Dyslipidemia treatment: current considerations and unmet needs

Risk reduction and tolerability of fluvastatin in patients with the metabolic syndrome: A pooled analysis of thirty clinical trials

Introduction: Dyslipidemia is one of the most common problems in hemodialysis patients and healthcare system. Some studies have suggested the use of carnitine in the treatment of dyslipidemia in hemodialysis patients. This study was carried out aiming to evaluate the effect of atorvastatin and carnitine combination versus atorvastatin alone on the lipid profile of hemodialyzed patients. Methods: In this clinical trial, 50 hemodialysis patients referred to the educational centres of Tabriz University of Medical Sciences, Tabriz, Iran, for haemodialysis were enrolled. Patients were randomly assigned into two groups. In the first group, patients were treated with carnitine (1000 mg three times daily) and atorvastatin (10-80 mg/day based on the baseline lipid profile of the patients) and in the second group, the patients were treated with atorvastatin alone for six months. The levels of triglyceride (TG), cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and haemoglobin before and after intervention were compared. The side effects of carnitine administration were also evaluated. Results: Results showed that TG, cholesterol, and LDL levels were significantly lower in the carnitine group compared to those in the other group at the end of study (P < 0.050). In addition, HDL and haemoglobin levels were significantly higher in the carnitine group in comparison to the other group (P < 0.050). No major side effects of carnitine were observed among the patients. Conclusion: The use of carnitine plus atorvastatin combination is an effective and safe method in the treatment of dyslipidemia in patients undergoing hemodialysis without imposing significant side effects.

8028 Background: Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action: directly activating NK cells and tagging myeloma cells for recognition/death via antibody-dependent cell-mediated cytotoxicity. In a 3-y FU, ELOQUENT-2 (NCT01239797) showed a sustained 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos et al, ASH 2015). Here we present extended 4-y FU data (median FU 46 mo). Methods: RRMM patients (pts) were randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS, ORR. Secondary endpoint: OS. Results: Of 646 RRMM pts, 321 were randomized to ELd, 325 to Ld; ~ twice as many pts remain on therapy in ELd vs Ld (17 vs 9%) at data cut-off (Oct 18, 2016). Discontinuation was mainly due to disease progression (both arms 54%). At 4-y FU, ELd had 29% reduction in risk of progression/death vs Ld (HR 0.71, 95% CI 0.59–0.86) and relative improvement of 50% in PFS (21 vs 14%). Pts with ≥VGPR (ELd 112 [35%], Ld 95 [29%]) had greatest reduction in risk of progression/death (HR 0.65, 95% CI 0.46–0.94). ORR was 79% (ELd) vs 66% (Ld). OS will be presented. G3–4 AEs in ≥5% of pts included second primary malignancies (SPMs), vascular diseases, cardiac disorders and infections (ELd vs Ld: 9 vs 6%, 10 vs 8%, 5 vs 8%, 33 vs 26%). Overall rate (any grade) of infection and SPMs was 84 vs 75% and 17 vs 11% for ELd vs Ld. However, pts had longer exposure to ELd vs Ld (median [Q1, Q3] treatment cycles (19 [9, 42] vs 14 [6, 25]). There were fewer deaths with ELd vs Ld (165 vs 186), mainly due to disease progression and infection in both arms. Conclusions: Elotuzumab in combination with Ld consistently met its efficacy objectives at 4-y FU. ELd showed durable, clinically relevant improvement in PFS, with 29% reduction in risk of progression/death, consistent with 2-y (30%) and 3-y FU (27%). Safety, including rate of SPMs, was consistent with previous findings, with minimal incremental AEs with addition of elotuzumab to Ld. These data represent the longest median FU of an immuno-oncology agent in MM. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01239797.

