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Abstract 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 β-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 -1 plus TG ≥150 mg.dL-1, and β-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 hsCRP, fibrinogen, uric acid, cystatin-C, Big ET-1, and 10-year UKPDS CV risk. AD correlated stepwise with lower β-cell function and hyperbolic product, and with accelerated loss of residual insulin secretion, higher HbA1c 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.

Cholesfytol®, a lipid-lowering dietary supplement with antioxidant and anti-atherosclerotic properties, combines red yeast rice (RYR) and olive extract (5mg hydroxytyrosol equivalent) and represents an alternative for patients who do not wish or are unable to use chemical statins, including individuals with previous statin-associated muscle symptoms (SAMS). A 2-months observational non-randomized study was performed to evaluate the efficacy, tolerance and safety of Cholesfytol® (1 tablet/day) in 642 hypercholesterolemic patients (mean age: 59 yrs; total cholesterol (TC) ≥200; LDL-C ≥140mg/dl). Patients were followed by 126 GPs, and included irrespective of SAMS history and/or diabetes. None of the patients were taking statins or other lipid-modifying therapy at inclusion. At baseline, 26% had fasting glucose >100 ≤125mg/dL, and 5% >125mg/dL; 32% (n=194) had a SAMS history; and 21% had atherogenic dyslipidemia (AD). In the entire cohort, pre-treatment TC; non-HDL-C; LDL-C; and TG were 259; 200; 168; 158mg/dL, respectively, and decreased significantly on treatment (-17.5% (TC) and -23.3% (LDL-C)). Fasting glucose and HbA1c decreased between visits. The reduction in lipids was greater in patients with higher values at baseline. For comparable pre-treatment values, patients with SAMS history had reductions in TC, LDL-C, non-HDL-C, and apoB100 slightly less than patients without myalgia. AD patients had greater on-treatment decrease in TG. Overall, 13 patients reported minor side-effects, and 4 patients reporting myalgia had antecedent SAMS. In conclusion, a substantial decrease in LDL-C was obtained with a combination of RYR and olive extract in high-risk hypercholesterolemic patients, without inducing new-onset SAMS. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Non-diabetic offspring from long-lived parents benefit from lowered CV risk. No study investigated the effects of parental lifespan on their progeny when offspring have T2DM. This study assessed CV and metabolic features of T2DM offspring according to parental lifespan. Patients & Methods: 558 T2DM patients were questioned on parental longevity (paternal and/or maternal lifespan ⩾80 years); mean age 66 (11) years; male:female 66:34; divided into 6 groups: long-lived father [LLF] (n = 143); short-lived father [SLF] (n = 262); long-lived mother [LLM] (n = 229); short-lived mother [SLM] (n = 176); long-lived father and long-lived mother [LLF & LLM] (n = 82); and short-lived father and/ or short-lived mother [SLF &/or SLM] (n = 323). Results: Age was similar in [LLF & LLM] and [SLF &/or SLM]. Diabetes duration was longer in [SLF &/or SLM] (p 0.0073). Body composition, hypertension, hepatic steatosis and metabolic syndrome (MetS) were similar in both groups, [SLF &/or SLM] having a higher MetS score: 3.79 (1.12) vs. 3.48 (1.12) (p 0.0257). Fasting insulinemia was higher in [SLF &/or SLM] (p 0.0001), who were more insulin resistant (+10%: p 0.0440). HbA1c was higher (+0.36%) in [SLF &/or SLM] (p 0.0138). LDL-C; non-HDL-C; and apoB100 were similar in both groups, whereas HDL-C and apoA-I were higher in [LLF & LLM] (p 0.0233 and p 0.0179). Prevalence and severity of atherogenic dyslipidemia were raised in [SLF &/or SLM], by 53% (prevalence) and 13% (log[TG]/ HDL-C) (p 0.0172 and p 0.0067). Conclusion: Bilateral reductions in parental longevity are linked to unfavorable cardiometabolic phenotype in T2DMdescendants,with worsened insulin resistance and atherogenic dyslipidemia among 1st-degree offspring. [ABSTRACT FROM AUTHOR]

