Fibrates, Hypertriglyceridemia, and CVD Risk: Where Do We Stand After the PROMINENT Trial for Triglyceride Lowering?

PURPOSE OF REVIEW: To evaluate recent clinical trials focusing on patients with hypertriglyceridemia. RECENT FINDINGS: Randomized clinical trials have recently been undertaken in hypertriglyceridemic patients to determine whether effective reductions in triglycerides would improve cardiovascular disease (CVD) outcomes. However, the fibric acid derivative, pemafibrate, failed to reduce cardiovascular events despite significant reductions (~ 25-35%) in triglyceride levels and despite background statin therapy. In contrast, icosapent ethyl, a highly purified omega-3 fatty acid was previously shown to reduce CVD events in hypertriglyceridemic patients, despite more modest reductions (~ 20%) in triglyceride levels in statin treated patients. The divergent results obtained in patients with hypertriglyceridemia (HTG), a group at particularly high risk of CVD, especially when coupled with other risk factors, indicates that triglyceride lowering in of itself is insufficient to offset CVD risk. Rather, the effectiveness of therapy in this high-risk cohort may be the result of the suppression of the inherent atherogenic properties associated with HTG.

Very severe hypertriglyceridemia complicating pediatric acute lymphoblastic leukemia treatment: a call for management guidelines.

OBJECTIVES: Severe and very severe hypertriglyceridemia although rare within the pediatric population occur more often among oncology patients, secondary to chemotherapeutic agents. Currently there exists minimal literature to guide management of severe hypertriglyceridemia among pediatric patients. Very-low-fat dietary restriction should be considered over nil per os (NPO) for initial management of severe hypertriglyceridemia in stable pediatric patients. Pediatricians caring for oncology patients must consider chylomicronemia as a potential etiology for presenting symptoms. Pediatric severe hypertriglyceridemia management guidelines are needed as pediatricians must currently rely on anecdotal experiences for management decisions. CASE PRESENTATION: Three children receiving treatment for acute lymphoblastic leukemia required hospitalization for very severe hypertriglyceridemia. Management varied among the cases but included: NPO or very-low-fat diet, insulin, intravenous fluids, fibrates, and omega-3 fatty acids. CONCLUSIONS: These cases suggest that pediatric severe hypertriglyceridemia management, in the absence of pancreatitis should allow a very-low-fat diet initially rather than NPO followed by pharmacologic therapies.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention.

PURPOSE OF REVIEW: Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. RECENT FINDINGS: The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Personalized medicine in lipid-modifying therapy.

The choice of lipid-modifying treatment is largely based on the absolute level of cardiovascular risk and baseline lipid profile. Statins are the first-line treatment for most patients requiring reduction of low-density-lipoprotein cholesterol (LDL-C) and ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors can be added to reach LDL-C targets. Statins have some adverse effects that are somewhat predictable based on phenotypic and genetic factors. Fibrates or omega-3 fatty acids can be added if triglyceride levels remain elevated. The RNA-targeted therapeutics in development offer the possibility of selective liver targeting for specific lipoproteins such as lipoprotein(a) and long-term reduction of LDL-C with infrequent administration of a small-interfering RNA may help to overcome the problem of adherence to therapy.

Triglyceride-Rich Lipoprotein Remnants and Cardiovascular Disease.

BACKGROUND: Triglycerides, cholesterol, and their metabolism are linked due to shared packaging and transport within circulating lipoprotein particles. While a case for a causal role of cholesterol-carrying low-density lipoproteins (LDLs) in atherosclerosis is well made, the body of scientific evidence for a causal role of triglyceride-rich lipoproteins (TRLs) is rapidly growing, with multiple lines of evidence (old and new) providing robust support. CONTENT: This review will discuss current perspectives and accumulated evidence that an overabundance of remnant lipoproteins stemming from intravascular remodeling of nascent TRLs-chylomicrons and very low-density lipoproteins (VLDL)-results in a proatherogenic milieu that augments cardiovascular risk. Basic mechanisms of TRL metabolism and clearance will be summarized, assay methods reviewed, and pivotal clinical studies highlighted. SUMMARY: Remnant lipoproteins are rendered highly atherogenic by their high cholesterol content, altered apolipoprotein composition, and physicochemical properties. The aggregate findings from multiple lines of evidence suggest that TRL remnants play a central role in residual cardiovascular risk.

