Konstantinos Paletas

Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis.

Objective To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers’ websites. Eligibility criteria Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA1c). Data extraction The primary outcome was the change in HbA1c. Secondary outcomes included the proportion of patients achieving the goal of HbA1c <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea. Results 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA1c (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, −0.07 to 0.24) in reducing HbA1c and had no advantage over sulfonylureas in the attainment of the HbA1c goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference −1.92, −2.34 to −1.49) or pioglitazone (−2.96, −4.13 to −1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators. Conclusion In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c, in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.

Prooxidant-antioxidant balance as a new risk factor in patients with angiographically defined coronary artery disease.

OBJECTIVES Determination of the prooxidant-antioxidant balance (PAB) in patients with angiographically defined coronary artery disease (CAD+) by a modified PAB assay and presentation of PAB value as a novel cardiovascular risk factor. DESIGN AND METHODS For 61 patients with CAD+ and 63 healthy volunteers, the PAB were measured and its correlation was determined with anthropological and clinical parameters. RESULTS A significant increase of the PAB value was observed in patients in comparison to control group. A correlation, which is not quite significant, was noted between angiographic finding (number of diseased vessel) and the PAB values in patients. A significant positive correlation was established between the PAB value and systolic blood pressure, diastolic blood pressure, smoking, fasting blood sugar and serum urea concentration; and a significant negative correlation was established between PAB value and serum creatinine and bilirubin. CONCLUSIONS This study shows that the PAB value may be considered as a cardiovascular risk factor. Further clinical research is needed to substantiate the potency of the PAB value as a cardiovascular risk factor.

Common Variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 Show Evidence of Association With Adult Obesity in the Greek Population

Twenty‐four single‐nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow‐up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver‐operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m2) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10−6) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.

Association between the changes in renal function and serum uric acid levels during multifactorial intervention and clinical outcome in patients with metabolic syndrome. A post hoc analysis of the ATTEMPT study

Abstract Aim: To assess the effects of long-term multifactorial intervention on renal function and serum uric acid (SUA) levels and their association with estimated cardiovascular disease (eCVD) risk and actual CVD events. Methods: This prospective, randomized, target-driven study included 1123 subjects (45.6% men, age 45–65 years) with metabolic syndrome (MetS) but without diabetes or CVD. Patients were randomized to multifactorial treatment. Atorvastatin was titrated from 10–80 mg/day aiming at a low density lipoprotein cholesterol (LDL-C) target of <100 mg/dl (group A) or an LDL-C target of <130 mg/dl (group B). Changes in estimated glomerular filtration rate (eGFR) and SUA levels were recorded in all patients and in the subgroup with stage 3 chronic kidney disease (CKD; eGFR = 30–59 ml/min/1.73 m2; n = 349). We used ANOVA to compare changes within the same group, unpaired Student t-test to compare results between groups at specific time points, and log-rank test to compare event free survival. Results: The eCVD-risk reduction was greater in group A. In the overall study population, eGFR increased by 3.5% (p < 0.001) and SUA levels fell by 5.6% (p < 0.001). In patients from group A with stage 3 CKD (group A1; n = 172), eGFR increased by 11.1% (p < 0.001) from baseline and by 7.5% (p < 0.001) in group B1 (n = 177; p < 0.001 vs. the change in group A1). The corresponding fall in SUA levels was 10.7% in group A1 (p < 0.001 vs. baseline) and 8.3% in group B1 (p < 0.001 vs. baseline and group A1). These changes were mainly attributed to atorvastatin treatment. Among the CKD stage 3 patients there were no CVD events in group A1, while 6 events occurred in group B1 (p = 0.014). Conclusions: Multifactorial intervention in patients with MetS without established CVD improved renal function and reduced SUA levels. These changes were more prominent in stage 3 CKD patients and might have contributed to the reduction in eCVD risk and clinical events. Trial registration: ClinicalTrials.gov identifier: NCT00416741.

Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): a prospective-randomized study in middle aged men and women.

