No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Nonstatin Therapies for Management of Dyslipidemia: A Review
Abstract
Purpose:
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia.
Methods:
Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles.
Findings:
Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials.
Implications:
Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.
... Participants, who had 250 mg/dL of total cholesterol or more for up to three years, were either treated with colestipol or a placebo. After one month of the study, colestipol showcased a significant decrease in total cholesterol by 32 mg/dL (p < 0.001) and an increase in TGs by 33 mg/dL (p ≤ 0.02) compared to the placebo [43]. Men experienced a significant reduction in cardiovascular-related deaths (p ≤ 0.02), while women did not [43]. ...
... After one month of the study, colestipol showcased a significant decrease in total cholesterol by 32 mg/dL (p < 0.001) and an increase in TGs by 33 mg/dL (p ≤ 0.02) compared to the placebo [43]. Men experienced a significant reduction in cardiovascular-related deaths (p ≤ 0.02), while women did not [43]. Adverse effects include GI issues [43]. ...
... Men experienced a significant reduction in cardiovascular-related deaths (p ≤ 0.02), while women did not [43]. Adverse effects include GI issues [43]. Additionally, colestipol is often explored in other studies when combined with niacin [43]. ...
... Объектом его воздействия является белок Ниманна-Пика тип C1, который задействован в поглощении ХС щеточной каймой тонкого кишечника. Подавление абсорбции ХС в этом месте приводит к замедлению его доставки в печень, снижению его запасов в этом органе и увеличению клиренса ХС из крови [35,40]. Эзетимиб не влияет на всасывание жирорастворимых питательных веществ или других лекарственных препаратов [13]. ...
... Эзетемиб также демонстрирует некоторые дополнительные эффекты помимо снижения содержания липидов − способность уменьшать интенсивность воспаления, резистентность к инсулину, холелитиаз и жировую болезнь печени, хотя механизмы, лежащие в основе этих эффектов, не до конца выяснены и не ассоциируются с улучшением клинических исходов [40]. ...
... Высокоперспективным является применение эзетимиба в комбинации со статинами в лечении пациентов высокого риска сердечно-сосудистых исходов, особенно перенесших острый коронарный синдром. Назначение эзетимиба в качестве монотерапии у этой категории больных не должно быть рутинной рекомендацией для достижения основной цели снижения сердечно-сосудистого риска [40]. ...
В обзоре освещаются особенности применения в клинической практике альтернативных гиполипидемических препаратов (не статинов), включая ингибиторы абсорбции холестерина, секвестранты жёлчных кислот, ингибиторы пропротеинконвертазы субтилизин/кексин типа 9, фибраты, омега–3 жирные кислоты, ломитапид, мипомерсен, никотиновую кислоту, ингибиторы белка-переносчика сложного эфира холестерина. Обсуждаются механизм действия нестатиновых гиполипидемических средств, их влияние на липидный спектр, сердечно-сосудистую заболеваемость и смертность, а также побочные эффекты и взаимодействия с другими препаратами. Описываются возможности применения нестатиновых препаратов в виде монотерапии, а также в сочетании со статинами, безопасность их применения в клинической практике.
The specifics of administration of alternative hypolipidemic drugs (nonststins) including cholesterol absorption inhibitors, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 inhibitors, fibrates, n-3 fatty acids, lomitapide, mipomersen, nicotinic acid, cholesteryl ester transfer protein inhibitors are described in the review. Mechanisms of action of non-statin hypolipidemic drugs, their influence on lipid profile, cardiovascular morbidity and mortality, adverse effects and interactions with other drugs are discussed. There is description of opportunities of use non-statin hypolipidemic drugs as monotherapy and in combination with statins, safety of their application in the clinical practice
... 25 Fibrates, or fibric acid derivatives, are a class of drugs prescribed as first line management of hyperlipidemia in people. 26,27 The mechanism of action of fibrates involves induction of lipoprotein lipase, increased hepatic fatty acid uptake and reduced hepatic TG production, increased removal of low-density lipoprotein cholesterol (LDL-C), and increase in high-density lipoprotein cholesterol (HDL-C) production. 26 These effects are mediated via peroxisome proliferator-activated receptor alpha. ...
... 26 In human patients, these drugs are efficacious and generally well tolerated; adverse effects include abdominal pain, emesis, diarrhea, elevated serum creatinine concentration, and increases in alanine aminotransferase (ALT) or creatine kinase (CK) activities. 27,28 Limited peer-reviewed data exist on the use of fibrates in veterinary medicine. Description of gemfibrozil use is anecdotal and its efficacy in dogs is questionable with gastrointestinal adverse effects frequently encountered. ...
... an association with fenofibrate can neither be proven nor excluded. 27 Gemfibrozil also has a 15-fold higher risk of inducing myopathy than fenofibrate in people. 43 No changes in ALT or CK activities were found in the earlier study assessing the utility of fenofibrate in management of hyperlipidemia in dogs. ...
Background
Safe, effective, and readily available drug therapies are required for the management of hyperlipidemia and its associated complications in dogs.
Objectives
To investigate the efficacy of a micronized, nanocrystal formulation of fenofibrate (Tricor) in the treatment of hyperlipidemia in dogs.
Animals
Ten client‐owned dogs with primary (n = 7) and secondary (n = 3) hyperlipidemia. All dogs had hypertriglyceridemia at baseline; 3 dogs also had hypercholesterolemia.
Methods
Prospective dose‐escalation study. Dogs were treated with fenofibrate orally once daily in up to 3 cycles of 21 days each. Fenofibrate dose was increased at the end of each cycle if hypertriglyceridemia persisted and adverse effects were not documented. Complete blood count, biochemistry, and urine protein:creatinine ratio were collected serially. Baseline (T0) parameters were compared to time of maximal reduction in serum triglyceride concentrations (T1) and reported as median (range).
Results
Triglycerides normalized in all dogs (T0 = 662 mg/dL [189‐2391]; T1 = 113 mg/dL [81‐132]; P = .002). Fenofibrate dose at T1 = 6.4 mg/kg PO q24h (range, 2.2‐13.5). T1 was achieved at 3 (n = 4), 6 (n = 4), and 9 (n = 2) weeks. Serum cholesterol concentrations decreased in 9 of 10 dogs. Quiet demeanor and firm stools in 1 dog were the only reported adverse reactions. Fenofibrate administration resulted in a significant reduction in median alkaline phosphatase activity (P = .049).
Conclusions and Clinical Importance
Over 21 to 63 days, TriCor was effective in the management of primary and secondary hyperlipidemia in dogs.
... Statins, by competitive inhibition of HMG-CoA reductase, decrease hepatic cholesterol synthesis, increase hepatic LDL receptor expression, and consequently increase LDL-C uptake from plasma, leading to a decrease in circulating LDL-C levels [7]. However, to increase the extent of LDL-C reduction and minimize the incidence of adverse reactions, including myopathy and hepatotoxicity, additional lipid-lowering drugs may be considered in certain clinical situations, especially in high-risk patients who do not tolerate or respond to high-inten-sity statin monotherapy [8,9]. Among nonstatin agents approved for treating dyslipidemia (ezetimibe, niacin, fibrates, and bile acid sequestrants), only ezetimibe shows a modest benefit for combination therapy over statin therapy in terms of cardiovascular risk reduction, per the IMPROVE-IT study [9,10,11,12]. ...
... However, to increase the extent of LDL-C reduction and minimize the incidence of adverse reactions, including myopathy and hepatotoxicity, additional lipid-lowering drugs may be considered in certain clinical situations, especially in high-risk patients who do not tolerate or respond to high-inten-sity statin monotherapy [8,9]. Among nonstatin agents approved for treating dyslipidemia (ezetimibe, niacin, fibrates, and bile acid sequestrants), only ezetimibe shows a modest benefit for combination therapy over statin therapy in terms of cardiovascular risk reduction, per the IMPROVE-IT study [9,10,11,12]. ...
... Ezetimibe is a selective cholesterol-absorption inhibitor that inhibits cholesterol uptake from the small intestine through its binding of the Niemann-Pick C1 Like 1 (NPC1L1) transporter [13]. Although ezetimibe is usually well tolerated and effectively lowers LDL-C by 13 -20% as monotherapy or in combination with statin therapy, coadministration of ezetimibe as an add-on to statin therapy has been recommended rather than monotherapy, as the effect of ezetimibe monotherapy on cardiovascular risk reduction has not yet been demonstrated [6,9,11]. After oral administration, ezetimibe is rapidly absorbed, and extensively metabolized (> 80%) in the small intestine and liver to its pharmacologically-active phenolic glucuronide by uridine 5-diphosphate (UDP)-glucuronosyl-transferase (UGT) 1A1, 1A3, and 2B15 [13,14]. ...
Objective:
The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated.
Materials and methods:
In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters.
Results:
The mean Cmax and AUC0-t values of rosuvastatin were 12.5 ng/mL and 115.6 ng×h/mL for the FDC, and 12.2 ng/mL and 115.1 ng×h/mL for the single agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng×h/mL for the FDC, and 4.5 ng/mL and 68.2 ng×h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin Cmax and AUC0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe Cmax and AUC0-t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported.
Conclusion:
The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.
.
... To further reduce this effect and improve patient compliance in the future, we may consider supplementing oral aspirin, which has been shown to reduce the incidence of cutaneous flushing [37,38]. Other known side effects of niacin that may necessitate discontinuation of therapy, such as abnormal LFTs or significant blood glucose elevations were not encountered [39]. The latter is an important consideration given that diabetes mellitus is a risk factor for CRVO, and 9 patients (23.7%) receiving niacin in our study were diabetic. ...
... The latter is an important consideration given that diabetes mellitus is a risk factor for CRVO, and 9 patients (23.7%) receiving niacin in our study were diabetic. Also of note, large doses of niacin may exacerbate episodes of gout due to impaired uric acid excretion [39]; however, four patients receiving niacin in the current study had a history of well-controlled gout, and did not experience any exacerbations during follow-up. With respect to ocular complications, there is a rare idiosyncratic form of CME associated with extremely high doses of niacin over 2 grams a day as originally described by Gass [40]. ...
... Beyond the ocular implications, there is likely added systemic benefit to oral niacin therapy in the patient demographic typically afflicted with CRVO. Notably, individuals with CRVO tend to have a higher incidence of cardiovascular events [39,41], emphasizing the importance of risk factor identification and treatment in conjunction with the patient's internist. Prior clinical trials have demonstrated that niacin helps prevent/treat cardiovascular disease, and reduces the overall mortality rate [39,42]. ...
PurposeNiacin, a treatment for dyslipidemia, is known to induce vasodilation as a secondary effect. Previous instances of patients with chronic central retinal vein occlusion (CRVO) and cystoid macular edema (CME) have been observed to spontaneously improve when placed on systemic niacin for hypercholesterolemia. The purpose of this study was to evaluate the effects of niacin on CRVO and associated ocular complications. MethodsA prospective, single-center, non-randomized, interventional case series of niacin for CRVO was conducted. Best-correct visual acuity (BCVA), central macular thickness (CMT), and ocular complications were analyzed in 50 patients over 1 year. Eight patients were controls. ResultsThe mean initial logMAR BCVA was 0.915, and improved with niacin to 0.745 (P = 0.12), 0.665 (P = 0.02) and 0.658 (P = 0.03) after 3, 6, and 12 months of follow-up, respectively. At baseline, mean CMT was 678.9 μm, and improved to 478.1 μm (P = 0.001), 388.6 μm (P < 0.001), and 317.4 μm (P < 0.001) for the same time points. The control group had a mean initial logMAR BCVA of 1.023, which gradually deteriorated to 1.162 (P = 0.36) after 12 months, and baseline CMT of 700.0 μm at baseline, which gradually improved to 490.9 μm (P = 0.06) after 12 months. Panretinal photocoagulation for neovascularization was required in 5 patients (13.2%) receiving niacin and 3 (37.5%) controls. Conclusions
These data suggest that niacin may be associated with functional and anatomic improvements in eyes with CRVO. Future investigations will help ascertain whether there is a role for niacin as an adjunct therapy to intravitreal injections in the management of CRVO.
... Omega-3 polyunsaturated acids (n-3 PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are essential fatty acids derived from fish that can be obtained through diet, prescription supplementation or over-the-counter [35]. N-3 PUFAs may confer cardioprotective effects though this remains a debatable issue [35,36]. ...
... Omega-3 polyunsaturated acids (n-3 PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are essential fatty acids derived from fish that can be obtained through diet, prescription supplementation or over-the-counter [35]. N-3 PUFAs may confer cardioprotective effects though this remains a debatable issue [35,36]. The JELIS study, a randomized trial of EPA in 18,645 Japanese hypercholesterolemic subjects, showed that EPA and statin combination therapy reduced incidence of cardiovascular events by 18 % in patients with a history of CAD compared to patients treated with statins alone [37]. ...
... Fibrates are amphipathic carboxylic acids that serve as ligands for the peroxisome-proliferator activated receptor alpha (PPARα) [35,36,43]. They reduce circulating TGs by 20-50 % through reducing both VLDL production and increasing TRL catabolism. ...
Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk.
