Body weight variability and the risk of liver-related outcomes in type 2 diabetes and steatotic liver disease: a cohort study.

OBJECTIVE: The objective of this study was to evaluate the effects of body weight variability (BWV) on the occurrence of adverse liver outcomes in individuals with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A total of 549 patients with T2D and MASLD had BWV parameters assessed during the first 2 years of follow-up. The associations between increasing BWV and liver outcomes (clinical cirrhosis or a liver stiffness measurement on transient elastography > 15 kPa, performed after a median of 7 years of cohort entry) were examined by multivariable logistic regressions. Interaction/subgroup analyses were performed according to participants' physical activity during the initial 2-year period. RESULTS: Individuals were followed up for an additional median 9.7 years, over which 34 liver outcomes occurred (14 with clinical cirrhosis and 20 with liver stiffness measurement > 15 kPa). A 1-SD increase in weight SD and average real variability was associated with 52% higher (95% CI: 4%-128%) odds of having an adverse liver outcome. Otherwise, in interaction/subgroup analyses, an increased BWV was associated with a higher likelihood of outcomes only in sedentary individuals. CONCLUSIONS: Increased BWV was associated with adverse liver outcomes in individuals with T2D and MASLD; however, in those who were physically active, it was not hazardous.

Impact of PNPLA3 and TM6SF2 polymorphisms on the prognosis of patients with MASLD and type 2 diabetes mellitus.

BACKGROUND/AIMS: Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and extrahepatic outcomes in T2DM-MASLD individuals. METHODS: Patients' polymorphisms were analysed as follows: PNPLA3 CC, CG and GG; TM6SF2 CC and CT + TT; combined comparing no mutant allele, one allele G or T or ≥2 alleles G or T. Hierarchical models were built to assess associations between polymorphisms and outcomes, independently of confounding factors. Multivariate logistic regression was used for cirrhosis and its complications and extrahepatic cancer, and Cox regression for cardiovascular events (CVEs) and all-cause mortality. RESULTS: In total, 407 T2DM-MASLD patients (62.1 ± 10.5 years, 67.6% women) were followed for 11 (6-13) years. Having at least one G or T allele independently increased the risk of cirrhosis in the separate analysis of PNPLA3 and TM6SF2. Combined polymorphism analysis demonstrated an even higher risk of cirrhosis if two or more risk alleles were present (OR 18.48; 95% CI 6.15-55.58; p < .001). Regarding cirrhosis complications, the risk was higher in PNPLA3 GG and TM6SF2 CT + TT, also with an even higher risk when two or more risk alleles were present in the combined evaluation (OR 27.20; 95% CI 5.26-140.62; p < .001). There were no associations with CVEs or mortality outcomes. CONCLUSION: In T2DM, PNPLA3 and TM6SF2 polymorphisms, individually and additively, impact MASLD severity, with an increased risk of cirrhosis and its complications.

Parental History of Type 2 Diabetes Mellitus and PNPLA3 Polymorphism Increase the Risk of Severe Stages of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), the influence of parental history of type 2 diabetes (T2D) allied to single nucleotide polymorphisms (SNPs) in the offspring is not known. We aimed to investigate the impact of the parental history of T2D, PNPLA3 and TM6SF2 polymorphisms in liver steatosis and fibrosis. METHODS: This was a case-control study involving the offspring of T2D patients and controls without a parental history of T2D. Participants underwent clinical and laboratory evaluation, transient elastography (TE) by Fibroscan® (Echosens, Fr) and genotyping for PNPLA3 and TM6SF2. Multivariate logistic regression evaluated the influence of parental history of T2D on liver steatosis and fibrosis, controlled for age, gender, metabolic traits and SNPs. RESULTS: 161 T2D offspring and 78 controls, 10-46 years old, were included. The offspring of T2D had higher prevalences of obesity, T2D, arterial hypertension and sedentarism. Parental history of T2D was associated with fibrosis ≥ F2 (OR 8.89, CI 95% 1.09-72.01, p = 0.041) after adjustment for age, gender, metabolic traits and SNPs. PNPLA3 GG genotype was independently associated with steatosis ≥ S1 (OR 8.15, CI 95% 1.93-34.38, p = 0.004) and fibrosis ≥ F2 (OR 4.31, CI 95% 1.11-16.61, p = 0.034). CONCLUSIONS: The offspring of T2D patients present a worse metabolic profile and the parental history of T2D confers an increased likelihood of hepatic fibrosis, independent of metabolic factors. PNPLA3 homozygous GG, but not TM6SF2 genotypes, also impacts on this phenotype.