Aim: To assess the reduction in estimated cardiovascular disease (e-CVD) risk after multifactorial treatment for 6 months and follow this change during the next 3-years. Patients-Methods: This prospective, randomized, target driven study included 1,123 subjects (512/611 men/women, aged 45-65 years) with metabolic syndrome (MetS) without diabetes or CVD referred to specialist outpatient clinics. Patients were randomized to two treatment groups: group A with low density lipoprotein cholesterol (LDL-C) target of > 100 mg/dl and group B with a target of 50%in all patients, but were superior in group A and in women. Reductions were even greater during the next 3-years and were mainly attributed to changes in lipid profile. Actual CVD events were 1 in group A and 13 in group B; p=0.0012. Conclusions: Attaining the treatment target of LDL-C < 100 mg/dl within multifactorial treatment of MetS by expert clinics, is achievable and beneficial even in patients without diabetes or known CVD. This induces a considerable e-CVD risk reduction in MetS patients. Actual CVD events were negligible, suggesting that e-CVD risk overestimates actual CVD risk in MetS, at least in patients achieving LDL-C < 100 mg/dl [ClinicalTrials.gov ID: NCT00416741].

The protective role of the Mediterranean diet on the prevalence of metabolic syndrome in a population of Greek obese subjects.

Background: Obesity is a rapidly expanding epidemic in Western societies, with rates of more than 30% across Europe, and it is associated with an increased risk of metabolic disturbances. Previous reports have documented an association of reduced physical activity and abstinence from the traditional Mediterranean diet (MD) with increased mortality rate and prevalence of obesity in a population of Greek subjects. Objective: The aim of the present study was to evaluate and analyze the dietary habits in a population of Greek overweight and obese subjects and to investigate the potential associations between those patterns and the prevalence of metabolic syndrome components. Methods: The study recruited 226 consecutive adult (30 men, 169 women) overweight or obese (body mass index >25 kg/m2) individuals attending the Metabolic Diseases Unit. Medical history, dietary history, and anthropometric parameters were recorded during the first visit. Fasting blood samples were collected for biochemistry assaying. Results: According to the nutrient intake history and Mediterranean Diet Scale (MDS), participants were divided into 3 groups: those adhering to the MD and those not following the MD, who were further subdivided into the high-carbohydrate (HC) and high-fat (HF) diet groups according to the source of maximum energy intake. Adherence to the MD was associated with a lower prevalence of metabolic syndrome (27.3%, 69.2%, and 60.4% in MD, HC, and HF respectively, p  =  0.006), lower low-density lipoprotein cholesterol (p  =  0.009, MD vs. HF), and lower postchallenge glucose values (p  =  0.028, MD vs. HF). Conclusions: Adherence to the MD seems to be declining among Greek overweight and obese subjects, a phenomenon that is associated with an increase in the prevalence of the metabolic syndrome.

Accuracy of the Neuropad Test for the Diagnosis of Distal Symmetric Polyneuropathy in Type 2 Diabetes

OBJECTIVE To estimate the accuracy of Neuropad for the diagnosis and staging of distal symmetric polyneuropathy (DPN) across different stages of neuropathy, using multiple-level likelihood ratios (LRs) to interpret the time necessary to complete the color change of the test. RESEARCH DESIGN AND METHODS We conducted a cross-sectional, cohort-type diagnostic accuracy study in 251 consecutive adult type 2 diabetic patients with no peripheral arterial disease or other potential causes of neuropathy, who were recruited between January 2005 and December 2008 from the diabetes outpatient clinics in Alexandroupolis Hospital, Greece. Patients were tested for DPN by means of the neuropathy disability score (NDS) and Neuropad. Multiple-level LRs for time to complete color change were calculated across different stages of neuropathy. RESULTS The areas under the curve for the diagnosis of any (NDS of ≥3), at least moderate (NDS of ≥6), or severe (NDS of ≥9) DPN were 0.91, 0.96, and 0.97, respectively. The calculation of multiple-level LRs showed that time to complete color change <360 s suggested the absence of neuropathy. Values between 360 and 1,000 s were indicative of mild neuropathy. Finally, values between 1,000 and 1,200 or >1,200 s were strongly suggestive of moderate or severe DPN, respectively. CONCLUSIONS Neuropad could be used as a triage test for the diagnosis and staging of DPN in patients with type 2 diabetes, prompting referral to specialized care setting.