Effects of Lipid Lowering Drugs on Arterial Stiffness: One More Way to Reduce Cardiovascular Risk?

Arterial stiffness (AS) is considered an independent predictor of cardiovascular disease (CVD) events. Among lipid lowering drugs, statins have a beneficial effect on AS, independent of their hypolipidaemic effect. Based on 3 meta-analyses and other studies, this effect is compound- and doserelated. Potent statins at high doses are more effective than less powerful statins. Ezetimibe (± statin) also seems to decrease AS in patients with dyslipidaemia. Fibrates have no effect on AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have data that beneficially affect all AS risk factors, suggesting a beneficial effect on artery compliance. However, there is no direct measurement of their effect on AS indices. In patients with dyslipidaemia, prescribing high dose statins (± ezetimibe) will not only decrease low-density lipoprotein cholesterol levels but also improve AS (in addition to other effects). This effect on AS may contribute to the observed reduction in vascular events.

Triglycerides and endothelial function: molecular biology to clinical perspective.

PURPOSE OF REVIEW: Recently, a high level of triglycerides has attracted much attention as an important residual risk factor of cardiovascular events. We will review and show the mechanisms underlying the association of endothelial dysfunction with hypertriglyceridemia and present clinical evidence for a relationship between endothelial function and triglycerides. RECENT FINDINGS: Clinical studies have shown that hypertriglyceridemia is associated with endothelial dysfunction. It is likely that hypertriglyceridemia impairs endothelial function through direct and indirect mechanisms. Therefore, hypertriglyceridemia is recognized as a therapeutic target in the treatment of endothelial dysfunction. Although experimental and clinical studies have shown that fibrates and omega-3 fatty acids not only decrease triglycerides but also improve endothelial function, the effects of these therapies on cardiovascular events are controversial. SUMMARY: Accumulating evidence suggests that hypertriglyceridemia is an independent risk factor for endothelial dysfunction. Triglycerides should be considered more seriously as a future target to reduce cardiovascular events. Results of ongoing studies may show the benefit of lowering triglycerides and provide new standards of care for patients with hypertriglyceridemia possibly through improvement in endothelial function.

The Chylomicronemia Syndrome Is Most Often Multifactorial: A Narrative Review of Causes and Treatment.

The chylomicronemia syndrome occurs when triglyceride levels are severely elevated (usually >16.95 mmol/L [1500 mg/dL]) and is characterized by such clinical features as abdominal pain, acute pancreatitis, eruptive xanthomas, and lipemia retinalis. It may result from 1 of 3 conditions: the presence of secondary forms of hypertriglyceridemia concurrent with genetic causes of hypertriglyceridemia, termed multifactorial chylomicronemia syndrome (MFCS); a deficiency in the enzyme lipoprotein lipase and some associated proteins, termed familial chylomicronemia syndrome (FCS); or familial partial lipodystrophy. Most chylomicronemia syndrome cases are the result of MFCS; FCS is very rare. In all these conditions, triglyceride-rich lipoproteins accumulate because of impaired plasma clearance. This review describes the 3 major causes of the chylomicronemia syndrome; their consequences; and the approaches to treatment, which differ considerably by group.

Management of dyslipidaemias in the elderly population-A narrative review.