Brazilian evidence-based guideline for screening, diagnosis, treatment, and follow-up of metabolic dysfunction-associated steatotic liver disease (MASLD) in adult individuals with overweight or obesity: A joint position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM), Brazilian Society of Hepatology (SBH), and Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso).

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in individuals with overweight or obesity. In this context, a panel of experts from three medical societies was organized to develop an evidence-based guideline on the screening, diagnosis, treatment, and follow-up of MASLD. Material and methods: A MEDLINE search was performed to identify randomized clinical trials, meta-analyses, cohort studies, observational studies, and other relevant studies on NAFLD. In the absence of studies on a certain topic or when the quality of the study was not adequate, the opinion of experts was adopted. Classes of Recommendation and Levels of Evidence were determined using prespecified criteria. Results: Based on the literature review, 48 specific recommendations were elaborated, including 11 on screening and diagnosis, 9 on follow-up,14 on nonpharmacologic treatment, and 14 on pharmacologic and surgical treatment. Conclusion: A literature search allowed the development of evidence-based guidelines on the screening, diagnosis, treatment, and follow-up of MASLD in individuals with overweight or obesity.

Effects of body weight variability on risks of macro- and microvascular outcomes in individuals with type 2 diabetes: The Rio de Janeiro type 2 diabetes cohort.

AIMS: To investigate the effects of body weight variability (BWV) on macro- and microvascular outcomes in a type 2 diabetes cohort. METHODS: BWV parameters were assessed in 684 individuals. Multivariable Cox regressions examined associations between BWV parameters and cardiovascular outcomes (total cardiovascular events [CVEs], major CVEs [MACEs], cardiovascular deaths),all-cause mortality and microvascular outcomes. Interaction/subgroup analyses were performed according to being physically-active/sedentary and having/not lost ≥ 5 % of weight. RESULTS: Median follow-up was 11 years over which 194 total CVEs (174 MACEs), and 223 all-cause deaths (110 cardiovascular), occurred. There were 215 renal, 152 retinopathy and 167 peripheral neuropathy development/worsening outcomes. In general, increased BWV was associated with higher risks of CVEs, MACEs, all-cause mortality, advanced renal failure and peripheral neuropathy outcomes, but not of microalbuminuria and retinopathy outcomes. On interaction/subgroup analyses, increased BWV was associated with higher risks of outcomes in sedentary individuals and in those who did not lose ≥ 5 % of body weight. In physically-active participants or in those who lost ≥ 5 % weight, the adjusted risks were null or protective. CONCLUSIONS: Increased BWV was associated with most adverse outcomes; however, in those who were physically-active or consistently losing weight, it was not hazardous and might be even beneficial.

Prognostic Impact of On-Treatment Cumulative Ambulatory Blood Pressures for Adverse Macro- and Microvascular Outcomes in Individuals With Type 2 Diabetes: The Rio de Janeiro Type 2 Diabetes Cohort.

BACKGROUND: The prognostic value of on-treatment mean cumulative ambulatory blood pressures (BPs) in type 2 diabetes has never been investigated. We aimed to assess it in a prospective cohort of 647 individuals with type 2 diabetes. METHODS: Clinic-office and ambulatory BPs were measured at baseline and serially during follow-up. Multivariable Cox analyses assessed the associations between baseline and mean cumulative BPs with the occurrence of cardiovascular events, major adverse cardiovascular events, all-cause and cardiovascular mortality, and microvascular outcomes (microalbuminuria, renal failure, retinopathy, and peripheral neuropathy). C statistics and the integrated discrimination improvement (IDI) index evaluated the improvement in risk discrimination by using cumulative ambulatory BPs instead of baseline BPs. RESULTS: Over a median follow-up of 10.6 years, there were 202 cardiovascular events (163 major adverse cardiovascular events), 254 all-cause deaths (118 cardiovascular); 125 individuals had microalbuminuria development/progression, 104 developed advanced renal failure, 159 had retinopathy, and 174 individuals had peripheral neuropathy development/progression. The risks associated with mean cumulative ambulatory BPs were in general higher than those associated with baseline BPs, particularly for cardiovascular (HR, 1.42 versus 1.25 for increments of 1 SD in 24-hour systolic blood pressure) and mortality outcomes (1.56 versus 1.26). Compared with cumulative clinic BPs, mean cumulative ambulatory BPs improved risk discrimination for most outcomes, with IDIs from 11% to 14% for major adverse cardiovascular events and mortality up to 24% to 26% for microalbuminuria and neuropathy. CONCLUSIONS: Compared with clinic-office BPs, mean cumulative ambulatory BPs during follow-up improve risk discrimination for most complications and mortality in individuals with type 2 diabetes. Serial ambulatory BP monitoring shall be more widely used in clinical management.