... Moreover, serum TG levels are biomarkers for TG-rich lipoproteins, which also are independent predictors of atherosclerotic cardiovascular disease (12). In addition, there is evidence to indicate that in certain clinical conditions, such as patients who cannot tolerate statin therapy or the recommended intensities of statin therapy, as well as those with persistent severe elevations in TG levels, or those at a high risk of developing cardiovascular disease, some non-statin therapies may be useful in the reduction of cardiovascular events (13). ...
... These extracts were found to increase the serum antioxidant potential and the hepatic catalase and superoxide dismutase activities (36). Additionally, there are studies that recommend supplementing with vitamin B3 (niacin) or a fibrate as suggested options for the correction of atherogenic dyslipidemia (13,24). Extracts from fruits of the Citrus family, have been mentioned as lipid-lowering components, with statin-like effects (37). ...
... Statin, feno brate and ezetimibe are all cholesterol-lowering drugs with distinct pharmacological mechanisms. In clinical practice, the combinations of statin with feno brate or ezetimibe respectively could bene t patients who have not achieved expected goals on hyperlipidemia-lowering management by monotherapy [19], [20]. By the mechanism of intracellular cholesterol and rotavirus interaction, we further investigated the anti-rotavirus effects of combining two statins, lovastatin and simvastatin, with FA or ezetimibe respectively. ...
... Feno brate / ezetimibe may be used in combination therapy with statin for the therapy of hyperlipidemia in clinical practice [19], [20], which inspired us to test the effects of these combinations on rotavirus. Statin has been indicated to be effective towards rotavirus by our previous experiment in vitro. ...
Despite the huge impact of rotavirus infection on global public health, there is no normally available drug against the virus worldwide. We have revealed the interaction of cholesterol metabolism and rotavirus replication, as well as identified statin as a promising drug to repress rotavirus infection, but the medical resources are greatly different across countries, so more drugs are needed for anti-rotavirus treatment in clinical activity. Two cell lines and a human small intestinal organoids were used as the models, which were infected by rotavirus SA11 strain. A clinically derived rotavirus virion, 026K strain, was measured intracellular virus RNA copies in Caco2 cells. We investigated the effects of different cholesterol-lowering drugs, including bisphosphonates (zoledronic acid, ZA), fibrate class (fenofibric acid, FA), vitamin B3 (nicotinic acid, NA), and ezetimibe on rotavirus replication in the pre-clinical models. All these cholesterol-lowering drugs resulted in significant decreases of rotavirus replication. The combinations of FA / ezetimibe with the statins had not the obvious synergies in the inhibition of rotavirus replication than any of them alone. Compared to the other drugs, ezetimibe showed the additional preventive and interference effects towards rotavirus infection. We describe an emerging application of clinical cholesterol-lowering therapy for anti-rotavirus treatment. These results could be directly considered when physicians treat with rotavirus-caused diseases worldwide.
... A hiperlipidemia primária é relativamente incomum em cães e ocorre com maior frequência em algumas raças específicas, como no Shnauzer Miniatura [35]. Já foi também relatada em Beagles [33], Shetland Shepdog [24], e recentemente em cão da raça West Highland White Terrier [9]. Não há relatos em cães da raça Maltês. ...
... Entre seus efeitos está a diminuição dos triglicerídeos hepáticos, síntese de lipoproteína de densidade muito baixa (VLDL), aumento da atividade da lipoproteína lipase, aumento da excreção vesical de carboidrato hepático e aumento na produção de HDL. A dinâmica resultante do aumento de excreção e produção diminuída geram efetiva redução de triglicerídeo circulante [5,24,29,30]. A literatura registra que o uso de bezafibrato na dose de 4-10 mg/kg apresenta bons resultados no controle de hipertrigliceridemia e hipercolesterolemia em cães com hiperlipidemia primária e secundária [8]. ...
Background: Primary hyperlipidemia is a condition that affects some specific breeds. It has been previously described in Miniature Shnauzer, Beagles, Shetland Shepdog and West Highland White Terrier. There are no reports of primary hyperlipidemia in Maltese dogs. It is a hereditary disorder of lipoprotein metabolism. The etiology is unknown and may be related to a genetic problem in lipoprotein lipase or to the absence of apaprotein CII. Clinical signs include spontaneous arterosclerosis, retinal lipemia, cutaneous xanthomas, abdominal pain, lethargy, vomiting and / or diarrhea. Neurological manifestations such as seizures and behavioral changes may also occur. The aim of this report is to describe a case of reactive seizures due to hyperlipidemia in a dog.Case: A 5-year-old male Maltese dog was admitted with a history of seizures. Hypertension and abdominal distension with large amounts of intestinal gases were found in general physical examination. Neurological examination revealed impaired nasal septum sensory perception, which was slightly bilaterally reduced, and pain on cervical palpation and in the brachial plexus region. Based on history and clinical examination, it was possible to locate the lesion in the thalamocortical region and to suspect idiopathic epilepsy, reactive seizures, and symptomatic epilepsy due to meningoencephalitis of unknown origin. The diagnosis of primary hyperlipidemia was made by exclusion with the aid of laboratory tests and ultrasound. After the establishment of a fat restriction diet, bezafibrate, phenobarbital, and omega-3 supplementation, the animal improved significantly with the reduction of epileptic seizures.Discussion: The initial clinical suspicion was hyperadrenocorticism as the primary cause of hyperlipidemia. This suspicion was based on the presence of polyphagia, polydipsia, polyuria and abdominal distension, together with laboratory results of thrombocytosis, increased ALT and AF, and hyposenuria; but ultrasound images and ACTH stimulation test ruled out this differential diagnosis. Hypothyroidism was also ruled out since LDL values were normal and the animal was extremely active. Regarding nephrotic syndrome, it was also excluded for some alterations would be present, such as severe proteinuria, cholesterol reduction and hypoalbuminemia. As for diabetes mellitus, it was discarded because of the dog’s young age and due to the absence of suggestive clinical signs. The suspicion of primary hyperlipidemia was based on increased levels of triglycerides, and the presumptive diagnosis was of reactive seizures due to hyperlipidemia. It is essential, when treating hyperlipidemia, to readjust to a low-calorie diet with fat concentration below 8% and protein level above 18%. Generally, these restricted diets are for life. Omega-3 supplementation can be performed to help maintain low levels of triglycerides. Drug therapy is usually carried out with bezafibrate, which is used in human medicine as treatment for hypertriglyceridemia, and has showed good results in the control of hypertriglyceridemia and hypercholesterolemia in dogs with primary and secondary hyperlipidemia. Six months after the beginning of the treatment, the animal no longer presented abdominal distension and pain, cholesterol values and its fractions were controlled, as well as triglycerides. Seizures were also under control. Therefore, hyperlipidemia is an important differential diagnosis in cases of patients presenting seizures, especially when dealing with young animals showing signs of metabolic diseases.
... First, treatment with bile-acid sequestrants which, by interrupting the enterohepatic circulation, deplete the bile acid pool, significantly increase CYP7A1 activity and de novo synthesis of bile acids, and lower plasma LDL cholesterol levels in a dose-dependent manner 5 by increased receptor-mediated clearance of LDL. 4,20,21 Treatment with bile-acid sequestrants decreases plasma LDL cholesterol by up to 25%, and reduces risk of coronary heart disease death and/or non-fatal MI when used as monotherapy. 9,[20][21][22] Due to the associated increase in CYP7A1 activity and bile acid synthesis, we speculate that bile acid sequestrants likely also reduce the risk of GSD, although this has not been tested directly. ...
... 4,20,21 Treatment with bile-acid sequestrants decreases plasma LDL cholesterol by up to 25%, and reduces risk of coronary heart disease death and/or non-fatal MI when used as monotherapy. 9,[20][21][22] Due to the associated increase in CYP7A1 activity and bile acid synthesis, we speculate that bile acid sequestrants likely also reduce the risk of GSD, although this has not been tested directly. Second, Rudling et al. 6 more recently showed that elobixibat, a minimally absorbed ileal bile acid transporter inhibitor, reduced LDL cholesterol and increased 7a-hydroxy-4-cholesten-3-one (C4) in a dose-dependent manner. ...
Aims:
Myocardial infarction (MI) and gallstone disease (GSD) are intrinsically linked via cholesterol metabolism. We tested the hypothesis that genetic variants in the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, are associated with risk of MI and GSD in the general population.
Methods and results:
We performed tests of association between lipid levels and eight rare non-synonymous mutations and two common variants, rs2081687 and rs3808607, in CYP7A1 in 100 149 individuals from the general population. We further tested whether weighted allele scores for rs2081687 and rs3808607, which were associated with increased plasma levels of low-density lipoprotein (LDL) cholesterol, were associated with an increased risk of both MI and symptomatic GSD. During a mean follow-up of 7 years (0-23 years), MI developed in 2326 individuals and GSD in 2007. For rare mutations, CYP7A1 allele count was associated with an increase in LDL cholesterol of 12% (0.4 mmol/L) for individuals with the highest vs. the lowest allele count (P for trend = 3 × 10-4). For common variants, CYP7A1 weighted allele scores in individuals with a score >0.04 vs. ≤0 were associated with stepwise increases in LDL cholesterol of up to 2.4% (0.08 mmol/L), and with corresponding multifactorially adjusted hazard ratios of 1.25 [95% confidence interval (CI) 1.10-1.41] for MI and 1.39 (95% CI 1.22-1.59) for GSD (P for trend = 5 × 10-4 and 2 × 10-7, respectively). Results were similar in meta-analyses including publicly available data from large consortia.
Conclusion:
Genetic variants in CYP7A1 which are associated with increased levels of LDL cholesterol, are associated with an increased risk of both MI and GSD.
... Hyperlipidemia treatments include diet and exercise, fibrates, bile acid sequestrants, nicotinic acid, statins, and selective inhibitors of cholesterol absorption. [1] Statin therapy is effective for both primary and secondary prevention for CAD and also improves a number of perioperative outcomes. Significant reductions in cardiovascular morbidity and mortality from lipid-lowering as well as pleiotropic effects have been demonstrated. ...
... [9,10] In addition, ezetimibe (Zetia ® ) was approved in the class of cholesterol absorption inhibitors which when used alone or with a high-intensity statin have proved effective in those patients with extremely high LDL-C levels. [1,11] ...
Statins are a mainstay of hyperlipidemia treatment. These drugs inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and have beneficial effects on atherosclerosis including plaque stabilization, reduction of platelet activation, and reduction of plaque proliferation and inflammation. Statins also have a benefit beyond atherosclerotic plaque, including anticoagulation, vasodilatation, antioxidant effects, and reduction of mediators of inflammation. In the perioperative period, statins appear to contribute to improved outcomes via these mechanisms. Both vascular and nonvascular surgery patients have been shown in prospective studies to have lower risk of adverse cardiac outcomes when initiated on statins preoperatively. However, not all patients can tolerate statins; the search for novel lipid-lowering therapies led to the discovery of the proprotein convertase subtilisin/kexin Type 9 (PCSK9) inhibitors. These drugs are fully-humanized, injectable monoclonal antibodies. With lower PCSK9 activity, low-density lipoprotein cholesterol (LDL-C) receptors are more likely to be recycled to the hepatocyte surface, where they serve to clear plasma LDL-C. Evidence from several prospective studies shows that these new agents can significantly lower LDL-C levels. While PCSK9 inhibitors offer hope of effective therapy for patients with familial hyperlipidemia or intolerance of statins, several important questions remain, including the results of long term cardiovascular outcome studies. The perioperative effects of new LDL-C-lowering drugs are unknown at present but are likely to be similar to the older agents. © 2016 Journal of Anaesthesiology Clinical Pharmacology Published by Wolters Kluwer - Medknow.
... In sitosterolemia, patients have mutations in ATP-binding cassette (ABC) subfamily G member solution and frequent gastrointestinal adverse effects limit their clinical use. Symptoms of bloating, abdominal pain, and diarrhea are commonly reported in children and adults [94,95]. Further, BAS are contraindicated in patients with triglycerides exceeding 300 mg/dL as they raise the triglyceride level [50]. ...
Lipid abnormalities in youth pose place patients at risk for the early development of atherosclerotic cardiovascular disease (ASCVD). A growing body of evidence supports early detection and treatment of dyslipidemia in youth. While lifestyle modifications remain the cornerstone of treatment, there are a growing number of safe and effective lipid-lowering therapies that providers can feel comfortable initiating in their patients with the appropriate patient selection and monitoring.
... 1,2) Approximately 17.9 million people died from CVDs in 2019, accounting for 32% of all global deaths, 3) and since 1985, heart disease has been the second leading cause of death in Japan. 4) The use of lipid-modifying agents (LMAs), which improve lipid levels and prevent cardiovascular events, [5][6][7][8] continues to grow globally. 9) Older people are vulnerable to CVDs and commonly use LMAs, but its use among older people aged ≥75 years for the primary prevention of CVDs remains controversial, [10][11][12][13][14] mainly due to a paucity of evidence in this group. ...
