Search

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral antidiabetic agents that exert their glucose-lowering effect by increasing renal excretion of glucose. These drugs have been reported to beneficially affect cardiovascular (CV) and renal outcomes. However, concerns have recently been raised in relation to increased risk of lower-extremities amputation with canagliflozin and it remains unclear whether and to what extent this side effect could also occur with other SGLT2i. The present expert panel overview focuses on the three SGLT2i available and widely used in the US and Europe, i.e. empagliflozin, canagliflozin and dapagliflozin and only refers briefly to other SGLT2i for which less data are available. The results of large CV outcome trials with these SGLT2i are presented, focusing specifically on the data in relation to amputation risk. The potential pathophysiological mechanisms involved in this side effect are discussed. Furthermore, available data reporting amputation cases in SGLT2i users are critically reviewed. The expert panel concludes that, based on current data, increased amputation risk seems to be related only to canagliflozin, thus representing a drug-effect rather than a SGLT2i class-effect. The exact pathways underlying this drug-induced adverse event, possibly related to off-target drug effects rather than SGLT2 inhibition per se, should be elucidated in future studies. Continuous monitoring and pharmacovigilance is necessary and head to head trials would also be essential to provide definitive conclusions. © 2019 Elsevier Inc.

The focus of this review is on the role of apolipoprotein C-II (apoC-II) in lipoprotein metabolism and the potential effects on the risk of cardiovascular disease (CVD). We searched PubMed/Scopus for articles regarding apoC-II and its role in lipoprotein metabolism and the risk of CVD. Apolipoprotein C-II is a constituent of chylomicrons, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein (HDL). Apolipoprotein C-II contains 3 amphipathic alpha-helices. The lipid-binding domain of apoC-II is located in the N-terminal, whereas the C-terminal helix of apoC-II is responsible for the interaction with lipoprotein lipase (LPL). At intermediate concentrations (approximately 4 mg/dL) and in normolipidemic subjects, apoC-II activates LPL. In contrast, both an excess and a deficiency of apoC-II are associated with reduced LPL activity and hypertriglyceridemia. Furthermore, excess apoC-II has been associated with increased triglyceride-rich particles and alterations in HDL particle distribution, factors that may increase the risk of CVD. However, there is not enough current evidence to clarify whether increased apoC-II causes hypertriglyceridemia or is an epiphenomenon reflecting hypertriglyceridemia. A number of pharmaceutical interventions, including statins, fibrates, ezetimibe, nicotinic acid, and orlistat, have been shown to reduce the increased apoC-II concentrations. An excess of apoC-II is associated with increased triglyceride-rich particles and alterations in HDL particle distribution. However, prospective trials are needed to assess if apoC-II is a CVD marker or a risk factor in high-risk patients. Metabolism

PURPOSE OF REVIEW: Lipoprotein glomerulopathy is a rare disorder characterized by proteinuria, renal insufficiency and disturbances in lipoprotein metabolism closely related to those observed in type III hyperlipidemia. Rare mutations in apolipoprotein E (apoE) gene may contribute to the pathogenesis of the disease. This article reviews the clinical and laboratory features of lipoprotein glomerulopathy, discusses the mechanisms that may be implicated in its pathogenesis and summarizes the currently available therapeutic options. RECENT FINDINGS: During the past years two new apoE gene mutations were described in Caucasian patients, apoE Modena (Arg150-->Cys) and apoE Las Vegas (Ala152-->Asp), a finding indicating that the disease may be more common in white populations than initially thought. Results from case studies suggest that fibrates improve renal pathology and may result in the complete clinical remission of the disease. LDL-apheresis or immunoadsorption onto staphylococcal protein A may also have a role in refractory cases. SUMMARY: Lipid glomerulopathy is a rare, poorly understood disorder with potentially detrimental consequences. The determination of the effects of apoE mutations on the structural and functional characteristics of the mature protein may provide new insights in the pathogenesis of the disease. Meanwhile, intensive lipid-lowering may reduce proteinuria and preserve renal function in this patient group. Curr Opin Lipidol