Effects of Weight Loss and Interaction with Physical Activity on Risks of Cardiovascular Outcomes in Individuals with Type 2 Diabetes.

BACKGRUOUND: This study investigated the effects of weight loss during follow-up on cardiovascular outcomes in a type 2 diabetes cohort and tested interactions with clinical and laboratory variables, particularly physical activity, that could impact the associations. METHODS: Relative weight changes were assessed in 651 individuals with type 2 diabetes and categorized as ≥5% loss, <5% loss, or gain. Associations between weight loss categories and incident cardiovascular outcomes (total cardiovascular events [CVEs], major adverse cardiovascular events [MACEs], and cardiovascular mortality) were assessed using multivariable Cox regression with interaction analyses. RESULTS: During the initial 2 years, 125 individuals (19.2%) lost ≥5% of their weight, 180 (27.6%) lost <5%, and 346 (53.1%) gained weight. Over a median additional follow-up of 9.3 years, 188 patients had CVEs (150 MACEs) and 106 patients died from cardiovascular causes. Patients with ≥5% weight loss had a significantly lower risk of total CVEs (hazard ratio [HR], 0.52; 95% confidence interval, 0.33 to 0.89; P=0.011) than those who gained weight, but non-significant lower risks of MACEs or cardiovascular deaths. Patients with <5% weight loss had risks similar to those with weight gain. There were interactions between weight loss and physical activity. In active individuals, ≥5% weight loss was associated with significantly lower risks for total CVEs (HR, 0.20; P=0.004) and MACEs (HR, 0.21; P=0.010), whereas in sedentary individuals, no cardiovascular protective effect of weight loss was evidenced. CONCLUSION: Weight loss ≥5% may be beneficial for cardiovascular disease prevention, particularly when achieved with regular physical activity, even in high-risk individuals with long-standing type 2 diabetes.

Relative prognostic importance of aortic and brachial blood pressures for cardiovascular and mortality outcomes in patients with resistant hypertension and diabetes: a two cohorts prospective study.

OBJECTIVE: The prognostic importance of derived central/aortic blood pressures (BPs) in relation to brachial office and ambulatory BPs has never been investigated in patients with resistant hypertension (RHT) or type 2 diabetes (T2D). We aimed to evaluate it in two cohorts with 532 individuals with RHT and 467 with T2D (median follow-ups 4.4 and 7.3 years, respectively). METHODS: Central/aortic pressure waveforms were estimated by radial tonometry by a type 1 device (SphygmoCor device/software), and other parameters of central hemodynamics (augmentation index and Buckberg indices) were calculated. Multivariate Cox regressions examined the associations between central and peripheral BPs with cardiovascular events incidence and mortality, and C -statistics and the integrated discrimination improvement index evaluated the improvement in risk discrimination. RESULTS: During follow-up, there were 52 cardiovascular events and 51 all-cause deaths in the RHT and 104 and 137 in the T2D cohort. No aortic BP was better than its brachial counterpart in predicting risk or improving discrimination for any outcome in either cohort. In the RHT cohort, ambulatory BPs were superior to central and office-brachial BPs. Otherwise, the augmentation index in RHT (hazard ratios: 1.5, for 1-SD increment) and the Buckberg index in T2D (hazard ratios: 0.7-0.8) were independent predictors of cardiovascular/mortality outcomes, and improved risk discrimination (integrated discrimination improvement up to 25% in RHT and 15% in T2D). CONCLUSION: Derived aortic BPs by a type 1 device did not improve cardiovascular/mortality risk prediction over brachial BPs in our cohorts of patients with RHT and T2D, but additional parameters of central hemodynamics may be useful.

Prognostic importance of cardiovascular autonomic neuropathy on cardiovascular and mortality outcomes in individuals with type 2 diabetes: The Rio de Janeiro type 2 diabetes cohort.

