Is Atorvastatin Associated with New Onset Diabetes or Deterioration of Glycemic Control? Systematic Review Using Data from 1.9 Million Patients.

BACKGROUND: Current evidence indicates that statins increase the risk of new onset diabetes mellitus (NOD) and also deteriorate the glycemic control in patients with known diabetes mellitus (DM) after high-dose statin therapy. AIMS: The aim of this review was to explore the effect of atorvastatin in causing NOD or deteriorating glycemic control in patients with DM. METHODS: Two independent reviewers conducted the literature search, through PubMed database searching for articles published in English until April 2015, and only primary studies were included. RESULTS: Of the 919 articles identified in our original search, 33 met the criteria for this review encompassing 1,951,113 participants. Twenty articles examined dysregulation of DM due to atorvastatin. Half of them showed that there was no significant change in glycemic control in patients treated with atorvastatin. Other studies showed that fasting plasma glucose and HbA1c levels were increased by atorvastatin. Thirteen articles examined if atorvastatin causes NOD. The majority of these articles showed that patients who used atorvastatin had a higher dose-dependent risk of developing NOD. CONCLUSION: This systematic review suggests that there is an association between atorvastatin treatment and NOD. Moreover, it showed that atorvastatin in high dose causes worsening of the glycemic control in patients with DM

Association of matrix γ-carboxyglutamic acid protein levels with insulin resistance and Lp(a) in diabetes: A cross-sectional study.

AIMS: The risk of cardiovascular disease (CVD) and mortality is increased in patients with chronic kidney disease (CKD), with a background role of vascular calcification in the development of CVD also reported. Studies have demonstrated that high lipoprotein(a) (Lp(a)) levels accelerate the development of atherosclerolsis and are potentially involved in the vascular calcification. Matrix Gla Protein (MGP) seems to play an important role in vascular calcification. The aim of the study was to examine the potential association of MGP concentrations with Lp(a) and insulin resistance. METHODS: The study involved 100patients divided in four groups: 25 with both CKD stage 4 and Type2 Diabetes (DM) (Group-A), 25 with CKD4 without DM (Group-B), 25 non uremic patients with DM (Group-C) and 25 healthy subjects (Group-D). Serum glucose, Lp(a), MGP, plasma HBA1c and insulin were measured in all patients. Insulin resistance was estimated by the homeostasis model assessment equation (HOMA-IR). RESULTS: A significant positive linear association between MGP and Lp(a) levels (r=0.272, p=0.006) was noted, as well as between MGP and HOMA-IR levels (r=0.308, p=0.002). However, no significant linear association between Lp(a) and HOMA-IR levels was recorded. A similar positive association between MGP and insulin levels (r=0.204, p=0.042) was also found. CONCLUSION: This study concluded that diabetes coexisting with renal disease leads to extreme vascular calcification expressed by elevated MGP levels, resulting in higher frequency of cardiovascular disease in comparison to CKD patients without diabetes. The detected Lp(a) and MGP association in CKD4 patients may also represent the key to the complicated mechanism of their coexisting accelerated atherosclerosis and vascular calcification

Latest data on metabolic diseases: Arterial Hypertension

Hypertension is closely related with increased cardiovascular risk and renal damage and its prevalence is even greater in elderly patients that are a highly heterogeneous group. The identification of hypertensive patients, as well as prompt initiation and timely titration of pharmacologic therapy in addition to lifestyle therapy in order to achieve blood pressure goals is of paramount importance. In general population, blood pressure goals of <140/90mmHg are recommended. However, treatment strategies and pharmacological therapy should be personalized depending on patient characteristics and comorbidities. Some drug agents or combinations should be considered as the preferential choice in specific conditions. However, the combination of two antagonists of the Renin Angiotensin System (RAS) is not recommended and should be discouraged. In elderly hypertensives, it is recommended to reduce Systolic Blood Pressure (SBP) between 150 and 140mmHg, provided they are in good physical and mental conditions, while a target of SBP <140mmHg may be considered, if treatment is also well tolerated. Lifestyle changes, and particularly weight loss and physical exercise, are to be recommended to all individuals with the metabolic syndrome. These interventions improve not only blood pressure, but the metabolic components of the syndrome. Antihypertensive agents that potentially improve or at least not worsen insulin sensitivity, such as RAS blockers and calcium antagonists, should be considered as the preferred drugs. Regarding patients with diabetes, lifestyle therapy and blood pressure goals of <140/90mmHg is generally recommended (American Diabetes Association, 2017). An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and albuminuria. Taking into account several studies and meta-analyses recently published, inquiries have been raised regarding the optimal systolic blood pressure goal and the need for reappraisal of blood pressure thresholds and targets in the forthcoming hypertension guidelines

Association of endothelial progenitor cells (EPCs) and asymmetric dimethylarginine (ADMA) with anthropometric and biochemical parameters of cardiometabolic risk in prediabetes

