[HDL-C/apoA-I]: A multivessel cardiometabolic risk marker in women with T2DM.

AIMS: Although women have higher high-density lipoprotein cholesterol (HDL-C) than have men, their HDL particles are also prone to become small, dense, and dysfunctional in case of type 2 diabetes mellitus (T2DM). To assess the vascular risk related to HDLs of different sizes/densities without direct measurement, we adjusted HDL-C to its main apolipoprotein (apoA-I) as [HDL-C/apoA-I]. This ratio estimates HDL sizes and provides indices as to their number, cholesterol load, and density. METHODS: We stratified 280 Caucasian T2DM women according to [HDL-C/apoA-I] quartiles (Q) to determine how they are segregated according to cardiometabolic risk, ß-cell function, glycaemic control, and vascular complications. Five parameters were derived from combined determination of HDL-C and apoA-I: HDL size, HDL number, cholesterol load per particle (pP), apoA-I pP, and HDL density. RESULTS: An adverse cardiometabolic profile characterized QI and QII patients whose HDLs were denser and depleted in apoA-I, whereas QIII patients had HDLs with characteristics closer to those of controls. QIV patients had HDLs of supernormal size/composition and a more favourable phenotype in terms of fat distribution; insulin sensitivity (64% vs 41%), metabolic syndrome, and ß-cell function (32% vs 23%); exogenous insulin (44 vs 89 U·d-1 ); and glycaemic control (glycated haemoglobin, 56 vs 61 mmol·mol-1 ), associated with lower prevalence of microvascular/macrovascular complications: all-cause microangiopathy 47% vs 61%; retinopathy 22% vs 34%; all-cause macroangiopathy 19% vs 31%; and coronary artery disease 6% vs 24% (P < .05). CONCLUSION: [HDL-C/apoA-I] can stratify T2DM women according to metabolic phenotype, macrovascular and coronary damage, ß-cell function, microangiopathic risk, and retinopathy. This ratio is a versatile and readily available marker of cardiometabolic status and vascular complications in T2DM women.

Testing for Soluble ST2 in Heart Failure Patients: Reliability of a Point of Care Method.

BACKGROUND: Our objective was to determine soluble ST2 (sST2) concentrations in heart failure (HF) patients with a point-of-care (POCT) assay. METHODS: sST2 levels were measured in 71 HF patients with both POCT and ELISA methods. The concentrations of sST2 were correlated to HF severity and to some established biomarkers of cardiovascular risk. RESULTS: sST2 levels measured with the ASPECT-PLUS POCT method were significantly correlated with the comparison ELISA assay (r = 0.94, p < 0.01) and were related to HF severity. Levels of sST2 measured with the POCT assay were significantly correlated to NT-proBNP (r = 0.57, p < 0.001), BNP (r = 0.75, p < 0.001), Galectin-3 (r = 0.40, p < 0.01) and PTH (1-84) (r = 0.39, p < 0.01). CONCLUSIONS: POCT and ELISA methods for sST2 testing were significantly correlated, and our results confirmed also the clinical reliability of the sST2 POCT assay. Furthermore, the POCT method allows a faster delivery of results to physicians.

The mixed benefit of low lipoprotein(a) in type 2 diabetes.

BACKGROUND: Lipoprotein(a) (Lp(a)), a variant low-density lipoprotein (LDL), is a major genetic risk factor for cardiovascular disease. It is unknown whether an inverse relationship exists between Lp(a) and ß-cell function (BCF), as for LDL-cholesterol (LDL-C) lowering by statins. We therefore assessedthe cardiometabolic phenotype of 340 men with type 2 diabetes mellitus (T2DM) in relation to Lp(a), focusing on BCF and hyperbolic product [BxS], which adjusts BCF to insulin sensitivity and secretion. METHODS: Two groups were analyzed according to Lp(a) quartiles (Q): a (very-)low Lp(a) (Q1;n = 85) vs a normal-to-high Lp(a) group (Q2-Q4;n = 255). RESULTS: In the overall cohort, mean Lp(a) was 52 nmol.L-1. Median Lp(a) was 6 nmol.L-1 (Q1) vs 38 nmol.L-1 (Q2-Q4). There were no differences between groups regarding age; education; diabetes duration; body mass index; body composition and smoking. Q1 had significantly worse glycemic control, higher systolic blood pressure, more severe metabolic syndrome, and more frequent hepatic steatosis. Insulin sensitivity was significantly lower (- 37%) in Q1, who also had lesser hyperbolic product (- 27%), and higher [BxS] loss rate (+ 15%). Q1 also had higher frequency (+31%) and severity (+20%) of atherogenic dyslipidemia. Microangiopathy and neuropathy were higher in Q1 (+ 34% and + 48%, respectively), whereas Q2-Q4 patients had increased macroangiopathy (+ 51%) and coronary artery disease (CAD; + 94%). CONCLUSIONS: Low Lp(a) appears both beneficial and unhealthy in T2DM. It is associated with unfavourable cardiometabolic phenotype, lesser BCF, poorer glycemic control, and increased microvascular damage despite being linked to markedly reduced CAD, suggesting that Lp(a)-related vascular risk) follows a J-shaped curve.