The use of lipid-modifying agents (LMAs) other than statins has rarely been reported in real clinical settings. We aimed to compare the initiation and subsequent use of LMA classes for prevention of cardiovascular diseases. Using the national claims database, this retrospective cohort study was conducted on patients aged ≥55 years who initiated to use statins, ezetimibe, or fibrates between Fiscal Years (FYs) 2014 and 2017 as the first pharmacotherapy for dyslipidemia in Japan. A permissible gap for defining persistence was set as the median days of supply of a class to an individual. Kaplan–Meier estimates were calculated for rates. Cohorts for primary prevention without/with risk and secondary prevention comprised 1307438, 908378, and 503059 initiators for statins; 44116, 34206, and 11373 for ezetimibe; and 124511, 96380, and 27751 for fibrates. The persistence rates declined shortly after the therapy initiation regardless of the classes, which was approximately 50% at 1 year for any class for primary prevention without risk. A notable sex difference in terms of persistence rates was observed only for statins of secondary prevention. The restarting rates were similar between prevention settings: approximately 50–60% for statins and 30–40% for ezetimibe and fibrates 1 year after first discontinuation. For ezetimibe and fibrates, approximately 10% of initiators were added or switched to statins within 1 year of initiation. Collectively, any class tended to be discontinued early and some restarted; however, there were some unique classes. The findings are useful for improvement of dyslipidemia therapy.
Fullsize Image
... Furthermore, many non-statin lipid lowing drugs, such as ezetimibe, bile acid sequestrants, fibrates, and niacin, have significant limitations. Their lipid lowering properties are limited, and they have a high incidence of AEs, thereby questioning their qualifications as an alternative LLT [39]. ...
Lipid-lowering therapy is of great importance in reducing the burden of atherosclerotic cardiovascular disease. Statins act as first-line therapy in the current lipid management guidelines. However, statin use is limited in (1) statin-induced adverse events, including statin-associated muscle symptoms, new-onset diabetes mellitus, drug-induced liver injuries, acute kidney injuries, cognitive effects, hemorrhagic strokes, and cataracts; (2) special populations, including pregnant and lactating patients, patients with decompensated cirrhosis, and patients on dialysis; (3) coadministration with statin-interactive drugs, such as anti-human immunodeficiency virus drugs, anti-hepatitis C virus drugs, and immunosuppressive drugs. These considerable statin-limited groups are in urgent need of safer alternative lipid-lowering options. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are attracting widespread attention for their documented safety in general populations and superior lipid-lowering properties. Therefore, questions have been raised whether PCSK9 inhibitors could be a safe alternative in patients who are intolerant to statin therapy. In this review, we discuss the safety of PCSK9 inhibitors in statin-limited conditions. We conclude that PCSK9 inhibitors are a safe alternative lipid-lowering therapy in various statin-limited conditions. Furthermore, we identify several limitations in the current literature and suggest future directions, for the refinement of lipid management regimens.
... 42 Trials exploring the use of fibrates in combination with statins have failed to show positive results, except in those with elevated TG (>200 mg/dL) or low HDL-C (<40 mg/dL). 43 These drugs also increase the risk of gallstones; therefore, they are not recommended in patients with history of biliary colic. They have also been associated with an increased risk of rhabdomyolysis. ...
Diabetic dyslipidaemia (DD) comprises a complex group of potentially atherogenic lipid and lipoprotein abnormalities, including both quantitative and qualitative changes. It is characterised by low high-density lipoprotein cholesterol, elevated low-density lipoprotein cholesterol (LDL-C), and a higher prevalence of small, dense LDL particles, as well as elevated fasting and postprandial triglycerides. Patients with Type 2 diabetes mellitus have an increased prevalence of lipid abnormalities and controlling dyslipidaemia in these patients has a big impact on morbidity and mortality. Lifestyle changes are still the pillar of treatment for DD and statins are the drugs of choice that decrease LDL-C and reduce cardiovascular events and cardiovascular death, either in primary or secondary prevention, in diabetic patients. Pitavastatin has a number of pleiotropic effects that reduce the metabolic changes associated with adiposity and improve glucose metabolism, which distinguishes it from other statins. New treatments, such as PCSK9 inhibitors, have proven to be powerful LDL-C-lowering agents; however, the need for long-term safety studies and the high associated costs are the main challenges. Future treatments, such as an intracellular PCSK9 inhibitor, a dual proliferator-activated receptor-alpha/gamma agonist, and bempedoic acid, are in development. The aim of this article is to review the pathophysiology of DD and discuss its role in cardiovascular event risk and treatment, as well as to study the effects of lipid-lowering therapy on glucose metabolism and the outcomes of antidiabetic treatment on dyslipidaemia.
... Except for statins, clinical drugs that can be used to treat HTG are fibrates, niacin, and omega-3 fatty acids (Preston Mason, 2019). Several previous reviews have summarized the effects of these clinically used drugs for TG-lowering (Sando and Knight, 2015;Simons, 2018;Feingold, 2021). Furthermore, our team demonstrated that exogenous supplement of N-acetylneuraminic acid can reduce TG by more than 60% in apoE (−/−) mice (Guo et al., 2016;Hou et al., 2019). ...
Cardiovascular disease (CVD) is still the leading cause of death globally, and atherosclerosis is the main pathological basis of CVDs. Low-density lipoprotein cholesterol (LDL-C) is a strong causal factor of atherosclerosis. However, the first-line lipid-lowering drugs, statins, only reduce approximately 30% of the CVD risk. Of note, atherosclerotic CVD (ASCVD) cannot be eliminated in a great number of patients even their LDL-C levels meet the recommended clinical goals. Previously, whether the elevated plasma level of triglyceride is causally associated with ASCVD has been controversial. Recent genetic and epidemiological studies have demonstrated that triglyceride and triglyceride-rich lipoprotein (TGRL) are the main causal risk factors of the residual ASCVD. TGRLs and their metabolites can promote atherosclerosis via modulating inflammation, oxidative stress, and formation of foam cells. In this article, we will make a short review of TG and TGRL metabolism, display evidence of association between TG and ASCVD, summarize the atherogenic factors of TGRLs and their metabolites, and discuss the current findings and advances in TG-lowering therapies. This review provides information useful for the researchers in the field of CVD as well as for pharmacologists and clinicians.
... Blood lipids are a general term for cholesterol, triacylglycerol (TG) and lipids (such as phospholipids) in serum, and the clinically relevant blood lipids are mainly cholesterol and TG. Dyslipidemia refers to abnormal metabolism of lipoproteins in the human body, mainly including elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triacylglycerol (TG) levels, or decreased high-density lipoprotein cholesterol (HDL-C) levels [1] . Some research reports have pointed out that the prevalence of dyslipidemia in people elder than 35 years in China was 34.7% from 2012 to 2015 [2] , the blood lipid level in the Chinese population gradually increased, and the detection rate of dyslipidemia signi cantly increased [3] . ...
Background: This study aimed to investigate the distribution of the incidence of dyslipidemia among the elderly in Wuwei, and explore the related factors affecting dyslipidemia.
Methods: The physical examination data of 43,092 elder people aged 60 and over from 2012 to 2019 in Wuwei city were collected to analyze the incidence of dyslipidemia, and the factors affecting dyslipidemia were evaluated by univariate and multivariate analysis.
Results: A total of 12,338 cases of dyslipidemia were reported in 43,092 patients, and the incidence of dyslipidemia was 28.6%. Among these dyslipidemia patients, the proportion of patients with low high-density lipoprotein cholesterol was the highest, and the proportion of patients with hypertriglyceridemia combined with low high-density lipoprotein cholesterol was the lowest. Univariate analysis showed that age, gender, smoking, alcohol consumption, blood glucose, blood pressure, weight, electrocardiogram, and total bilirubin were the influencing factors of dyslipidemia in the elderly, and the differences were statistically significant (P < 0.05). Multivariate logistic regression analysis indicated that female gender, overweight/obesity, abnormal blood glucose, and high alanine aminotransferase were independent risk factors for dyslipidemia in the elderly (P < 0.05).
Conclusions: The age with the highest prevalence of dyslipidemia among the elderly in Wuwei city is 70–80 years old. Elderly women should strengthen the prevention and treatment of dyslipidemia. In order to avoid the occurrence of dyslipidemia, it is necessary to control body weight, blood glucose and improve liver function.
... But inorder to reach LDL and triglycerides and HDL target in high risk cardiovascular patients combinations of drugs like ezetimibe, fibrates with statins play a important role. In patients who are intolerant to statins and those have constant elevation of triglycerides non-statin therapy with drugs like CETP inhibitors (Cholesteryl Ester Transfer Protein inhibitiors)) and PCSK9 inhibitors (Proprotein Convertase subtilisin/kexin type 9 inhibitors) are useful to reduce cardiovascular risk [3]. Effective and safe use of drugs and lower the lipoproteins level to the target level should be the motive in drug prescribing and drug usage by the patients. ...
... The main cause of CVD is atherosclerosis, a multifactorial disorder induced and augmented by risk factors such as dyslipidemia, oxidative and inflammatory stress, diabetes mellitus, hypertension, smoking, ageing and genetic mutations [3]. Many therapies designed to treat atherosclerosis either have failed completely or partially (cholesteryl ester transfer protein (CETP) inhibitors, antioxidants, vitamins), or were too expensive to be applied to the entire population at CVD risk (apoA-I Milano); others, though successful, induced considerable side-effects (statins) [4,5]. Thus, the quest for strategies to prevent or treat CVD is of high and continued interest. ...
Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search for new alternatives worthwhile. The focus of the scientific world turned to the potential of natural active compounds to prevent and treat CVD. Essential for effective prevention or treatment based on phytochemicals is to know their mechanisms of action according to their bioavailability and dosage. The present review is focused on the latest data about phenolic compounds and aims to collect and correlate the reliable existing knowledge concerning their molecular mechanisms of action to counteract important risk factors that contribute to the initiation and development of atherosclerosis: dyslipidemia, and oxidative and inflammatory-stress. The selection of phenolic compounds was made to prove their multiple benefic effects and endorse them as CVD remedies, complementary to allopathic drugs. The review also highlights some aspects that still need clear scientific explanations and draws up some new molecular approaches to validate phenolic compounds for CVD complementary therapy in the near future.
... Nevertheless, the benefits of statin therapy are limited in patients with resistance or intolerance to high-dose statin therapy. In addition to statin therapy, other lipidlowering drugs can also be prescribed including bile acid resin sequestrants (cholestyramine, colestipol, colesevelam), cholesterol absorption inhibitors (ezetimibe), fibrates (gemfibrozil, bezafibrate, fenofibrate), nicotinic acid (niacin), and omega-3 polyunsaturated fatty acids (Grundy et al., 2018;Bhatt et al., 2019;Sando et al., 2015;NCEP, 2002). The overall efficacy of non-statin drugs on cardiovascular disease outcomes is much less robust than that of statins. ...
The clinical benefit of lipid-lowering therapies is to reduce circulating levels of atherogenic particles and to ameliorate the risk of atherosclerotic cardiovascular disease (ASCVD). The completion of two major clinical trials on PCSK9 inhibitors (PCSK9i), the FOURIER and the ODYSSEY outcome trials, has marked the beginning of a new era of lipid-lowering drugs. PCSK9i, evolocumab and alirocumab, are monoclonal antibodies that inactivate the liver proprotein convertase subtilisin kexin 9 (PCSK9). Inhibition of PCSK9 increases the number of low-density lipoprotein (LDL) receptors available leading to a profound reduction in circulating LDL particles. By preventing LDL receptor destruction, PCSK9i as adjunct to statin therapy can reduce LDL-C by 50–60% above that achieved by statin therapy alone. In addition, PCSK9i in combination with high-dose statins may reduce cardiovascular events and all-cause mortality in patients with clinical ASCVD. Based on evidence from clinical trials, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias now include the use of PCSK9i to very high-risk ASCVD patients who are not achieving treatment goals on a maximum tolerated dose of a statin and ezetimibe. However, the cost-effectiveness of PCSK9i therapy is limited to secondary prevention in high-risk patients. This review outlines the main clinical trials leading to a change in the guidelines, clinical practice as well as the future challenges of PCSK9i therapy.
... 7 It is also to be noted that fibrates have been prescribed to high-risk patients, given that recent trials have shown that these medications have failed to achieve a statistically significant reduction in lipid levels and, when combined with statins, have shown an increase in side effects. 8 Moreover, the use of ezetimibe, particularly in association with statins, was found to be reduced. This may be explained by the fact that ezetimibe is not included in the National Essential Medicines List, which is a mandatory reference in public institutions. ...
Background: The Adult Treatment Panel III (ATPIII) guidelines aim to reduce cardiovascular morbidity and mortality. In Ecuador, 20% of people have high LDL cholesterol levels, and 39% have high triglyceride levels.
Objective: To analyze lipid-lowering regimens in Ecuadorian patients and determine the achievement rate of the ATPIII goals for lipid profile.
Methods: Using a retrospective analysis, 385 subjects older than 30 years, who received pharmacological treatment for dyslipidemia for at least three months was randomly selected from institutions at two large cities in Ecuador. Data were collected from patients’ medical records and analyzed by chi-square test or paired t-test; p-values less than 0.05 were considered significant.
Results: Baseline total cholesterol values were above 200 mg/dL in 75% of subjects, LDL-c values above 129 mg/dL in 83% of subjects and triglycerides values above 150 mg/dL in 79% of subjects. Most (n = 253, 95.8%) patients at very high cardiovascular risk were taking statins, 50% of them atorvastatin. Considering the ATPIII guidelines’ goals, only 24 subjects (19%) at high CV risk achieved an LDL-c < 100 mg/dl, while a significantly lower percentage (p = 0.04) of patients at very high risk reached an LDL-c < 70mg/dl (11%; n = 30).