AIMS: To investigate whether tests for cardiovascular autonomic neuropathy (CAN) and 24-hour heart rate variability (HRV) could improve the prediction for outcomes in type 2 diabetes. METHODS: 541 type 2 diabetic individuals performed tests of CAN. A subsample (313) had 24-hour HRV (the standard deviation of all normal RR intervals [SDNN] and the standard deviation of the averaged normal RR intervals for all 5 min segments [SDANN]). Multivariate Cox regressions examined the associations between CAN/low HRV with cardiovascular events (CVEs) and all-cause mortality. The improvement in risk discrimination of adding CAN/HRV was tested by C-statistics and by the Integrated Discrimination Improvement (IDI) index. RESULTS: 25% had CAN, and 17-18% had low HRV, respectively by SDANN-SDNN. Over a median follow-up of 12 years, there were 177 CVEs and 236 all-cause deaths in the whole cohort, and 96 CVEs and 129 all-cause deaths in the subsample. CAN was associated with 40% excess risks of CVEs/all-cause mortality, low HRV was associated with 2-fold higher risks of outcomes. HRV improved risk discrimination for CVEs/mortality with increases in C-statistics up to 0.039 and IDIs up to 25%. CONCLUSIONS: Low HRV was a better predictor of outcomes than tests of CAN, and it improved risk discrimination.

Brazilian evidence-based guideline for screening, diagnosis, treatment, and follow-up of metabolic dysfunction-associated steatotic liver disease (MASLD) in adult individuals with overweight or obesity: A joint position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM), Brazilian Society of Hepatology (SBH), and Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso)

ABSTRACT Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Nonalcoholic fatty liver disease (NAFLD), is one of the most common hepatic diseases in individuals with overweight or obesity. In this context, a panel of experts from three medical societies was organized to develop an evidence-based guideline on the screening, diagnosis, treatment, and follow-up of MASLD. Material and methods: A MEDLINE search was performed to identify randomized clinical trials, meta-analyses, cohort studies, observational studies, and other relevant studies on NAFLD. In the absence of studies on a certain topic or when the quality of the study was not adequate, the opinion of experts was adopted. Classes of Recommendation and Levels of Evidence were determined using prespecified criteria. Results: Based on the literature review, 48 specific recommendations were elaborated, including 11 on screening and diagnosis, 9 on follow-up, 14 on nonpharmacologic treatment, and 14 on pharmacologic and surgical treatment. Conclusions: A literature search allowed the development of evidence-based guidelines on the screening, diagnosis, treatment, and follow-up of MASLD in individuals with overweight or obesity.

Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.

Prognostic impact of changes in aortic stiffness for cardiovascular and mortality outcomes in individuals with type 2 diabetes: the Rio de Janeiro cohort study.

BACKGROUND: The prognostic importance of changes in aortic stiffness for the occurrence of adverse cardiovascular outcomes and mortality has never been investigated in patients with type 2 diabetes. We aimed to evaluate it in a cohort of 417 patients. METHODS: Changes in aortic stiffness were assessed by 2 carotid-femoral pulse wave velocity (CF-PWV) measurements performed over a 4-year period. Multivariable Cox analysis examined the associations between changes in CF-PWV, evaluated as a continuous variable with splines and as categorical ones (quartiles and stable/reduction/increase subgroups), and the occurrence of total cardiovascular events (CVEs), major adverse CVEs (MACEs), and all-cause and cardiovascular mortality. RESULTS: Over a median follow-up of 8.2 years after the 2nd CF-PWV measurement, there were 101 total CVEs (85 MACEs) and 135 all-cause deaths (64 cardiovascular). As a continuous variable, the lowest risk nadir was at -2.5%/year of CF-PWV change, with significantly higher risks of mortality associated with CF-PWV increases, but no excess risks at extremes of CF-PWV reduction. Otherwise, in categorical analyses, patients in the 1st quartile (greatest CF-PWV reductions) had excess risks of all-cause and cardiovascular mortality (hazard ratios [HRs]: 2.0-2.7), whereas patients in 3rd quartile had higher risks of all outcomes (HRs: 2.0-3.2), in relation to the lowest risk 2nd quartile subgroup. Patients in the 4th quartile had higher risks of all-cause mortality. Categorization as stable/reduction/increase subgroups was confirmatory, with higher risks at greater reductions (HRs: 1.7-3.3) and at greater increases in CF-PWV (HRs: 1.9-3.4), in relation to those with stable CF-PWV. CONCLUSIONS: Changes in aortic stiffness, mainly increases and possibly also extreme reductions, are predictors of adverse cardiovascular outcomes and mortality in individuals with type 2 diabetes.