Elevated triglyceride levels have been associated with an elevated risk of cardiovascular disease, even when triglyceride levels are below common guidelines. This elevated risk of cardiovascular disease exists independent of total cholesterol or low-density lipoprotein cholesterol levels. Genetic analyses have demonstrated that elevated remnant lipoprotein, a product of triglyceride-rich lipoprotein, is a factor for coronary heart disease, indicating that the association between elevated triglyceride levels and elevated cardiovascular disease risk is causal rather than correlated. Despite this correlation between triglyceride levels and cardiovascular disease risk, treatments targeted at lowering triglyceride levels in patients receiving statin therapy, such as niacin or fibrates, have not demonstrated reduction in cardiovascular disease risk despite lowering triglyceride levels. In addition, omega-3 fatty acids containing a combination of docosahexaenoic acid plus eicosapentaenoic acid failed to demonstrate significant reductions in cardiovascular events in similar patients. Triglyceride-lowering therapies in development include monoclonal antibodies targeted against angiopoietin-like 3 (ANGPTL3); however, these newer ANGPTL3-targeted agents have not yet demonstrated a reduction in cardiovascular disease risk. In contrast, the landmark REDUCE-IT trial demonstrated significant cardiovascular protective effects for icosapent ethyl (IPE) in high cardiovascular risk patients with hypertriglyceridemia despite statin therapy. The protective effects of IPE may be due to unique mechanisms affecting the metabolism of E-series resolvins that may reduce atherosclerotic plaque. IPE also exhibits antiplatelet, antithrombotic, anti-inflammatory, and anti-oxidant effects, all of which contribute to an overall anti-atherosclerotic effect and an overall reduction in cardiovascular disease risk. As a result, treatment guidelines in the United States, China, and other countries recommend IPE for patients with hypertriglyceridemia that persists despite statin therapy.

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Bile acid sequestrants (BAS) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol (LDL-C) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia in the United States: the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl). Compared with conventional BAS, colesevelam HCl has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its polymer structure engineered for bile acid sequestration. BAS are not absorbed by the intestine and thus have no systemic drug-drug interactions, but may interfere with the absorption of some drugs. Although BAS monotherapy effectively lowers LDL-C, combination therapy, especially with BAS and statins, is becoming increasingly common due to complementary mechanisms of action. Low-dose statin plus BAS combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile. Combinations of BAS with nonstatin lipid-lowering agents, including niacin, fibrates, and cholesterol absorption inhibitors, may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease (CAD) progression and the risk of CAD-associated outcomes. It is also becoming clear that BAS and other therapies that manipulate the bile acid synthetic pathway may have clinically useful therapeutic effects on other metabolic disorders including type 2 diabetes.

Background Ulcerative colitis (UC) is a chronic and relapsing disease for which the number of biological therapies available are increasing over the years. Data comparing the effectiveness of a second anti-TNFɑ (aTNF) and the switch to a different mechanism of action (MoA) such as Ustekinumab (UST), Vedolizumab (VDZ), Filgotinib or Tofacibinib (JAK) is lacking. Methods We performed a multicenter and retrospective study (6 Andalusian sites) in which patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA (UST, VDZ, JAK) were included. Clinical response and remission were assessed at weeks 16 and 52. The aim of our study was to evaluate the effectiveness of a second-line biological therapy with aTNF compared to a different MoA after a first aTNF failure. Results 185 UC patients were included. There were no differences in the demographic data except for disease duration (9 years with MoA vs 13 years in aTNF, p=0.02). As first aTNF, infliximab (IFX) was the most common in both groups (49% MoA group, 56% second aTNF), followed by adalimumab (ADA) (48% MoA group, 33% second aTNF). In the second aTNF group, immunomodulators were significatively more used (60% vs 38%, p=0.003). There were no differences in the concomitant use of steroids. 80 patients received a different MoA (37 VDZ, 24 UST, 7 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). At week 16, 52% of patients were in clinical response (70% with another MoA vs 54% with second aTNF, p=0.07; IFX 65%, ADA 53%, VDZ 68%, UST 71%, JAK 74%, p=0.07), being 15.6% more likely to achieve response with another MoA. Clinical remission at week 16 was obtained by 36% (39% with another MoA vs 33% with second aTNF, p=0.6; IFX 47%, ADA 30%, VDZ 35%, UST 46%, JAK 37%, p=0.1). At week 52, 48% achieved clinical response (51% with another MoA vs 45% with second aTNF, p=0.8; IFX 50%, ADA 42%, VDZ 49%, UST 54%, JAK 53%, p=0.5) and 39% were in clinical remission (40% with another MoA vs 38% with second aTNF, p=0.53; IFX 50%, ADA 32%, VDZ 35%, UST 38%, JAK 53%; p=0.06) (figure 1). When the effectiveness is analyzed by first aTNF used, independently of the aTNF, subsequent use of a different MoA achieves better results although not significant compared to a second aTNF. Partial Mayo and calprotectin showed a significant decrease at weeks 16 and 52 in both groups. Hemoglobin and albumin levels remained similar during follow-up in both groups. Conclusion Second-line biological therapy is effective regardless of biological therapy used in UC, but switching to a different MoA tend to achieve better results in terms of clinical response and remission compared to a second aTNF.

