Challenges in the treatment of hypertriglyceridemia: glass half empty or half full?

Abstract

Fasting and postprandial hypertriglyceridemia appear to be causally related to atherosclerotic cardiovascular disease, and plasma triglyceride (TG) concentrations above 10 mmol/l increase susceptibility to acute pancreatitis. Exclusion of secondary causes of hypertriglyceridemia and implementation of lifestyle measures are the initial treatment in all types of hypertriglyceridemia. Current evidence regarding the benefit of adding non-statin agents, i.e. fibrates and n-3 polyunsaturated fatty acids, to statins in patients with hypertriglyceridemia (plasma 2.3 < TG ≤ 5.7 mmol/l) is insufficient. Therefore, the clinical use of non-statin agents in this context requires a careful trade-off between anticipated benefits and potential adverse events within the context of a clinical consultation. It is reasonable to consider adding fenofibrate to a maximally tolerated dose of a statin with or without ezetimibe in higher risk patients with metabolic syndrome or established atherosclerotic cardiovascular disease with persistent, residual elevation in TG > 2 mmol/l. Patients with very high fasting plasma TG levels (>10 mmol/l) need immediate expert review to offset pancreatitis and, along with strict dietary control and triglyceride-lowering pharmacotherapy, may need lipoprotein apheresis or plasma exchange.

Definition: diagnostic value

Hypertriglyceridemia generally refers to an increase of plasma triglyceride (TG) concentrations above the 95th percentile for age and gender of a reference population [1]. Most guidelines employ threshold plasma concentrations of 1.7, 2.3 and 5.7 mmol/l to define hypertriglyceridemia as mild, moderate and severe, respectively [1]. Hypertriglyceridemia above the lower thresholds is common in the population and co-expresses with obesity and the insulin resistance syndrome. Hypertriglyceridemia may also point to inherited dyslipidemias, typically familial hypertriglyceridemia, dysbetalipoproteinemia or familial combined hyperlipidemia that may have wider clinical implications for relatives of a proband [2].

Causal risk factor

Fasting and postprandial hypertriglyceridemia were formerly considered markers for other risk factors for atherosclerotic cardiovascular disease (CVD), but their probable causal role has been recently proposed by new epidemiological and Mendelian randomization studies and by the demonstration that they reflect the accumulation in plasma of atherogenic remnant lipoproteins [1]. However, interventional evidence from outcome trials to substantiate the causal association between hypertriglyceridemia and CVD is still insufficient. Hypertriglyceridemia is also related to non-alcoholic fatty liver disease, an emerging risk factor per se for CVD, and a level of TG above 10 mmol/l is related to the development of life-threatening acute pancreatitis [3]. Acute pancreatitis is a medical emergency that, in the present context, is due to hyperchylomicronemia, involving the in situ hydrolysis of chylomicrons by pancreatic lipase with release of free fatty acids that are cytotoxic to the pancreatic tissue [3].

Etiology & metabolic basis

Rare loss-of-function gene variants lead to major deficiency in lipoprotein lipase (LPL) that impairs the catabolism of large TG-rich lipoproteins (TRLs) and, if untreated, presents with the chylomicronemia syndrome [2]. More commonly, hypertriglyceridemia is due to the interaction of several less-severe mutations that interact with a multiplicity of secondary factors, typically obesity, diabetes and adverse lifestyles, impairing the metabolism of TRLs. Insulin resistance often underpins the development of hypertriglyceridemia by inducing hepatic de novo lipogenesis and oversecretion of large TG-rich VLDL particles, as well as increased chylomicron biogenesis by enterocytes. Conversely, insulin resistance reduces the catabolism of TRLs by decreasing peripheral LPL activity and the hepatic expression of clearance receptors, such as LDL-receptor related protein [1,4].

Role in atherogenesis

The remnants of lipolysis of the larger TRLs (specifically smaller VLDLs, chylomicron remnants and intermediate-density lipoproteins) can promote atherothrombosis via several mechanisms, including induction of foam cell formation, promotion of vascular inflammation and oxidative stress, activation of platelets and coagulation, and impairment of endothelial function. Moreover, metabolism of TRLs by cholesteryl ester transfer protein (CETP) and LPL generates small dense LDL particles that are more prone to oxidative modification and are more atherogenic than large buoyant LDL particles [5].