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 β-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. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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Urate, a naturally-occurring antioxidant, is a marker/factor for cardiovascular disease. Hyperuricaemia is associated with IR, MetS and endothelial dysfunction. We characterised the associations between neurohormones, uricaemia, and glucose homeostasis in type 2 diabetes mellitus (T2DM) males. Cross-sectional; 705 T2DM males divided into two groups: uric acid < 7.0 mg/dl (normouricaemic; n=476) versus uric acid ≥ 7.0 mg/dl (hyperuricaemic; n=229). HOMA beta-cell function (B), insulin sensitivity (S), hyperbolic product (B×S), and (B×S) loss rate were determined alongside neurohormones (Nt-proANP, BNP, Big ET-1 and UII). Mean age and diabetes duration were not different between groups. Hyperuricaemics had more macroangiopathy, total/central adiposity, IR, hypertension, dyslipidemia and MetS prevalence. Nt-proANP and BNP levels were more than twice as high in hyperuricaemics, whereas Big ET-1 and UII were higher by 46% and 14%, respectively. HOMA (B×S) was higher in hyperuricaemics: 31 (16)% vs. 26 (18)% (p=0.0004). B×S loss rate was faster in normouricaemics: 1.36 (0.54)% vs. 1.20 (0.43)%/year-1 (p<0.0001 ). The proportion with HbA1C < 7.0% was 39% (normouricaemics) vs. 49% (hyperuricaemics; p=0.0091). In T2DM males, hyperuricaemia is associated with raised neurohormones together with better beta-cell indices. Urate's dual properties may translate into beneficial (glucose homeostasis) and detrimental (raised neurohormones) effects. [ABSTRACT FROM PUBLISHER]

Summary: Aims: An unfavourable upregulation of neurohormonal profile is present in type 2 diabetes (T2DM). Little is known regarding neurohormonal profile and cardiovascular (CV) risk in diabetic women in primary prevention. Methods: We therefore explored gender-associated disparities in neurohormonal profile and modeled cardiovascular risk in this population (n =231) and modeled its 10-year risk of lethal and non-lethal coronary heart disease (CHD) and stroke using the UKPDS Risk Engine, a diabetes-specific risk calculator. Results: There were significant differences between female and male patients (n =311) with respect to all measured neurohormones, which were higher in women by a mean 27% for N-terminal pro-atrial natriuretic peptide, 8% for Big endothelin-1 (Big ET-1), 25% for brain natriuretic peptide and 24% for urotensin II. While risk estimates for women were significantly lower than those in males with respect to non-fatal and fatal CHD, fatal CHD, non-fatal and fatal stroke, they were nevertheless worryingly high for females, reaching 68%, 72%, and 76% of the corresponding risks in males. Female patients with T2DM in primary prevention with a high prevalence of hypertension and metabolic syndrome (MetS) exhibit a significant sexual dimorphism in circulating neurohormones. Conclusions: We conclude that these incremental differences may intervene in raising the true CV risk observed in female subjects with diabetes or insulin resistance, or in accruing the predicted risk computed by models such as the UKPDS Risk Engine. [Copyright &y& Elsevier]

Summary: Background and objectives: Insulin modulates key regulators of vascular tone, including endothelin-1 (ET-1), hence insulin resistance (IR) and/or hyperinsulinemia may contribute to the pathogenesis of hypertension and cardiovascular disease (CVD). Imbalance in ET-1/nitric oxide may link IR to CVD. Little is known on the relation between neurohormones, metabolic syndrome (MetS) categories (1–5/5) in type 2 diabetes (T2DM). We therefore sought to assess the relationship between neurohormonal profile, CVD and MetS in a large T2DM cohort, as well as the associations between neurohormones, insulinaemia, insulin sensitivity, CVD markers and events within MetS categories. Methods: In 455 consecutive T2DM patients with or without MetS [MetS (+)/(−)] defined according to AHA/NHLBI, we assessed the following: MetS categories, HOMA-S, circulating Big-endothelin-1 (Big ET-1), natriuretic peptides and macroangiopathy [Macro (+)/(−)]. Results: Big ET-1 was higher by 30%, in MetS (+) (median [IQ range]): 5.2 [4.3–6.0]pgml−1 in MetS (−) (n =75) versus 6.7 [5.2–9.1]pgml−1 in MetS (+) (n =380; P <0.0001). There was a progression in Big ET-1 across MetS scores: 6.3 [5.2–8.5]pgml−1 in MetS (+) 3/5; 6.9 [5.1–9.4]pgml−1 in MetS (+) 4/5 and 7.3 [5.6–9.5]pgml−1 in MetS (+) 5/5 (NS). The incremental difference in Big ET-1 between MetS (+) and MetS (−) was found out both in the absence or presence of macroangiopathy: 4.55 [4.03–5.25]pgml−1 in MetS (−) Macro (−) versus 5.70 [4.60–7.50]pgml−1 in MetS (+) Macro (−) (P <0.0001), and 5.70 [5.20–7.60]pgml−1 in MetS (−) Macro (+) versus 7.60 [5.80–10.13]pgml−1 in MetS (+) Macro (+) (P <0.0001), respectively. Such patterns were not observed with natriuretic peptides. Comparison between MetS (+) Macro (−) versus MetS (−) Macro (+) confirms that such incremental differences should not be solely ascribed to parallel shifts in IR and/or compensatory hyperinsulinaemia. Conclusions: Big ET-1 is raised in T2DM patients with MetS, and its level proceeds stepwise to MetS categories. Elevated Big ET-1 is present in all categories of MetS patients, with or without macroangiopathy. The ascent in Big ET-1 found in MetS (+) without macrovascular disease is of the same magnitude as that conferred by the presence of macroangiopathy. [Copyright &y& Elsevier]

