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.

Risk of heart failure in ambulatory resistant hypertension: a meta-analysis of observational studies.

The impact of ambulatory resistant hypertension (ARH) on the occurrence of heart failure (HF) is not yet completely known. We performed for the first time a meta-analysis, by using published data or available data from published databases, on the risk of HF in ARH. Patients with ARH (24-h BP ≥ 130/80 mmHg during treatment with ≥3 drugs) were compared with those with controlled hypertension (CH, clinic BP < 140/90 mmHg and 24-h BP < 130/80 mmHg regardless of the number of drugs used), white coat uncontrolled resistant hypertension (WCURH, clinic BP ≥ 140/90 mmHg and 24-h BP < 130/80 mmHg in treated patients) and ambulatory nonresistant hypertension (ANRH, 24-h BP ≥ 130/80 mmHg during therapy with ≤2 drugs). We identified six studies/databases including 21,365 patients who experienced 692 HF events. When ARH was compared with CH, WCURH, or ANRH, the overall adjusted hazard ratio for HF was 2.32 (95% confidence interval (CI) 1.45-3.72), 1.72 (95% CI 1.36-2.17), and 2.11 (95% CI 1.40-3.17), respectively, (all P < 0.001). For some comparisons a moderate heterogeneity was found. Though we did not find variables that could explain the heterogeneity, sensitivity analyses demonstrated that none of the studies had a significant influential effect on the overall estimate. When we evaluated the potential presence of publication bias and small-study effect and adjusted for missing studies identified by Duval and Tweedie's method the estimates were slightly lower but remained significant. This meta-analysis shows that treated hypertensive patients with ARH are at approximately twice the risk of developing HF than other ambulatory BP phenotypes.

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 obstructive sleep apnea and CPAP treatment for cardiovascular and mortality outcomes in patients with resistant hypertension: a prospective cohort study.

The prognostic importance of obstructive sleep apnea (OSA) severity and other polysomnographic parameters in patients with resistant hypertension (RHT) has never been evaluated. We aimed to assess it in a prospective cohort of 422 individuals with RHT. OSA presence/severity was ascertained by complete polysomnography (PSG) at baseline. Multivariable Cox regressions assessed the risks associated with OSA severity and other PSG parameters (apnea-hypopnea index, sleep duration, nocturnal hypoxemia and periodic limb movements) for the primary (total cardiovascular events [CVEs] and all-cause mortality) and secondary outcomes (major CVEs). In the subgroup of patients with moderate/severe OSA, the risks associated with CPAP treatment were also estimated in relation to untreated individuals. One-hundred and eighty-six participants (44%) had no/mild OSA and 236 (56%) had moderate/severe OSA, and 67 of them were CPAP-treated. Over a mean follow-up of 5 years, there were 46 CVEs (37 major ones) and 44 all-cause deaths. Neither the presence of moderate/severe or severe OSA, nor being untreated during follow-up, was associated with significant excess risks for any outcome in relation to the subgroup with no/mild OSA. Similarly, no other PSG-derived parameter predicted any adverse outcome. Otherwise, CPAP treatment was associated with non-significant risk reductions of 37% for total CVEs, 49% for major CVEs and 63% for all-cause mortality in relation to those who remained untreated during follow-up. In conclusion, the presence/severity of OSA and its related PSG parameters were not associated with worse cardiovascular/mortality prognosis in patients with RHT. However, CPAP treatment might be protective in individuals with moderate/severe OSA.

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.

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.

Refractory Hypertension: a Narrative Systematic Review with Emphasis on Prognosis.

PURPOSE OF REVIEW: To perform a narrative systematic review on refractory hypertension (RfHT) with particular emphasis on prognosis. RECENT FINDINGS: There were 37 articles on RfHT, 13 non-systematic reviews, and 24 original studies. RfHT, a recently described extreme phenotype of anti-hypertensive treatment failure, shall be defined as uncontrolled out-of-office blood pressure (BP) levels despite the use of at least 5 anti-hypertensive drugs, including a long-acting diuretic and a mineraloreceptor antagonist. Its prevalence ranges from 0.5 to 4.3% of general treated hypertensives and between 3.6 and 51.4% of patients with resistant hypertension (RHT). RfHT is associated with younger age, African ancestry, obesity, hypertension-mediated organ damage and clinical cardiovascular diseases, and with some comorbidities, such as diabetes and obstructive sleep apnea. Its physiopathological mechanisms probably involve sympathetic overactivity and not volume overload. Patients with RfHT have a worse prognosis than non-refractory RHT individuals, with higher risks of adverse cardiovascular and renal outcomes and of mortality. RfHT represents a rare but true extreme phenotype of anti-hypertensive treatment failure distinct from RHT and with a significantly worse prognosis. Identifying such individuals is important to tailor specific interventions.

Prognostic Value of Changes in Aortic Stiffness for Cardiovascular Outcomes and Mortality in Resistant Hypertension: a Cohort Study.

