Association between Diet Quality and Risk of Type 2 Diabetes Mellitus in Patients with Coronary Heart Disease: Findings from the CORDIOPREV Study.

The incidence of type 2 diabetes mellitus (T2DM) is growing in Western countries. Nutritional interventions that promote high-quality dietary patterns could help reverse this trend. We aimed to evaluate whether changes in Nutrient-Rich Food Index 9.3 (NRF9.3) were related to the risk of developing T2DM in patients with coronary heart disease (CHD). The study was carried out in the context of two healthy dietary interventions (a Mediterranean and a low-fat diet). For this purpose, we evaluated all the patients in the CORDIOPREV study without T2DM at baseline. Data were obtained during the first 5 years of dietary intervention. The score was calculated using the Food Frequency Questionnaires at baseline and after 1 year of intervention. After 5 years of follow-up, 106 patients developed T2DM (incident-T2DM), while 316 subjects did not (non-T2DM). Total NRF9.3 score and changes during the first year of intervention were compared between incident-T2DM and non-T2DM. Incident-T2DM showed less improvement in NRF9.3 than non-T2DM (p = 0.010). In the multi-adjusted Cox proportional hazard study, patients with greater improvement in NRF9.3 had over 50% less risk of developing T2DM compared with the lowest tertile (HR 2.10, 95%, CI = 1.12-3.56). In conclusion, improved diet quality in terms of nutrient density after the dietary intervention was associated with a lower risk of T2DM in patients with CHD.

Maturity-onset diabetes of the young (MODY) - in search of ideal diagnostic criteria and precise treatment.

Maturity-onset diabetes of the young (MODY) is a spectrum of clinically heterogenous forms of monogenic diabetes mellitus characterized by autosomal dominant inheritance, onset at a young age, and absence of pancreatic islets autoimmunity. This rare form of hyperglycemia, with clinical features overlapping with type 1 and type 2 diabetes mellitus, has 14 subtypes with differences in prevalence and complications occurrence which tailor therapeutic approach. MODY phenotypes differ based on the gene involved, gene penetrance and expressivity. While MODY 2 rarely leads to diabetic complications and is easily managed with lifestyle interventions alone, more severe subtypes, such as MODY 1, 3, and 6, require an individualized treatment approach to maintain a patient's quality of life and prevention of complications. This review summarizes current evidence on the presentation, diagnosis, and management of MODY, an example of a genetic cause of hyperglycemia that calls for a precision medicine approach.

Residual cardiovascular risk: When should we treat it?

Cardiovascular disease (CVD) still being the most common cause of death in worldwide. In spite of development of new lipid-lowering therapies which optimize low-density lipoprotein cholesterol (LDL-c) levels, recurrence of CVD events implies addressing factors related with residual cardiovascular (CV) risk. The key determinants of residual CV risk include triglyceride-rich lipoproteins (TRLs) and remnant cholesterol (RC), lipoprotein(a) [Lp(a)] and inflammation including its biochemical markers such as high sensitivity C reactive protein (hs-CRP). On the other hand, unhealthy lifestyle habits, environmental pollution, residual thrombotic risk and the residual metabolic risk determined by obesity and type 2 diabetes (T2D) have a specific weight in the residual CV risk. New pharmacologic therapies and pathways are being explored such as inhibition of apolipoprotein C-III (apoC-III) and angiopoietin-related protein 3 (ANGPTL3) in order to explore if a reduction in TRLs and RC reduce CVD events. Therapeutic target of inflammation plays an attractive way to reduce the atherosclerotic process and to date, approved therapies as colchicine plays a beneficial effect in chronic inflammation and residual CV risk. Lp(a) constitutes one of the most residual CV risk factor due to linkage with CVD and aortic valve stenosis. New and hopeful treatments including antisense oligonucleotides (ASO) and small-interfering ribonucleic acid (siRNA) which interfere in LP(a) codification have been developed to achieve an adequate control in Lp(a) levels. This review points out the paradigms of residual CV risk, discus how we should manage their features and summarize the different therapies targeting each residual CV risk factor.

Consumption of Ultra-Processed Food and Drink Products in a Greek Christian Orthodox Church Fasting Population.