Conclusion: These data indicate a low rate of compliance with the ATPIII guidelines, independent of the medication used or duration of the treatment. This may be attributed to the prescription of low doses of medication and a therapy targeting isolated lipid fractions rather than a complete lipid profile
... These effects were mainly mediated by the peroxisome proliferator-activated receptor α (PPARα) and PPARα-independent mechanisms. Elucidation of the key role of PPARα in the induction of CPT1A has been provided by drug studies with synthetic ligands like clofibrate or gemfibrozil, which are used in the clinic to stimulate fat oxidation and reduce triglycerides in blood (56). Additionally, using a bioinformatic approach, a putative PPAR binding site has been located 3 kb downstream of the transcription start site, and its mutation abolished any response to fatty acids (57). ...
Energy homeostasis during fasting or prolonged exercise depends on mitochondrial fatty acid oxidation (FAO). This pathway is crucial in many tissues with high energy demand and its disruption results in inborn FAO deficiencies. More than 15 FAO genetic defects have been currently described, and pathological variants described in circumpolar populations provide insights into its critical role in metabolism. The use of fatty acids as energy requires more than two dozen of enzymes and transport proteins, which are involved in the activation and transport of fatty acids into the mitochondria. As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and disease, including cancer. The CPT1 family of proteins contains three isoforms: CPT1A, CPT1B and CPT1C. This review focusses on CPT1A, the liver isoform that catalyzes the rate limiting step of converting acyl-CoA’s into acyl-carnitines, which can then cross membranes to get into the mitochondria. The regulation of CPT1A is complex and has several layers that involve genetic, epigenetic, physiological and nutritional modulators. It is ubiquitously expressed in the body and associated with dire consequences linked with genetic mutations, metabolic disorders and cancers. This makes CPT1A an attractive target for therapeutic interventions. This review discusses our current understanding of CPT1A expression, its role in heath and disease and the potential for therapeutic opportunities targeting this enzyme.
... Fibrates reduce plasma triglycerides by approximately 20% to 50%. 16 Fibrate therapy has been shown to reduce cardiovascular disease (CVD) risk in patients with high triglycerides, low HDL-C or both (RR 0.75, 95% CI 0.65 to 0.86; RR 0.84, 95% CI 0.77 to 0.91 and RR 0.71, 95% CI 0.62 to 0.82, respectively), but not in patients with normal triglycerides or HDL-C (RR 0.96, 95% CI 0.85 to 1.09). 17 Most patients with high triglyceride levels respond well to a low-fat diet, that contains 10 to 15 g of fat daily. ...
A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass index 29.7 kg/m ² ). Diabetes mellitus was ruled out, as were nephrotic syndrome, alcohol abuse, hypothyroidism and dysbetalipoproteinaemia. Genetic analysis revealed mutations in two genes involved in triglyceride metabolism (apolipoprotein A5 and lipoprotein lipase [LPL]). The LPL activity was 45% compared with pooled healthy controls. The post-heparin triglyceride reduction was 6%, compared with a normal reduction of >20%. The patient was initially treated with gemfibrozil, but this was discontinued due to side effects. Dietary triglyceride restriction and discontinuation of the oral contraceptives lowered the plasma triglycerides within 2 weeks to 3.4 mmol/L. Hypertriglyceridaemia is a risk factor for pancreatitis and cardiovascular disease, and has a broad differential diagnosis including genetic causes. Patients can achieve near-normal triglyceride values with a low-fat diet only.
... The results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial indicated that significantly more CHD patients treated with a combination of a statin and ezetimibe met LDL-C goals than patients treated with statin alone (14,15). Ezetimibe-statin combination therapy reduces cardiovascular outcomes in patients following vascular surgery or acute coronary syndrome (16). The effectiveness and safety of combined therapy with statins and other lipid-lowering agents is worthy of further investigation. ...
Reducing the plasma levels of low-density lipoprotein-cholesterol (LDL-C) is critical for patients with coronary heart disease (CHD). Conventional treatment with statins alone may not achieve the goal of lowering LDL-C due to drug intolerance or resistance. The present study evaluated the effectiveness and safety of combining statin with another lipid-lowering agent in the management of dyslipidemia in CHD patients. A total of 180 patients with CHD were divided into three therapeutic groups (n=60 in each): Statin/colesevelam group (20 mg atorvastatin and 10 mg colesevelam daily), statin/ezetimibe group (20 mg atorvastatin and 10 mg ezetimibe daily) and high-intensity statin monotherapy group (30 mg atorvastatin daily). The baseline plasma lipid levels were measured. The duration of the treatment was eight weeks and the side effects were noted at one year's follow-up. After eight weeks' treatment, the mean plasma level of LDL-C was reduced by 45.2, 44.8 and 30.0% in the statin/colesevelam, statin/ezetimibe and statin monotherapy group, respectively. The reduction of LDL-C in the combinational therapy groups was greater than that in the statin monotherapy group (P<0.05). The proportion of patients achieving the goal of lowering LDL-C in the combinational therapy groups was higher than that in the statin monotherapy group. The effectiveness of reducing lipids was similar in the two combinational statin/colesevelam and statin/ezetimibe groups. Rates of adverse events were not significantly different among the three groups. In conclusion, statins combined with colesevelam or ezetimibe were more effective in reducing plasma LDL-C levels than high-intensity statin monotherapy. This combinational therapeutic strategy may be an alternative for patients that are resistant or intolerant to statins.
... It is confirmed that high levels of cholesterol, chylomicron, low-density lipoprotein, and apolipoprotein B are risk factors of cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease and ischemic stroke [4][5][6][7], and chronic kidney disease [8], which have negative effects on human health. The primary choice of therapy for controlling lipidemia has been statins, which are not completely effective [9,10]. Screening for dyslipidemia in childhood could delay or reduce cardiovascular events in adulthood [11]. ...
Objective
To study the correlation between Traditional Chinese Medicine (TCM) constitution and dyslipidemia.
Methods
CNKI, VIP, Wanfang database, CBMdisc, PubMed, and Embase were searched, and meta-analysis was performed by Review Manager 5.2 software.
Results
Altogether 11 studies were included with 12890 individuals. The results showed that balanced constitution was a protective factor of dyslipidemia (OR = 0.62, 95% CI 0.47~0.82) while phlegm-dampness constitution was a risk factor of it (OR = 2.50, 95% CI 2.22~2.80), and the effect of phlegm-dampness constitution in South China (OR = 3.31, 95% CI 1.71~6.43) was more obvious than that in East (OR = 2.40, 95% CI 2.06~2.80) and North China (OR = 2.24, 95% CI 1.81~2.78).
Conclusion
This study provides evidence for the prevention and treatment of dyslipidemia in TCM. However, most of the studies included are of moderate quality; more high quality, multicenter, large-sample studies are expected to provide higher level evidence.
... Bile acid resins such as cholestyramine and colestipol bind bile acids in the intestine via anion exchange which results in decreased enterohepatic reuptake of the bile acids thus leading to fecal loss of LDL [66]. These agents are contraindicated in patients with baseline fasting triglycerides >300 mg/dL or type III hyperlipoproteinemia as they can exacerbate hypertriglyceridemia. ...
Chronic kidney disease (CKD) is associated with high risk for cardiovascular disease (CVD). This association is multifactorial, but CKD is often associated with dyslipidemia, which likely contributes. Patients with CKD have dyslipidemia even at early stages of renal dysfunction and dyslipidemia tends to progress with deterioration of kidney function. The dyslipidemia in CKD is largely due to increased triglyceride levels, decreased HDL-C and varying levels of LDL-C. Current management of CKD may also affect lipid levels. Robust clinical trials demonstrate that statins are safe and efficacious in both lipid lowering and prevention of CVD events in pre-end stage CKD and post-transplant. However, there is no evidence of improved CVD outcomes with statin use in dialysis patients. This review will focus on mechanisms underlying dyslipidemia in CKD and clinical trial evidence for lipid lowering therapy in patients with CKD.
... Recently, the European Food Safety Authority has endorsed the average total NA intakes, which ranged from 5.5 to 6.6 mg NA equivalent per consumed 1000 kcal in adults, as being necessary for catabolic and anabolic processes [1]. In addition, pharmacological doses of NA (1500-3000 mg/day) can be effective for treatment of chronic high-grade inflammatory diseases such as atherosclerosis [2]. In patients with myocardial infarction, NA reduces long-term mortality [3] and may confer additional antiatherogenic benefits when used in conjunction with statins [4]. ...
... Niacin (also commonly known as nicotinic acid or vitamin B3) is well established for the treatment of dyslipidemia [1] and reduction of cardiovascular risk [2]. However, its clinical use has been greatly limited due to an intense skin flush within a few minutes of niacin ingestion [3]. ...
Metabolic disorders (MDs), including dyslipidemia, non-alcoholic fatty liver disease, diabetes mellitus, obesity and cardiovascular diseases are a significant threat to human health, despite the many therapies developed for their treatment. Different classes of bioactive compounds, such as polyphenols, flavonoids, alkaloids, and triterpenes have shown therapeutic potential in ameliorating various disorders. Most of these compounds present low bioavailability when administered orally, being rapidly metabolized in the digestive tract and liver which makes their metabolites less effective. Moreover, some of the bioactive compounds cannot fully exert their beneficial properties due to the low solubility and complex chemical structure which impede the passive diffusion through the intestinal cell membranes. To overcome these limitations, an innovative delivery system of phytosomes was developed. This review aims to highlight the scientific evidence proving the enhanced therapeutic benefits of the bioactive compounds formulated in phytosomes compared to the free compounds. The existing knowledge concerning the phytosomes’ preparation, their characterization and bioavailability as well as the commercially available phytosomes with therapeutic potential to alleviate MDs are concisely depicted. This review brings arguments to encourage the use of phytosome formulation to diminish risk factors inducing MDs, or to treat the already installed diseases as complementary therapy to allopathic medication.
Hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) persist despite statin therapy, contributing to residual atherosclerotic cardiovascular disease (ASCVD) risk. Asian subjects are metabolically more susceptible to hypertriglyceridemia than other ethnicities. Fenofibrate regulates hypertriglyceridemia, raises HDL-C levels, and is a recommended treatment for dyslipidemia. However, data on fenofibrate use across different Asian regions are limited. This narrative review summarizes the efficacy and safety data of fenofibrate in Asian subjects with dyslipidemia and related comorbidities (diabetes, metabolic syndrome, diabetic retinopathy, and diabetic nephropathy). Long-term fenofibrate use resulted in fewer cardiovascular (CV) events and reduced the composite of heart failure hospitalizations or CV mortality in type 2 diabetes mellitus. Fenofibrate plays a significant role in improving irisin resistance and microalbuminuria, inhibiting inflammatory responses, and reducing retinopathy incidence. Fenofibrate plus statin combination significantly reduced composite CV events risk in patients with metabolic syndrome and demonstrated decreased triglyceride and increased HDL-C levels with an acceptable safety profile in those with high CV or ASCVD risk. Nevertheless, care is necessary with fenofibrate use due to possible hepatic and renal toxicities in vulnerable individuals. Long-term trials and real-world studies are needed to confirm the clinical benefits of fenofibrate in the heterogeneous Asian population with dyslipidemia.
Fibrinolysis is an enzymatic process that breaks down fibrin clots, while dyslipidemia refers to abnormal levels of lipids and lipoproteins in the blood. Both fibrinolysis and lipoprotein metabolism are critical mechanisms that regulate a myriad of functions in the body, and the imbalance of these mechanisms is linked to the development of pathological conditions, such as thrombotic complications in atherosclerotic cardiovascular diseases. Accumulated evidence indicates the close relationship between the two seemingly distinct and complicated systems-fibrinolysis and lipoprotein metabolism. Observational studies in humans found that dyslipidemia, characterized by increased blood apoB-lipoprotein and decreased high-density lipoprotein, is associated with lower fibrinolytic potential. Genetic variants of some fibrinolytic regulators are associated with blood lipid levels, supporting a causal relationship between these regulators and lipoprotein metabolism. Mechanistic studies have elucidated many pathways that link the fibrinolytic system and lipoprotein metabolism. Moreover, pro-fibrinolytic therapies improve lipid panels toward an overall cardiometabolic healthier phenotype, while some lipid-lowering treatment increases fibrinolytic potential. The complex relationship between lipoprotein and fibrinolysis warrants further research to improve our understanding of the bidirectional regulation between the mediators of fibrinolysis and lipoprotein metabolism.
Effective management of dyslipidemia is of paramount importance to prevent cardiovascular (CV) complications. Using current clinical practice guidelines is recommended to correct lipid levels and prevent further pathologic processes. This article presents an overview of treatment options for patients with dyslipidemia and CV disease, with a special focus on the following drug classes: HMG-CoA reductase inhibitors (also called statins), cholesterol absorption inhibitors (ezetimibe), bile acid sequestrants, fibrates, icosapent ethyl, and PCSK9 inhibitors.
