How to Handle Elevated Triglycerides: Life after PROMINENT.

PURPOSE OF REVIEW: Hypertriglyceridaemia (HTG) is a common condition characterised by elevated levels of plasma triglycerides (TG), which are transported in the blood mainly by TG-rich lipoproteins (TRL). Elevated TG levels (150-400 mg/dL) are associated with increased cardiovascular risk. Severe HTG (>880 mg/dL) is associated with a risk of acute pancreatitis only. Randomised clinical trials investigating the clinical benefit of TG-lowering drugs in patients with elevated TG levels have provided conflicting results. RECENT FINDINGS: Elevated TG levels are only one marker of altered lipid/lipoprotein metabolism and indeed reflect altered concentrations of one or more classes or subfractions of TRL, which in turn may have a different association with CV risk. Fibrates, the drugs most commonly used to treat HTG, provide cardiovascular benefits to only a specific subgroup of patients. The lack of clinical benefit from pemafibrate has emphasised the concept that lowering TG levels is not sufficient to reduce the CV risk unless it is accompanied by a reduction in the number of circulating atherogenic lipoproteins, which can be assessed by determining apolipoprotein B levels. Treatment with omega-3 fatty acids was also ineffective in reducing CV risk, with the exception of icosapent ethyl, which, however, appears to have beneficial effects beyond lipids. New drugs are currently being developed that aim to lower TG levels by targeting apolipoprotein C-III or angiopoietin-like-3, both of which are involved in the metabolism of TGs. TG reduction can be achieved by various drugs, but most of them are ineffective in reducing CV risk. The results of outcome studies on new TG-lowering drugs will clarify whether lowering apoB levels is critical to achieve clinical benefit.

Omega n-3 Supplementation: Exploring the Cardiovascular Benefits Beyond Lipoprotein Reduction.

PURPOSE OF REVIEW: Hypertriglyceridaemia is a highly prevalent disorder worldwide. Genetic and Mendelian randomization studies have suggested that triglyceride (TG)-rich lipoproteins are causal risk factors for coronary heart disease and contribute to the residual cardiovascular risk observed in patients optimally treated with statins. However, clinical trials failed to show cardiovascular benefits of TG-lowering; in this context, trials with omega-3 fatty acids provided contrasting results. Few trials have tested the supplementation of EPA alone rather than the combination of EPA + DHA. The JELIS study showed that EPA 1.8 g/day significantly reduced CV events in hypercholesterolaemic patients given statins, an effect that was independent on lipid reduction. RECENT FINDINGS: The REDUCE-IT trial showed that high-dose (4 g/day) EPA significantly reduces the incidence of major cardiovascular events compared with placebo in patients with elevated TG levels. The clinical benefit was higher than expected by the reduction of TG-rich lipoprotein levels. Recent data support the efficacy of high-dose EPA supplementation on a background of optimal LDL-C-lowering therapy as a key approach to achieve a further and significant reduction of CV events in very-high CV risk patients with persistent hypertriglyceridaemia. The effect on lipids does not appear to fully explain the CV benefit, and additional mechanisms of action of EPA likely contribute to the cardiovascular protection, including the reduction of inflammation and platelet aggregation. Current guidelines recommend using high-dose EPA in combination with a statin in high/very-high CV risk patients with mild-to-moderate elevation of plasma TG to reduce the residual CV risk.

Hypercholesterolemia and cardiovascular disease: What to do before initiating pharmacological therapy.

The availability of efficient lipid-lowering drugs has substantially reduced the incidence and mortality for cardiovascular disease (CVD). Despite that, CVD still represents a major cause of death and disability; efforts are thus required to prevent this disease, since reducing the established CV risk factors may slow or prevent the onset of cardiovascular events. Current guidelines recommend a healthier lifestyle for all CV risk categories, as it may have a beneficial impact on several risk factors; in individuals with a low-to-moderate hypercholesterolemia, which are not eligible for a pharmacological approach and are not far from the cholesterol target recommended for their risk category, functional foods or nutraceuticals may be considered as supplement to reduce their CV risk status. Of note, counseling and lifestyle intervention in people at moderate CV risk represents a major issue for both preventing a further risk increase and reducing the need for drugs. Studies on general populations have clearly indicated that lifestyle interventions translate into a clinical benefit, with reduction of the incidence of myocardial infarction and the risk of developing type 2 diabetes.

Berberine, a plant alkaloid with lipid- and glucose-lowering properties: From in vitro evidence to clinical studies.

Berberine (BBR) is an isoquinoline plant alkaloid endowed with several pharmacological activities, including anti-microbial, glucose- and cholesterol-lowering, anti-tumoral and immunomodulatory properties. The main mechanism by which BBR exerts a protective role in atherosclerosis relates to its cholesterol-lowering activity. BBR significantly increases hepatic low density lipoprotein receptor (LDLR) expression and reduces the expression and secretion of the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). In addition to this, several other atheroprotective effects have been ascribed to BBR, including anti-inflammatory and anti-oxidant properties, inhibition of vascular smooth muscle cell proliferation and improvement of endothelial dysfunction. BBR also increases glucose utilization in adipocytes and myocytes, while decreases glucose absorption in intestinal cells, resulting in a net hypoglycemic effect. In hypercholesterolemic animals, BBR significantly decreases LDL-C and total cholesterol (TC) levels and reduces aortic lesions, an effect similar to that of statins. In diabetic animals, BBR significantly reduces glucose levels, improves glucose tolerance, reduces body weight gain and adipose tissue mass. Several clinical studies have also tested the efficacy of BBR in humans. In hypercholesterolemic subjects, BBR induces a significant reduction of TC, triglycerides and LDL-C levels and a significant increase of HDL-C levels, without major adverse effects. BBR also reduces glycemia and plasma cholesterol in diabetic patients, improves lipid and glucose profile and decreases body mass index and waist circumference in subjects with metabolic syndrome. These findings, together with the good tolerability, suggest that BBR administration might be considered a potential therapeutic approach for the treatment of hypercholesterolemia or diabetes. Given the level of evidence available to date well-designed randomized controlled trials to test safety and efficacy of BBR are warranted.