In China, cardiovascular disease (CVD) risk reduction strategies are not systematically implemented in primary healthcare (PHC). We conducted an exploratory study to evaluate the preliminary effectiveness of our systematic CVD risk reduction package in one township hospital of Zhejiang. Using the Asian Equation, we selected subjects aged 40-74 years with a calculated 10-year CVD risk of 20% or higher from the existing resident health records and research checkup. The subjects were provided, as appropriate, with the low-dose combination of CVD-preventive drugs (antihypertensive drugs, aspirin, statin), lifestyle modification and adherence strategies monthly. The intervention was piloted for three months in 2012, preceding the conduct of a cluster-based randomized controlled trial (RCT). A total of 153 (40%) subjects were recruited, with an average total 10-year risk of CVD of 28.5 ± 7.9%. After intervention, the appointment rate was up to 90%. An upward trend was observed for the use of CVD-preventive drugs. The smoking rates significantly reduced from 38 to 35%, with almost no change for salt reduction. The systolic blood pressure (BP) and diastolic BP decreased slightly. A holistic CVD risk reduction approach shows preliminary effects in a rural PHC setting of Zhejiang, China. However, further understanding is needed regarding its long-term effectiveness and feasibility in PHC practices. Our cluster-based RCT will provide the highest level of evidence for the policy development of preventing CVD in a rural PHC of China.

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

With the development of nanotechnology, new scientific directions have been initiated and a significant amount of researches has been carried out, dedicated to the creation and search for promising applications in medicine, in particular, oncology, of nanocomposites based on bioinert, biocompatible and bioactive nanoparticle materials and modern chemotherapeutic drugs with different mechanisms of action. These works contain data indicating the advantages to introduce nanocomposite drugs into clinical practice, compared to the traditional use of chemotherapeutic drugs. The research results confirm the priority of works in the field of creation of new nanocomposite chemotherapeutic drugs for use in antitumor therapy and overcoming of drug resistance of malignant cells and neoplasms. The purpose of the review is to generalize and analyze the authors’ experimental works performed at Chuiko Institute of Surface Chemistry of National Academy of Sciences of Ukraine, concerning the specifics of the effect of chemotherapeutic drugs with different mechanisms of action and related nanocomposites, on cellular systems and tumors. Such data are relevant to determine promising directions and ways of creation of new effective nanocomposite drugs for use, in particular, in antitumor chemotherapy. At Chuiko Institute of Surface Chemistry of National Academy of Sciences of Ukraine, using the chemical engineering method, magnetically sensitive core-shell nanocomposites were synthesized with a multi-level hierarchical nanoarchitecture capable of performing a complex of diagnostic and therapeutic functions with various mechanisms of action, characteristic of medico-biological nanorobots. Their use makes it possible to implement the principle of targeted delivery of antitumor drugs, to carry out real-time local therapy by various methods and MRI diagnosis of the disease, to realize the synergy of treatment with antitumor drugs of different mechanisms of action, to reduce the toxic side effects of oncological drugs on the body. The combination of the above features of nanocomposites, as well as their role in overcoming the drug resistance of cells of malignant neoplasms to cisplatin, testify to the perspective of creation and research of nanocomposite drugs in solving the problem of increase in the efficiency of chemotherapy.

The uncontrolled growth of abnormal cells in the body is Cancer. With the rapid progression of molecular biology and genetics, emerging targets and therapeutics provides new opportunities for the prevention and treatment of several major disease systems. During drug discovery research many targets against cancer were also discovered. Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs. The function of Hsp90 includes assisting in protein folding, cell signaling, and tumor repression. Tumour-based Hsp90 has a significantly higher sensitivity than that in normal cells to inhibitors. Hsp90 activity inhibition in tumours leads to a suppression of cellular signaling in many different oncogenic pathways. Several inhibitors of Hsp90 are currently undergoing clinical evaluation and new agents with different mechanisms of action are continually being identified.