How to transform a metabolic syndrome score into an insulin sensitivity value?

BACKGROUND: The metabolic syndrome (MetS) predicts cardiovascular risk and incident type 2 diabetes mellitus. The presence of a MetS is defined by the clustering of ≥3 out of 5 cardiometabolic criteria (hyperglycemia; hypertension; enlarged waist; low high-density lipoprotein-cholesterol; and hypertriglyceridemia), each of which is connected with insulin resistance. It is not known whether the severity of MetS, ranked from the sextet of scores range [0/5 to 5/5], is linearly related to reduced insulin sensitivity (IS) and/or lesser hyperbolic product across the glycemic spectrum. PATIENTS AND METHODS: A total of 839 adults (54 normoglycemic; 785 with abnormal glucose homeostasis, among whom 711 type 2 diabetes mellitus) had insulin sensitivity assessed together with their cardiometabolic phenotype. RESULTS: There was a significant gradient according to interval-scale MetS score in insulinemia; body mass index; (visceral) fat; hepatic steatosis; and macroangiopathy. There was an inverse linear relationship between increasing MetS scores and decreased insulin sensitivity, allowing to define an insulin resistance-predicting linear equation: IS (%) = [-15.1 × MetS score] + 109.4 (R(2) = 0.221). For each MetS category, mean IS values did not significantly differ between groups of patients across the glycemic spectrum. The hyperbolic product (ß-cell function × IS) and/or its loss rate were inversely related to MetS severity. CONCLUSION: Insulin sensitivity is linearly and inversely related to MetS severity across the 6 scores. This novel way to exploit information intrinsic to the MetS criteria provides an easy and low cost means to quantify insulin sensitivity across the glycemic spectrum. Moreover, a higher MetS score is associated with lesser residual insulin secretion, and faster B-cell function loss. Copyright © 2015 John Wiley & Sons, Ltd.

Sflt-1 in heart failure: relation with disease severity and biomarkers.

Soluble fms-like tyrosine kinase-1 (sFlt-1) is an endogenous inhibitor of endothelial growth factors, such as placental growth factor (PlGF), which modulates cardiovascular (CV) remodeling. We determine sFlt-1 levels in patients with heart failure (HF) and its relationship to adverse cardiovascular (CV) events and biomarkers of cardiovascular risk. Levels of sFlt-1 and PlGF levels were also determined in healthy volunteers and patients with type 2 diabetes mellitus (T2DM). SFlt-1 and PlGF were clearly increased in HF patients in comparison to T2DM patients or healthy subjects (p < 0.01). Concentration of sFlt-1 was related to HF severity (p < 0.001) and was correlated to NT-proBNP (ρ = 0.37, p < 0.01), soluble ST2 (ρ = 0.52, p < 0.01), Galectin-3 (ρ = 0.38, p < 0.01), aldosterone (ρ = 0.25, p = 0.01) and PTH(1-84) (ρ = 0.38, p < 0.01). Furthermore, sFlt-1 levels were associated to long-term CV risk. These results suggest a potential role of sFlt-1 in HF and its potential role as biomarker of CV risk.

Baseline diabetes as a way to predict CV outcomes in a lipid-modifying trial: a meta-analysis of 330,376 patients from 47 landmark studies.