NHE-1: a molecular target for signalling and cell matrix interactions.

The activation of sodium/hydrogen exchanger (NHE) is associated with a variety of cell functions like cell adhesion, migration, proliferation, and apoptosis. Since its discovery, 9 NHE isoforms have been identified, but the most widely spread and the most important for the cellular functions is NHE-1. This ubiquitously expressed sodium/hydrogen exchanger (NHE-1) plays a central housekeeping role in all cells regulating cell volume and internal pH (pHi). At physiological pHi, NHE-1 is essentially inactive but it is extremely sensitive to pHi changes, being rapidly activated by small intracellular hydrogen concentration increases. NHE-1 activity can be stimulated via a series of cell surface receptors, including tyrosine kinase, G-protein-coupled, and integrin receptors. These signals converge, regulating the affinity of the internal hydrogen-binding site. NHE-1 also is a plasma membrane-anchoring protein for the cytoskeleton. Cytoskeleton anchoring of NHE-1 is important for cell adhesion to extracellular matrix proteins and cell migration. Moreover, NHE-1 plays the role of a “scaffold” for the building of various intracellular signaling molecule clusters.

Effect of endothelin on sodium/hydrogen exchanger activity of human monocytes and atherosclerosis-related functions.

Abstract:  The objective of this article is to investigate the influence of endothelin‐1 (ET‐1) on human monocyte Na+/H+ exchanger (NHE) activity and on the atherosclerosis‐related monocyte functions. ET‐1 caused an increase in pHi and in 22Na influx of monocytes. A reversal of ET‐1 effect on pHi was observed in the presence of the NHE1 inhibitor, cariporide. In addition, the activation of NHE1 by ET‐1 was mediated via protein kinase C (PKC), mitogen‐activated protein kinase (MAPK), phosphatidylinositol 3‐kinase (PI3K), and NADPH oxidase. Also, a link between ET‐1 and nitric oxide (NO) was observed. Furthermore, after ET‐1 treatment, an increase of the adhesive capacity, the migration ability on laminin and CD36 expression of monocytes, was observed; using cariporide this increase was abolished. Our results showed that ET‐1 induces a signaling pathway with the involvement of PKC, MAPK, PI3K, and NADPH oxidase where NHE1 plays a key role. ET‐1 also plays a significant role in atherosclerosis‐related functions of human monocytes, via NHE1 activation.

Signaling Components Involved in Leptin-Induced Amplification of the Atherosclerosis-Related Properties of Human Monocytes

Background/Aims: Leptin, a 16-kDa cytokine that is released mainly by the adipose tissue, is known to affect a wide assortment of processes, ranging from energy homeostasis to angiogenesis and the immune response. In the present study, the effect of leptin on atherosclerosis-related properties of human monocytes was investigated. Methods: Monocytes were isolated from whole blood obtained from healthy donors who had normal body mass index values. Pharmacological inhibition of specific signaling proteins was implemented. Fluorescence spectrometry and immunofluorescence techniques, as well as ELISA methods, were utilized. Leptin dose response curves were determined for each type of experiment. Results: Leptin (160 ng/ml) was found to augment monocyte adhesion to laminin-1 and its migration through this glycoprotein, which is one of the main components of the extracellular matrix. Additionally, leptin increased CD36-receptor surface expression, as well as moderately oxidized low-density lipoprotein (oxLDL3) uptake levels. Conclusion: Leptin amplifies the pro-atheromatic properties of human monocytes through a complex signaling net which involves the Na+/H+ exchanger isoform-1, the actin cytoskeleton, phosphoinositide 3-kinase, certain conventional isoforms of protein kinase C and NADPH oxidase.