Cutaneous manifestations can be an early sign or a late presentation of systemic diseases. All practitioners should be familiar with dermatological lesions of underlying diseases so that they may properly diagnose and treat the patient or refer to the specialist.This chapter addresses dyslipidemias including epidemiology, etiopathogenesis, classification, and their characteristic skin manifestation: xanthomas. Acknowledging clinical features, histopathology, and differential diagnosis of xanthomas helps providing an early diagnosis and follow-up of types of dyslipidemia. Dermatologists must be aware that is of no help removing xanthomas, while the underlying cause is not therapeutically approached at all.KeywordsXanthomasHyperlipidemiaHypercholesterolemiaTuberous xanthomasXanthelasma
The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the ⁷⁵SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.
The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.
Hypertriglyceridemia is associated with an increased risk of atherosclerotic cardiovascular (CV) disease. Clinical trials have demonstrated the effectiveness of eicosapentaenoic acid ethyl ester (EPA), an omega-3 polyunsaturated fatty acid, on triglyceride lowering and on CV risk reduction. However, many clinicians have limited understanding of the effects of EPA and limited experience using EPA to reduce the risk of CV disease. An analysis was conducted to determine whether an online continuing medical education (CME) intervention could improve knowledge and competence of primary care physicians (PCPs) and cardiologists related to the role of EPA in management of CV risk in patients with dyslipidemia. The intervention comprised 2 online video-based CME activities. The effects of education were assessed for learners who completed 4 pre- and post-assessment questions for each activity, using a matched pre-/post-assessment design. For all questions combined, a McNemar's chi-square test assessed differences from pre- to post-assessment. Matched-learner data indicated that 34% of PCPs improved their knowledge as a result of participating in the activities, and 42% had their knowledge reinforced. Among cardiologists, 28% improved their knowledge, and 61% had their knowledge reinforced. For these learner subsets, there was a significant 17% relative increase in self-assessed confidence in appropriate use of EPA for PCPs (n=1644, P<.001) and a 12% increase for cardiologists (n=524; P<.001). The improvements observed in this online CME intervention demonstrate the benefits of educating the appropriate target audience base and suggest that this type of intervention can translate into improvements in clinical care.
The purpose of this report is to inform nurse practitioners and other health care providers about how to treat dyslipidemia in the statin-intolerant patient while simultaneously achieving optimal cardiovascular outcomes for this patient population. This report will briefly explain how to rechallenge the statin-intolerant patient and the secondary therapies that are available to decrease cardiovascular morbidity and mortality. Algorithms for rechallenging the statin-intolerant patient and secondary therapies are also provided.
Zusammenfassung
Die chologene Diarrhö ist eine der häufigsten nicht diagnostizierten Ursachen der chronischen Diarrhö. Zahlreiche verschiedene Pathophysiologien können einer chronischen Diarrhö zugrunde liegen. Auch nach Ausschlussdiagnostik der häufigeren Ursachen verbleiben bis zu 5 % der Bevölkerung von einer ungeklärten chronischen Diarrhö betroffen. In diesem Kollektiv findet sich in bis zu 50 % als Ursache eine chologene Diarrhö.
Die verschiedenen Pathophysiologien, die zu einer chologenen Diarrhö führen, sind gut charakterisiert. Danach lässt sich die chologene Diarrhö in einen primären, einen sekundären und einen tertiären Subtyp unterteilen. Allen Ursachen gemein sind die erhöhte Menge an Gallensäuren im Kolon und im Fäzes und die dadurch bedingte sekretorisch-osmotische Diarrhö, bei schwereren Formen in Kombination mit einer Steatorrhö. Die Diagnostik der chologenen Diarrhö folgt einem klaren Algorithmus, der neben der Ursachensuche und dem diagnostischen Therapieversuch den 75SeHCAT-Test als Referenzverfahren für den Nachweis eines Gallensäurenverlusts angibt. Aufgrund der Chronizität der Beschwerden und der Notwendigkeit einer dauerhaften, lebenslangen Therapie scheint eine einmalige sichere Diagnosestellung prinzipiell sinnvoll; der Test ist allerdings derzeit nur an wenigen Zentren verfügbar. Die Therapie umfasst neben der Behandlung identifizierbarer Grundkrankheiten den Einsatz von Gallensäuren bindenden Arzneimitteln, Ernährungsempfehlungen und Vitaminsubstitutionen.
Der vorliegende Übersichtsartikel fasst Pathophysiologie und Stellenwert der chologenen Diarrhö zusammen und diskutiert die aktuelle Diagnostik und Therapie.
Osteoporosis is a chronic disease in adult women caused by menopause and some other factors, which entails deficiency of calcium in diet. Natural products are the best source of nutriments to reduce the risk of chronic diseases. Nopal (Opuntia ficus-indica) is a plant characterized by its nutritional components and benefits to health. Its calcium content increases with maturation process that could be beneficial for consumers. Nopal powder (NP) was elaborated from nopal harvested within 16-24 weeks of maturation, and the nutritional content was determined. An experimental clinical trial was performed to evaluate the effect of NP. A total of 69 women between 40 and 60 years old participated in the study. During 24 weeks, experimental group (n = 56) consumed a daily dose of 5 g of NP and control group (n = 13) continue with habitual diet. Changes in bone mineral density (BMD), body mass index (BMI), body fat percentage and serum calcium were assessed. Between baseline and after 24 weeks of consumption, no significant changes were found in BMD P = .885 experimental group and P = .970 control group, BMI P = .865 experimental group and P = .984 control group, body fat P = .744 experimental group and P = .740 control group and serum calcium P = .282 experimental group and P = .959 control group. These results indicate that advanced maturation NP does not have influence in bone health, BMI, and body composition in adult women.
Lipid metabolism abnormality in myotonic dystrophy (DM) was reviewed. Dyslipidemia is frequently seen in patients with DM. Hypertriglyceridemia, low HDL cholesterolemia, high LDL cholesterolemia, and exceeded visceral fat accumulation are common as abnormal lipid metabolism findings in DM. Dyslipidemia is one of risk factors for metabolic syndrome or nonalcoholic fatty liver disease and is closely relevant to insulin resistance. Careful follow-up for dyslipidemia in DM, especially complicated with glucose intolerance, should be required.
Background:
Statins, known to possess anti-inflammatory characteristics, have recently been identified as potentially reducing the risk of developing thyroid eye disease (TED) in Graves disease patients. The current study investigates the effect of oral statin therapy on strabismus related to TED.
Methods:
This is a retrospective review of patients with a diagnosis of both TED and restrictive strabismus. Oral statin users and nonusers were analyzed for smoking status, previous radioactive iodine, thyroidectomy, number of decompressions, motility restriction, amount of strabismus, number of surgeries, surgical dose, and number of muscles involved on radiography.
Results:
Thirty patients (average age, 63.9 years; 50% male; 59% current/former smokers) were included: 12 statin users and 18 nonusers. Statin users averaged fewer decompressions (1.3 in users vs 2.4 in nonusers [P = 0.04]). Statin users on average had 15 mm of total strabismus surgery compared with 21.4 mm in the nonuser group (P = 0.09) and had fewer muscles involved radiographically (4.3 vs 5.1 [P = 0.08]) CONCLUSIONS: Compared to nonusers, statin users tended to have fewer decompressions, less restriction, fewer surgeries, and fewer muscles involved despite having more current smokers (36% vs 5%), more males, more RAI, and fewer thyroidectomies, all of which are associated with worse TED. In our cohort of patients with TED and strabismus, statin therapy significantly reduced the number of orbital decompressions. Oral statin therapy also trended toward reducing the number and amount of strabismus surgeries as well as radiographic indication of muscle involvement, although these did not meet statistical significance.
Polymeric bile acid sequestrants (BAS) have recently attracted much attention as lipid-lowering agents. These non-absorbable materials specifically bind bile acids (BAs) in the intestine, preventing bile acid (BA) reabsorption into the blood through enterohepatic circulation. Therefore, it is important to understand the structure-property relationships between the polymer sequestrant and its ability to bind specific BAs molecules. In this review, we describe pleiotropic effects of bile acids, and we focus on BAS with various molecular architectures that result in different mechanisms of BA sequestration. Here, we present 1) amphiphilic polymers based on poly(meth)acrylates, poly(meth)acrylamides, polyalkylamines and polyallylamines containing quaternary ammonium groups, 2) cyclodextrins, and 3) BAS prepared via molecular imprinting methods. The synthetic approaches leading to individual BAS preparation, as well as results of their in vitro BA binding activities and in vivo lipid-lowering activities, are discussed.
Brain aging is a balance between homeostatic processes and harmful interactions with the environment. Each individual has a unique aging path. Healthy neurological aging requires maintenance of normal brain functioning and prevention of neuronal damage. Diet is a cornerstone of disease prevention and health promotion. B group vitamins (BGVs) and choline are micronutrients that share a key role in multiple metabolic pathways related to the nervous system’s structural and functional integrity. Almost all BGVs show clinically relevant neurological manifestations in case of insufficient dietary intake. BGVs and choline seem to have a role in optimizing brain energy metabolism, containing oxidative stress and inflammation, maintaining deoxyribonucleic acid stability and regulation of gene expression, modulating neurotransmission, and preventing vascular damage. A possible role in neurodegenerative disease prevention has been hypothesized. BGV deficiency-related disturbances in homocysteine metabolism result in hyperhomocysteinemia, a plausible contributor in many of these processes.
The efficacy and safety of Salvia officinalis combined with statin have not been evaluated in dyslipidemic diabetes mellitus type 2 (DDMT2) so far. The plant extract antioxidant activity was determined by the DPPH radical scavenging assay. The total flavonoid, total phenolic and quercetin contents of the capsules containing the plant extract were also measured. Moreover, the effects of 2-month extract intake (500 mg capsule three times a day) as add-on to daily use of 15 mg glyburide, 2000 mg metformin and 10 mg atorvastatin on the blood levels of fasting glucose (FG), 2 h postprandial glucose (2hPPG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride, high-density lipoprotein cholesterol (HDL-C), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), creatinine and body mass index were studied in 50 patients and compared with the placebo group (n=50).The extract IC50 in the DPPH assay was 87.26±0.003 µg/mL (mean±SD), whereas the ascorbic acid IC50 was 5.626± 0.001 µg/mL (mean±SD). The total flavonoid, total phenolic and quercetin contents of the capsule containing the plant extract were 39.76±3.58 mg of rutin equivalents (mean±SD), 30.33±1.23 mg of gallic acid (mean±SD) and 0.13 mg, respectively. The extract lowered FG, 2hPPG, HbA1c, TC, LDL-C and triglyceride levels, but increased HDL-C level compared to the placebo at the endpoint (P<0.05). The extract did not affect the other parameters significantly and no adverse effect was reported. The extract has substantial antioxidant activity which may be beneficial for the prevention of the cardiovascular complications of DDMT2. Moreover, addition of the extract to statin therapy is apparently safe and further improves lipid profile.
Introduction:
Lipid profile management is even more critical in patients treated for secondary prevention, since patients with established coronary heart disease are at higher risk of developing events. Current guidelines encourage lifestyle modification and patient engagement in disease prevention. However, the American College of Cardiology/American Heart Association guidelines seem to differ considerably from their predecessors, having an impact on clinical practice of lipid management.
Area covered:
This review article discusses and provides a summary of the current recommendations for lipid profile management in patients with coronary heart disease, with a view to present lifestyle modification and novel treatment strategies, and to indicate areas of dispute among recent guidelines. Expert commentary: Existing controversies between current guidelines concerning treatment goals and therapeutic decisions may have potential implications on the clinical management of patients. In the meantime, we eagerly wait for the results of randomized controlled trials evaluating promising, potent, safe and prolonged drugs that are in progress.
Introduction:
Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3.
Areas covered:
This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail.
Expert opinion:
Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.
Introduction: Statins are powerful lipid-modifying agents; however, they have dose-dependent risk for liver dysfunction. Ezetimibe possesses a relatively low lipid-modifying activity, but is less likely to cause liver dysfunction. This study aimed to evaluate the clinical efficacy of ezetimibe-based therapy in hyperlipidemia patients with concomitant liver dysfunction. This study aimed to explore the efficacy of ezetimibe combined with metformin and simvastatin in the treatment of hyperlipidemia patients with liver dysfunction. Materials and methods: From January 2012 to March 2014, 210 hyperlipidemia patients with liver dysfunction were enrolled and assigned to control (a low-dose sinzvastatin), ezetimibe + a low-dose simvastatin (ES) or ezetimibe + metformin + a low-dose simvastatin (EMS) groups (n=70 per group). Before treatment, the blood lipids, glucose, creatine kinase (CK), and liver and kidney functions were detected. Patients with >= 2x upper limit of normal values of transaminases were excluded. Treatment was conducted for 3 months. CK, aspartate transminase (AST), alanine transaminase (ALT) and bilirubin were measured after 3-month treatment. Results: After 3-month treatment, significant reductions were found in total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in three groups. The CK, TC, TG, HDL-C, LDL-C and liver function were significantly different among 3 groups after 3-month treatment. Conclusion: Ezetimibe-based therapy has more potent lipid-modifying capability in hyperlipidemia patients with liver dysfunction, without deteriorating liver function.
Background:
Bezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in human patients, but there are no data on its use in dogs.