BACKGROUND: Diabetes is a major cardiovascular risk factor. However, its influence on the rate of occurrence of cardiovascular (CV) events during a clinical trial that included a diabetes subgroup has not yet been quantified. AIMS: To establish equations relating baseline diabetes prevalence and incident CV events, based on comparator arms data of major lipid-modifying trials. METHODS: Meta-analysis of primary outcomes (PO) rates of key prospective trials, for which the baseline proportion of diabetics was reported, including studies having specifically reported CV outcomes within their diabetic subgroups. RESULTS: 47 studies, representing 330,376 patients (among whom 124,115 diabetics), were analyzed as regards the relationship between CV outcomes rates (including CHD) and the number of diabetics enrolled. Altogether, a total of 18,445 and 16,156 events occurred in the comparator and treatment arms, respectively. There were significant linear relationships between diabetes prevalence and both PO and CHD rates (%/year): y = 0.0299*x + 3.12 [PO] (p = 0.0128); and y = 0.0531*x + 1.54 [CHD] (p = 0.0094), baseline diabetes predicting PO rates between 3.12 %/year (no diabetic included) and 6.11 %/year (all patients diabetic); and CHD rates between 1.54 %/year (no diabetic) and 6.85 %/year (all patients diabetic). The slopes of the equations did not differ according to whether they were derived from primary or secondary prevention trials. CONCLUSIONS: Absolute and relative CV risk associated with diabetes at inclusion can be readily predicted using linear equations relating diabetes prevalence to primary outcomes or CHD rates.

Novel unbiased equations to calculate triglyceride-rich lipoprotein cholesterol from routine non-fasting lipids.

BACKGROUND: Non-fasting triglyceride-rich lipoproteins cholesterol (TRL-C) contributes to cardiovascular risk, in that it includes remnant cholesterol (RC). TRL-C is computed as total C - [LDL-C + HDL-C]. Such calculation applies only if LDL-C is directly measured, or obtained from a non-Friedewald's formula, a method as yet never benchmarked against independent markers of TRL burden. METHODS: The Discriminant Ratio (DR) methodology was used in 120 type 2 diabetic patients in order: (i) to compute TRL-C from non-fasting lipids; (ii) to establish the performance of TRL-C and TRL-C/apoA-I (vs. TG-based markers) to grade TRLs and atherogenic dyslipidemia (AD); and (iii) to relate TRL-C with non-fasting TG. RESULTS: Depending on apoB100 availability, TRL-C (mg/dL) can be derived from non-fasting lipids in two ways: (a) total cholesterol (TC) - [(0.0106 * TC - 0.0036 * TG + 0.017 * apoB100 - 0.27) * 38.6] - HDL-C; and (b) TC - [(0.0106 * TC - 0.0036 * TG + 0.017 * [0.65 * (TC - HDL-C) + 6.3] - 0.27) * 38.6] - HDL-C. Discrimination between log[TG] and TRL-C was similar (DR 0.94 and 0.84, respectively), whereas that of log[TG]/HDL-C was better than TRL-C/apoA-I (DR 1.01 vs. 0.65; p 0.0482). All Pearson's correlations between pairs reached unity, allowing formulation of two unbiased equivalence equations: (a) TRL-C = 97.8 * log[TG] - 181.9; and (b) TRL-C/apoA-I = 8.15 * (log[TG]/HDL-C) - 0.18. CONCLUSIONS: TRL-C and log[TG] are as effective and interchangeable for assessing remnant atherogenic particles. For grading TRL-AD, it is best to use log[TG]/HDL-C, inherently superior to TRL-C/apoA-I, while measuring the same underlying variable.

Discriminant ratio and biometrical equivalence of measured vs. calculated apolipoprotein B100 in patients with T2DM.

BACKGROUND: Apolipoprotein B100 (ApoB100) determination is superior to low-density lipoprotein cholesterol (LDL-C) to establish cardiovascular (CV) risk, and does not require prior fasting. ApoB100 is rarely measured alongside standard lipids, which precludes comprehensive assessment of dyslipidemia. OBJECTIVES: To evaluate two simple algorithms for apoB100 as regards their performance, equivalence and discrimination with reference apoB100 laboratory measurement. METHODS: Two apoB100-predicting equations were compared in 87 type 2 diabetes mellitus (T2DM) patients using the Discriminant ratio (DR). Equation 1: apoB100 = 0.65*non-high-density lipoprotein cholesterol + 6.3; and Equation 2: apoB100 = -33.12 + 0.675*LDL-C + 11.95*ln[triglycerides]. The underlying between-subject standard deviation (SDU) was defined as SDU = √ (SD2B - SD2W/2); the within-subject variance (Vw) was calculated for m (2) repeat tests as (Vw) = Σ(xj -xi)2/(m-1)), the within-subject SD (SDw) being its square root; the DR being the ratio SDU/SDW. RESULTS: All SDu, SDw and DR's values were nearly similar, and the observed differences in discriminatory power between all three determinations, i.e. measured and calculated apoB100 levels, did not reach statistical significance. Measured Pearson's product-moment correlation coefficients between all apoB100 determinations were very high, respectively at 0.94 (measured vs. equation 1); 0.92 (measured vs. equation 2); and 0.97 (equation 1 vs. equation 2), each measurement reaching unity after adjustment for attenuation. CONCLUSION: Both apoB100 algorithms showed biometrical equivalence, and were as effective in estimating apoB100 from routine lipids. Their use should contribute to better characterize residual cardiometabolic risk linked to the number of atherogenic particles, when direct apoB100 determination is not available.

