Non-alcoholic fatty liver disease(NAFLD)is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2diabetes are at a particularly high risk for ...developing the progressive forms of NAFLD,non-alcoholic steatohepatitis and associated advanced liver fibrosis.Moreover,diabetes is an independent risk factor for NAFLD progression,and for hepatocellular carcinoma development and liver-related mortality in prospective studies.Notwithstanding,patients with NAFLD have an elevated prevalence of prediabetes.Recent studies have shown that NAFLD presence predicts the development of type2 diabetes.Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients.The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods,although histopathological evaluation is still considered the gold standard diagnostic method.An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking.We sought to outline the published data including epidemiology,pathogenesis,diagnosis and treatment of NAFLD in diabetic patients,in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus.
Diabetic retinopathy (DR) is a chronic microvascular complication associated a worse prognosis. We aimed to evaluate the predictors of development/progression of DR in a cohort of 544 high-risk ...patients with type 2 diabetes who had annual ophthalmologic examinations over a median follow-up of 6 years. Ambulatory blood pressure (BP) monitoring and aortic stiffness by carotid-femoral pulse wave velocity were performed. Multivariate Cox survival analysis examined the independent predictors of development or progression of DR. During follow-up, 156 patients either newly-developed or worsened DR. Patients who developed/progressed DR had longer diabetes duration, higher ambulatory and clinic BP levels, higher aortic stiffness, and poorer glycemic control than patients who did not developed/progressed DR. After adjustments for baseline retinopathy prevalence, age and sex, a longer diabetes duration (p < 0.001), higher baseline ambulatory BPs (p = 0.013, for 24-hour diastolic BP), and higher mean cumulative exposure of HbA
(p < 0.001), clinic diastolic BP (p < 0.001) and LDL-cholesterol (p = 0.05) during follow-up were the independent predictors of development/progression of DR. BP parameters were only predictors of DR development. In conclusion, a longer diabetes duration, poorer glycemic and lipid control, and higher BPs were the main predictors of development/progression of DR. Mean cumulative clinic diastolic BP was the strongest BP-related predictor.
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.
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.
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.
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.
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.
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.
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.
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.
Aims/hypothesis
Diabetic kidney disease (DKD) is a microvascular complication associated with poor control of blood glucose and BP. We aimed to evaluate the predictors of development and progression ...of DKD in a cohort of high-risk individuals with type 2 diabetes, placing emphasis on ambulatory BP and arterial stiffness.
Methods
In a prospective study, 629 individuals without advanced renal failure had their renal function evaluated annually over a median follow-up period of 7.8 years. Ambulatory BP was monitored and aortic stiffness was assessed by carotid–femoral pulse wave velocity at baseline. Multivariate competing risks analysis with all-cause mortality, using the Fine and Gray approach, was used to examine the independent predictors of development and progression of DKD, a composite of development or progression of abnormal albuminuria and worsening of renal function (doubling of serum creatinine or progression to end-stage renal disease).
Results
At baseline, 197 individuals had DKD. During follow-up, DKD developed or progressed in 195 individuals, abnormal albuminuria developed or progressed in 125 individuals and renal function deteriorated in 91. After adjustments for baseline albuminuria and renal function, age, sex, diabetes duration and use of renin–angiotensin antagonists, poorer control of blood glucose (HR 1.17; 95% CI 0.98, 1.40;
p
= 0.09 for each 1 SD increment in mean first-year HbA
1c
), higher ambulatory systolic BP (HR 1.28; 95% CI 1.09, 1.50;
p
= 0.003, for each 1 SD increase in daytime systolic BP SBP) and increased aortic stiffness (HR 1.16; 95% CI 1.00, 1.34;
p
= 0.05) were independent predictors of development or progression of DKD. At baseline, ambulatory BP was a stronger predictor than BP measured in the clinic. Aortic stiffness predicted abnormal albuminuria development or progression (HR 1.26; 95% CI 1.02, 1.56;
p
= 0.036) whereas ambulatory BP was a stronger predictor of renal function deterioration (HR 1.32; 95% CI 1.09, 1.60;
p
= 0.005 for daytime SBP).
