in patients with T2DM., Methods: We retrospectively analyzed a hospital-based sample of 967 patients with T2DM discharged from our Division of Endocrinology over the years 2007-2014. Standard electrocardiograms were performed on all patients and were interpreted by expert cardiologists., Results: Overall, 267 (27.6%) patients had some type of conduction defects on electrocardiograms (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block). Patients in the 3rd serum uric acid tertile had a higher prevalence of any cardiac conduction defects than those belonging to 2nd or 1st tertile, respectively (35.8% vs. 25.0% vs. 22.6%; p<0.0001). Elevated serum uric acid levels were associated with a nearly twofold increased risk of cardiac conduction defects after adjustment for age, sex, hemoglobin A1c, diabetes duration, metabolic syndrome, chronic kidney disease, chronic obstructive pulmonary disease, ischemic heart disease, valvular heart disease and medication use (adjusted-odds ratio 1.84, 95% confidence intervals 1.2-2.9; p=0.009)., Conclusions: Moderately elevated serum uric acid levels are associated with an increased prevalence of any cardiac conduction defects in hospitalized patients with T2DM, independent of multiple risk factors and potential confounding variables., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Although diabetes mellitus is frequently associated with heart failure (HF), the association between elevated admission glucose levels and adverse outcomes has not been well established in hospitalized patients with acute HF., Methods: We prospectively evaluated in-hospital mortality, post-discharge 1-year mortality and 1-year re-hospitalization rates in the Italian Network on Heart Failure (IN-HF) Outcome registry cohort of 1776 patients hospitalized with acute HF and stratified by their admission glucose levels (i.e., known diabetes, newly diagnosed hyperglycemia, no diabetes)., Results: Compared with those without diabetes (n = 586), patients with either known diabetes (n = 749) (unadjusted-odds ratio [OR] 1.64, 95%CI 0.99–2.70) or newly diagnosed hyperglycemia (n = 441) (unadjusted-OR 2.34, 95%CI 1.39–3.94) had higher in-hospital mortality, but comparable post-discharge 1-year mortality rates. After adjustment for age, sex, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, HF etiology and HF worsening/de novo presentation, the results remained unchanged in patients with known diabetes (adjusted-OR 1.86, 95%CI 1.01–3.42), while achieved borderline significance in those with newly diagnosed hyperglycemia (adjusted-OR 1.81, 95%CI 0.95–3.45). One-year re-hospitalization rates were lower in patients with newly diagnosed hyperglycemia (adjusted-hazard ratio 0.74, 95%CI 0.56–0.96) than in other groups., Conclusions: Elevated admission blood glucose levels are associated with poorer in-hospital survival outcomes in patients with acute HF, especially in those with previously known diabetes. This finding further highlights the importance of tight glycemic control during hospital stay and address the need of dedicated intervention studies to identify customized clinical protocols to improve in-hospital survival of these high-risk patients.