Sleep apnoea syndrome and 10-year cardiovascular risk in females with type 2 diabetes: relationship with insulin secretion and insulin resistance.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) is a risk factor for type 2 diabetes mellitus (T2DM) and promotes cardiovascular events, especially in men. The prevalence of sleep apnoea and its association with microvascular and macrovascular diseases and glycaemic control are poorly documented in T2DM women. METHODS: A total of 305 T2DM women were sleep apnoea diagnosed through (hetero)anamnesis, Epworth's score, oximetry and polysomnography. Sleep apnoea[+] (n = 25) were compared with sleep apnoea[-] (n = 280) regarding cardiovascular risk factors, glucose homeostasis, micro/macrovascular complications and the United Kingdom Prospective Diabetes Study (UKPDS) 10-year risk. RESULTS: Mean (1 SD) age was 66 (12) years, diabetes duration 15 (9) years, sleep apnoea prevalence 8.2% and metabolic syndrome 86%. There were no differences in age, diabetes duration, education, smoking and blood pressure between groups. Sleep apnoea[+] had significantly higher values of body mass index, waist, relative/absolute fat, conicity, visceral fat (all p < 0.0001) and lower skeletal muscle (p = 0.0008). The sleep apnoea[+] group was more insulin resistant [homeostasis model assessment (HOMA S): 37 (20)% versus 59 (44)%; p < 0.0001] and had lesser residual insulin secretion (HOMA B × S: 20 (12)% versus 30 (19)%; p = 0.0006), increased hyperbolic product loss (p = 0.0442) and poorer glycaemic control (HbA1c 69 (12) versus 62 (13) mmol mol(-1) ; p = 0.0099). All atherogenic dyslipidaemia components and inflammatory markers were worsened in sleep apnoea[+]. Women with sleep apnoea had higher UKPDS risk of CAD: 18 (11)% versus 12 (10)% (p = 0.0136). Prevalent micro/macrovascular complications were not different between groups. CONCLUSIONS: Sleep apnoea, a frequent comorbidity of T2DM women, is associated with central fat, atherogenic dyslipidaemia, inflammation, worsening ß-cell function, poorer glycaemic control and coronary artery disease risk. Sleep apnoea may increase residual vascular risk for microvascular and macrovascular events in T2DM women.

Measurement Nt-proBNP circulating concentrations in heart failure patients with a new point-of-care assay.

BACKGROUND: BNP (Brain Natriuretic Peptide) and Nt-proBNP (N-terminal-pro-Brain Natriuretic Peptide) are valuable markers for the diagnosis and prognosis of heart failure (HF). The AQT90 FLEX is a newly released random access analyzer for point-of-care (POCT) measurement. The aim of our study was to determine Nt-pro-BNP concentrations in HF patients with the POCT assay. METHODS: Nt-proBNP levels were measured in seventy seven HF patients and in thirty seven healthy volunteers. The results were compared with a central laboratory assay. RESULTS: Nt-proBNP levels measured with the AQT90 FLEX were significantly correlated with the comparison Nt-proBNP assay and were related to HF severity. CONCLUSIONS: Nt-proBNP testing with the AQT 90 FLEX analyzer is comparable to the central lab assay and may offer the advantages of POCT testing for the diagnosis and prognosis of heart failure.

CA125, Galectin-3 and FGF-23 are interrelated in heart failure with reduced ejection fraction.