The positive effects of the Mediterranean diet on healthy living are widely known, while the health effects of religious fasting have received increased attention during the last decade. However, no study has focused on the consumption of ultra-processed foods (UPFs) in such populations. Therefore, our aim was to investigate UPF intake and its association with metabolic syndrome (MetS) in a Christian Orthodox church (COC) religious fasting population in Greece. In this cross-sectional study, 400 individuals who follow the Mediterranean diet were included, stratified as COC fasters and non-fasters. Dietary intake data were collected via three 24 h diet recalls and a monthly food frequency questionnaire (FFQ). The NOVA food classification system was used to identify the level of processing and categorize all food items. Fasters consumed significantly less chicken, turkey, and beef and significantly more seafood, fish, snails, soy products, and fresh fruits, in terms of unprocessed or minimally processed foods, as well as significantly more fried potatoes and olives in terms of processed foods when compared with non-fasters. Regarding UPFs, a significantly lower intake of pork sausages, ketchup, and mustard as well as a significantly higher consumption of margarine and tarama dip were recorded in fasters compared with non-fasters. Fasters with MetS more frequently consumed UPFs (such as cheese pastries, biscuits, and cakes) than fasters without MetS (p < 0.05 for all comparisons). Similarly, non-fasters with MetS had an increased intake of UPFs (such as Cypriot bread and Coco Pops breakfast cereals) than non-fasters without MetS. Future research should focus on UPF consumption and its associations with clinical outcomes in such populations, thus providing further data for the potential health effects of COC fasting.

Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery.

The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon. Even though leptin was eventually not proven to be the "standalone magic bullet" for the treatment of common/polygenic obesity, it has been successful in the treatment of monogenic obesity syndromes. Additionally, it shifted the paradigm of treating obesity from a condition due to "lack of willpower" to a disease due to distinct underlying biological mechanisms for which specific pharmacotherapies would be needed in addition to lifestyle modification. Subsequently, the melanocortin pathway proved to be an equally valuable pathway for the pharmacotherapy of obesity. Melanocortin receptor agonists have recently been approved for treating certain types of syndromic obesity. Other molecules- such as incretins, implicated in energy and glucose homeostasis- are secreted by the gastrointestinal tract. Glucagon-like peptide 1 (GLP-1) is the most prominent one, with GLP-1 analogs approved for common/polygenic obesity. Unimolecular combinations with other incretins, e.g., GLP-1 with gastric inhibitory polypeptide and/or glucagon, are expected to be approved soon as more effective pharmacotherapies for obesity and its comorbidities. Unimolecular combinations with other compounds and small molecules activating the receptors of these molecules are currently under investigation as promising future pharmacotherapies. Moreover, metabolic and bariatric surgery has also demonstrated impressive results, especially in the case of morbid obesity. Consequently, this broadening therapeutic armamentarium calls for a well-thought-after and well-coordinated multidisciplinary approach, for instance, through cardiometabolic expertise centers, that would ideally address effectively and cost-effectively obesity and its comorbidities, providing tangible benefits to large segments of the population.

Association between Dietary Patterns and Metabolic Syndrome Risk Factors: A Cross-Sectional Study of Christian Orthodox Church Fasters and Non-Fasters in Greece.

It is well known that the Mediterranean diet contributes to healthy living, prevention of non-communicable diseases, and longevity. A cross-sectional study was conducted with participants from Greece who follow the Mediterranean diet and were further divided into two categories: (i) Christian Orthodox Church (COC) religious fasters and (ii) non-fasters. Four-hundred individuals underwent anthropometric measurements, whereas information regarding dietary intake was collected via three 24 h diet recalls and a monthly food frequency questionnaire. Principal component analysis was performed to derive dietary patterns, whereas associations between dietary patterns and metabolic syndrome (MetS) risk factors were investigated with the general linear model. Non-fasters (n = 200) were found to consume significantly more beef, chicken, turkey, sausage, broth, fried potatoes, ketchup, and mustard, while consuming less seafood, snails, soya, tarama salads, fresh fruits, margarine, olives, and decaf coffee. Two distinct dietary patterns were identified in fasters: (i) the "Mixed Diet" and (ii) the "Plant-based/Fasting Diet" pattern. Moreover, three patterns were identified in non-fasters, and were identified as follows: (i) the "Western Diet", (ii) the "Mixed Diet", and (iii) the "Mediterranean-like Diet" pattern. No significant association was observed between dietary patterns and the prevalence of MetS in our population. Further epidemiological studies should evaluate the links between dietary patterns and MetS prevalence within the adult Greek population.

Gait Analysis, Metabolic Parameters and Adherence to the Mediterranean Diet in Patients with Type 2 Diabetes Mellitus Compared with Healthy Controls: A Pilot Study.