It has been suggested that impaired endothelial function is present even in early states of diabetes. Endothelial Progenitor Cells (EPCs) are bone marrow-derived cells, which take part in postnatal neovascularization and promote vascular homeostasis. EPCs have been considered as a potential biological marker of cardiovascular disease. Asymmetric dimethylarginine (ADMA) an endogenous inhibitor of nitric oxide synthase is a novel marker of endothelial dysfunction and atherosclerosis in humans. The aim of this study was to investigate the potential associations of EPC levels and ADMA with several cardiovascular risk factors among patients with prediabetes.Fifty-nine participants with newly diagnosed prediabetes and 32 controls were enrolled. Medical history, anthropometric and biochemical parameters, including traditional cardiometabolic risk factors and high sensitivity C-reactive protein (hsCRP), were obtained. Homeostasis model assessment of insulin resistance (HOMA-IR) was estimated. ADMA concentrations were determined by ELISA method. Flow cytometry identified and quantified EPCs (CD34+ KDR+ CD133+cells). Univariate and stepwise multivariate ordinal logistic regression analyses were performed using STATA 11.1 statistical software. The level of statistical significance was set at 0.05. A two-step statistical approach was followed: univariate and multivariate analysis. As appropriate, factors proven significant at the univariate analysis were tested in the multivariate model as independent variables. In multivariate analysis between the two groups ADMA (OR=2.459, 95%CI:1.522-3.974, p<0.0001), HOMA-IR (OR=1.296, 95%CI: 1.029-1.633, p=0.027) and hs-CRP levels (OR=1.171, 95%CI:1.011-1.356, p=0.035) were higher in prediabetes. Moreover, statistical analysis was performed for each group. After performing the multivariate analysis in the control group ADMA levels were significantly associated with: exercise (OR=0.247, 95%CI:0.061-0.996, p=0.049) and smoking (OR=10.522, 95%CI: 1.541-71.854, p=0.016). In prediabetes group ADMA levels were were significantly associated with: age (OR=1.048, 95%CI: 1.006-1.091, p=0.024), ΒΜΙ (OR=1.082, 95%CI: 1.006-1.162, p=0.033) and statins (OR=0.261, 95%CI: 0.081-0.840, p=0.024). Moreover, in control group EPC levels were significantly associated with: age (OR: 0.783, 95%CI:0.683-0.898, p<0.0001), exercise (OR: 65.577, 95%CI:6.080-707.264, p=0.001), smoking (OR:0.006 95%CI:0.0002-0.156, p=0.002) family history of diabetes mellitus (OR: 0.013, 95%CI:0.001-0.164, p=0.001), while in prediabetes group EPCs levels were associated with: ΒΜΙ (OR: 0.845, 95%CI: 0.780-0.916, p<0.0001) and statins (OR: 4.066, 95%CI:1.141-14.494, p=0.031). According to the findings of the present study higher levels of HOMA-IR, hs-CRP and ADMA were observed in prediabetes group in contrast to control group. Taking into account that reduced EPCs and increased ADMA levels are strongly associated with endothelial dysfunction and high cardiometabolic risk, an additional pathophysiological link could be proposed between obesity (negative effect) and statin intake (beneficial effect) with cardiovascular disease even in early stages of prediabetes.