Background: Carbohydrate Antigen 125 (CA125) is the most widely used biomarker in ovarian cancer screening. In patients with heart failure (HF), increased levels of CA125 have been observed and related to disease severity. Our objective was to determine the association of CA125 levels with two biomarkers of adverse remodeling in HF patients with reduced ejection fraction (HFrEF). Methods: CA125 circulating levels were determined with an electrochemiluminscent immunoassay. Concentrations of B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and Fibroblast Growth Factor 23 (FGF23) were also measured by immunoassays. Results: CA125 levels were increased in HFrEF, were associated to disease severity according NYHA classes. Median CA125 concentration was also significantly related to cardiovascular mortality. CA125 concentrations were positively and significantly associated to Galectin-3 and FGF23. Conclusions: Concentrations of CA125 are increased in patients with HFrEF, associated to disease severity and adverse cardiovascular outcomes. CA125 levels are also correlated to Galectin-3 and FGF-23, two biomarkers related to fibrosis and cardiovascular remodeling.

The antihyperlipidemic effect of a combined supplement of standardized dry extracts of amla (Emblica officinalis), walnut (Juglans regia), olive (Olea europaea) and red yeast rice (Monascus purpureus) powder: Reduction in circulatory low-density lipoprotein-cholesterol (LDL-C) and remnant cholesterol (RC) levels in patients with hypercholesterolemia.

Background: Hyperlipidemia is associated with a higher rate of cardiovascular, cerebrovascular, and peripheral vascular disease. Conventional drugs such as statins are effective in controlling hyperlipidemia; however, they are associated with various side effects, especially myalgia. Nutraceutical lipid-lowering interventions are becoming increasingly popular, particularly among patients who are intolerant or refractory to statins. Substantial preclinical and clinical evidence suggests that extracts of amla, walnut, and olive, and red yeast rice (RYR) powder possess significant antihyperlipidemic effects. Aims: This study aimed to evaluate the efficacy, safety, and patient satisfaction of a combined supplementation of standardized dry extracts of amla fruit (500 mg), walnut leaves (50 mg), olive fruit (25 mg), and RYR powder (33.6 mg) (Cholesfytol NG®) in hypercholesterolemic patients. Methods: This was a real-life setting, retrospective, observational, single-arm, non-randomized study in hypercholesterolemic patients (total cholesterol (TC) ≥ 200 mg/dL or low-density lipoprotein-cholesterol (LDL-C) ≥ 130 mg/dL), enrolled at 57 general practitioner (GP) surgeries in Belgium from March 2020 to January 2022. These patients received a GP-prescribed daily single dosage of two oral tablets of Cholesfytol NG® supplementation for 2 months to overcome their hypercholesterolemia in the absence of a conventional lipid-lowering drug (n = 208) or with a lipid-lowering drug (n = 13). At 2-month follow-up, the lipid profile was re-evaluated, alongside a patient's questionnaire on treatment general satisfaction and willingness to pursue supplementation. Results: After supplementation, TC decreased by 15%, LDL-C by 19%, non-high-density lipoprotein-cholesterol (non-HDL-C) by 20% (all p < 0.0001), triglycerides (TG) by 9% (p = 0.0028) (-18.4%, p = 0.0042, in patients with baseline TG > 180 mg/dL, n = 58), and remnant cholesterol (RC) by 12% (p = 0.0001). These changes were unaffected by statin intolerance status in patients who received Cholesfytol NG® alongside statin. The supplement was well tolerated by all patients, and no serious adverse events or supplement-emergent effects were reported. Most patients were satisfied with the supplementation and wanted to pursue the nutraceutical. Conclusion: According to the results of this study, a combined supplementation of amla, walnut, and olive extracts, and RYR powder exerts a significant antihyperlipidemic effect, leading to a decrease in circulatory LDL-C and RC levels in patients with hypercholesterolemia. The supplementation bears excellent safety and tolerability, and is rated as satisfactory and pursuable, even among patients with statin intolerance. Clinical Trial Registration: clinicaltrials.gov; identifier number: NCT06002893.

eNOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes.