BACKGROUND AND PURPOSE: Patients with type 2 diabetes mellitus (T2DM) are prone to developing diabetic peripheral neuropathy (DPN) with an increased risk of injuries while walking, potentially leading to plantar ulcers. We aimed to assess the early gait changes in T2DM patients without clinical signs of DPN in comparison to age-matched healthy controls (HC). SUBJECTS AND METHODS: One hundred T2DM patients (78 women, mean age: 66.4 ± 11.5 years) and 50 age-matched HC (34 women, mean age 62.1 ± 7.9 years) were evaluated with the PODOSmart® gait analysis device. Anthropometric and biochemical data, as well as dietary habits were collected for all participants. T2DM patients also completed the Diabetes Distress (DS) self-report validated questionnaire. RESULTS: One patient was excluded from the study due to lack of recent biochemical data. Among the T2DM patients, 88.9% reported little or no DS and 11.1% moderate DS. The T2DM group had higher body mass index, waist circumference, systolic blood pressure, glycated hemoglobin A1c, sodium, white blood cell count, triglycerides and low-density lipoprotein cholesterol, but lower high-density lipoprotein cholesterol than HC (p < 0.05 for all comparisons). The MedDiet score was satisfactory in both groups (p > 0.05). Significant differences were found between the two study groups in gaitline heel off, propulsion speed, foot progression angle, time taligrade phase, stride length, walking speed, angle attack, oscillation speed, pronation-supination toe off and clearance. CONCLUSIONS: The T2DM patients without self-reported DS or clinical signs of DPN may exhibit significant differences in several gait parameters analyzed with PODOSmart®. Whether gait analysis can be used as an early diagnostic tool of T2DM complications should be further explored.

Ferroptosis, a new pathogenetic mechanism in cardiometabolic diseases and cancer: Is there a role for statin therapy?

One of the newly recognized types of cell death is ferroptosis which is related to the accumulation of iron and lipid-reactive oxygen species. Ferroptosis is considered a programmed cell death with a different mechanism from apoptosis, necrosis, and autophagy. Emerging evidence suggests that ferroptosis may occur in the context of cardiovascular disease (CVD), cancer, neurodegenerative diseases, and non-alcoholic fatty liver disease (NAFLD). Statins are the first-line therapy for dyslipidemia. The suppression of the HMG-CoA reductase by statins leads to decreased expression of glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation, which in turn results in lipid ROS production and induction of ferroptosis. Experimental data suggest that statins may act as anti-cancer drugs by enhancing tumor cells' ferroptosis. In contrast, statins have also been reported to mitigate ferroptosis in animal models of myocardial ischemia-reperfusion and heart failure. This mini-review presents statin effects on the ferroptosis pathway, based on up-to-date in vivo and in vitro research. Furthermore, the potential impact of these effects on cardiometabolic diseases (e.g., CVD and NAFLD) and cancer is briefly discussed. Overall, there is a need for future studies focusing on statin-induced changes in ferroptosis as a therapeutic approach to such diseases.

Nutrient Intake and Risk Factors for Metabolic Syndrome in Christian Orthodox Church Religious Fasters.

OBJECTIVE: Studies regarding health effects of religious fasting have been increased during the last decade. Our aim was to investigate the impact of adherence to the periodic Christian Orthodox Church (COC) fasting on nutrient intake, body composition, and risk factors for metabolic syndrome (MetS). METHODS: Four-hundred individuals aged 42.6 ± 17.0 years participated in this cross-sectional study. Two-hundred subjects followed the COC fasting since childhood or at least the last twelve consecutive years, and two-hundred subjects did not follow the COC fasting regimes or any other restrictive dietary pattern. Socioeconomic data, lifestyle habits, and physical activity data were collected. Nutritional assessment was performed via two 24 h recalls and a food frequency questionnaire. Anthropometric data and biochemical parameters were also measured. RESULTS: Fasters had a significantly lower daily intake of calories (1547 vs. 1662 kcals, p = 0.009), protein (52 vs. 59 g, p = 0.001), fat (82 vs. 89 g, p = 0.012), and cholesterol (147 vs. 178 g, p = 0.001) compared with non-fasters. Furthermore, fasters reported a healthier way of living, with lower rates of smoking and alcohol consumption (p < 0.001 and 0.002, respectively). Insulin and magnesium levels were significantly higher, whereas levels of urea, transaminases, glucose, and phosphorus were significantly lower, as was DBP in fasters versus non-fasters. Furthermore, MetS prevalence was non-significantly higher in non-faster compared with fasters. CONCLUSION: During a non-fasting period, individuals following the COC fasting recommendations reported lower intake of calories, protein, fat, and cholesterol compared with non-fasters. Fasters tended to have a healthier lifestyle pattern and a lower risk for MetS versus non-fasters. Some biochemical parameters also significantly differed between the two study groups. Further research is warranted to establish the long-term clinical impact of these findings.