Liver Growth and Portal Hypertension Improvement After Percutaneous Recanalization of Chronic Portal Vein Thrombosis in Non-Cirrhotic Participants.

PURPOSE: To evaluate liver function improvement and volume gain after percutaneous recanalization of chronic portal vein thrombosis (PVT) in non-cirrhotic patients. MATERIALS AND METHODS: In this retrospective study, five non-cirrhotic participants between 21 and 67 years old with secondary chronic PVT (4-21 years from diagnose) were submitted to percutaneous portal vein recanalization, followed by varices and shunts embolization. RESULTS: After a mean of 12.6 months, all portal veins remained patent and there was complete resolution of portal hypertension (PH) symptoms in all participants. There was a significant increase in liver volume of 39.8 ± 19.0% (p = 0.042), platelets count of 53120 ± 20188/µl (p = 0.042), and a significant decrease in total bilirubin levels from 1.04 ± 0.23 mg/dL to 0.51 ± 0.09 mg/dL (p = 0.043). We also found a non-significant increase in albumin levels from 3.88 ± 0.39 g/dL to 4.38 ± 0.27 g/dL (p = 0.078) and decrease in spleen diameter from 16.88 ± 4.03 cm to 14.15 ± 2.72 cm (p = 0.068). DISCUSSION: In this retrospective study, even with a small number of participants, we were capable of showing a median of 39.8% increase in liver volume, laboratorial liver function improvement, platelets count and resolution of PH symptoms, including gastroesophageal varices disappearance after portal vein recanalization followed by shunt embolization. CONCLUSION: In this small series of cases, recanalization of chronic PVT in non-cirrhotic participants was feasible, successful and safe despite the prolonged time of occlusion. This is a new and promising approaching to an old and still challenging disease.

Validation and Performance of FibroScan®-AST (FAST) Score on a Brazilian Population with Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIM: FAST score has a good performance for diagnosing the composite of NASH + NAS ≥ 4 + F ≥ 2. However, it has not been evaluated in Latin American individuals with nonalcoholic fatty liver disease (NAFLD). We aimed to analyze the performance of the FAST score in a Brazilian NAFLD population. METHODS: Cross-sectional study was held in ≥ 18 years NAFLD patients diagnosed by ultrasonography and submitted to liver biopsy (LB). Liver stiffness (LSM) and CAP measurements were performed with FibroScan®, using M (BMI < 32 kg/m2) or XL probes. Area under receiver operating characteristic (AUROC) curves were calculated as well as sensitivity (S), specificity (Spe), positive predictive value (VPP) and negative predictive value (NPV) for the previously established FAST score cut-offs. RESULTS: Among 287 patients included (75% female; mean age 55 ± 10 years), NASH + NAS ≥ 4 + F ≥ 2 was reported in 30% of LB. For the FAST cut-off of 0.35, the S and NPV to rule out NASH + NAS ≥ 4 + F ≥ 2 were 78.8% and 87.8%, respectively. Regarding the cut-off of 0.67, the Spe and PPV to rule-in NASH + NAS ≥ 4 + F ≥ 2 were 89.1%, 61.8%, respectively. The AUROC of FAST for all included patients was 0.78 (95% CI 0.72-0.84) and for those with ≥ 32 kg/m2 was 0.81 (95% CI 0.74-0.88). CONCLUSION: FAST score has a good performance in a Brazilian NAFLD population, even in patients with higher BMI when the XL probe is adopted. Therefore, FAST can be used as a noninvasive screening tool mainly for excluding the diagnosis of progressive NASH, reducing the number of unnecessary liver biopsies.

Differential effects of treatment targets on risks of adverse outcomes according to diabetes duration, age and complications: Can these characteristics be used to individualize diabetes treatment? The Rio de Janeiro type 2 diabetes cohort.