BACKGROUND: Imbalance in nitric oxide (NO), an atheroprotective vasodilator, is associated with endothelial dysfunction, cardiovascular diseases (CVD) and diabetic complications. Various endothelial NO synthase (eNOS) polymorphisms may affect NO bioavailability, thereby promoting adverse cardiovascular milieu. MATERIALS AND METHODS: To analyze glucose homeostasis, cardiometabolic phenotype, and micro- and macroangiopathies associated with eNOS G894T gene polymorphism in type 2 diabetes (T2DM). 210 T2DM outpatients (mean age (1SD) 70 (12); diabetes duration 19 (9) years; males:females 64:36%; metabolic syndrome 87%) had insulin sensitivity and b-cell function modelled with HOMA, alongside routine laboratory and endothelin measurements. RESULTS: GG, GT and TT genotypes represented 48% (n = 100), 39% (n = 83) and 13% (n = 27). Overall microangiopathy (retinopathy, neuropathy and/or nephropathy) was present in 74%, and overall macroangiopathy (CAD, PAD and/or TIA/stroke) in 45%. The TT genotype did not translate into a more severe vascular phenotype, as TT patients carrying the proposed risk genotype did not suffer a higher rate of micro- and macrovascular complications. On the other hand, erectile dysfunction, present in 60% of males (n = 135), was much more prevalent in TT males: 57% [GG & GT] vs. 93% in TT (p 0.0088). Ocular hypertension/glaucoma frequency (18% of the whole group) was also markedly different, albeit in opposing directions, between eNOS G894T gene polymorphism subgroups: 21% [GG & GT] vs. 0% prevalence (TT; p 0.0057). CONCLUSIONS: eNOS G894T gene polymorphism in homozygous TT carriers translates into opposing effects on erectile function (detrimental) and ocular hypertension/glaucoma (protective) in T2DM, without affecting glucose homeostasis determinants or the presence of micro- and macrovascular complications.

The atherogenic dyslipidemia ratio [log(TG)/HDL-C] is associated with residual vascular risk, beta-cell function loss and microangiopathy in type 2 diabetes females.

BACKGROUND: Atherogenic dyslipidemia (AD), defined as low HDL-C plus elevated triglycerides (TG), comorbid to T2DM, increases cardiometabolic risk for CAD even when LDL-C is at target. In T2DM males, AD was shown to correlate with ß-cell function loss, yet it is not established whether this applies across gender. AIM: To establish the prevalence and severity of AD in T2DM females, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year absolute CV risk (UKPDS Risk Engine). METHODS: 340 T2DM females were ranked according to quintiles (Q) of the continuous variable log(TG)/HDL-C, with AD prevalence defined as HDL-C <50 mg.dL(-1) plus TG ≥150 mg.dL(-1), and ß-cell function assessed with HOMA. RESULTS: AD prevalence was 35%; mean HDL-C and TG were 52 (15) and 160 (105) mg.dL(-1). AD was significantly related to central fat, metabolic syndrome, sedentarity and skeletal sarcopenia, as well as to (hs)CRP, fibrinogen, uric acid, cystatin-C, Big ET-1, and 10-year UKPDS CV risk. AD correlated stepwise with lower ß-cell function and hyperbolic product, and with accelerated loss of residual insulin secretion, higher HbA(1c) and prevalent microangiopathy. CONCLUSIONS: log(TG)/HDL-C is a simple means to grade AD and residual macrovascular risk in T2DM females. This ratio associates with major non-LDL cardiometabolic variables and ranks predicted CAD risk. In addition, log(TG)/HDL-C identifies worsening glucose homeostasis, poorer glycemic control, and prevalent microangiopathy.

Treatment with sodium-glucose cotransporter-2 inhibitors in heart failure patients: The potential benefits of monitoring FGF-23 levels?

Inhibitors of sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown effective glucose-lowering effects associated with improved clinical outcomes in diabetic patients and heart failure patients. As SGLT2 inhibitors can increase phosphate levels, they can also modulate FGF-23 production, a hormone directly involved in regulation of bone and mineral metabolism, but also a strong predictor of adverse cardiovascular events. We therefore discuss the relevance of FGF-23 as a companion testing of SGLT2 treatment, in addition to standard clinical biology tests.