The Interplay between Metabolic Syndrome and Religious Fasting in Postmenopausal Women.

Religious fasting that involves abstinence from specific food(s) is part of many religions worldwide and has been gaining attention by the research community during the last years. The study aimed to investigate whether the periodic Christian Orthodox fasting mitigates the changes in body composition, dietary intake, and metabolic syndrome (MetS) in postmenopausal women. One hundred and thirty-four postmenopausal women aged 57.3 ± 6.7 years participated in this study. The Christian Orthodox fasting was followed by 68 postmenopausal women since their childhood, whereas 66 postmenopausal women were non-fasters. Data collection involved anthropometric, biochemical, clinical, and dietary information. Postmenopausal women who fasted according to Christian Orthodox Church recommendations had significantly higher mean fat free mass (45 vs. 44 kg, p = 0.002), hip circumference (104 vs. 99 cm, p = 0.001), and diastolic blood pressure (79 vs. 82 mmHg, p = 0.024). No other differences were found with regards to anthropometric data. Fasters also consumed significantly less fat (78 vs. 91 g, p = 0.006), as well as saturated (19 vs. 23 g, p = 0.015), monounsaturated (41 vs. 47 g, p = 0.018), and polyunsaturated fat (8.5 vs. 10 g, p = 0.023), trans fatty acids (0.5 vs. 2.3 g, p = 0.035), and cholesterol (132 vs. 176 g, p = 0.011). In terms of MetS features, non-fasters had more frequently elevated fasting blood glucose (11.8 vs. 24.2%, p = 0.039) and elevated blood pressure (13.2 vs. 36.4%, p = 0.041) compared with fasters. MetS was more common in non-fasters versus fasters with a marginal level of significance (30.3 vs. 23.5%, p = 0.052). Postmenopausal women who follow the Christian Orthodox fasting regime had lower fat intake, and no other difference in nutrient intake, compared with non-fasters. The latter were more likely to have MetS and some of its components. Overall, periodic abstinence from meat, dairy products, and eggs might play a protective role in postmenopausal women with regard to MetS.

Inclisiran, Low-Density Lipoprotein Cholesterol and Lipoprotein (a).

Dyslipidemia treatment is of major importance in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), which is still the most common cause of death worldwide. During the last decade, a novel lipid-lowering drug category has emerged, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Apart from the two available anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab), other nucleic acid-based therapies that inhibit or "silence" the expression of PCSK9 are being developed. Among them, inclisiran is the first-in-class small interfering RNA (siRNA) against PCSK9 that has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. Importantly, inclisiran therapy may improve low-density lipoprotein cholesterol (LDL-C) target achievement by offering a prolonged and significant LDL-C-lowering effect with the administration of only two doses per year. The present narrative review discusses the ORION/VICTORION clinical trial program that has been designed to investigate the impact of inclisiran on atherogenic lipoproteins and major adverse cardiac events in different patient populations. The results of the completed clinical trials are presented, focusing on the effects of inclisiran on LDL-C and lipoprotein (a) (Lp(a)) levels as well as on other lipid parameters such as apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C). Ongoing clinical trials with inclisiran are also discussed.

Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP).

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.

Higher Plasma Levels of Valerate Produced by Gut Microbiota May Have a Beneficial Impact on Renal Function.

OBJECTIVE: Observational studies have evaluated the relationships among plasma short chain fatty acids (SCFA) produced by gut microbiota, renal function, and risk of chronic kidney disease (CKD). In the present study, Mendelian Randomization (MR) analysis was applied to obtain unconfounded estimates of the casual association of genetically determined plasma valerate (an SCFA) with kidney function and risk of CKD. METHOD: MR was performed by using summary-level data from the largest genome-wide association studies (GWAS) conducted on plasma valerate, CKD, and estimated glomerular filtration rate (eGFR; separately in diabetic and nondiabetic individuals). Inverse variance weighted method (IVW), weighted median-based method, MR-Egger, as well as MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method. RESULTS: No significant association was observed between plasma valerate and CKD (IVW: ß = 0.234, p = 0.744). In contrast, plasma valerate was positively associated with eGFR in the total population (IVW: ß = 0.049, p = 0.022) and among nondiabetic individuals (IVW: ß = 0.058, p = 0.009), but not in the diabetic population (IVW: ß = -0.052, p = 0.603). None of the estimated associations was subjected to significant level of heterogeneity. Furthermore, MR-PRESSO analysis did not show any chance of outlier for all estimates. The pleiotropy test, with very a negligible intercept and insignificant p value, also indicated no chance of pleiotropy for all of our estimations (all p > 0.539). The results of the MR-Robust Adjusted Profile Score were identical with the IVW estimates, highlighting again no possibility of pleiotropy. Results of the leave-one-out method demonstrated that the links were not driven by single-nucleotide polymorphisms. CONCLUSIONS: Individuals with higher plasma valerate levels had better renal function, defined by eGFR. This finding was observed in the total population and in nondiabetic subjects, but not in those with diabetes. Further research is needed to elucidate the links among plasma valerate, kidney function, and CKD.