AIMS: To investigate interactions between more/less strict treatment targets (HbA1c, systolic blood pressure, LDL-cholesterol) and clinical characteristics (age, diabetes duration and presence of complications) for occurrence of cardiovascular/microvascular complications and mortality in type 2diabetes. METHODS: 690 individuals were followed-up for 10 years (median). Interactions between treatment targets, estimated as mean values during the first 2-years, and clinical characteristics were tested in multivariable Cox regressions adjusted for other risk factors. Hazard ratios (HRs) were estimated in stratified analyses for cardiovascular/microvascular outcomes and mortality. RESULTS: During follow-up, 214 patients had a cardiovascular event (175 MACEs); and 265 died (132 cardiovascular deaths); there were 206 renal, 161 retinopathy and 181 peripheral neuropathy events. There were interactions between treatment parameters and clinical characteristics, in most of them the HRs were higher in older individuals, in those with longer diabetes durations and with complications, particularly for the cardiovascular outcomes and mortality. For microvascular outcomes the opposite was observed. For cardiovascular mortality, the HRs of higher HbA1c were 1.31 (1.08-1.58) and 1.09 (0.88-1.34), respectively with longer/shorter diabetes duration (p-for-interaction 0.11); and 1.43 (1.14-1.79) and 1.02 (0.85-1.23) in older/younger individuals (p-for-interaction 0.019). CONCLUSIONS: Our findings do not support less strict treatment targets for older individuals, with longer diabetes duration or with complications, particularly for cardiovascular and mortality prevention.

Prognostic impact of liver fibrosis and steatosis by transient elastography for cardiovascular and mortality outcomes in individuals with nonalcoholic fatty liver disease and type 2 diabetes: the Rio de Janeiro Cohort Study.

BACKGROUND: Liver stiffness measurement (LSM, which reflects fibrosis) and controlled attenuation parameter (CAP, which reflects steatosis), two parameters derived from hepatic transient elastography (TE), have scarcely been evaluated as predictors of cardiovascular complications and mortality in individuals with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). METHODS: Four hundred type 2 diabetic patients with NAFLD had TE examination (by Fibroscan®) performed at baseline. Multivariate Cox analyses evaluated the associations between TE parameters and the occurrence of cardiovascular events (CVEs) and mortality. TE parameters were assessed as continuous variables and dichotomized at low/high values reflecting advanced liver fibrosis (LSM > 9.6 kPa) and severe steatosis (CAP > 296 or > 330 dB/m). Improvements in risk discrimination were assessed by C-statistic and by the relative Integrated Discrimination Improvement (IDI) index. RESULTS: During a median follow-up of 5.5 years, 85 patients died (40 from cardiovascular causes), and 69 had a CVE. As continuous variables, an increasing LSM was a risk marker for total CVEs (hazard ratio [HR]: 1.05; 95% CI: 1.01-1.08) and all-cause mortality (HR: 1.04; 95% CI: 1.01-1.07); whereas an increasing CAP was a protective factor for both outcomes (HR: 0.93; 95% CI: 0.89-0.98; and HR: 0.92; 95% CI: 0.88-0.97; respectively). As dichotomized variables, a high LSM remained a risk marker of adverse outcomes (with HRs ranging from 2.5 to 3.0) and a high CAP was protective (with HRs from 0.3 to 0.5). The subgroup of individuals with low-LSM/high-CAP had the lowest risks while the opposite subgroup with high-LSM/low-CAP had the highest risks. Both LSM and CAP improved risk discrimination, with increases in C-statistics up to 0.037 and IDIs up to 52%. CONCLUSIONS: Measured by hepatic TE, advanced liver fibrosis is a risk marker and severe steatosis is a protective factor for cardiovascular complications and mortality in individuals with type 2 diabetes and NAFLD.

Importance of hematological parameters for micro- and macrovascular outcomes in patients with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort study.