Objective:
To assess the safety of BZF in hyperlipidemic dogs and its efficacy in decreasing serum triglyceride (TG) and cholesterol (CHO) concentrations.
Animals:
Forty-six dogs, 26 females and 20 males, mean (±SD) age of 9 (±3) years, with TG ≥150 mg/dL (33 dogs also were hypercholesterolemic [>300 mg/dL]).
Methods:
Prospective, uncontrolled clinical trial. Dogs were treated with bezafibrate once daily, using 200 mg tablets at a dosage of 4-10 mg/kg (depending on body weight). Serum TG and CHO concentrations and alanine aminotransferase (ALT) and creatine kinase (CK) activity before and after 30 days of treatment were compared.
Results:
Sixteen dogs (34.8%) had primary hyperlipidemia, and 30 dogs (65.2%) had secondary hyperlipidemia (including spontaneous hyperadrenocorticism [41.3%, n = 19/46], chronic treatment with glucocorticoids [10.8%, n = 5/46], and hypothyroidism [15.2%, n = 7/46]). After 30 days, serum TG concentration normalized (<150 mg/dL) in 42 dogs (91.3%) and CHO concentration normalized (<270 mg/dL) in 22 of 33 dogs (66.7%). There was no difference in baseline TG concentration between the primary and secondary hyperlipidemia subgroups, but the decrease in TG concentration after treatment was greater in the primary hyperlipidemia subgroup. No adverse effects were observed, but ALT activity decreased significantly after 30 days of treatment.
Conclusions and clinical importance:
Over 30 days, BZF was safe and effective in treatment of primary and secondary hyperlipidemia in dogs.
BACKGROUND
Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib.
METHODS
We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina.
RESULTS
At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.
CONCLUSIONS
Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264. opens in new tab.)
Background:
Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.
Methods:
We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.
Results:
The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.
Conclusions:
When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).
This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 12 http://www.thecochranelibrary.com Buprenorphine for treating cancer pain (Protocol)
Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9 (PCSK9), which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels ≥80 mg/dL on stable statin therapy were randomized to Q14d subcutaneous placebo or bococizumab 50 mg, 100 mg or 150 mg; or Q28d subcutaneous placebo or bococizumab 200 mg or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently fell to ≤25 mg/dL. The primary endpoint was the absolute change in LDL-C levels from baseline to week 12 following placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Among the 354 subjects randomized, 351 received treatment [placebo (n=100) or bococizumab (n=251)]. The most efficacious bococizumab doses were 150-mg Q14d and 300-mg Q28d. Compared with placebo, bococizumab 150-mg Q14d reduced LDL-C at week 12 by 53.4 mg/dL, and bococizumab 300-mg Q28d reduced LDL-C by 44.9 mg/dL; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted bococizumab would lower LDL-C levels by 72.2 mg/dL and 55.4 mg/dL, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment due to treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14d regimen is being evaluated in phase 3 clinical trials.
Objective To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.
Design Meta-analysis.
Studies reviewed Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).
Results 117 411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference.
Conclusions Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.
The leadership of the National Lipid Association convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. An Executive Summary of those recommendations was previously published. This document provides support for the recommendations outlined in the Executive Summary. The major conclusions include (1) an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins (non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol [LDL-C], termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascular disease (ASCVD) events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk; (6) nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus; and (7) the measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.
Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.
BackgroundIndividuals with peripheral arterial disease are at higher risk for cardiovascular events than the general population. While supplementation with omega-3 polyunsaturated fatty acids (PUFA) has been shown to improve vascular function, it remains unclear if supplementation decreases serious clinical outcomes. We conducted a systematic review and meta-analysis to determine whether omega-3 PUFA supplementation reduces the incidence of cardiovascular events and complications in adults with peripheral arterial disease.MethodsWe searched five electronic databases (MEDLINE, EMBASE, CENTRAL, Scopus and the International Clinical Trials Registry Platform) from inception to 6 December 2013 to identify randomized trials of omega-3 PUFA supplementation (from fish or plant oils) that lasted ≥12 weeks in adults with peripheral arterial disease. No language filters were applied. Data on trial design, population characteristics, and health outcomes were extracted. The primary outcome was major adverse cardiac events; secondary outcomes included myocardial infarction, cardiovascular death, stroke, angina, amputation, revascularization procedures, maximum and pain-free walking distance, adverse effects of the intervention, and quality of life. Trial quality was assessed using the Cochrane Risk of Bias tool.ResultsOf 741 citations reviewed, we included five trials enrolling 396 individuals. All included trials were of unclear or high risk of bias. There was no evidence of a protective association of omega-3 PUFA supplementation against major adverse cardiac events (pooled risk ratio 0.73, 95% CI 0.22 to 2.41, I
2
75%, 2 trials, 288 individuals) or other serious clinical outcomes. Adverse events and compliance were poorly reported.ConclusionsOur results showed that insufficient evidence exists to suggest a beneficial effect of omega-3 PUFA supplementation in adults with peripheral arterial disease with regard to cardiovascular events and other serious clinical outcomes.
The cardiovascular effects of seafood-derived n-3 polyunsaturated fatty acids (n-3 PUFA) have been examined in a diverse and continually expanding array of studies ranging from in vitro molecular experiments to large randomised controlled trials. In contrast to earlier trials, recent clinical trials have not observed significant effects of n-3 PUFA supplementation on cardiovascular disease (CVD) events.1 ,2 These mixed findings have stimulated renewed debate and interest about the role of n-3 PUFA for CVD prevention and treatment.
Sekikawa and colleagues investigated whether circulating n-3 PUFA levels were associated with differences in new-onset of coronary artery calcification (CAC) between middle-aged men in Japan and the USA.3 Measurement of CAC by electron beam CT provides an estimate of overall coronary atherosclerotic burden. While CAC does not necessarily identify with plaque morphology or propensity for rupture, overall CAC burden does predict future risk of clinical CVD events. In this case, investigating the association of circulating n-3 PUFA with serial measures of CAC addresses the interesting hypothesis that these fats might slow atherosclerosis progression, providing mechanistic insight that would be complimentary to studies of clinical endpoints. In this investigation, Japanese men had substantially (∼150%) higher circulating n-3 PUFA than did US men, consistent with much higher levels of seafood consumption in Japan. Japanese men also had a substantially lower incidence of new CAC (rate ratio=0.26, 95%CI=0.09 to 0.73), compared with US men, which was not explained by adjustment for conventional CVD risk factors including age, systolic blood pressure, cholesterol, triglycerides, BMI, diabetes, smoking and hypertension medication. In contrast, the association between country (Japan vs USA) and incident CAC was attenuated following adjustment for serum n-3 PUFA. The authors concluded that n-3 PUFA may have antiatherosclerotic effects at levels observed in Japan.
While this analysis has several strengths, including use of objective …
Among the range of lipid modifying medications currently available, statins clearly stand as the primary agent capable of reducing cardiovascular risk. While non-statin lipid-lowering drugs improve lipid parameters, their impact on clinical outcomes is less clear, thus necessitating an even closer look at ancillary effects. Recent studies have reported the potential cardiometabolic effects of statins, yet considerably less information has been published about cardiometabolic changes associated with non-statin lipid-lowering agents. This review describes the cardiometabolic profile of non-statin lipid-lowering agents-fibrates, niacin, omega-3 polyunsaturated fatty acids, ezetimibe, and bile acid sequestrants-and therefore aims to facilitate informed decision-making in the pharmacologic management of lipid abnormalities.
Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction.
In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes.
Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points.
In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).
Context.—
Dietary fish intake has been associated with a reduced risk of fatal
cardiac end points, but not with nonfatal end points. Dietary fish intake
may have a selective benefit on fatal arrhythmias and therefore sudden cardiac
death.Objective.—
To investigate prospectively the association between fish consumption
and the risk of sudden cardiac death.Design.—
Prospective cohort study.Setting.—
The US Physicians' Health Study.Patients.—
A total of 20551 US male physicians 40 to 84 years of age and free of
myocardial infarction, cerebrovascular disease, and cancer at baseline who
completed an abbreviated, semiquantitative food frequency questionnaire on
fish consumption and were then followed up to 11 years.Main Outcome Measure.—
Incidence of sudden cardiac death (death within 1 hour of symptom onset)
as ascertained by hospital records and reports of next of kin.Results.—
There were 133 sudden deaths over the course of the study. After controlling
for age, randomized aspirin and beta carotene assignment, and coronary risk
factors, dietary fish intake was associated with a reduced risk of sudden
death, with an apparent threshold effect at a consumption level of 1 fish
meal per week (P for trend=.03). For men who consumed
fish at least once per week, the multivariate relative risk of sudden death
was 0.48 (95% confidence interval, 0.24-0.96; P =.04)
compared with men who consumed fish less than monthly. Estimated dietary n-3
fatty acid intake from seafood also was associated with a reduced risk of
sudden death but without a significant trend across increasing categories
of intake. Neither dietary fish consumption nor n-3 fatty acid intake was
associated with a reduced risk of total myocardial infarction, nonsudden cardiac
death, or total cardiovascular mortality. However, fish consumption was associated
with a significantly reduced risk of total mortality.Conclusion.—
These prospective data suggest that consumption of fish at least once
per week may reduce the risk of sudden cardiac death in men.
Figures in this Article
SOME1- 6
but not all7- 10
prospective cohort studies of the association between fish consumption and
cardiovascular mortality have reported inverse associations. In general, fish
consumption has been associated with lower cardiac mortality in populations
characterized by low fish intake in which a substantial proportion rarely
or never consumed fish1- 6
and not in those with higher levels of fish intake.7- 10
Studies in which nonfatal coronary heart disease was examined have shown no
relationship.9- 10 Randomized trial
data are limited, but 1 secondary prevention trial showed an association between
fish intake and reduction in cardiovascular mortality but not reinfarction.11 Based on these results, it has been hypothesized
that low levels of dietary fish intake may be unrelated to the incidence of
myocardial infarction, but could reduce coronary disease mortality by decreasing
fatal arrhythmias and therefore sudden cardiac death.12
Experimental data in dogs13 and primates14 suggest that the n-3 fatty acids in fish have antiarrhythmic
properties. Further, a retrospective case-control study found that, when compared
with no intake, n-3 fatty acid consumption equivalent to 1 fatty fish meal
per week was associated with a 50% reduction in the risk of primary cardiac
arrest,15 suggesting that antiarrhythmic effects
occur at the low levels of fish intake that have been associated with reduced
coronary heart disease mortality. Contrary to these findings, no association
was found between low levels of fish consumption and sudden death from myocardial
infarction in a recent prospective study,5
but a strong inverse association was observed with nonsudden death from myocardial
infarction as determined by death certificates. We addressed this controversy
further by prospectively examining the association between fish consumption
and sudden cardiac death ascertained from medical records and firsthand reports
among male physicians enrolled in the Physicians' Health Study.
Background:
Carotid plaque echolucency as detected by Color Doppler ultrasonography (CDUS) has been used as a potential marker of plaque vulnerability. However, contrast-enhanced ultrasound (CEUS) has recently been shown to be a valuable method to evaluate the vulnerability and neovascularization within carotid atherosclerotic plaques. The aim of this study was to compare CEUS and CDUS in the assessment of plaque vulnerability using transcranial color Doppler (TCD) monitoring of microembolic signals (MES) as a reference technique.
Methods:
A total of 46 subjects with arterial stenosis (≥ 50%) underwent a carotid duplex ultrasound, TCD monitoring of MES and CEUS (SonoVue doses of 2.0 mL) within a span of 3 days. The agreement between the CEUS, CDUS, and MES findings was assessed with a chi-square test. A p-value less than 0.05 was considered statistically significant.
Results:
Neovascularization was observed in 30 lesions (44.4%). The vascular risk factors for stroke were similar and there were no age or gender differences between the 2 groups. Using CEUS, MES were identified in 2 patients (12.5%) within class 1 (non-neovascularization) as opposed to 15 patients (50.0%) within class 2 (neovascularization) (p = 0.023). CDUS revealed no significant differences in the appearance of the MES between the 2 groups (hyperechoic and hypoechoic) (p = 0.237).
Conclusion:
This study provides preliminary evidence to suggest that intraplaque neovascularization detected by CEUS is associated with the presence of MESs, where as plaque echogenicity on traditional CDUS does not. These findings argue that CEUS may better identify high-risk plaques.
Monoclonal antibodies (mAbs) are established therapies for many conditions, including cancers, autoimmune conditions and infectious diseases. mAbs can offer benefits over conventional pharmacotherapy in terms of potency, dosing frequency and specificity for their target antigen. Mouse-derived antibodies were initially used in humans; however, patients often developed human anti-mouse antibodies, resulting in rapid antibody clearance (and a resulting loss of efficacy) and hypersensitivity reactions. Chimeric, humanized, and fully human antibodies were thus developed, with increasing amounts of human sequence, to reduce immunogenicity. Although generally well tolerated, mAbs may be associated with adverse events (AEs). Many AEs are target-related, and will be specific to the antibody target and the therapeutic area of use. However, off-target AEs, such as hypersensitivity reactions, are observed with many antibodies. Within the realm of cardiovascular medicine, new antibody-based therapies are under investigation to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL-C levels by increasing degradation of the LDL receptor (LDLR). Therefore, inhibition of the interaction between PCSK9 and the LDLR with mAbs targeting PCSK9 has great potential for patients with hypercholesterolaemia. Early clinical phase studies suggest these mAbs are effective and well tolerated; however, further studies are required to assess their long-term safety.