The role of asymmetric dimethylarginine in endothelial dysfunction and abnormal nitric oxide metabolism in systemic sclerosis: results from a pilot study.

INTRODUCTION/OBJECTIVES: Systemic sclerosis (SSc) is characterized by generalized vasculopathy affecting mainly small vessels while macrovascular involvement is less investigated. The aim of this study was to examine associations between asymmetric dimethylarginine (ADMA) - a biomarker of atherosclerosis - and assessments of macrovascular endothelial function in patients with SSc. METHODS: This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA measurement in serum samples was based on an enzyme immunoassay technique. Participants underwent blood pressure measurement according to 2018 ESC/ESH Guidelines, applanation tonometry for the evaluation of arterial stiffness, and carotid ultrasound for the measurement of the intima-media thickness (cIMT). RESULTS: Eighty-one Caucasians (82.3% female) SSc individuals with mean age 55.44 ± 13.4 years were included in this analysis. The correlation analysis of ADMA levels (unadjusted and adjusted values) with functional and morphological parameters of atherosclerosis revealed no statistically significant associations. Subgroup analysis based on disease duration (≤ 4 years), immunologic profile (SCL-70 and ACA antibodies), disease type (limited, diffuse), and inflammatory status (erythrocyte sedimentation rate [ESR] > 25 mm/h and C-reactive protein [CRP] > 5 mg/L) showed no associations, except from a significant positive correlation between ADMA levels and cΙΜΤmean (r = 0.370, p = 0.044) in individuals with early SSc. CONCLUSIONS: The results of the study suggest that ADMA may be related with accelerated atherosclerosis in early stages of the disease. However, the lack of association between other morphological and functional parameters of endothelial dysfunction may suggest that other regulators of nitric oxide metabolism may contribute to macrovascular injury in SSc in various phases of the disease. Key Points • ADMA is a biomarker of atherosclerosis and has been linked with microvascular complications of SSc. •ADMA was not correlated with morphological and functional parameters of atherosclerosis in the population of the study. •The demonstrated association between ADMA and cIMT in patients with early SSc may suggest a role of NO/ADMA pathway in the initiation of macrovascular injury in SSc.

Adherence to a Mediterranean lifestyle improves metabolic status in coronary heart disease patients: A prospective analysis from the CORDIOPREV study.

BACKGROUND AND OBJECTIVES: A Mediterranean lifestyle may prevent and mitigate cardiometabolic disorders. We explored whether adherence to a Mediterranean lifestyle was prospectively associated with the risk of metabolic syndrome (MetS) among coronary heart disease (CHD) patients. METHODS: The Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study was an interventional diet study to compare a Mediterranean diet with a low-fat diet, in 1002 CHD patients. The Mediterranean lifestyle (MEDLIFE) index was used to assess adherence to a MEDLIFE at baseline, and after 5 years, in 851 participants from the CORDIOPREV study. Subjects were classified as having high (>13 points), moderate (12-13 points), and low (<12 points) adherence to the MEDLIFE. Multivariable logistic regression models were used to determine the association between MEDLIFE adherence and the risk of MetS development or reversal. RESULTS: During the 5-year follow-up, CORDIOPREV participants with high adherence to MEDLIFE had a lower risk of MetS development (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.75, p < 0.01) and a higher likelihood of reversing preexisting MetS (OR 2.08 CI 95% 1.11-3.91, p = 0.02) compared with participants in the low MEDLIFE adherence group. Each additional one-point increment in the MEDLIFE index was associated with a 24% lower risk of MetS development (OR 0.76, 95% CI 0.64-0.90, p < 0.01) and a 21% higher likelihood of reversing preexisting MetS (OR 1.21 CI 95% 1.04-1.41, p = 0.01). CONCLUSIONS: Our results showed that greater adherence to a MEDLIFE reduced the risk of subsequent MetS development and increased the likelihood of reversing preexisting MetS among patients with CHD at baseline.