Background and Aims: Type 2 diabetes, one of the most important non-communicable diseases, represents a major health problem worldwide. Immigrants may contribute relevantly to the increase in diabetes. The aim of the study was to investigate variability in diabetes prevalence across different immigrant groups in the Veneto Region (northeastern Italy)., Methods and Results: Diabetic subjects on January 2013 were identified by record linkage of hospital discharge records, drug prescriptions, and exemptions from medical charges for diabetes. Immigrant groups were identified based on citizenship. Age-standardized prevalence rates were obtained for residents aged 20-59 years by the direct method, taking the whole regional population as reference. Prevalence rate ratios (RR) with 95% Confidence Intervals (CI) were computed with respect to Italian citizens. Among residents aged 20-59 years, 45280 Italian and 7782 foreign subjects affected by diabetes were identified. Prevalence rates were highest among immigrants from South-East Asia, RR 4.9 (CI 4.7-5.1) among males, and 7.6 (7.2-8.1) among females, followed by residents from both North and Sub-Saharan Africa. Citizens from Eastern Europe (the largest immigrant group) showed rates similar to Italians. Most South-Asian patients aged 20-39 years were not insulin-treated, suggesting a very high risk of early onset type 2 diabetes in this ethnic group., Conclusion: Large variations in diabetes prevalence by ethnicity should prompt tailored strategies for primary prevention, diabetes screening, and disease control. An increased demand for prevention and health care in selected population groups should guide appropriate resource allocation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Mortality from chronic liver diseases (CLDs) is increased in diabetes, but little is known about the etiology. The aim of this study was to assess mortality rates from CLD by etiology in known diabetic subjects living in the Veneto Region, Northern Italy., Methods: A total of 167,621 diabetic subjects, aged 30-89 years (54.6% men), were identified in the year 2007 and their vital status was assessed between 2008 and 2010. Standardized mortality ratios (SMR) with 95% confidence intervals (CIs) were computed with regional mortality rates as reference. The underlying cause of death and all comordidities reported on the certificate were scrutinized in order to identify CLD deaths and their main etiologies. The latter were grouped into the following three categories: (i) virus-related, (ii) alcohol-related, and (iii) non-virus, non-alcohol-related (mainly represented by nonalcoholic fatty liver disease, NAFLD)., Results: Analyses were based upon 473,374 person-years of follow-up and 17,134 deaths. We observed an increased risk of dying from CLD in diabetic subjects with an SMR of 2.47 (95% CI=2.19-2.78) in men and 2.70 (2.24-3.23) in women. SMRs were 2.17 (1.90-2.47), 2.25 (1.98-2.54), and 2.86 (2.65-3.08) for virus-related, alcohol-related, and non-virus, non-alcohol-related CLD, respectively., Conclusions: Diabetic patients have a twofold to threefold higher risk of dying of CLD, mainly associated with a non-virus and non-alcohol-related etiology, which is largely attributable to NAFLD. An early diagnosis and treatment of NAFLD, if any, may have a beneficial clinical impact on the survival of diabetic patients.

The association between serum uric acid (SUA) levels and atrial fibrillation (AF) is currently poorly known. We examined the association between SUA levels and risk of incident AF in patients with type 2 diabetes mellitus. We followed for 10 years a random sample of 400 type 2 diabetic outpatients, who were free from AF at baseline. A standard 12-lead electrocardiography was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. Over 10 years, there were 42 incident AF cases (cumulative incidence of 10.5%). Elevated SUA level was associated with an increased risk of incident AF (odds ratio 2.43, 95% confidence interval 1.8 to 3.4, p <0.0001 for each 1-SD increase in SUA level). Adjustments for age, gender, body mass index, hypertension, chronic kidney disease, electrocardiographic features (left ventricular hypertrophy and PR interval), and use of diuretics and allopurinol did not attenuate the association between SUA and incident AF (adjusted odds ratio 2.44, 95% confidence interval 1.6 to 3.9, p <0.0001). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Results remained unchanged even when SUA was modeled as a categorical variable (stratifying by either SUA median or hyperuricemia), and when patients with previous coronary heart disease or heart failure were excluded from analysis. In conclusion, our findings suggest that elevated SUA levels are strongly associated with an increased incidence of AF in patients with type 2 diabetes mellitus even after adjustment for multiple clinical risk factors for AF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes., Research Design and Methods: We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2))., Results: During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71-3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA(1c), eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16-3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD., Conclusions: In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.