The impact of dyslipidaemias on the risk of cardiovascular disease (CVD) is well documented. However, it is often under-estimated and, sometimes, suboptimally managed in the elderly population. The prevalence of dyslipidaemias seems to decline from the 7th decade of life in both genders. The association of dyslipidaemias with CVD weakens after the 7th decade, perhaps due to other age-related comorbidities. Low-density lipoprotein cholesterol remains the main target in the management of CVD risk. Although the evidence is not robust for the elderly, statins are the cornerstone of the management of CVD. Statins do have a potentially beneficial role in elderly individuals with established CVD and/or a history of type 2 diabetes mellitus. Data on their use in other elderly populations are inconsistent. There is no clear evidence for a beneficial effect of other hypolipidaemic drug categories in the elderly, such as ezetimibe, fibrates, niacin, omega-3 fatty acids and the new proprotein convertase subtilisin/kexin type 9 inhibitors. Their use should be balanced against possible adverse effects, such as the increased risk of myopathy with fibrates. Potential drug-drug interactions should be also taken into account. In conclusion, there is a need to establish the most effective lipid-lowering strategy in the elderly population with respect to CVD risk reduction, in future well-designed trials.

Lipid management in patients with chronic kidney disease.

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.

Hypertriglyceridemia: A review of the evidence.

Elevated triglycerides are independently associated with increased atherosclerotic cardiovascular disease risk. Hypertriglyceridemia is often a polygenic condition that can be affected by numerous interventions. Primary care NPs are well positioned to appropriately evaluate and manage hypertriglyceridemia, improving overall health outcomes.

Approach to Hypertriglyceridemia in the Pediatric Population.

Hypertriglyceridemia is increasingly identified in children and adolescents, owing to improved screening and higher prevalence of childhood obesity. Hypertriglyceridemia can result from either increased triglyceride (TG) production or reduced TG clearance. The etiologic origin can be primary (genetic) or secondary, but it is often multifactorial. Management is challenging because of the interplay of genetic and secondary causes and lack of evidence-based guidelines. Lifestyle changes and dietary interventions are most important, especially in hypertriglyceridemia associated with obesity. Dietary restriction of fat remains the mainstay of management in primary hypertriglyceridemia. When fasting TG concentration is increased above 500 mg/dL (5.65 mmol/L), fibrates may be used to prevent pancreatitis. Omega-3 fatty acids are often used as an adjunctive therapy. When the fasting TG concentration is less than 500 mg/dL (5.65 mmol/L) and if the non-high-density lipoprotein cholesterol level is above 145 mg/dL (3.76 mmol/L), statin treatment can be considered.

Treatment of primary biliary cholangitis ursodeoxycholic acid non-responders: A systematic review.

BACKGROUND: Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic cholestatic liver disease characterized by an immune mediated destruction of intrahepatic bile ducts. Ursodeoxycholic acid (UDCA) has been the primary medication for the treatment of PBC, resulting in improved liver tests, resolution of symptoms and increased transplant free survival. However, not all patients respond to UDCA. The aim of this systematic review is to provide an evidence based assessment of the medications that have been studied in patients who are refractory to UDCA. METHODS: We performed a systematic literature search on MEDLINE and the Cochrane Database of Systematic Reviews of the published literature. A total of 23 articles fulfilling our inclusion criteria were found. RESULTS: Several studies have shown an improvement in liver biochemistries with the use of obeticholic acid in conjunction with UDCA. Fibrates, including fenofibrate and bezafibrate, have evidence supporting benefit in this population but need more robust studies to confirm these observational results. Neither obeticholic acid nor fibrates have shown to increase transplant free survival. While there may be some benefit with methotrexate, colchicine, budesonide, mycophenolate mofetil and azathioprine, these findings were not consistent and the benefits were marginal. Further investigation is needed. CONCLUSION: In patients with PBC refractory to UDCA, obeticholic acid or a fibrate is a reasonable choice as an adjunctive treatment to UDCA. Further investigation with randomized controlled trials is needed to provide high quality evidence to formulate standardized therapies in this difficult to treat population.