Background
Fibrates has been extensively used to improve plasma lipid levels and prevent adverse cardiovascular outcomes. However, the effect of fibrates on stroke is unclear at the present time. We therefore carried out a comprehensive systematic review and meta-analysis to evaluate the effects of fibrates on stroke.
Methods
We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies for our analysis. We included randomized placebo controlled trials which reported the effects of fibrates on stroke. Relative risk (RR) was used to measure the effect of fibrates on the risk of stroke under random effect model. The analysis was further stratified by factors that could affect the treatment effects.
Results
Overall, fibrate therapy was not associated with a significant reduction on the risk of stroke (RR, 1.02, 95% CI, 0.90 to 1.16, P = 0.78). In the subgroup analyses, we observed that gemfibrozil therapy showed a beneficial effect on stroke (RR, 0.72, 95% CI, 0.53 to 0.98, P = 0.04). Similarly, fibrate therapy comparing to placebo had no effect on the incidence of fatal stroke. Subgroup analysis suggested that fibrate therapy showed an effect on fatal stroke when the Jadad score more than 3 (RR, 0.41, 95% CI, 0.17 to 1.00, P = 0.049). Furthermore, a sensitivity analysis indicated that fibrate therapy may play a role in fatal stroke (RR, 0.49, 95% CI, 0.26 to 0.93, P = 0.03) for patients with previous diabetes, cardiovascular disease or stroke.
Conclusions
Our study indicated that fibrate therapy might play an important role in reducing the risk of fatal stroke in patients with previous diabetes, cardiovascular disease or stroke. However, it did not have an effect on the incidence of stroke.
Background:
LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin.
Methods:
In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730.
Findings:
631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.
Interpretation:
The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.
Funding:
Amgen.
Background:
Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels.
Methods:
We performed a phase 2, multicenter, double-blind, placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter (2.6 mmol per liter) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks. Patients were randomly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks, 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks, or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment.
Results:
The least-squares mean (±SE) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo (P<0.001) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter).
Conclusions:
In a randomized trial involving patients with primary hypercholesterolemia, adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin resulted in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01288469.).
To clarify associations of fish consumption and long chain omega 3 fatty acids with risk of cerebrovascular disease for primary and secondary prevention.
Systematic review and meta-analysis.
Studies published before September 2012 identified through electronic searches using Medline, Embase, BIOSIS, and Science Citation Index databases. ELIGIBILITY CRITERIA: Prospective cohort studies and randomised controlled trials reporting on associations of fish consumption and long chain omega 3 fatty acids (based on dietary self report), omega 3 fatty acids biomarkers, or supplementations with cerebrovascular disease (defined as any fatal or non-fatal ischaemic stroke, haemorrhagic stroke, cerebrovascular accident, or transient ischaemic attack). Both primary and secondary prevention studies (comprising participants with or without cardiovascular disease at baseline) were eligible.
26 prospective cohort studies and 12 randomised controlled trials with aggregate data on 794 000 non-overlapping people and 34 817 cerebrovascular outcomes were included. In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease for 2-4 servings a week versus ≤1 servings a week was 0.94 (95% confidence intervals 0.90 to 0.98) and for ≥5 servings a week versus 1 serving a week was 0.88 (0.81 to 0.96). The relative risk for cerebrovascular disease comparing the top thirds of baseline long chain omega 3 fatty acids with the bottom thirds for circulating biomarkers was 1.04 (0.90 to 1.20) and for dietary exposures was 0.90 (0.80 to 1.01). In the randomised controlled trials the relative risk for cerebrovascular disease in the long chain omega 3 supplement compared with the control group in primary prevention trials was 0.98 (0.89 to 1.08) and in secondary prevention trials was 1.17 (0.99 to 1.38). For fish or omega 3 fatty acids the estimates for ischaemic and haemorrhagic cerebrovascular events were broadly similar. Evidence was lacking of heterogeneity and publication bias across studies or within subgroups.
Available observational data indicate moderate, inverse associations of fish consumption and long chain omega 3 fatty acids with cerebrovascular risk. Long chain omega 3 fatty acids measured as circulating biomarkers in observational studies or supplements in primary and secondary prevention trials were not associated with cerebrovascular disease. The beneficial effect of fish intake on cerebrovascular risk is likely to be mediated through the interplay of a wide range of nutrients abundant in fish.
A cooperative study in 20 Veterans Administration hospitals investigated the effect of clofibrate on morbidity and mortality due to atherosclerotic vascular disease in men with either an established cerebral infarction or transient cerebrovascular ischemic attacks (TIA). Follow-up observations were made for up to 4.5 years in 532 patients assigned on a random basis to placebo medication or to treatment with 2 gm of clofibrate daily. Baseline and follow-up cholesterol and triglyceride levels were measured.
Recurrence of cerebral infarction was increased in patients receiving clofibrate as compared to controls. The incidence of new myocardial infarction and new TIA was similar in both groups. Despite the more frequent strokes in treated patients, they had a decrease in mortality, partially explained by a lower death rate from these recurrences. There was no correlation between pretreatment lipid (cholesterol and triglyceride) values and the result of therapy. Use of clofibrate, however, was associated with a slight reduction of cholesterol and a sustained fall in triglyceride.
These findings do not support recently published reports that clofibrate reduces the occurrence of myocardial ischemia; however, the investigative design and type of data collected in these various studies are different and make it difficult to compare results.
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (P<.05) of the primary end point—definite CHD death and/or definite nonfatal myocardial infarction—reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.
Background:
Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain.
Methods:
After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).
Results:
During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).
Conclusions:
Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).
Background and purpose:
In Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, addition of extended-release niacin (ERN) to simvastatin in participants with established cardiovascular disease, low high-density lipoprotein cholesterol, and high triglycerides had no incremental benefit, despite increases in high-density lipoprotein cholesterol. Preliminary analysis based on incomplete end point adjudication suggested increased ischemic stroke risk among participants randomized to ERN.
Methods:
This final analysis was conducted after complete AIM-HIGH event ascertainment to further explore potential relationship between niacin therapy and ischemic stroke risk.
Results:
There was no group difference in trial primary composite end point at a mean 36-month follow-up among 3414 patients (85% men; mean age, 64±9 years) randomized to simvastatin plus ERN (1500-2000 mg/d) versus simvastatin plus matching placebo. In the intention-to-treat analysis, there were 50 fatal or nonfatal ischemic strokes: 18 (1.06%) in placebo arm versus 32 (1.86%) in ERN arm (hazard ratio [HR], 1.78 [95% confidence interval {CI}, 1.00-3.17; P=0.050). Multivariate analysis showed independent associations between ischemic stroke risk and >65 years of age (HR, 3.58; 95% CI, 1.82-7.05; P=0.0002), history of stroke/transient ischemic attack/carotid disease (HR, 2.18; 95% CI, 1.23-3.88; P=0.0079), elevated baseline Lp(a) (HR, 2.80; 95% CI, 1.25-6.27 comparing the middle with the lowest tertile; HR, 2.31; 95% CI, 1.002-5.30 comparing the highest with the lowest tertile; overall P=0.042) but a nonsignificant association with ERN (HR, 1.74; 95% CI, 0.97-3.11; P=0.063).
Conclusions:
Although there were numerically more ischemic strokes with addition of ERN to simvastatin that reached nominal significance, the number was small, and multivariable analysis accounting for known risk factors did not support a significant association between niacin and ischemic stroke risk.
Clinical trial registration url:
http://www.clinicaltrials.gov. Unique identifier: NCT00120289.
The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
Background:
Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.
Methods:
We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.
Results:
At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).
Conclusions:
Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).
Background:
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data.
Methods:
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined.
Results:
As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).
Conclusions:
During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).
Our review has limitations. We did not examine all possible medication combinations, doses, or patient populations. Some combinations may prove to be useful for selected lipid profiles or in patients who do not reach targets despite maximal therapy. Assessments of clinical outcomes, harms, and treatment adherence were limited by the shortage of long-term studies, with relatively few studies for combination therapies other than statin–ezetimibe and, for surrogate outcomes, by the statistical limitations of the outcome measures. The extent to which short-term surrogate measures correlate with outcome is well demonstrated for statin monotherapy but remains unclear for combination therapies. We did not attempt imputation, because the possibility of double counting could not be ruled out, limiting inclusion of composite outcomes. Our statistically conservative approach to meta-analyses precluded analyses in many instances. We rated the strength of the evidence as very low for the main outcomes (Table) because reports directly addressing the specified patient samples and comparators are lacking. The available evidence supporting the use of combination therapies over high-dose statin monotherapy, including long-term clinical benefits and reduced risks, is insufficient to guide many clinical decisions. The effectiveness of statins in reducing vascular events suggests that the benefits of additional therapies need to be clearly defined along with attendant risks and costs before widespread use of combination treatments can be advocated.
Background
Hypercholesterolemia is a pivotal risk factor for cardiovascular and cerebrovascular disease and is treated with many effective lipid-lowering agents. Statins are often used alone or in combination with ezetimibe. Combination therapy is more effective because of its complementary approach, which has major benefits for patients with unmanageable lipid levels. Extensive application of combination therapy has resulted in an increased incidence of side effects, which has raised our concern.AimsTo evaluate the evidence associated with the safety of coadministration of ezetimibe with statins.Methods
Three electronic databases were searched (PubMed, EMBASE, and Cochrane Library) from January 2002 to October 2014. Two independent reviewers critically identify randomized controlled trials (RCTs), extracted the data, and assessed trial quality. Twenty RCTs met inclusion criteria, including 14,856 patients. A fixed-effects model was used for meta-analysis to assess the safety of combination therapy.ResultsCoadministration of ezetimibe and statins did not result in significant increases in total adverse events (30% vs 29%, p=0.34), serious adverse events (2% vs 1.6%, p=0.81), treatment discontinuation (3.5% vs 2.9%, p=0.22), gastrointestinal adverse events (5% vs 4%, p=0.08), allergic reaction or rash (0.9% vs 1.3%, p=0.33), creatine kinase(CK) >10× upper limit of normal (ULN) (0.2% vs 0.2%, p=0.86), alanine aminotransferase(ALT) >3× ULN (0.5% vs 0.4%, p=0.96) and aspartate aminotransferase(AST) >3× ULN (0.4% vs 0.4%, p=0.58).Conclusion
The incidence of adverse events was similar between ezetimibe–statin combination therapy and statin monotherapy, thus, we recommend combination therapy for patients with hypercholesterolemia at high risk for cardiovascular and cerebrovascular disease.
Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 (PCSK9). Although statins and fibrates have been reported to increase plasma PCSK9 levels, the effect of niacin on PCSK9 is unknown. We investigated the impact of niacin, atorvastatin, and fenofibrate on PCSK9 levels in 3 distinct studies. A statin-only study randomized 74 hypercholesterolemic patients to placebo, atorvastatin 10 mg/day, or atorvastatin 80 mg/day for 16 weeks. A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean +27% (95% confidence interval [CI] +12 to +42), confirming the effect of statin therapy on raising PCSK9. A second study randomized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day, simvastatin 80 mg/day, or simvastatin 20 mg/extended-release (ER) niacin 2 g/day. PCSK9 levels were increased with statin therapy, but decreased with the simvastatin 20 mg/ER niacin combination (mean -13%, CI -3 to -23). A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of fenofibric acid 150 mg followed by ER niacin 2 g/day. Fenofibric acid led to a +23% (CI +10 to +36, p = 0.001) increase in PCSK9; the addition of niacin resulted in a subsequent -17% decrease (CI -19 to -5, p = 0.004). A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels (r = 0.62, p = 0.006) with the addition of niacin. In conclusion, niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy. A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9.
Copyright © 2014 Elsevier Inc. All rights reserved.
Patients with elevated triglycerides (TG) may be at a higher risk for cardiovascular (CV) disease. Omega-3 fatty acids (OM3FAs), particularly the long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), effectively reduce TG and thus may impact CV outcomes; however, clinical data have been inconsistent. This review discusses the efficacy, safety, and key considerations of currently approved prescription OM3FA products in patients with elevated TG with or without concomitant elevations in other atherogenic parameters. Currently, 6 prescription OM3FA formulations are approved in the United States: omega-3-acid ethyl esters (Lovaza, Omtryg, and 2 generic formulations), omega-3-carboxylic acids (Epanova), which contain both EPA and DHA, and icosapent ethyl (Vascepa), which is an EPA-only formulation. All prescription OM3FA products effectively lower TG, with the magnitude of TG reduction affected by baseline TG level. Products that contain DHA can raise levels of low-density lipoprotein cholesterol, which is of particular concern in patients with atherosclerosis; Vascepa, however, does not raise these levels and therefore provides these patients with another option. Long-term outcomes trials for Vascepa (ongoing) and Epanova (planned) will help clarify the potential CV benefits in patients with persistent hypertriglyceridemia despite statin therapy.
This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the clinical benefit and harm of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of CVD events and mortality.