Conclusions/interpretation
Poor blood glucose and BP control and increased aortic stiffness were the main predictors of development or progression of DKD; ambulatory SBP was a better predictor than BP measured in the clinic. Ambulatory BP monitoring and assessment of aortic stiffness should be more widely used in clinical type 2 diabetes management.
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).
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.
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%.
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.
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).
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.
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).
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.
The prognostic importance of an increased visit-to-visit blood pressure variability (BP-VVV) for the future development of micro- and macrovascular complications in type 2 diabetes has been scarcely ...investigated and is largely unsettled. We aimed to evaluate it in a prospective long-term follow-up study with 632 individuals with type 2 diabetes.
BP-VVV parameters (systolic and diastolic standard deviations SD and variation coefficients) were measured during the first 24-months. Multivariate Cox analysis, adjusted for risk factors and mean BP levels, examined the associations between BP-VVV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications (total cardiovascular events CVEs, major adverse CVEs MACE and cardiovascular and all-cause mortality). Improvement in risk discrimination was assessed by the C-statistic and integrated discrimination improvement (IDI) index.
Over a median follow-up of 11.3 years, 162 patients had a CVE (132 MACE), and 212 patients died (95 from cardiovascular diseases); 153 newly-developed or worsened diabetic retinopathy, 193 achieved the renal composite outcome (121 newly-developed microalbuminuria and 95 deteriorated renal function), and 171 newly-developed or worsened peripheral neuropathy. Systolic BP-VVV was an independent predictor of MACE (hazard ratio: 1.25, 95% CI 1.03-1.51 for a 1-SD increase in 24-month SD), but not of total CVEs, cardiovascular and all-cause mortality, and of any microvascular outcome. However, no BP-VVV parameter significantly improved cardiovascular risk discrimination (increase in C-statistic 0.001, relative IDI 0.9%).
Systolic BP-VVV was an independent predictor of MACE, but it did not improve cardiovascular risk stratification. The goal of anti-hypertensive treatment in patients with type 2 diabetes shall remain in controlling mean BP levels, not on decreasing their visit-to-visit variability.
To investigate the effects of body weight variability (BWV) on macro- and microvascular outcomes in a type 2 diabetes cohort.
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.
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.
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.
The prognostic importance of carotid atherosclerosis in individuals with diabetes is unsettled. We aimed to evaluate the relationships between parameters of carotid atherosclerosis and the future ...occurrence of micro- and cardiovascular complications in individuals with type 2 diabetes.
Ultrasonographic parameters of carotid atherosclerosis, intima-media thickness (CIMT) and plaques, were measured at baseline in 478 participants who were followed-up for a median of 10.8 years. Multivariate Cox analysis was used to examine the associations between carotid parameters and the occurrence of microvascular (retinopathy, renal, and peripheral neuropathy) and cardiovascular complications (total cardiovascular events CVEs and cardiovascular mortality), and all-cause mortality. The improvement in risk stratification was assessed by using the C-statistic and the integrated discrimination improvement (IDI) index.
During follow-up, 116 individuals had a CVE and 115 individuals died (56 from cardiovascular diseases); 131 newly-developed or worsened diabetic retinopathy, 156 achieved the renal composite outcome (94 newly developed microalbuminuria and 78 deteriorated renal function), and 83 newly-developed or worsened peripheral neuropathy. CIMT, either analysed as a continuous or as a categorical variable, and presence of plaques predicted CVEs occurrence and renal outcomes, but not mortality or other microvascular complications. Individuals with an increased CIMT and plaques had a 1.5- to 1.8-fold increased risk of CVEs and a 1.6-fold higher risk of renal outcome. CIMT and plaques modestly improved cardiovascular risk discrimination over classic risk factors, with IDIs ranging from 7.8 to 8.4%; but more markedly improved renal risk discrimination, with IDIs from 14.8 to 18.5%.
Carotid atherosclerosis parameters predicted cardiovascular and renal outcomes, and improved renal risk stratification. Ultrasonographic carotid imaging may be useful in type 2 diabetes management.
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