Background and Aims: To assess all-cause and cardiovascular mortality in type 2 diabetic individuals according to estimated glomerular filtration rate (eGFR) and albuminuria., Methods and Results: We followed 2823 type 2 diabetic outpatients for a median period of 6 years for the occurrence of all-cause and cardiovascular mortality. eGFR was estimated using the abbreviated Modification of Diet in Renal Disease study equation. At baseline, an eGFR < 60 ml/min/1.73 m² and abnormal albuminuria were present in 22.5% and 26.0% of participants, respectively. During follow-up, a total of 309 patients died, 53% of deaths were secondary to cardiovascular causes. Risks of all-cause and cardiovascular mortality increased progressively with decreasing eGFR and increasing albuminuria. After adjustment for age, sex, body mass index, smoking, hypertension, diabetes duration, hemoglobin A1c, plasma lipids, medications use (hypoglycemic, anti-hypertensive, anti-platelet or lipid-lowering drugs) and albuminuria, the hazard ratios of all-cause and cardiovascular mortality per 1-SD decrease in eGFR were 1.53 (95%CI 1.2-2.0; p < 0.0001) and 1.51 (95%CI 1.05-2.2; p=0.023), respectively. A similar pattern in the risk of all-cause and cardiovascular mortality was seen for albuminuria (1.14, 1.01-1.3, p=0.028 and 1.19, 1.01-1.4, p=0.043 per 1-SD increase in albuminuria, respectively) after adjustment for eGFR and other potential confounders., Conclusions: These findings suggest that both decreasing eGFR and rising albuminuria are associated with all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of traditional risk factors and diabetes-related variables., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Objective: An increased level of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been identified as an independent predictor for cardiovascular events in the general population and in some groups of high-risk patients, such as type 2 diabetes. The aim of this study was to evaluate whether a high TG/HDL-C ratio is associated with an increased risk of all-cause and cardiovascular mortality in type 2 diabetic subjects, and whether this risk is modified by the presence of kidney dysfunction., Methods: We followed 3084 type 2 diabetic outpatients for a mean period of 4.9 years for the occurrence of mortality. The independent association between the TG/HDL-C ratio and all-cause and cardiovascular mortality was analyzed by Cox proportional hazard models and adjusted for several potential confounders, including kidney function measures., Results: During follow-up, 356 (12%) participants died, 46% of whom from cardiovascular causes. Higher TG/HDL-C ratio (third vs. first tertile) was associated with an increased hazard ratio of all-cause (hazard ratio 1.51, CI 95% 1.13-2.00, p=0.005) and cardiovascular (hazard ratio 1.70, 1.12-2.59, p=0.015) mortality after adjustment for traditional risk factors, body mass index, hemoglobin A1c and medication use. After additional adjustment for renal function measures (estimated glomerular filtration rate or albuminuria), the association between the TG/HDL-C ratio and the risk of mortality was abolished., Conclusion: Our findings suggest that the predictive role of a high TG/HDL-C ratio in type 2 diabetes on cardiovascular and all-cause mortality might be largely mediated by the presence of kidney dysfunction., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Elevated levels of uric acid in serum (SUA) or plasma (PUA) are increasingly related to cardiovascular disease. It is unclear whether they are independent risk factors or simply markers, reflecting association with other traditional risk factors., Methods: We retrospectively assessed results of a lipid profile, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol to HDL-C ratio (TC/HDL-C), the atherogenic index of plasma (AIP), and lipoprotein(a) (Lp[a]), in a large cohort of unselected adult outpatients., Results: Hyperuricemic men displayed significantly increased values of triglycerides and AIP when compared with men with normal PUA levels. In hyperuricemic women, significant differences were observed for HDL-C, triglycerides, TC/HDL-C, and AIP compared with women with normal PUA levels. The percentage of patients with unfavorable values was statistically higher for triglycerides and AIP in hyperuricemic men; for HDL-C, triglycerides, TC/HDL-C, and AIP in hyperuricemic women. In multivariable linear regression analysis triglycerides, AIP, and TC/HDL-C were independently associated with PUA in women, whereas no significant association was observed in men., Conclusion: PUA measurement might be advisable in patients to identify those at increased risk of cardiovascular disease (CVD) who might benefit from further triage and intervention., (Copyright 2010 Wiley Periodicals, Inc.)