Background:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of LDL-cholesterol receptor homeostasis and emerges as a therapeutic target in the prevention of cardiovascular (CV) disease. This prospective cohort study analyzes risk prediction with PCSK9 serum concentrations in patients with stable coronary artery disease (CAD) on statin treatment.
Methods and results:
Fasting PCSK9 concentrations were measured in 504 consecutive patients with stable CAD confirmed by angiography. Oral glucose tolerance tests were performed in all patients without known diabetes. Patients were followed up for 48months. The primary outcome was the composite of cardiovascular death and unplanned cardiovascular hospitalization. Serum concentrations of PCSK9 predicted CV outcomes (PCSK9>622 ng/ml vs. <471 ng/ml: HR 1.55, 95%-CI 1.11-2.16, p=0.009). Higher PCSK9 concentrations were associated with female gender, hypertension, statin treatment, C-reactive protein, HbA1c, insulin, total cholesterol and fasting triglycerides, but not with LDL- or HDL-cholesterol. The association of PCSK9 levels with CV events was reduced after adjustment for fasting TG.
Conclusion:
PCSK9 concentrations predict cardiovascular events in patients with coronary artery disease on statin treatment. Serum triglycerides are correlated with PCSK9 and modify risk prediction by PCSK9.
Hypercholesterolemia is a key risk factor for atherosclerosis. Because of its role in controlling serum levels of low-density lipoprotein (LDL) through the regulation of hepatic LDL-receptors, the recently discovered proprotein convertase subtilisin/kexin-type 9 (PCSK9) is a promising pharmacological target. This review aims to discuss the impact of natural mutations in the PCSK9 gene on cholesterol metabolism and thus coronary artery disease, as well as molecular mechanisms and therapeutic strategies for PCSK9 inhibition. We summarize data from recent clinical trials using fully humanized monoclonal antibodies, showing that PCSK9 inhibition results in a significant reduction in LDL-cholesterol in high-risk cardiovascular patients. Future studies will have to address the long-term safety and efficacy as well as the impact of PCSK9-targeting therapies on cardiovascular outcomes.
A detailed study of the energy transfer between Er3+ and
Ce3+ ions and its enhanced effects on the 1.53 µm band
signal gain in Er3+/Ce3+ codoped tellurite glass
fiber under the excitation of 980 nm is reported. The absorption
spectra, visible upconversion spectra, infrared fluorescence spectra of
Er3+ doped and Er3+/Ce3+ codoped glass
samples were measured, and the 1.53 µm band signal gain of
Er3+ doped and Er3+/Ce3+ codoped glass
fiber was calculated based on the rate and power propagation equations.
Codoping Ce3+ with Er3+ ions can significantly
suppress the visible upconversion emission and meanwhile improves the
1.53 µm band fluorescence, and an increment of about 6.4 dB signal
gain at 1532 nm was found in a 40 cm glass fiber with 150 mW pumping
power at 980 nm, which is ascribed to the energy transfer between
Er3+ and Ce3+ ions. The quantitative analysis
showed that the energy transfer between Er3+ and
Ce3+ ions is a one phonon and two phonon-assisted energy
transfer process. The results indicated that
Er3+/Ce3+ codoping is a suitable scheme for low
phonon energy tellurite glass fiber applied for broadband and high gain
EDFA.
Some patients do not tolerate or respond to high-intensity statin monotherapy. Lower-intensity statin combined with nonstatin medication may be an alternative, but the benefits and risks compared with those of higher-intensity statin monotherapy are unclear.
To compare the clinical benefits, adherence, and harms of lower-intensity statin combination therapy with those of higher-intensity statin monotherapy among adults at high risk for atherosclerotic cardiovascular disease (ASCVD).
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to July 2013, with an updated MEDLINE search through November 2013.
Randomized, controlled trials published in English.
Two reviewers extracted information on study design, population characteristics, interventions, and outcomes (deaths, ASCVD events, low-density lipoprotein [LDL] cholesterol, adherence, and adverse events). Two independent reviewers assessed risk of bias.
A total of 36 trials were included. Low-intensity statin plus bile acid sequestrant decreases LDL cholesterol 0% to 14% more than does mid-intensity monotherapy among high-risk hyperlipidemic patients. Mid-intensity statin plus ezetimibe decreases LDL cholesterol 5% to 15% and 3% to 21% more than does high-intensity monotherapy among patients with ASCVD and diabetes mellitus, respectively. Evidence was insufficient to evaluate LDL cholesterol for fibrates, niacin, and ω-3 fatty acids. Evidence was insufficient for long-term clinical outcomes, adherence, and harms for all regimens.
Many trials had short durations and high attrition rates, lacked blinding, and failed to assess long-term clinical benefits or harms.
Clinicians could consider using lower-intensity statin combined with bile acid sequestrant or ezetimibe among high-risk patients intolerant of or unresponsive to statins; however, this strategy should be used with caution given the lack of evidence on long-term clinical benefits and harms.
Agency for Healthcare Research and Quality.This article was published online first at www.annals.org on 11 February 2014.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism mainly by targeting the low-density lipoprotein receptor (LDLR) for degradation in the liver. Gain-of-function mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolaemia. Conversely, loss-of-function mutations are associated with lower concentrations of LDL cholesterol (LDL-C) and reduced coronary heart disease. As these loss-of-function mutations are not associated with apparent deleterious effects, PCSK9 inhibition is an attractive new strategy for lowering LDL-C concentration. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. A dramatic decrease in LDL-C up to 70% can be obtained with the most efficacious doses. Efficacy has been evaluated so far in addition to statins in hypercholesterolaemic patients with or without familial hypercholesterolaemia, in patients with intolerance to statin therapy and in monotherapy. Large phase III programmes are ongoing to evaluate the long-term efficacy and safety of these very promising new agents.
Background
Several epidemiological and experimental studies suggest that n-3 polyunsaturated fatty acids (PUFA) can exert favourable effects on atherothrombotic cardiovascular disease, including arrhythmias. We investigated whether n-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause.
Methods
We undertook a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy. We enrolled patients with chronic heart failure of New York Heart Association class II–IV, irrespective of cause and left ventricular ejection fraction, and randomly assigned them to n-3 PUFA 1 g daily (n=3494) or placebo (n=3481) by a concealed, computerised telephone randomisation system. Patients were followed up for a median of 3·9 years (IQR 3·0–4·5). Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00336336.
Findings
We analysed all randomised patients. 955 (27%) patients died from any cause in the n-3 PUFA group and 1014 (29%) in the placebo group (adjusted hazard ratio [HR] 0·91 [95·5% CI 0·833–0·998], p=0·041). 1981 (57%) patients in the n-3 PUFA group and 2053 (59%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 0·92 [99% CI 0·849–0·999], p=0·009). In absolute terms, 56 patients needed to be treated for a median duration of 3·9 years to avoid one death or 44 to avoid one event like death or admission to hospital for cardiovascular reasons. In both groups, gastrointestinal disorders were the most frequent adverse reaction (96 [3%] n-3 PUFA group vs 92 [3%] placebo group).
Interpretation
A simple and safe treatment with n-3 PUFA can provide a small beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure in a context of usual care.
Funding
Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca.
Purpose
Experimental and epidemiological studies suggest that omega-3 fatty acids have an antiarrhythmic effect. However, evidence from randomized controlled trials (RCTs) for prevention of sudden cardiac death (SCD) remains controversial. This study sought to evaluate the efficacy of omega-3 fatty acids for secondary prevention of SCD in patients with cardiovascular disease (CVD) in the era of guidelines-based therapy.
Methods
We conducted a PubMed/EMBASE/CENTRAL search for RCTs evaluating omega-3 fatty acids for CVD secondary prevention with at least 6 months follow-up and with data on SCD. Primary outcome was SCD. Secondary outcomes were cardiovascular mortality and all-cause mortality.
Results
Ten randomized controlled trials were identified evaluating a total of 33,429 patients with CVD. In patients with guidelines-adjusted therapy, omega-3 fatty acids did not reduce the risk ratio (RR) of SCD (RR:0.96; 95% CI: 0.84-1.10). In patients with non- guidelines-adjusted therapy, omega-3 fatty acids reduced the RR of SCD (RR: 0.64; 95% CI: 0.51-0.80). Overall, RR for cardiac death and all-cause mortality were 0.81 (95% CI: 0.69-0.95) and 0.89 (95% CI: 0.79-1.01), respectively.
Conclusions
In the era of guidelines-adjusted treatment for CVD secondary prevention, omega-3 fatty acids do not appear to reduce SCD.
Background:
We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease.
Methods:
We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
Results:
The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction).
Conclusions:
The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
Objectives:
This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
Background:
Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy.
Methods:
Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events.
Results:
Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes.
Conclusions:
The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.
Background:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment.
Methods:
In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18-75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777.
Findings:
406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg -41·0% [95% CI -46·2 to -35·8]; 105 mg -43·9% [-49·0 to -38·7]; 140 mg -50·9% [-56·2 to -45·7]; every 4 weeks AMG 145 280 mg -39·0% [-44·1 to -34·0]; 350 mg -43·2% [-48·3 to -38·1]; 420 mg -48·0% [-53·1 to -42·9]; placebo every 2 weeks -3·7% [-9·0 to 1·6]; placebo every 4 weeks 4·5% [-0·7 to 9·8]; and ezetimibe -14·7% [-18·6 to -10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported.
Interpretation:
The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance.
Funding:
Amgen.
BACKGROUND: In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes.
METHODS: We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation.
RESULTS: At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons).
CONCLUSIONS: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).
Background:
Despite statin treatment, many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol (LDL-C) targets. AMG 145, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease, demonstrated significant reductions in LDL-C in phase 1 studies. This phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients.
Methods and results:
Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L (100 mg/dL) despite statin therapy with or without ezetimibe were randomized 1:1:1 to AMG 145 350 mg, AMG 145 420 mg, or placebo-administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline in LDL-C at week 12. Of 168 patients randomized, 167 received investigational product and were included in the full analysis set (mean [SD] age, 50 [13] years; 47% female; 89% white; mean [SD] baseline LDL-C, 4.0 [1.1] mmol/L (156 [42] mg/dL)). At week 12, LDL-C reduction measured by preparative ultracentrifugation (least squares mean [standard error (SE)]) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg, respectively, compared with 1 (3)% increase with placebo (P<0.001 for both dose groups). Serious adverse events (not considered treatment-related) occurred in 2 patients on AMG 145.
Conclusions:
AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use, with or without ezetimibe, with minimal adverse events and good tolerability.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01375751.
Context:
An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels.
Objective:
To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects.
Design, setting, and patients:
A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites.
Intervention:
Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks.
Main outcome measures:
The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe.
Results:
Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.
Conclusion:
In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.
Background:
Early trials evaluating the effect of omega 3 fatty acids (ω-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of ω-3 FA on cardiovascular and other important clinical outcomes.
Methods and results:
We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end-stage kidney disease. Twenty studies including 63030 participants were included. There was no overall effect of ω-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90-1.03; P=0.24) or on total mortality (RR=0.95; 95% CI, 0.86-1.04; P=0.28). ω-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75-0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67-1.11; P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85-1.16; P=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92-1.16; P=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02-1.37; P=0.03), predominantly because of an excess of gastrointestinal side effects.
Conclusions:
ω-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed.
OBJECTIVES: The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of fibrate therapy in the chronic kidney disease (CKD) population. BACKGROUND: Fibrate therapy produces modest cardiovascular benefits in people at elevated cardiovascular risk. There is limited evidence about the clinical benefits and safety of fibrate therapy in the CKD population. METHODS: MEDLINE, EMBASE, and the Cochrane Library were systematically searched (1950 to January 2012) for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes were included. RESULTS: Ten studies including 16,869 participants were identified. In patients with mild-to-moderate CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min/1.73 m(2)), fibrates improved lipid profiles (lowered total cholesterol [-0.32 mmol/l, p = 0.05] and triglyceride levels [-0.56 mmol/l, p = 0.03] but not low-density lipoprotein cholesterol [-0.01 mmol/l, p = 0.83]; increased high-density lipoprotein cholesterol [0.06 mmol/l, p = 0.001]). In people with diabetes, fibrates reduced the risk of albuminuria progression (relative risk [RR]: 0.86; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.02). Serum creatinine was elevated by fibrate therapy (33 μmol/l, p < 0.001), calculated GFR was reduced (-2.67 ml/min/1.73 m(2), p = 0.01) but there was no detectable effect on the risk of end-stage kidney disease (RR: 0.85; 95% CI: 0.49 to 1.49; p = 0.575). In patients with eGFR of 30 to 59.9 ml/min/1.73 m(2), fibrates reduced the risk of major cardiovascular events (RR: 0.70; 95% CI: 0.54 to 0.89; p = 0.004) and cardiovascular death (RR: 0.60; 95% CI: 0.38 to 0.96; p = 0.03) but not all-cause mortality. There were no clear safety concerns specific to people with CKD but available data were limited. CONCLUSIONS: Fibrates improve lipid profiles and prevent cardiovascular events in people with CKD. They reduce albuminuria and reversibly increase serum creatinine but the effects on major kidney outcomes remain unknown. These results suggest that fibrates have a place in reducing cardiovascular risk in people with mild-to-moderate CKD.