Treatment & guidelines

The above premises provide a compelling argument for the detection and treatment of hypertriglyceridemia, but what are the current recommendations and the shortfalls in evidence? Lifestyle modifications, including a calorie-controlled heart-healthy diet, aerobic exercise, weight regulation, smoking cessation and restricted alcohol intake, form the basis in treating all types of hypertriglyceridemia. Correction of any of the multitude secondary causes, such as poor glycemic control in diabetes and untreated hypothyroidism, also forms critical first-stage management. The subsequent use of drug therapy to treat residual hypertriglyceridemia is predicated by a higher absolute risk of CVD, first-line use of a statin with attainment of lower LDL-cholesterol (LDL-C) regimen and use of new therapeutic lipoprotein targets, typically non-HDL cholesterol and/or apoB. With the exception of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines that were based on the outcome of statin trials in undifferentiated higher risk subjects (with no recommendation on the management of hypertriglyceridemia) [6], all international expert guidelines are concordant on the value of additional drug therapy, typically a fibrate or high-dose n-3 fatty acids, in regulating TRLs in high-risk patients on statin with residual mild-to-moderate hypertriglyceridemia [7]. A former recommendation of the value of using niacin has now been dispelled by recent clinical trials showing futility or net harm to patients [8,9].

Fibrates & n-3 polyunsaturated fatty acids

But how strong is the evidence supporting the use a fibrate and n-3 polyunsaturated fatty acids (n-3 PUFAs)? In statin trials of patients with established coronary artery disease, mild-to-moderate hypertriglyceridemia remains predictive of recurrent coronary events [7]. Both fibrates and higher doses of n-3 PUFAs are effective agents for lowering plasma concentration of TG and TRL remnants by metabolic mechanisms that are independent of statins. Earlier trials in the pre-statin era provided compelling evidence that in subjects with high TG and low HDL-cholesterol concentrations, typically with co-existent diabetes or insulin resistance, a fibrate could reduce CVD events and progression of coronary atherosclerosis. In the Helsinki Heart Study, gemfibrozil reduced cardiovascular (CV) events only in the subgroup of patients with a high CV risk and plasma TG levels >2.3 mmol/l [10]. In the Veterans Affairs high-density lipoprotein intervention trial (VA-HIT) in patients with low HDL-cholesterol, hypertriglyceridemia and relatively low LDL-C, gemfibrozil significantly reduced the incidence of non-fatal myocardial infarction and CV mortality, most notably in those with hyperinsulinemia [11]. In the Bezafibrate Infarction Prevention (BIP) trial, although no effect on endpoints was observed in the entire study population, a significant reduction in the risk of fatal/non-fatal myocardial infarction and sudden death was observed in the subgroup of patients with baseline TG >2.3 mmol/l [12]. The benefit of fenofibrate as monotherapy and as an addition to a statin was more recently tested in two large-scale outcome trials in diabetic patients, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) [13] and Action to Control Cardiovascular Risk in Diabetes (ACCORD) [14] studies, respectively. While both trials did not find any treatment effect on the primary outcome in the entire population, a significant improvement in total macrovascular events was observed in a post hoc analysis in a subgroup with high TG and low HDL-cholesterol, that is with ‘atherogenic dyslipidemia’, a statistically significant result that was, however, only found in men [15]. This notion for the specific benefit of fibrates is likely to be tested prospectively in a trial with fenofibrate planned by the Veterans Affairs in the US. It is also noteworthy that in both diabetic trials, there was a significant reduction in the incidence of microvascular events, including retinopathy, but this was unrelated to the change in plasma TG levels and reflects a direct benefit of fenofibrate on microangiopathy [16]. Hence, the notion of adding a fibrate to a statin is most compelling with fenofibrate in subjects with residual diabetic dyslipidemia. However, better quality evidence from prospective trials is required to increase the strength of recommendation.

Supplemental n-3 PUFAs, enriched in eicosapentenoic acid (EPA) and docosahexaenoic acid, dose-dependently diminish hypertriglyceridemia and atherogenic TRLs, either alone or in combination with statins. However, the findings of randomized controlled trials and meta-analyses on the benefits of n-3 PUFAs acids in reducing CV outcomes have been controversial [4]. This is in part related to differences in study populations and formulations of n-3 PUFA used. Most importantly, however, as with the aforementioned fibrate trials, subjects in those trials were not selected for having hypertriglyceridemia and lower doses of n-3 PUFA preparations with lower systemic bioavailability were employed. Icosapent ethyl (Vascepa^®) is a newer n-3 formulation which contains pure EPA ethyl ester and lacks the LDL-elevating effect of mixed EPA/docosahexaenoic acid formulations (Lovaza^®). Another advance has been the introduction of n-3 free (carboxylic) fatty acid formulation (Epanova^®). The n-3 PUFAs have been shown to have better absorption and oral bioavailability in the free fatty acid, compared with ethyl ester form [17]. In addition, intestinal absorption of Epanova is not dependent on the pancreatic enzyme activity (which is required for the absorption of n-3 ethyl esters), thus allowing its consumption with a low-fat meal. Lovaza, Vascepa and Epanova have all been approved by the US FDA for the treatment of severe hypertriglyceridemia. The efficacy of newer n-3 formulations has already been shown in hypertriglyceridemic populations [18,19], and both Vascepa and Epanova are currently being studied in Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT; [20]) and Statin Residual Risk Reduction with Epanova in High CV Risk Patients with Hypertriglyceridemia (STRENGTH; [21]) outcome trial, respectively. Both trials are studying high CV risk statin-treated subjects with 2.2 mmol/l ≤ TG <5.5 mmol/l. These trials are essential for confirming whether the benefits of adding Vascepa and Epanova to statin therapy outweigh potential risks. To date, no clinical endpoint trial has been undertaken with Lovaza.