Background: Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long-term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients., Methods: Fasting glycaemia, BMI and pulse pressure values were collected over a period of 3 years in 1 319 type 2 diabetic patients who were subsequently followed up for 10 years. For each patient, the means and the coefficients of variation of fasting glycaemia, BMI and pulse pressure were computed. The adverse impact of these risk factors on total mortality was assessed in patients aged < 65 years (n = 565) and in those aged > or = 65 years (n = 754), separately., Results: During the 10 years of follow-up, 438 patients died. In younger diabetic patients, the means of fasting glycaemia [hazard ratio (HR) of III tertile versus I tertile = 2.11, 95% confidence interval (CI): 1.22-3.64], BMI (HR = 1.88, 1.12-3.14) and pulse pressure (HR = 2.36, 1.34-4.16) were independently associated with total mortality, while in older patients they were not. In contrast, the coefficients of variation of glycaemia (HR = 1.56, 1.17-2.08), BMI (HR = 1.34, 1.03-1.75) and pulse pressure (HR = 1.34, 1.03-1.74) independently predicted total mortality only in older patients., Conclusions: Our findings suggest that the variability of fasting glycaemia, body weight and blood pressure (BP) is independently associated with an increased risk of all-cause mortality in older type 2 diabetic patients. Future studies are required to confirm the reproducibility of our findings., (Copyright 2008 John Wiley & Sons, Ltd.)

It is unknown whether chronic kidney disease (CKD) is associated with nonalcoholic fatty liver disease among patients with type 2 diabetes. We followed 1760 outpatients with type 2 diabetes and normal or near-normal kidney function and without overt proteinuria for 6.5 yr for the occurrence of CKD (defined as overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m(2)). During follow-up, 547 participants developed incident CKD. Nonalcoholic fatty liver disease, diagnosed by liver ultrasound and exclusion of other common causes of chronic liver disease, was associated with a moderately increased risk for CKD (hazard ratio 1.69; 95% confidence interval 1.3 to 2.6; P < 0.001). Adjustments for gender, age, body mass index, waist circumference, BP, smoking, diabetes duration, glycosylated hemoglobin, lipids, baseline estimated GFR, microalbuminuria, and medications (hypoglycemic, lipid-lowering, antihypertensive, or antiplatelet drugs) did not appreciably attenuate this association (hazard ratio 1.49; 95% confidence interval 1.1 to 2.2; P < 0.01). In conclusion, our findings suggest that nonalcoholic fatty liver disease is associated with an increased incidence of CKD in individuals with type 2 diabetes, independent of numerous baseline confounding factors.

Although macrocytosis might occur with frequency in patients with thyroid disorders, there is controversial information on the metabolic relationship between thyroid stimulating hormone (TSH), folic acid and B12 in the general population. We performed a retrospective analysis to retrieve results of serum folic acid, B12, and TSH performed on consecutive outpatients referred by general practitioners for routine blood testing over the last 2 years. A positive, significant trend towards increased values of folic acid, but not of B12, could be observed across the spectrum of TSH values suggestive for hypo- and hyperthyroidism. However, the prevalence of subjects with folic acid or B12 deficiency did not differ significantly among the subgroups of subjects. In multivariable linear regression analysis folic acid, but not B12, was associated with TSH levels. These results do not support the routine screening for either B12 or folic acid deficiency in subjects with subclinical disturbances of thyroid function, though we can not rule out that it might still be useful in patients with overt thyroid dysfunction.

The prevalence of atherosclerotic cardiovascular disorders is constantly increasing worldwide, and the aging of the population will make this trend rather unlikely to be reversed. It is a diffuse, systemic, chronic disorder that starts early in childhood and progresses asymptomatically throughout the adult life. Later in life, it is clinically manifested as coronary artery disease, stroke, transient ischemic attack and peripheral occlusive arterial disease. The notions on the pathogenesis have been almost revolutionized over the past decades and over 300 risk factors have been associated with genesis, progression and complication of this challenging disorder. Particularly, biochemical risk factors and markers play a crucial role in all steps of atherosclerosis process, and entail a great relevance in risk stratification and early prevention.