Σύμφωνα με μελέτες έχει προταθεί πως διαταραγμένη ενδοθηλιακή λειτουργία παρατηρείται ήδη από τα πρώιμα στάδια του σακχαρώδη διαβήτη. Τα προγονικά ενδοθηλιακά κύτταρα (EPCs) προέρχονται από τον μυελό των οστών, συμμετέχουν στη νεοαγγειογένεση και συμβάλλουν στην ομοιόσταση των αγγείων. Τα προγονικά ενδοθηλιακά κύτταρα θεωρούνται ως ένας δυνητικός δείκτης καρδιαγγειακής νόσου. Επιπρόσθετα, η ασύμμετρη διμεθυλαργινίνη (ADMA), αποτελεί έναν ενδογενή αναστολέα της συνθετάσης του μονοξειδίου του αζώτου και έχει επίσης προταθεί ως ένας πιθανός νέος δείκτης της ενδοθηλιακής δυσλειτουργίας και της αθηροσκλήρωσης. Σκοπός της παρούσας μελέτης ήταν η διερεύνηση των πιθανών συσχετίσεων που εμφάνιζαν τα EPCs και η ADMA με ανθρωπομετρικές, βιοχημικές και λοιπές παραμέτρους καρδιομεταβολικού κινδύνου σε νεοδιαγνωσθέντα άτομα με προδιαβήτη. Στη μελέτη συμπεριλήφθησαν 59 άτομα με νεοδιαγνωσθέντα προδιαβήτη (ομάδα προδιαβήτη) και 32 υγιείς-μάρτυρες (ομάδα ελέγχου). Σε κάθε συμμετέχοντα λήφθηκε υπόψιν το πλήρες ιατρικό ιστορικό και επιπρόσθετα προσδιορίσθηκαν ανθρωπομετρικά και βιοχημικά δεδομένα συμπεριλαμβανομένων διαφόρων παραγόντων καρδιομεταβολικού κινδύνου, καθώς επίσης της υψηλής ευαισθησίας C-αντιδρώσας πρωτεΐνης και του δείκτη ινσουλινοαντίστασης (HOMA-IR). Η ADMA ανιχνεύθηκε και προσδιορίσθηκε ανοσολογικά με την ποσοτική μέθοδο της ανταγωνιστικής ELISA. Τα EPCs ταυτοποιήθηκαν και ποσοτικοποιήθηκαν με τη μέθοδο της κυτταρομετρίας ροής χρησιμοποιώντας τα μονοκλωνικά αντισώματα (CD34+ KDR+ CD133+). Η στατιστική ανάλυση πραγματοποιήθηκε με τη χρήση του στατιστικού προγράμματος STATA 11.1 statistical software. Το επίπεδο της στατιστικής σημαντικότητας ορίστηκε στο p<0.05. Μονομεταβλητές αναλύσεις πραγματοποιήθηκαν για όλες τις παραμέτρους. Οι παράμετροι που αναδείχθηκαν στατιστικά σημαντικές εντάχθηκαν στο πολυμεταβλητό μοντέλο ανάλυσης. Από την πολυπαραγοντική ανάλυση μεταξύ των δύο ομάδων διαπιστώθηκε πως η ομάδα του προδιαβήτη χαρακτηρίζεται από υψηλότερα επίπεδα ADMA (OR=2.459, 95%CI:1.522-3.974, p<0.0001), ινσουλινοαντίστασης εκτιμώμενα με τον δείκτη HOMA-IR (OR=1.296, 95%CI: 1.029-1.633, p=0.027) και hs-CRP (OR=1.171, 95%CI:1.011-1.356, p=0.035). Κατόπιν, πραγματοποιήθηκε επιμέρους στατιστική ανάλυση κατά ομάδες. Συγκεκριμένα, στην ομάδα ελέγχου μετά την πραγματοποίηση και της πολυμεταβλητής ανάλυσης διαπιστώθηκε στατιστικά ανεξάρτητη συσχέτιση των επιπέδων της ADMA με την άσκηση (OR=0.247, 95%CI:0.061-0.996, p=0.049) και το κάπνισμα (OR=10.522, 95%CI: 1.541-71.854, p=0.016). Αντίστοιχα, για την ομάδα του προδιαβήτη σημαντική συσχέτιση διαπιστώθηκε μεταξύ των επιπέδων της ADMA με την ηλικία (OR=1.048, 95%CI: 1.006-1.091, p=0.024) το ΒΜΙ (OR=1.082, 95%CI: 1.006-1.162, p=0.033) και τη λήψη στατινών (OR=0.261, 95%CI: 0.081-0.840, p=0.024). Αναφορικά με τα επίπεδα των EPCs στην ομάδα ελέγχου στατιστική συσχέτιση παρατηρήθηκε με τις παραμέτρους: ηλικία (OR: 0.783, 95%CI:0.683-0.898, p<0.0001), άσκηση (OR: 65.577, 95%CI:6.080-707.264, p=0.001), το κάπνισμα (OR:0.006 95%CI:0.0002-0.156, p=0.002) και το θετικό οικογενειακό ιστορικό σακχαρώδη διαβήτη (OR: 0.013, 95%CI:0.001-0.164, p=0.001) ενώ στην ομάδα του προδιαβήτη με το ΒΜΙ (OR: 0.845, 95%CI: 0.780-0.916, p<0.0001) και τη λήψη στατινών (OR: 4.066, 95%CI:1.141-14.494, p=0.031). Σύμφωνα με τα αποτελέσματα της παρούσας μελέτης τα άτομα με προδιαβήτη συγκριτικά με την ομάδα ελέγχου εμφάνιζαν σημαντικά μεγαλύτερο βαθμό ινσουλινοαντίστασης και φλεγμονής (εκτιμώμενες με το δείκτη HOMA-IR και τα επίπεδα της hs-CRP, αντίστοιχα) καθώς και σημαντικά υψηλότερα επίπεδα ADMA. Δεδομένου, ότι τα μειωμένα επίπεδα των EPCs και αντίστοιχα τα αυξημένα επίπεδα της ADMA συνδέονται με την ενδοθηλιακή δυσλειτουργία και τον υψηλό καρδιομεταβολικό κίνδυνο, καταδεικνύεται ένας πιθανός επιπρόσθετος παθοφυσιολογικός μηχανισμός σύνδεσης της παχυσαρκίας (αρνητική επίδραση) και των στατινών (ευεργετικής δράσης) στην καρδιαγγειακή νόσο ακόμη και από τα πρώιμα στάδια του προδιαβήτη