Enfermedad renal crónica y dislipidemia / Chronic kidney disease and dyslipidaemia

La enfermedad renal crónica (ERC) ha de ser considerada como una situación de alto e incluso muy alto riesgo cardiovascular, ya que provoca un aumento de la mortalidad cardiovascular que va incrementándose a medida que progresa la enfermedad. Es preciso realizar un diagnóstico precoz de la ERC junto con la adecuada identificación de los factores de riesgo, al objeto de frenar su evolución a estadios más severos, evitar las complicaciones y retrasar, en lo posible, la necesidad de tratamiento sustitutivo renal. La dislipidemia es un factor de progresión de la ERC que aumenta el riesgo de desarrollo de aterosclerosis y sus complicaciones. Su adecuado control contribuye a reducir la elevada morbimortalidad cardiovascular que presentan estos pacientes. En esta revisión se evalúan las medidas terapéuticas hipolipemiantes necesarias para el logro de los objetivos recomendados, ajustando el tratamiento a la evolución de la enfermedad y a las características del paciente. En la ERC parece prioritaria una intervención precoz e intensiva de la dislipidemia antes de que se produzca una disminución importante de la función renal. El tratamiento con estatinas ha demostrado ser seguro y eficaz en la disminución del cLDL y en la reducción de episodios cardiovasculares en individuos con ERC o después del trasplante renal; sin embargo, la evidencia en los pacientes dializados es menor

Chronic kidney disease (CKD) has to be considered as a high, or even very high risk cardiovascular risk condition, since it leads to an increase in cardiovascular mortality that continues to increase as the disease progresses. An early diagnosis of CKD is required, together with an adequate identification of the risk factors, in order to slow down its progression to more severe states, prevent complications, and to delay, whenever possible, the need for renal replacement therapy. Dyslipidaemia is a factor of the progression of CKD that increases the risk in developing atherosclerosis and its complications. Its proper control contributes to reducing the elevated cardiovascular morbidity and mortality presented by these patients. In this review, an assessment is made of the lipid-lowering therapeutic measures required to achieve to recommended objectives, by adjusting the treatment to the progression of the disease and to the characteristics of the patient. In CKD, it seems that an early and intensive intervention of the dyslipidaemia is a priority before there is a significant decrease in kidney function. Treatment with statins has been shown to be safe and effective in decreasing LDL-Cholesterol, and in the reduction of cardiovascular events in individuals with CKD, or after renal transplant, although there is less evidence in the case of dialysed patients

Effect of Combination Cholesterol-Lowering Therapy and Triglyceride-Lowering Therapy on Medical Costs in Patients With Type 2 Diabetes Mellitus.

High triglyceride (TG) levels among patients with type 2 diabetes mellitus (DM) are associated with higher medical costs. We analyzed the economic impact of TG-lowering therapies and whether the association between medical costs and therapy differed according to TG reduction. We conducted an observational cohort study of 184,932 patients with diabetes mellitus who had a TG measurement between January 2012 and June 2013 and a second TG measurement 3 to 15 months later. We identified 4 therapy groups (statin monotherapy, TG-specific monotherapy, statin/TG-specific combination therapy, or no therapy) and stratified those groups by percent change in TG (increased ≥5%, change of ≤4.9%, decreased 5% to 29%, decreased ≥30%). We compared change in medical costs between the year before and after therapy, adjusted for demographic and clinical characteristics. Of the 184,932 total patients, 143,549 (77.6%) received statin monotherapy, 900 (0.5%) received TG-specific monotherapy, 1,956 (1.1%) received statin and TG-specific combination therapy, and 38,527 (20.8%) received no prescription lipid agents. After covariate adjustment, statin/TG-specific agent recipients had a mean 1-year total cost reduction of $1,110. The greatest cost reduction was seen among statin/TG-specific combination therapy patients who reduced TG levels by ≥30% (-$2,859). Statin monotherapy patients who reduced TG by ≥30% also had a large reduction in adjusted costs (-$1,079). In conclusion, we found a substantial economic benefit to treating diabetic patients with statin/TG-specific combination lipid therapy compared with monotherapy of either type or no lipid pharmacotherapy. A TG reduction of ≥30% produced a particularly large reduction in 1-year medical costs.

TRIGLYCERIDES, ATHEROSCLEROSIS, AND CARDIOVASCULAR OUTCOME STUDIES: FOCUS ON OMEGA-3 FATTY ACIDS.