Summary: Objectives: We sought to use the Discriminant Ratio (DR) method to compare the respective performance of low-density lipoprotein-cholesterol (LDL-C)/high-density lipoprotein (HDL)-C and apolipoprotein B (ApoB)/ApoA1 ratios to rank diabetics according to dyslipidemia severity. Background: ApoB/ApoA1 was proposed as robust alternative to well-established LDL-C/HDL-C in ranking subjects according to their cardiovascular risk, while non-HDL-C was advocated as secondary target in metabolic syndrome. Nevertheless, the discriminatory superiority of these new markers remains unknown in diabetes. Methods: Forty-five subjects with types 1 (n =23) and 2 diabetes (n =22) were studied. Total-, HDL-C and triglycerides were measured by enzymatic assays and ApoB and ApoA1 by immunonephelometry. DR is the ratio of the underlying between-subject standard deviation (S.D.) to the within-subject S.D., calculated from log duplicates sampled on different days. Correlation coefficients between pairs of measurements were adjusted to include an estimate of the underlying correlation, since standard coefficients tend to underestimate the true correlation between tests due to the presence of within-subject variation. Results: Mean values (day 1 (±1S.D.)) were 2.25 (0.87) for LDL-C/HDL-C, and 0.63 (0.20) for ApoB/ApoA1, respectively. The highest DRs were those of total C/HDL-C and non-HDL-C/HDL-C (2.33 and 2.38; p <0.05 and <0.02 versus the DR of LDL-C/HDL-C). The DR of ApoB/ApoA1 (2.12) was non-significantly higher than that of LDL-C/HDL-C (1.45). Conclusions: ApoB/ApoA1 does not provide greater discrimination than LDL-C/HDL-C to rank a diabetic population. The best approach is obtained with total C/HDL-C and new candidate marker non-HDL-C/HDL-C, both easy and cost-effective means to stratify diabetics according to their lipid profile. [Copyright &y& Elsevier]

Background Type 2 diabetes (T2DM) is associated with obesity, insulin resistance and the metabolic syndrome (MetS). In non-diabetic populations, features of metabolic obesity (MO) are observed in a minority of normal-weight (NW) subjects. The cardiometabolic status of metabolically obese but normal-weight (MONW) individuals has not yet been phenotyped in T2DM. Patients and methods Prevalence and features of MONW were analyzed in 1244 T2DM patients, in whom MONW was identified as a BMI <25.0 and a MetS score ≥3/5. Among NW ( n = 262; 21%), those without MetS ( n = 152; NW-MetS[−]) were compared to NW-MetS[+] ( n = 110; i.e. 42% of NW and 9% of all T2DM). Results There were no differences between groups in age; gender; diabetes duration; smoking; BP; and LDL-C. NW-MetS[+] had higher BMI; waist; fat mass; visceral fat; liver steatosis and HbA 1c , and lower insulin sensitivity. Non-right-handedness was twice-higher (18%) in NW-MetS[−]. NW-MetS[+] had higher apoB 100 and triglycerides, and lower HDL-C and LDL size. Macroangiopathy was present in 39% of NW-MetS[+] vs. 22% of NW-MetS[−], as coronary (23% vs. 14%) or peripheral artery disease (14% vs. 5%) and TIA/stroke (15% vs. 7%). Microangiopathy was present in 54% of NW-MetS[+] vs. 32% of NW-MetS[−], as retinopathy (25% vs. 13%); neuropathy (29% vs. 18%); and albuminuria (39% vs. 20%). Conclusions MONW among T2DM represents a significant minority (about 1 in 10). Their cardiometabolic phenotype deserves attention due to multiple comorbidities, including a twice-higher prevalence of micro-/macrovascular damage in patients wrongly perceived at lower risk due to normal BMI. Unexpectedly, non-right-handedness was over-represented among metabolically healthy patients. [ABSTRACT FROM AUTHOR]

Abstract Fibroblast growth factor 23 (FGF-23), a key hormone for the regulation of the phosphorus homeostasis, has also several direct effects on cardiac function. In heart failure (HF), the increase of FGF-23 participates to cardiac hypertrophy and remodeling. Measurement of the intact, biologically active hormone is now available. We determined intact FGF-23 in HF patients with reduced ejection fraction and assess its prognosis value for cardiovascular death over a long-term follow-up. We observed that intact FGF-23 is an independent predictor of cardiovascular death in HF patients and provides added value to the standard of care, natriuretic peptide, for risk estimation. Highlights • FGF-23 is a key regulator of the phosphorus homeostasis. • FGF-23 has several direct effects on cardiac function. • We showed that intact FGF-23 is an independent predictor of cardiovascular death in HF. • Intact FGF-23 provides added value to NT-proBNP for prognostication of HF patients. [ABSTRACT FROM AUTHOR]