BACKGROUND: The prognostic importance of several hematological parameters has been scarcely investigated in type 2 diabetes. So, we aimed to evaluate their prognostic importance for development of complications in a cohort of type 2 diabetes. METHODS: In a prospective study, 689 individuals with type 2 diabetes had blood red cell, platelet and leukocyte parameters obtained at baseline. Multivariate Cox analyses examined the associations between several hematological parameters (including neutrophyl-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and monocyte-to-HDL ratios) and the occurrence of microvascular (retina, renal and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs], and major adverse CVEs [MACEs]), and all-cause and cardiovascular mortality. Improvements in risk discrimination were assessed by C-statistics and Integrated Discrimination Improvement (IDI) index. RESULTS: During a median follow-up of 10.5 years, 212 patients had a CVE (174 MACEs), 264 patients died (131 cardiovascular deaths); 206 had a renal, 161 a retinopathy and 179 patients had a neuropathy outcome. In multivariate-adjusted analyses, the lymphocytes count and lymphocyte-to-monocyte ratio were protective (hazard ratios [HRs]: 0.77 and 0.72, respectively), whereas the neutrophyl-to-lymphocyte and platelet-to-lymphocyte ratios were associated with increased risks (HRs: 1.19 and 1.17) for all-cause mortality. For cardiovascular mortality, the monocytes count, the neutrophyl-to-lymphocyte and monocyte-to-HDL ratios were associated with increased risks and the lymphocyte-to-monocyte ratio was protective. Higher lymphocyte-to-monocyte ratio was protective for renal failure outcome. However, none of them improved risk discrimination. CONCLUSIONS: Low lymphocytes count and leukocyte ratios that mainly included lymphocytes were predictors of macrovascular complications and mortality in individuals with type 2 diabetes. However, they did not improve risk prediction over traditional risk factors.

Importance of non-invasive liver fibrosis scores for mortality and complications development in individuals with type 2 diabetes.

AIMS: To evaluate the non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) and Fibrosis-4 score (FIB4) as predictors of complications development and mortality in a cohort of type 2 diabetes. METHODS: 554 type 2 diabetic subjects had NFS and FIB4 calculated at baseline. Multivariate Cox and Poisson analyses evaluated the associations between fibrosis scores and the occurrence of microvascular and cardiovascular complications, and all-cause mortality. RESULTS: According to recommended cut-offs of NFS, 12.8% had advanced fibrosis and 45.9% had absence of advanced fibrosis and of FIB4, 3.8% and 86.1%, respectively. During a median follow-up of 11 years, 217subjects died, 172 had cardiovascular events (CVEs), 184 had renal events, and 139 had retinopathy and 185 neuropathy events. As continuous variables, both scores predicted all-cause mortality: NFS, HR: 1.30 (p = 0.032) and FIB4, HR: 1.24 (p = 0.021); an increased NFS implied in a significant 90% excess risk of mortality, whereas a higher FIB4 in a borderline 69% higher risk. The scores were mainly predictors of mortality in women and for non-cardiovascular deaths. The NFS was a predictor of renal events, mainly for renal function deterioration. CONCLUSIONS: The NFS and FIB4 predicted all-cause mortality, particularly in women and for non-cardiovascular causes. The NFS predicted adverse renal outcomes. These liver fibrosis scores may improve stratification risk in individuals with diabetes and NAFLD.

Traditional and non-traditional risk factors for peripheral artery disease development/progression in patients with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort study.

BACKGROUND: The prognostic importance of non-traditional risk factors for peripheral artery disease (PAD) development/progression is scarcely studied in diabetes. We investigated if carotid intima-media thickness (CIMT) and carotid-femoral pulse wave velocity (cf-PWV) added prognostic information beyond traditional cardiovascular risk markers for PAD outcomes. METHODS: Ankle-brachial index (ABI) was measured at baseline and after a median of 91 months of follow-up in 681 individuals with type 2 diabetes. Multivariate Cox regressions examined the associations between the candidate variables and the outcome. PAD development/progression was defined by a reduction in ABI ≥ 0.15 (to a level < 0.9) or limb revascularization procedures, lower-extremity amputations or death due to PAD. The improvement in risk discrimination was assessed by increases in C-statistics of the models. RESULTS: Seventy-seven patients developed/progressed PAD: 50 reduced ABI to < 0.9, seven had lower-limb revascularizations, and 20 had amputations or death. Age, male sex, diabetes duration, presence of microvascular complications (peripheral neuropathy and diabetic kidney disease), baseline HbA1c, 24-h systolic BP (SBP) and mean cumulative office SBP and LDL-cholesterol were associated with PAD development/progression in several models. CIMT and cf-PWV were additionally associated with PAD outcomes, and their inclusion further improved risk discrimination (with C-statistic increases between 0.025 and 0.030). The inclusion of ambulatory 24-h SBP, instead of office SBP, also improved PAD risk discrimination. CONCLUSIONS: Increased CIMT and aortic stiffness are associated with greater risks of developing/progressing PAD, beyond traditional risk factors, in type 2 diabetes.