Neurohormonal Changes in the Gut–Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery

Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut–brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut–brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed

A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64&ndash;10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC

Acute steatohepatitis, due to extreme metabolic dysregulation, as the first presentation of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a slowly progressive chronic disease, with a high prevalence among obese, dyslipidemic or diabetic people, commonly presented as an asymptomatic mild elevation of serum aminotransferases. We report a patient who experienced an acute form of non-alcoholic steatohepatitis, as the first manifestation of NAFLD, due to exacerbation of pre-existing metabolic disorders by an extremely unhealthy lifestyle. A 50-year old, obese, diabetic man presented with a one-week history of jaundice and malaise. Analysis revealed elevated liver enzymes, bilirubin, lipids, and glucose. Based on patient’s history, physical examination, laboratory results, and imaging findings, acute non-alcoholic steatohepatitis was established as a diagnosis of exclusion. The patient was started on a low-calorie diet free of carbohydrates and fats, in combination with insulin. A dramatic improvement of clinical and laboratory parameters was observed. In the context of extreme metabolic dysregulation, induced by unhealthy diet, NAFLD may present as an acute steatohepatitis

HOXB9 Overexpression Promotes Colorectal Cancer Progression and Is Associated with Worse Survival in Liver Resection Patients for Colorectal Liver Metastases

As is known, HOXB9 is an important factor affecting disease progression and overall survival (OS) in cancer. However, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the role of HOXB9 in CRC progression and its association with OS in colorectal liver metastases (CRLM). We analysed differential HOXB9 expression in CRC using the Tissue Cancer Genome Atlas database (TCGA). We modulated HOXB9 expression in vitro to assess its impact on cell proliferation and epithelial-mesenchymal transition (EMT). Lastly, we explored the association of HOXB9 protein expression with OS, using an institutional patient cohort (n = 110) who underwent liver resection for CRLM. Furthermore, HOXB9 was upregulated in TCGA-CRC (n = 644) vs. normal tissue (n = 51) and its expression levels were elevated in KRAS mutations (p &lt; 0.0001). In vitro, HOXB9 overexpression increased cell proliferation (p &lt; 0.001) and upregulated the mRNA expression of EMT markers (VIM, CDH2, ZEB1, ZEB2, SNAI1 and SNAI2) while downregulated CDH1, (p &lt; 0.05 for all comparisons). Conversely, HOXB9 silencing disrupted cell growth (p &lt; 0.0001). High HOXB9 expression (HR = 3.82, 95% CI: 1.59&ndash;9.2, p = 0.003) was independently associated with worse OS in CRLM-HOXB9-expressing patients after liver resection. In conclusion, HOXB9 may be associated with worse OS in CRLM and may promote CRC progression, whereas HOXB9 silencing may inhibit CRC growth

Association of matrix gamma-carboxyglutamic acid protein levels with insulin resistance and Lp(a) in diabetes: A cross-sectional study

Aims: The risk of cardiovascular disease (CVD) and mortality is increased in patients with chronic kidney disease (CKD), with a background role of vascular calcification in the development of CVD also reported. Studies have demonstrated that high lipoprotein(a) (Lp(a)) levels accelerate the development of atherosclerolsis and are potentially involved in the vascular calcification. Matrix Gla Protein (MGP) seems to play an important role in vascular calcification. The aim of the study was to examine the potential association of MGP concentrations with Lp(a) and insulin resistance. Methods: The study involved 100patients divided in four groups: 25 with both CKD stage 4 and Type2 Diabetes (DM) (Group-A), 25 with CKD4 without DM (Group-B), 25 non uremic patients with DM (Group-C) and 25 healthy subjects (Group-D). Serum glucose, Lp(a), MGP, plasma HBA1c and insulin were measured in all patients. Insulin resistance was estimated by the homeostasis model assessment equation (HOMA-IR). Results: A significant positive linear association between MGP and Lp(a) levels (r = 0.272, p = 0.006) was noted, as well as between MGP and HOMA-IR levels (r = 0.308, p = 0.002). However, no significant linear association between Lp(a) and HOMA-IR levels was recorded. A similar positive association between MGP and insulin levels (r = 0.204, p = 0.042) was also found. Conclusion: This study concluded that diabetes coexisting with renal disease leads to extreme vascular calcification expressed by elevated MGP levels, resulting in higher frequency of cardiovascular disease in comparison to CKD patients without diabetes. The detected Lp(a) and MGP association in CKD4 patients may also represent the key to the complicated mechanism of their coexisting accelerated atherosclerosis and vascular calcification. (C) 2017 Elsevier B.V. All rights reserved