The current focus of lipid management is on the treatment of elevated low density lipoprotein (LDL) cholesterol (>160 mg/dl) to decrease the risk of coronary heart disease (CHD), as well as less commonly to treat markedly elevated triglyceride levels (>1,000 mg/dl) to decrease the risk of pancreatitis. However, physicians and scientists have recognized that despite lifestyle and statin therapy, there is still a substantial residual risk of CHD, especially in patients with low high density lipoprotein (HDL) cholesterol levels (<40 mg/dl). In this atlas and book, the reader has been introduced to lipoprotein composition and metabolism, as well as lipid disorders. Thereafter, the focus has been on the regulation of apolipoprotein (apo) A-I gene expression, the composition of HDL particles, the modeling and metabolism of these particles, as well as HDL structure, function, and its anti-inflammatory properties. Next, we have provided the reader with information on disease states characterized by apoA-I deficiency, apoA-I variants, Tangier disease due to lack of ABCA1 function, the ABCG1 transporter, the interaction of HDL particles with transporters and receptors, human lecithin:cholesterol acyl transferase (LCAT) deficiency, human cholesteryl ester transfer protein (CETP deficiency, and the role of the scavenger receptor BI (SR-B1) in HDL metabolism. Thereafter, we provide the reader with information on the genetics of HDL in the general population, the role of nutrition, alcohol, and exercise in modulating HDL metabolism, and the effects of estrogens, niacin, statins, fibrates, CETP inhibitors, and HDL infusion therapy on HDL metabolism and coronary heart disease (CHD) risk reduction. Our goal in this concluding chapter is to focus on the current and future status of CHD risk assessment, the diagnosis and management of lipoprotein disorders, with a special focus on HDL. In our view, HDL raising is the next frontier in CHD risk reduction, and we will be using niacin products, CETP inhibitors, and HDL infusion therapy.

Treatment of Diabetic Dyslipidemia

Probiotics and postbiotics mechanisms of action and applications in early-onset colorectal cancer (EOCRC) prevention and treatment have significant importance but are a matter of debate and controversy. Therefore, in this review, we aimed to define the probiotics concept, advantages and limitations in comparison to postbiotics, and proposed mechanisms of anti-tumor action in EOCRC prevention and treatment of postbiotics. Biotics (probiotics, prebiotics, and postbiotics) could confer the health benefit by affecting the host gut microbiota directly and indirectly. The main mechanisms of action of probiotics in exerting anticancer features include immune system regulation, inhibition of cancer cell propagation, gut dysbiosis restoration, anticancer agents’ production, gut barrier function renovation, and cancer-promoting agents’ reduction. Postbiotics are suggested to have different mechanisms of action to restore eubiosis against EOCRC, including modulation of gut microbiota composition, gut microbial metabolites regulation, and intestinal barrier function improvement via different features such as immunomodulatory, anti-inflammatory, antioxidant, and anti-proliferative properties. A better understanding of postbiotics challenges and mechanism of action in therapeutic applications will allow us to sketch accurate trials in order to use postbiotics as bio-therapeutics in EOCRC.

We have studied the uptake and metabolism of phosphatidylcholine (PC), the major phospholipid of low density lipoproteins (LDL), by cultures of primary hepatocytes. Strikingly, in the absence of the LDL receptor, PC incorporation into hepatocytes was inhibited by only 30%, whereas cholesteryl ether uptake was inhibited by 60-70%. On the other hand, scavenger receptor class B, type I, the other important receptor for LDL in the liver, was found to be responsible for the uptake of the remaining 30-40% of LDL-cholesteryl ether. PC uptake was, however, only partially inhibited (30%) in scavenger receptor class B, type I, knock-out hepatocytes. Once LDL-PC was taken up by hepatocytes, approximately 50% of LDL-[(3)H]oleate-PC was converted to triacylglycerol rather than degraded in lysosomes as occurs for LDL-derived cholesteryl esters. The remainder of the LDL-derived PC was not significantly metabolized to other products. Triacylglycerol synthesis from LDL-PC requires a PC-phospholipase C activity as demonstrated by inhibition with the phospholipase C inhibitor D609 or activation with rattlesnake venom. Small interfering RNA-mediated suppression of acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), but not DGAT1, decreased the acylation of the LDL-derived diacylglycerol. These findings show that PC in LDL particles is taken up not only by the classical receptors but also by additional mechanism(s) followed by metabolism that is completely different from the cholesteryl esters or apoB100, the other main components of LDL.