OBJECTIVE: To provide an overview of the roles of triglycerides and triglyceride-lowering agents in atherosclerosis in the context of cardiovascular outcomes studies. METHODS: We reviewed the published literature as well as ClinicalTrials.gov entries for ongoing studies. RESULTS: Despite improved atherosclerotic cardiovascular disease (ASCVD) outcomes with statin therapy, residual risk remains. Epidemiologic data and recent genetic insights provide compelling evidence that triglycerides are in the causal pathway for the development of atherosclerosis, thereby renewing interest in targeting triglycerides to improve ASCVD outcomes. Fibrates, niacin, and omega-3 fatty acids (OM3FAs) are three classes of triglyceride-lowering drugs. Outcome studies with triglyceride-lowering agents have been inconsistent. With regard to OM3FAs, the JELIS study showed that eicosapentaenoic acid (EPA) significantly reduced major coronary events in statin-treated hypercholesterolemic patients. Regarding other agents, extended-release niacin and fenofibrate are no longer recommended as statin add-on therapy (by some guidelines, though not all) because of the lack of convincing evidence from outcome studies. Notably, subgroup analyses from the outcome studies have generated the hypothesis that triglyceride lowering may provide benefit in statin-treated patients with persistent hypertriglyceridemia. Two ongoing OM3FA outcome studies (REDUCE-IT and STRENGTH) are testing this hypothesis in high-risk, statin-treated patients with triglyceride levels of 200 to 500 mg/dL. CONCLUSION: There is consistent evidence that triglycerides are in the causal pathway of atherosclerosis but inconsistent evidence from cardiovascular outcomes studies as to whether triglyceride-lowering agents reduce cardiovascular risk. Ongoing outcomes studies will determine the role of triglyceride lowering in statin-treated patients with high-dose prescription OM3FAs in terms of improved ASCVD outcomes. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes apo = apolipoprotein ASCEND = A Study of Cardiovascular Events in Diabetes ASCVD = atherosclerotic cardiovascular disease BIP = Bezafibrate Infarction Prevention CHD = coronary heart disease CI = confidence interval CV = cardiovascular CVD = cardiovascular disease DHA = docosahexaenoic acid DO-IT = Diet and Omega-3 Intervention Trial EPA = eicosapentaenoic acid FIELD = Fenofibrate Intervention and Event Lowering in Diabetes GISSI-HF = GISSI-Heart Failure HDL-C = high-density-lipoprotein cholesterol HPS2-THRIVE = Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events HR = hazard ratio JELIS = Japan Eicosapentaenoic Acid Lipid Intervention Study LDL = low-density lipoprotein LDL-C = low-density-lipoprotein cholesterol MI = myocardial infarction OM3FAs = omega-3 fatty acids VITAL = Vitamin D and Omega-3 Trial.

The future of n-3 polyunsaturated fatty acid therapy.

PURPOSE OF REVIEW: This article focuses on the potential role by which a complex mixture of omega-3 fatty acids (OM3-FAs) may beneficially modify cardiovascular risk by modifying the cholesterol composition of atherogenic lipoproteins. This hypothesis is being tested in the STRENGTH trial, which is enrolling 13 000 patients on statins at high cardiovascular risk with hypertriglyceridemia and low HDL cholesterol (HDL-C) treated with an OM3-carboxylic acid. RECENT FINDINGS: Complex mixtures of OM3-FAs containing predominately eicosapentanoic acid and docosahexanoic acid in combination with statins lowers non-HDL by reducing triglyceride-rich lipoprotein cholesterol (TRL-C) while shifting small LDL cholesterol (LDL-C) to large LDL-C. Recent genomic and epidemiological studies have implicated TRL-C and small LDL-C as causal for cardiovascular disease. Therefore OM3-FAs containing both eicosapentanoic acid and docosahexanoic acid in combination with statins may beneficially modify the high residual risk for patients with hypertriglyceridemia and low HDL-C. SUMMARY: Although outcome trials are underway, subgroup analyses of data from previous randomized controlled trials are suggestive of a reduction in coronary artery disease and atherosclerotic cardiovascular disease event rates with triglyceride and TRL-C lowering therapies, particularly if accompanied by low HDL-C. Although the limitations of such data are acknowledged, clinicians must make treatment decisions while awaiting more definitive results from well-designed large-scale randomized controlled trials.