The prognostic importance of changes in aortic stiffness for the occurrence of adverse cardiovascular outcomes and mortality has never been investigated in patients with resistant hypertension. We aimed to evaluate it in a prospective cohort of 442 resistant hypertension individuals. Changes in aortic stiffness were assessed by 2 carotid-femoral pulse wave velocity (CF-PWV) measurements performed over a median time interval of 4.7 years. Multivariate Cox analysis examined the associations between changes in CF-PWV (evaluated as continuous variables and categorized into quartiles and as increased/persistently high or reduced/persistently low) and the occurrence of total cardiovascular events (CVEs), major adverse CVEs, and cardiovascular/all-cause mortalities. During a median follow-up of 4.1 years after the second CF-PWV measurement, there were 49 total CVEs (42 major adverse CVEs) and 53 all-cause deaths (32 cardiovascular). As continuous variables, increments in absolute and relative changes in CF-PWV were associated with higher risks of CVEs and major adverse CVEs occurrence, but not of mortality. Divided into quartiles of CF-PWV changes, risks increased in the third and fourth quartile subgroups in relation to the reference first quartile subgroup (those with greatest CF-PWV reductions) for all outcomes. Patients who either increased or persisted with high CF-PWV had excess risks of cardiovascular morbidity/mortality, with hazard ratios ranging from 2.7 to 3.0, in relation to those who reduced or persisted with low CF-PWV values. In conclusion, reducing or preventing progression of aortic stiffness was associated with significant cardiovascular protection in patients with resistant hypertension, suggesting that it may be an additional clinical target of antihypertensive treatment.

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 Home Blood Pressures for Adverse Cardiovascular Outcomes and Mortality in Patients With Resistant Hypertension: A Prospective Cohort Study.

[Figure: see text].

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.

Associations Between Achieved Ambulatory Blood Pressures and Its Changes With Adverse Outcomes in Resistant Hypertension: Was There a J-Curve for Ambulatory Blood Pressures?

[Figure: see text].

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.

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.

Associations of the nocturnal blood pressure fall and morning surge with cardiovascular events and mortality in individuals with resistant hypertension.

OBJECTIVE: The prognostic importance of the nocturnal blood pressure (BP) fall and early-morning surge were scarcely investigated in patients with resistant hypertension (RHT). We investigated them in a prospective cohort of 1726 RHT individuals. METHODS: The nocturnal fall and morning surge were calculated from the baseline ambulatory BP monitoring (ABPM) and also as mean cumulative values using all ABPMs performed during follow-up. Dipping patterns (normal, extreme, reduced, and reverse) were defined by classic cut-off values of the night-to-day ratio, while MS (difference between early-morning and night-time BP) was categorized into quartiles and at the extremes of its distribution (5th, 10th, 90th, and 95th percentiles). The primary outcomes were total cardiovascular events (CVEs), major adverse cardiovascular events (MACEs), all-cause and cardiovascular mortalities. Multivariate Cox analyses examined the associations between nocturnal BP fall and morning surge and outcomes. RESULTS: Over a median follow-up of 8.3 years, 417 CVEs occurred (358 MACEs), and 391 individuals died (233 cardiovascular deaths). Reduced and reverse dipping patterns were significant predictors of CVEs and MACEs, with hazard ratios between 1.6 and 2.5, whereas extreme dipping was a protective factor in younger individuals (hazard ratios 0.3--0.4) but a hazardous factor in elderly (hazard ratios 3.7--5.0) and in individuals with previous cardiovascular diseases (hazard ratios 2.6--4.4). No morning surge parameter was predictive of any outcome in fully adjusted analyses. CONCLUSION: Abnormal dipping patterns but not the early-morning BP surge, were important prognostic markers for future cardiovascular morbidity in RHT patients. The prognosis of extreme dippers depended on age and the presence of cardiovascular diseases.

Prognostic impact of short-term ambulatory blood pressure variability for microvascular and macrovascular outcomes in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study.

OBJECTIVE: To evaluate the prognostic importance of short-term blood pressure variability (BPV) for the occurrence of macrovascular and microvascular complications in individuals with type 2 diabetes. METHODS: Six hundred and forty patients had 24-h ambulatory BP monitoring performed at baseline and were followed-up over a median of 11.2 years. Daytime, night-time and 24-h SBP and DBPV parameters (standard deviations and variation coefficients) were calculated. Multivariate Cox analysis, adjusted for risk factors and mean BPs, examined the associations between BPV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications [total cardiovascular events (CVEs), major adverse CVEs [MACEs]), and cardiovascular and all-cause mortalities. Improvements in risk discrimination were assessed by the C-statistic and Integrated Discrimination Improvement (IDI) index. RESULTS: During follow-up, 186 patients had a CVE (150 MACEs), and 237 patients died (107 from cardiovascular diseases); 155 newly developed or worsened diabetic retinopathy, 200 achieved the renal composite outcome (124 newly developed microalbuminuria and 102 deteriorated renal function), and 170 newly developed or worsened peripheral neuropathy. Daytime DBPV was the best predictor for all cardiovascular outcomes and mortality, with hazard ratios (for increments of 1SD) ranging from 1.27 (95% CI 1.09-1.48) for all-cause mortality to 1.55 (1.29-1.85) for MACEs, and it improved cardiovascular risk discrimination (with increases in C-statistic of up to 0.026, and IDIs of up to 22.8%). No BPV parameter predicted any microvascular outcome. CONCLUSION: Short-term BPV, particularly daytime DBPV, predicts future development of macrovascular complications and mortality and improves cardiovascular risk discrimination in patients with diabetes.