Objective: Mixed dyslipidemia, oxidative stress and inflammation are related to a high risk for cardiovascular events. The aim of this open-label randomized study was to compare the effects of high-dose rosuvastatin, low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega 3 fatty acids on inflammation and oxidative stress indices in patients with mixed dyslipidemia. Methods: Ninety patients with mixed dyslipidemia participated in the study. Patients were randomly allocated to receive rosuvastatin 40 mg (n = 30, group R), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, group RF) or rosuvastatin 10 mg plus omega 3 fatty acids 2 g daily (n = 30, group R Omega). Plasma and high-density lipoprotein (HDL)-associated lipoprotein-associated phospholipase A2 (LpPLA2) activities, high-sensitivity C reactive protein (hsCRP), plasma isoprostane and paraoxonase (PON1) activities were measured at baseline and after 3 months of treatment. Results: Serum concentrations of non-HDL cholesterol and low-density lipoprotein cholesterol (LDL-C) were significantly reduced in all study groups. However, these changes were more pronounced in the rosuvastatin monotherapy group. In all treatment groups a significant reduction in total plasma LpPLA2 activity was observed (by 41, 38 and 30% for groups R, RF and RW, respectively). This decrease was greater in the R and RF groups compared with the RW combination (p < 0.05). HDL-LpPLA2 activity was increased more in the RF group (+43%) compared with the R and RW groups (+ 18% and + 35%, respectively; p < 0.05 for both comparisons). In all treatment groups there was a nonsignificant reduction in plasma 8-iso-PGF2 alpha levels. A 53% reduction of hsCRP levels was observed in the R group, while in the RF and RW groups the reduction was 28 and 23%, respectively (p < 0.05 and p < 0.01 for the comparisons of group R with groups RF and RW, respectively). No significant changes were observed in PON activities in all treatment groups. Conclusion: The greater non-HDL-C- and LDL-C-lowering efficiency of rosuvastatin monotherapy along with its more potent effect on LpPLA2 activity and hsCRP levels indicate that this regimen is a better treatment option for patients with mixed dyslipidemia. Expert Opinion on Pharmacotherapy

In this article we discuss the available data on the effects of combined therapy of ezetimibe with agents affecting lipid metabolism other than statins. We consider studies evaluating the effects of combined therapy of ezetimibe with bile acid sequestrants, fenofibrate, niacin, n-3 fatty acids, plant sterols, orlistat, metformin, acarbose and glitazones. Combination of ezetimibe with bile acid sequestrants (especially colesevelam) was shown to have additional effects on lipid parameters in patients with hyperlipidemia. Combination of ezetimibe with fenofibrate may be a good approach to improve the overall lipid profile of patients with mixed hyperlipidemia. The addition of ezetimibe to niacin-based therapy can be useful for high-risk patients with dyslipidemia who are not achieving their assigned treatment goals. For patients who cannot tolerate statins there are useful combinations of ezetimibe with other drugs affecting lipid metabolism. These combinations improve many metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular disease prevention. Expert Rev Cardiovasc Ther

Atherosclerosis Supplements

BACKGROUND AND AIMS: Visfatin is associated with atherosclerosis-related diseases. We assessed in non-diabetic individuals the association of plasma visfatin levels with cardiovascular disease (CVD) risk and the atherosclerosis-related metabolic variables. METHODS AND RESULTS: When study population (n = 179, age 49 +/- 11 years) was divided according to visfatin tertiles, the 10-year CVD Framingham risk scores were significantly increased in the top visfatin tertile. We observed a positive association between visfatin tertiles with waist circumference and blood pressure, as well as with total cholesterol and triglyceride levels, but not with apolipoprotein C-III, fibrinogen or pre-beta1 high density lipoprotein (HDL). The percentage of large HDL subclasses was significantly lower and the percentage of small HDL subclasses over the HDL-C concentration was significantly higher in the top visfatin tertile compared with the other tertiles. The atherogenic small dense low density lipoprotein subclasses (sdLDL-C) were significantly increased in the top visfatin tertile compared with the lower tertiles. High sensitivity C-reactive protein (hsCRP) concentration was significantly increased in the top visfatin tertile compared with the lower tertiles. Although age and sex distribution did not differ between visfatin tertiles, the simultaneous adjustment for these parameters attenuated the significance of the differences observed in sdLDL-C and hsCRP levels. Similarly, after adjustment for hsCRP or waist circumference, only triglycerides and blood pressure levels, as well as the distribution of HDL subclasses, remained significantly different between visfatin tertiles. CONCLUSIONS: Our results support a role for visfatin in the detection of subjects with many metabolic abnormalities, which result in increased CVD risk. Nutr Metab Cardiovasc Dis

Open Cardiovasc Med J

Introduction. Adipose tissue contributes to atherosclerosis with mechanisms related to adipokine secretion. Polyphenols may exhibit antiatherogenic properties. The aim of the study was to investigate the effects of three polyphenols, namely, quercetin, epigallocatechin gallate (EGCG), and resveratrol on adipokine secretion from cultured human adipocytes. Methods. Human SGBS adipocytes were treated with quercetin, EGCG, and resveratrol for 24 and 48 hours. Visfatin, leptin, and adiponectin were measured in the supernatant. Results. Visfatin secretion was inhibited by quercetin 10 muM by 16% and 24% at 24 and 48 hours respectively. The corresponding changes for quercetin 25 muM were 47% and 48%. Resveratrol 25 muM reduced visfatin by 28% and 38% at 24 and 48 hours. EGCG did not have an effect on visfatin. None of tested polyphenols influenced leptin and adiponectin secretion. Conclusion. Quercetin and resveratrol significantly decreased visfatin secretion from SGBS adipocytes. This effect may contribute to their overall antiatherogenic properties. Biochem Res Int