Background: Population-based epidemiological studies have shown a convincing association between increased gamma-glutamyltransferase (GGT) activity and components of the metabolic syndrome, type 2 diabetes, hypertension, ischaemic stroke and myocardial infarction. However, little information is available on the interaction between GGT activity and traditional or emerging markers of cardiovascular risk., Methods: We performed a retrospective analysis to retrieve results of serum GGT, fasting plasma glucose (FPG), creatinine, LDL-cholesterol, HDL-cholesterol, triglycerides and lipoprotein(a) tests performed on outpatients referred by the general practitioners to our laboratory for routine blood testing during the last 5 years., Results: The concentrations of most lipid parameters varied with increasing GGT activities. There were graded, positive, associations of GGT concentrations with LDL-cholesterol, triglycerides, atherogenic index of plasma (AIP) and the total to HDL-cholesterol ratio, whereas a negative association was observed with HDL-cholesterol. Lipoprotein(a) concentrations increased in parallel with GGT activity, though such trend did not reach statistical significance. The frequencies of subjects with undesirable values according to the NCEP-ATP III and AHA/ACC thresholds increased across the spectrum of GGT thresholds for all lipids parameters but lipoprotein(a). These associations remained statistically significant even after adjustment for gender, age, FPG and creatinine concentrations. In multiple linear regression analyses GGT activity predicted plasma concentrations of LDL-cholesterol, triglycerides, HDL-cholesterol (negatively), AIP and the total to HDL-cholesterol ratio independently of age, gender, impaired fasting glucose/diabetes and creatinine levels., Conclusions: The results of this large retrospective study indicate that increased GGT activities are independently associated with a more atherogenic lipid profile in general population.

The associations between fasting plasma insulin concentration and risk factors for cardiovascular disease were examined in 979 18-year-old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. Body mass index (BMI), waist-to-hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high-density lipoprotein (HDL)-total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low-density lipoprotein cholesterol, concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F = 7.1; P < 0.001). However, systolic blood pressure and uric acid were close to statistical significance (P = 0.06-0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e, three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F = 4.0; P < 0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides.

The aim of this work was to evaluate whether hyperuricaemia correlates with the cluster of metabolic and haemodynamic disorders closely associated with insulin resistance syndrome (IRS) in young apparently healthy individuals also, and, if so, whether hyperinsulinaemia itself or some other component of this syndrome, are independently associated with hyperuricaemia. The subjects were a random population sample of 181 (M = 94/F = 87) 38-year-old apparently healthy subjects, non-diabetic, without a history of gout. Obesity (overall and regional), serum lipid profile, uric acid, fasting glucose and insulin, 2 h insulin after glucose-load (only in men), blood pressure and main behavioural variables were measured. As expected, most parameters were statistically different between men and women. In particular, serum uric acid levels were significantly higher in the male group than in female group (348 +/- 59 mumol l-1 vs 277 +/- 59 mumol l-1, P < 0.0001). After adjustment for sex, in pooled individuals, serum uric acid concentration showed positive associations with BMI (r = 0.21; P < 0.001), waist/hip girth (WHR; r = 0.45; P < 0.0001), waist/thigh girth (WTR; r = 0.35; P < 0.0001) and subscapula/triceps skinfold ratios (STR; r = 0.30; P < 0.001). Furthermore, serum uric acid was also positively correlated with fasting insulin (r = 0.23; P < 0.001), serum triglycerides (r = 0.34; P < 0.0001), LDL cholesterol (r = 0.16; P = < 0.01), diastolic blood pressure (r = 0.26; P < 0.001), and negatively with HDL/total cholesterol ratio (r = 0.28; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)