Fatty liver and atherogenic dyslipidemia have opposite effects on diabetic micro- and macrovascular disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver (FL) is comorbid with obesity, metabolic syndrome and type 2 diabetes. Atherogenic dyslipidaemia (AD), frequent in FL, is associated with risk of micro- and macrovascular complications. Given the paradoxical ocular protection of FL in T2DM, we studied how FL modulates micro- and macrovascular complications as a function of AD. METHODS: Cross-sectional factorial analysis of 744 diabetic patients in whom FL, identified by ultrasonography, was present in 68%. AD, defined by low HDL-C plus elevated TG, was present in 45%. Four groups were analysed as regards cardiometabolic features, micro-/macroangiopathies, cataract and ocular hypertonia: FL[-]AD[-] (n = 171); FL[-]AD[+] (n = 66); FL[+]AD[-] (n = 235); and FL[+]AD[+] (n = 272). RESULTS: Age, gender and glycemic control were similar across groups. Prevalence of overall macroangiopathy and coronary artery disease were higher in patients with AD, irrespective of FL. Overall macroangiopathy was higher, by 64% in FL[-]AD[+] and by 38% in FL[+]AD[+]. Coronary artery disease was higher, by 128%, in FL[-]AD[+], and by 67%, in FL[+]AD[+]. (Micro)albuminuria was more frequent (+55%) in FL[-] AD[+] compared to FL[-] AD[-]. Retinopathy prevalence was 35% in FL[-], unaffected by AD. Retinopathy frequency was much lower in FL[+], irrespective of AD, decreased by -47% in FL[+]AD[-] and -32% in FL[+]AD[+] (vs. FL[-]AD[-]). Ocular hypertonia was present in 13%, and its prevalence was also markedly lower (-31%) in FL[+]. Cataract frequency was 29%, also lesser in FL[+] (24% vs. 39%), irrespective of AD. CONCLUSIONS: Multi-level eye protection in diabetes is linked to non-alcoholic fatty liver independently of atherogenic dyslipidemia.

Non-HDL-cholesterol as valid surrogate to apolipoprotein B100 measurement in diabetes: Discriminant Ratio and unbiased equivalence.

BACKGROUND: Apolipoprotein B100 (apoB) is a superior indicator of CV risk than total or LDL-C. Non-HDL-C represents a simple surrogate for apoB in hypertriglyceridemic and/or T2DM patients. ApoB and non-HDL-C show high correlation, although the degree of mutual concordance remains debated in CV risk evaluation. OBJECTIVES: We used the Discriminant Ratio (DR) methodology to compare the performance of non-HDL-C with that of apoB to rank diabetic patients according to dyslipidemia and to establish the underlying relationship between these variables taking measurement noise and intra-/intersubject variation into account, and to derive an unbiased equivalence equation. METHODS: Fasting total C, HDL-C, apoB and triglycerides were measured in 45 diabetic patients. The DR of the underlying between-subject standard deviation (SD) to the within-subject SD was calculated from duplicates. Correlation coefficients between pairs were adjusted to include an estimate of the underlying correlation. RESULTS: Mean values [day 1 (1SD)] were 143 (36) mg/dl (non-HDL-C) and 98 (24) mg/dl (apoB). The DR's of both parameters were similar (1.76 and 1.83) (p = 0.83). Pearson's product-moment correlation coefficient between tests was very high (0.94), reaching unity (1.00) after attenuation adjustment. The unbiased equation of equivalence relating apoB to non-HDL-C had a slope of 0.65 and an intercept of 6.3 mg/dl. CONCLUSIONS: The discrimination power of non-HDL-C is similar to that of apoB to rank diabetic patients according to atherogenic cholesterol and lipoprotein burden. Since true correlation between variables reached unity, non-HDL-C may provide not only a metabolic surrogate but also a candidate biometrical equivalent to apoB, as non-HDL-C calculation is readily available.

Lipid and cardiometabolic features of T2DM patients achieving stricter LDL-C and non-HDL-C targets in accordance with ESC/EAS 2019 guidelines.