Objective: Experimental studies have shown that the pre beta-1 subclass of high-density lipoprotein particles (pre beta-1 HDL) may play an important role in the reverse cholesterol transport pathway as the initial acceptors of cellular cholesterol. The aim of the present study was the direct comparison of pre beta-1 HDL values in individuals with various types of primary dyslipidemias. Methods: Four hundred and eighty-six unrelated individuals were included in the study. According to their lipid values study participants were subdivided into four groups: control group (n = 206), type IIA dyslipidemia group (n = 148), type IIB dyslipidemia group (n = 49) and type IV dyslipidemia group (n = 83). Results: All dyslipidemic patients displayed higher concentrations of pre beta-1 HDL compared to control individuals. However, patients with dyslipidemias characterized by an abnormal catabolism of triglyceride-rich lipoproteins (such as dyslipidemias of type IIB and IV) tend to have higher pre beta-1 HDL values compared to patients with hypercholesterolemia, and this increase is proportional to the degree of hypertriglyceridemia. In addition, patients with metabolic syndrome exhibited significantly higher levels of pre beta-1 HDL compared to individuals that do not fulfill the criteria for the diagnosis of this syndrome. Multiple regression analysis revealed that serum triglyceride concentrations and body mass index (BMI) values were the most important determinants of pre beta-1 HDL levels in our population. Conclusion: All dyslipidemic patients exhibit increased pre beta-1 HDL concentrations as compared to normolipidemic individuals. Whether this increase represents a defensive mechanism against atherosclerosis or it is indicative of impaired maturation of HDL particles and thus of a defective reverse cholesterol transport mechanism remains to be established. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Atherosclerosis

Atherosclerosis Supplements

Background To assess the metabolic profile and the Prevalence of the metabolic triad (i.e. hyperinsulinaemia, hyperapobetalipoproteinaemia, and decreased low-density lipoprotein particle size) in women characterized by the hypertriglyceridaemic waist (HTGW) phenotype and to identify cut-off values for triglycerides and waist circumference, effectively discriminating women with the metabolic triad. Methods Two hundred and twenty-eight female subjects without any history of vascular disease or diabetes mellitus attending an Outpatient Lipid Clinic setting at the University Hospital of Ioannina, Greece were studied. Results Currently available HTGW criteria for women were unable to detect any significant differences in the metabolic profile either in the pre- or postmenopausal women, and proved similar in terms of sensitivity and specificity in identifying women with the metabolic triad. A cut-off value of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference were determined by Receiver-operating Curve evaluation. Women with both triglycerides and waist circumference above these thresholds had four-fold higher odds of presenting with the metabolic triad compared with women with non-HTGW phenotype. Conclusions AHTGW phenotype definition of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference may effectively identify Mediterranean women with the atherogenic metabolic triad. Whether these criteria are also associated with a higher incidence of vascular disease and/or new-onset diabetes in women remains to be investigated. Copyright (C) 2007 John Wiley & Sons, Ltd. Diabetes-Metabolism Research and Reviews

The National Cholesterol Education Programme Adult Treatment Panel III accepted the predominance of small dense low-density lipoprotein (sdLDL) as an emerging cardiovascular disease (CVD) risk factor. Most studies suggest that measuring low-density lipoprotein (LDL) particle size, sdLDL cholesterol content and LDL particle number provides additional assessment of CVD risk. Therapeutic modulation of small LDL size, number and distribution may decrease CVD risk; however, no definitive causal relationship is established, probably due to the close association between sdLDL and triglycerides and other risk factors (e.g., high-density lipoprotein, insulin resistance and diabetes). This review addresses the formation and measurement of sdLDL, as well as the relationship between sdLDL particles and CVD. The effect of hypolipidaemic (statins, fibrates and ezetimibe) and hypoglycaemic (glitazones) agents on LDL size and distribution is also discussed. Expert Opin Biol Ther

Atherosclerosis Supplements

Atherosclerosis Supplements

Atherosclerosis Supplements

BACKGROUND: The Friedewald formula (LDL-F) for the estimation of low-density lipoprotein (LDL) cholesterol concentrations is the most often used formula in clinical trials and clinical practice. However, much concern has been raised as to whether this formula is applicable in all patient populations such as the presence of chylomicronaemia and/or hypertriglyceridaemia. The aim of the present study was to evaluate various LDL cholesterol calculation formulas as well as LDL cholesterol levels provided by the Lipoprint LDL System (LDL-L) in patients with the metabolic syndrome (MetSyn). RESULTS: LDL-F showed significant differences from other formulas in the total cohort, as well as in MetSyn individuals. This was not the case in nonMetSyn subjects, where LDL-F did not differ with other formulas, with the exception of one formula (LDL by Planella, LDL-P). The bias between LDL-F and other LDL estimation formulas were significantly higher in MetSyn subjects compared to nonMetSyn individuals, except for LDL-L which produced similar bias with LDL-F in both study groups. CONCLUSION: LDL-F seems to exhibit some limitations as far as the calculation of LDL-C levels in patients with the MetSyn is concerned. LDL-L might be more accurate in MetSyn subjects, but so far its use is limited for the estimation of small, dense LDL (sdLDL) cholesterol levels and mean LDL particle size for research purposes only. Lipids Health Dis

Journal of Hypertension

Atherosclerosis Supplements