Statin intolerance: diagnosis and remedies.

Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.

Update on the management of severe hypertriglyceridemia--focus on free fatty acid forms of omega-3.

High levels of plasma triglycerides (TG) are a risk factor for cardiovascular diseases, often associated with anomalies in other lipids or lipoproteins. Hypertriglyceridemia (HTG), particularly at very high levels, significantly increases also the risk of acute pancreatitis. Thus, interventions to lower TG levels are required to reduce the risk of pancreatitis and cardiovascular disease. Several strategies may be adopted for TG reduction, including lifestyle changes and pharmacological interventions. Among the available drugs, the most commonly used for HTG are fibrates, nicotinic acid, and omega-3 polyunsaturated fatty acids (usually a mixture of eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). These last are available under different concentrated formulations containing high amounts of omega-3 fatty acids, including a mixture of EPA and DHA or pure EPA. The most recent formulation contains a free fatty acid (FFA) form of EPA and DHA, and exhibits a significantly higher bioavailability compared with the ethyl ester forms contained in the other formulations. This is due to the fact that the ethyl ester forms, to be absorbed, need to be hydrolyzed by the pancreatic enzymes that are secreted in response to fat intake, while the FFA do not. This higher bioavailability translates into a higher TG-lowering efficacy compared with the ethyl ester forms at equivalent doses. Omega-3 FFA are effective in reducing TG levels and other lipids in hypertriglyceridemic patients as well as in high cardiovascular risk patients treated with statins and residual HTG. Currently, omega-3 FFA formulation is under evaluation to establish whether, in high cardiovascular risk subjects, the addition of omega-3 to statin therapy may prevent or reduce major cardiovascular events.

Omega-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia.

Epidemiological studies have established an association between high triglycerides (TG) plasma levels and increased cardiovascular risk. Increased TG levels, commonly coupled with low HDL-C levels, are common in high cardiovascular risk subjects including those with dyslipidemia, metabolic syndrome and type 2 diabetes. Management of hypertriglyceridemia (HTG) includes lifestyle modification for mild-to-moderate HTG and pharmacological therapies for the treatment of high and very high TG levels. Among drugs, fibrates, nicotinic acid and omega-3 polyunsaturated fatty acids may be considered. Omega-3 fatty acids reduce plasma TG levels by several mechanisms; beside the effects on TG, omega-3 can also influence the levels of other lipids and lipoproteins including HDL-C and LDL-C. Clinical trials have also shown that omega-3 fatty acid supplementation is effective also when added in combination with other lipid-lowering drugs. These findings suggest that omega-3 fatty acids may be usefully considered for the management of high TG levels.

Omega-3 polyunsaturated fatty acids in the treatment of hypertriglyceridaemia.

Hypertriglyceridaemia (HTG) is an independent risk factor for cardiovascular disease; high-risk patients with HTG, such as those with metabolic syndrome or diabetes, may benefit from hypolipidaemic therapies. Several lipid-lowering drugs act by reducing triglyceride (TG) levels, including fibrates, nicotinic acid and omega-3 fatty acids. The omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) dose-dependently reduce plasma TG levels; the effect tends to be greater in patients with higher TG levels at baseline. Evidence from clinical trials suggests that EPA+DHA doses of ≥ 2 g/day are required to achieve significant effects. The optimal TG-lowering doses of EPA+DHA are 3-4 g/day, with little evidence to support lipid-altering efficacy of doses of EPA and DHA <1g/day. Predicted changes in fasting serum TG levels at the recommended dietary intakes of EPA and/or DHA of 200-500 mg/day are -3.1% to -7.2%. Reductions of plasma TG levels at the optimal doses are from 25-35% up to 45% in the presence of severely elevated TG levels (≥ 500 mg/dl; ≥ 5.65 mmol/l), along with a reduction in non-high-density lipoprotein-cholesterol (non-HDL-C) and an increase in HDL-C. This observation has also been confirmed in statin-treated patients.

High-density lipoprotein subfractions--what the clinicians need to know.

Although the inverse relationship between plasma levels of high-density lipoprotein (HDL) and cardiovascular disease has been largely demonstrated, many observations have suggested that the assessment of HDL functionality might be more informative than a simple measurement of HDL-cholesterol plasma levels. HDLs are a class of structurally and functionally heterogeneous particles; in atherosclerosis-related diseases, changes in HDL subfraction levels and functions are frequently observed. Circulating levels of large HDL particles are decreased in dyslipidaemic conditions, while levels of small dense HDL particles are increased in patients with coronary heart disease. Furthermore, specific genetic defects in proteins involved in HDL metabolism significantly impact the distribution of HDL subpopulations. Finally, many drugs used for dyslipidaemia induce changes in HDL subfractions strictly related to cardiovascular disease. Although several methods exist to evaluate HDL subclass levels, most of them are not easily applicable in clinical practice, due to the costs and high variability. However, the possibility to measure the levels of specific HDL subfractions in patients with atherosclerosis-related diseases might help to better define their cardiovascular risk.