BACKGROUND: New recommendations call for lowering LDL-C < 55 mg/dL and non-HDL-C < 85 mg/dL in very-high cardiovascular risk (VH-CVR) patients with type 2 diabetes (T2DM). This study assessed the proportion of VH-CVR diabetics currently meeting these primary and secondary lipid targets, and which therapies/phenotypes predict combined goals achievement. METHODS: We analysed the cardiometabolic phenotype, use of lipid-modulatind drugs (LMD), pre- and post-LMD lipids levels, and CV complications among 1196 T2DM with high (n = 221; 18%) or VH-CVR (n = 975; 82%). Among the latter, the characteristics of combined lipid goal-achievers (n = 158) were compared to those of non-achievers (n = 817), with subgroup analyses of on-statin patients (n = 732) and those with established CVD taking statins (n = 362). Presence of statin-associated muscle symptoms (SAMS) was also recorded. RESULTS: 75% of VH-CVR patients were on statins. Both LDL-C and non-HDL-C goals were achieved by 16.2% of all VH-CVR, 19.3% of on-statin VH-CVR, and 24.3% of patients with established CVD taking statins. Achieving both targets was associated with high-intensity statins, specifically rosuvastatin, [statin + ezetimibe] combination, lower baseline LDL-C, smaller LDLs, lower TG and lipoprotein(a), and reduced metabolic syndrome frequency. SAMS reporting did not differ between achievers and non-achievers. CONCLUSIONS: More than 80% of patients are above targets. To bridge this gap, apart from treating more LMD-naive/refractory diabetics, one should consider for LDL-C to put most patients on high-intensity statins, more often with ezetimibe and, within statins, to switch preferably to rosuvastatin. As regards non-HDL-C, the off-target patients' phenotype suggests that intensifying lifestyle measures against metabolic syndrome should supplement current therapies.

Heart-type fatty acid binding protein is related to severity and established cardiac biomarkers of heart failure.

Objectives: To determine concentrations of heart-type fatty acid-binding protein (HFABP) in patients with heart failure with reduced ejection fraction (HFrEF) and its potential value for prognostic assessment. Methods: Circulating levels of HFABP were measured with an automated chemiluminescent immunoassay in 25 healthy volunteers and 60 HFrEF patients. Results: Concentrations of HFABP were significantly increased in heart failure patients in comparison to healthy volunteers. HFABP levels were significantly correlated to New York Heart Association classes and to established biomarkers of cardiac dysfunction and remodeling (amino-terminal pro-B-type natriuretic peptide [NT-proBNP], fibroblast growth factor 23, and galectin-3). HFABP concentrations were also predictive of cardiovascular (CV) death and combination with NT-proBNP might be synergistic for risk assessment. Conclusions: HFABP levels are increased in HFrEF patients, related to adverse CV outcomes, and might assist physicians for patient's management.

Prognostic Value of Pulmonary Transit Time by Cardiac Magnetic Resonance on Mortality and Heart Failure Hospitalization in Patients With Advanced Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Pulmonary transit time (PTT) from first-pass perfusion imaging is a novel parameter to evaluate hemodynamic congestion by cardiac magnetic resonance (cMR). We sought to evaluate the additional prognostic value of PTT in heart failure with reduced ejection fraction over other well-validated predictors of risk including the Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. METHODS: We prospectively followed 410 patients with chronic heart failure with reduced ejection fraction (61±13 years, left ventricular (LV) ejection fraction 24±7%) who underwent a clinical cMR to assess the prognostic value of PTT for a primary endpoint of overall mortality and secondary composite endpoint of cardiovascular death and heart failure hospitalization. Normal reference values of PTT were evaluated in a population of 40 asymptomatic volunteers free of cardiovascular disease. Results PTT was significantly increased in patients with heart failure with reduced ejection fraction as compared to controls (9±6 beats and 7±2 beats, respectively, P<0.001), and correlated not only with New York Heart Association class, cMR-LV and cMR-right ventricular (RV) volumes, cMR-RV and cMR-LV ejection fraction, and feature tracking global longitudinal strain, but also with cardiac output. Over 6-year median follow-up, 182 patients died and 200 reached the secondary endpoint. By multivariate Cox analysis, PTT was an independent and significant predictor of both endpoints after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. Importantly in multivariable analysis, PTT in beats had significantly higher additional prognostic value to predict not only overall mortality (χ2 to improve, 12.3; hazard ratio, 1.35 [95% CI, 1.16-1.58]; P<0.001) but also the secondary composite endpoints (χ2 to improve=20.1; hazard ratio, 1.23 [95% CI, 1.21-1.60]; P<0.001) than cMR-LV ejection fraction, cMR-RV ejection fraction, LV-feature tracking global longitudinal strain, or RV-feature tracking global longitudinal strain. Importantly, PTT was independent and complementary to both pulmonary artery pressure and reduced RV ejection fraction<42% to predict overall mortality and secondary combined endpoints. CONCLUSIONS: Despite limitations in temporal resolution, PTT derived from first-pass perfusion imaging provides higher and independent prognostic information in heart failure with reduced ejection fraction than clinical and other cMR parameters, including LV and RV ejection fraction or feature tracking global longitudinal strain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03969394.