Pipeline therapies

New pipeline therapies for hypertriglyceridemia? Several agents have been developed which regulate the synthesis (secretion) and/or catabolism (clearance) of TRLs. Inhibitors of microsomal TG transfer protein and acyl-CoA:diacylglycerol acyltransferase-1, apoB-targeted antisense oligonucleotides, dual PPAR a/γ agonists and incretin mimetics can correct hypertriglyceridemia by reducing hepatic synthesis and secretion of TRLs [1,4]. Inhibitors of angiopoietin-like proteins 3 and 4, apoC-III–targeted antisense oligonucleotides and selective PPAR modulators enhance TG catabolism and clearance from plasma [1,4]. The impact of these agents on CV endpoints is yet to be determined, though the AleCardio outcome trial with aleglitazar (a dual PPAR a/γ agonist) in patients with Type 2 diabetes and a recent acute coronary syndrome [22] was halted owing to the safety concerns and lack of efficacy. Liraglutide Effect and Action in Diabetes (LEADER; [23]) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; [24]) trials are the ongoing studies with incretin mimetic agents to assess their effect on CV outcomes in Type 2 diabetic subjects. Finally, lomitapide (a microsomal TG transfer protein inhibitor) and mipomersen (an apoB antisense oligonucleotide) have been approved by the FDA (lomitapide has been also approved by the EMA) for the treatment of patients with homozygous familial hypercholesterolemia. Lomitapide inhibits hepatic production of apoB-100 and the enterocytic secretion of apoB-48 and can lower TG, but still does not have an approved indication for this purpose [1,4]. Proprotein convertase subtilisin kexin type 9 inhibitors are the most potent class of LDL-lowering medications [1,4,25], and could also potentially lower TG in moderately hypertriglyceridemic subjects by increasing the receptor-mediated clearance of TG-rich lipoprotein remnants [1,4], but proprotein convertase subtilisin kexin type 9 inhibitors have not been fully tested in this setting. The acceptance and survival of any new agent in the lipid therapy market is critically dependent on the outcome of high-quality clinical trials that confirm its net benefit and cost–effectiveness against statin therapy. A separate opportunity for highly potent TG-lowering agents is to gain an orphan drug indication, as exemplified by alipogene tiparvovec (Glybera^®) as the first ever approved (by the EMA) form of gene therapy, specifically for the treatment of rare chylomicronemic patients with inherited LPL deficiency [1,4].

Clinical guidance

Ruling out secondary causes of hypertriglyceridemia and implementation of lifestyle measures, including adherence to a heart-healthy diet, aerobic exercise, weight control, smoking cessation, restriction of alcohol intake and glycemic control in diabetics, should be regarded as the initial treatment in all types of hypertriglyceridemia. Current evidence regarding the benefit of adding non-statin agents, that is, fibrates and n-3 PUFAs, to statins in patients with hypertriglyceridemia (plasma 2.3 < TG ≤ 5.7 mmol/l) is insufficient. Therefore, the clinical use of non-statin agents in this context requires a careful trade-off between anticipated benefits and potential adverse events. However, on the basis of the available evidence, our opinion is that it is reasonable to consider adding fenofibrate to a maximally tolerated dose of a statin in higher risk patients with metabolic syndrome or established CVD, if they have attained or are close to target levels of LDL-C, secondary causes of hypetriglyceridemia have been corrected, contraindications (history of cholelithiasis or statin-associated myalgia) have been excluded and there is residual elevation in TG >2 mmol/l [1,4]. Fenofibrate is well tolerated and safe in combination with all statins and can reduce the risk of retinopathy in diabetic patients. However, in post-acute coronary syndrome patients on a statin with even marginally elevated LDL-C and irrespective of mild-to-moderate elevation in TG, serious consideration should also be given to adding ezetimibe before fenofibrate [26]. Patients with very high fasting plasma TG levels (>10 mmol/l) need immediate expert review to offset pancreatitis. Beyond a very low-fat diet, they may need a fibrate or high-dose n-3 PUFA and, more rarely, inpatient treatment with exclusion of fat intake and intravenous dextrose and insulin regimen and/or a heparin infusion or – in the most severe cases – lipoprotein apheresis or plasma exchange [1,4]. These are well-tested acute measures that can be life-saving and need to be administered, as in all best practices, with good clinical judgment.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.