Search

High circulating fetuin-A has recently been linked to risk of primary cardiovascular disease (CVD). The clinical importance of fetuin-A in patients at markedly increased cardiovascular risk, however, has not been fully elucidated. We studied the association between serum fetuin-A and future cardiovascular outcome in patients with prevalent coronary heart disease (CHD). Fetuin-A levels were measured in 1,049 patients with CHD. Associations with traditional cardiovascular risk factors and with secondary CVD events during 6 years of follow-up (median 73.4 months, interquartile range 57.4 to 74.3) were analyzed. Serum fetuin-A levels were significantly increased in patients with prevalent hypertriglyceridemia (0.71 vs 0.69 g/L, p = 0.013). No association with baseline metabolic syndrome was found (odds ratio 0.95 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.59 to 1.53, p = 0.82). In Cox proportional hazards analyses, serum fetuin-A levels were not significantly associated with secondary CVD events (hazard ratio 0.67 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.37 to 1.21, p = 0.18). In conclusion, fetuin-A is significantly associated hypertriglyceridemia but not with other traditional cardiovascular risk factors or metabolic syndrome in patients with manifest CHD. Measurement of serum fetuin-A levels may not emerge as a valuable tool for evaluating future CVD risk in patients aggressively treated for advanced atherosclerosis. [Copyright &y& Elsevier]

Abstract: Objective: Adiponectin has anti-atherogenic properties and low circulating adiponectin has been linked to coronary atherosclerosis. Yet, there is considerable evidence that the high-molecular weight (HMW) complex of adiponectin is the major active form of this adipokine. We therefore investigated whether HMW adiponectin is associated with the extent of coronary artery disease (CAD) in men. Research design and methods: Associations among CAD, HMW adiponectin and the HMW/total-adiponectin ratio were assessed in 240 male patients undergoing elective coronary angiography. Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. Results: We found significant inverse correlations between angiographic scores and HMW adiponectin [Extent Score (ES): r =−0.39; Gensini Score (GS): r =−0.35; and Severity Score (SS): r =−0.40, all P <0.001], and the HMW/total-adiponectin ratio (ES: r =−0.49; GS: r =−0.46; SS: r =−0.46; all P <0.001). Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both P <0.001). ROC analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (P <0.001, P =0.010, respectively). Conclusions: HMW adiponectin and the HMW/total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin. [Copyright &y& Elsevier]

Purpose: Long duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM. Methods: Data from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy. Findings: Long-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placeboadjusted mean change in HbA1c from baseline of -0.66% (95% CI, -0.95 to -0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of -15.5 mg/dL (95% CI, -29.6 to -1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigatorreported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients' mean weight remained unchanged in both groups. Implications: This pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005). [ABSTRACT FROM AUTHOR]

Purpose: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. Methods: Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase IIII, placebo-controlled clinical trials of ≤ 102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). Findings: Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for > 5 years; approximately 75% were receiving ≥ 1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptinand placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/ 1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. Implications: This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. [ABSTRACT FROM AUTHOR]

Abstract: Background: In kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-molecular weight (HMW) multimer is the major active form, exerting anti-inflammatory and anti-apoptotic effects on endothelial cells. This study evaluated, whether pre-transplant total and HMW multimer adiponectin levels are associated with markers of endothelial dysfunction and arteriosclerosis and predict long-term graft survival in patients after kidney transplantation. Methods: In 206 renal transplant recipients pre-transplant total and HMW adiponectin levels were measured in serum by ELISA and Western blot, respectively. During the 36months active follow up (median [interquartile range] 1249 [1020; 1445] days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). Results: Pre-transplant total and HMW adiponectin levels were significantly associated with lipid and glucose parameters at baseline. After 3years follow-up pre-transplant total and HMW adiponectin levels were significantly inversely associated with the incidence of allograft failure (adiponectin: r=−0.216; p=0.002: HMW: r=−0.218; p=0.002). In multivariable adjusted Cox proportional hazard regression models patients in the lowest total and HMW adiponectin quartile had a significantly increased risk for allograft failure within 3years post-transplantation: odds ratio [95%CI]: total adiponectin: 4.25 [1.27–14.24; p=0.019], and HMW multimers: 3.35 [1.04–10.76; p=0.042], respectively. Conclusion: Low pre-transplant levels of total and HMW adiponectin reflect a pro-atherogenic endothelial milieu and independently predict an increased risk of allograft failure in kidney-transplant recipients. Measurement of adiponectin levels may identify patients at risk for adverse allograft outcomes after kidney transplantation. [Copyright &y& Elsevier]

Abstract: Aim: To evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function. Introduction: The aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects. Materials and methods: We studied 116 subjects with normal kidney function (age 47±12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined. Results: Fetuin-A levels were negatively correlated with aPWV (r =−0.21, p =0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r =−0.30, p =0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9±29.0 μg/ml; aPWV: 14.3±0.9 m/s) as compared to ThrThr (fetuin-A: 109.9±54.9 μg/ml; aPWV: 6.4±1.3 m/s) and ThrSer carrier (fetuin-A: 100.8±52.5 μg/ml; aPWV: 6.6±1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness. Conclusion: With respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk. [Copyright &y& Elsevier]

Objectives: In this study we tested the hypothesis that lipopolysaccharide-binding protein (LBP) might be able to be used as a biomarker for coronary artery disease (CAD). Background: The mechanisms by which the innate immune recognition of pathogens could lead to atherosclerosis remain unclear. Lipopolysaccharide-binding protein is the first protein to encounter lipopolysaccharide and to deliver it to its cellular targets, toll-like receptors; therefore, its presence might be a reliable biomarker that indicates activation of innate immune responses. Methods: A total of 247 men undergoing elective coronary angiography were studied, and the extent of coronary atherosclerosis was assessed by 2 established scores: “extent score” and “severity score.” Levels of LBP, markers of inflammation, and traditional risk factors for CAD were assessed. Results: Serum LBP concentration was significantly increased in 172 patients with angiographically confirmed CAD compared with 75 individuals without coronary atherosclerosis (20.6 ± 8.7 pg/ml vs. 17.1 ± 6.0 pg/ml, respectively; p = 0.002). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of prevalent CAD (p < 0.05 in all models). Conclusions: Lipopolysaccharide-binding protein might serve as a novel marker for CAD in men. The present results underlie the potential importance of innate immune mechanisms for CAD. Further studies are warranted to bolster the data and to identify pathogenetic links between innate immune system activation and atherosclerosis. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "A nephrologist's point of view on sodium-glucose linked transporter-2 inhibitors: not all that glitters is gold" by Claudio Musetti, Marco Quaglia, and Piero Stratta.

Abstract: Background: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy. Objective: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU. Methods: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A1c from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview. Results: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA1c from baseline (8.6%) to 18 weeks of −0.47% (−0.70 to −0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA1c target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7–24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA1c reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7–9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs −0.01 kg; P = 0.12). Conclusions: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA1c compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091. [Copyright &y& Elsevier]