Cardiovascular prevention studies in a population with hypertriglyceridemia

Abstract

Although hypertriglyceridemia (>150 mg/dL) has been considered a risk factor for the development of atherosclerotic vascular disease, this relationship is not as linear or robust as that for LDL cholesterol, and the reduction of plasma triglyceride levels has not been consistently related to the reduction of this complication. Thus, in general terms and in the absence of a conclusive clinical benefit, current evidence does not support treatment with fibrates, niacin or omega-3 fatty acids routinely to reduce cardiovascular risk. The recommendation, especially the former, is limited to some subjects already treated with statins and with optimal LDL cholesterol levels in whom elevated triglyceride levels persist. As an exception, only purified icosapent ethyl at a high dose (4 g daily) has demonstrated a reduction in cardiovascular morbidity and mortality and has been authorized for this indication, following the results of the REDUCE-IT trial.

Resumen

Aunque la hipertrigliceridemia (> 150 mg/dL) se ha considerado como un factor de riesgo para desarrollo de enfermedad vascular aterosclerótica, tal relación no es tan lineal ni robusta como para el colesterol LDL, y la reducción de los niveles plasmáticos de triglicéridos tampoco se ha relacionado de forma consistente con la disminución de tal complicación. Así pues, en líneas generales y en ausencia de un beneficio clínico concluyente, la evidencia actual no apoya el tratamiento con fibratos, niacina o ácidos omega-3 de forma rutinaria para reducir el riesgo cardiovascular, quedando limitada la recomendación -especialmente los primeros- a algunos sujetos ya tratados con estatinas y con cifras óptimas de colesterol LDL en los que persisten cifras elevadas de triglicéridos. Como excepción, tan solo icosapento de etilo purificado a alta dosis (4 g diarios) ha demostrado reducción de la morbimortalidad cardiovascular y ha sido autorizado con tal indicación, a raíz de los resultados del ensayo REDUCE-IT.

Introduction

Hypertriglyceridaemia, which is defined as values ​​in adults above 150 mg/dL, is an independent risk factor for the development of atherosclerotic vascular disease (AVD) and all-cause mortality, although the association is not as robust or increases as linear as that of hypercholesterolaemia, especially when corrected for other factors such as HDL cholesterol and the remnant cholesterol contained in triglyceride-rich particles.¹ In contrast to LDL cholesterol or lipoprotein (a), whose relationship with the risk of AVD is continuous and linear, higher triglyceride (TG) levels, especially those above 1,000 mg/dL, are not clearly associated with an increased cardiovascular risk but rather with the development of acute pancreatitis. They are mostly related to a congenital or acquired deficiency of lipoprotein lipase (LPL) activity. Therefore, for practical purposes, we will refer to TG-induced vascular risk when its levels are moderately elevated, generally between 150 and 500 mg/dL, particularly if accompanied by low HDL cholesterol levels.

Treatments aimed at reducing LDL cholesterol (statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid) have demonstrated a clear and robust reduction in cardiovascular events in primary and secondary prevention, and are therefore a well-established part of any current AVD prevention strategy. Furthermore, lowering TG concentrations is associated with a reduction in AVD-related morbidity and mortality in some patient subgroups, although systematic reviews point to discrepancies and inconsistencies between some studies, and the quality of the evidence generated is not generally high. There is a parallel debate about whether the reduction of remnant cholesterol transported in TG-rich particles is responsible for this benefit rather than the reduction in triglycerides per se.

Until the advent of icosapent ethyl (IPE), available studies on the prevention of cardiovascular events in patients with hypertriglyceridaemia analysed the effects of fibrates, niacin, and omega-3 fatty acid combinations; these studies will be briefly discussed in this review.

Fibrates

Fibrates are a family of peroxisome proliferator-activated receptor (PPARα) agonists that reduce TG levels and increase Apo A-I and high-density lipoprotein (HDL) levels. The intermediate mechanisms resulting from this agonist action are multiple and complex, but include, among others, the regulation of the expression of various genes involved in lipid metabolism (promoting tissue beta-oxidation of free fatty acids, which results in reduced availability for TG synthesis and incorporation into very low-density lipoproteins (VLDL), repression of Apo C-III expression, and the increase, through various pathways, of LPL activity, accelerating the elimination of TG-rich particles.²

The benefits of fibrate monotherapy are initially based on four randomised, placebo-controlled clinical trials: the Helsinki Heart Study (HHS),³ the Veteran Affairs High-density Lipoprotein Intervention Trial (VA-HIT),⁴ the Bezafibrate Infarction Prevention Study (BIP),⁵ and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD).⁶ Data from these trials show a slight decrease in the incidence of non-fatal heart attacks and a lower rate of revascularisations in patients with moderate hypertriglyceridaemia and low HDL cholesterol levels (mostly after post-hoc analysis), although the efficacy is much less robust than statins and there is no clear benefit in other MACE treatments.

The Action to Control Cardiovascular Risk in Diabetes Lipid Trial (ACCORD-Lipid) study⁷ was designed to test the benefit of adding fenofibrate to simvastatin treatment in patients with type 2 diabetes mellitus and high cardiovascular risk. The rate of fatal and non-fatal cardiovascular events was not different in the group of patients randomized to simvastatin and placebo versus the group receiving the combination of simvastatin and fenofibrate.

Finally, high expectations were placed on Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT),⁸ since pemafibrate had been shown to be more potent and selective in modulating PPARα and more effective in reducing triglycerides along with a greater increase in HDL cholesterol levels than other fibrates in phase 2 of its clinical development. PROMINENT considered 2 cohorts of high-risk diabetic patients with and without previous clinical cardiovascular disease with moderate elevation of TG and HDL cholesterol less than 40 mg/dL and, despite its efficacy in improving both lipid parameters, no lower incidence of cardiovascular events was

observed in either group. Pemafibrate was never marketed in Spain following these results, and this failure, along with previous ones, has influenced the perception of the practical utility of this therapeutic family in cardiovascular risk control.

Currently, there is a shared consensus in clinical practice guidelines that statins are the first step in the treatment of moderate hypertriglyceridaemia and that routinely offering fibrates to reduce cardiovascular risk is not indicated, given the lack of evidence of their benefit. Their use is limited to patients with isolated hypertriglyceridaemia or diabetic and/or AVD patients in whom elevated TG9 levels persist while on statin treatment and with optimal LDL cholesterol levels.⁹

Niacin

Niacin, or nicotinic acid, is a water-soluble vitamin of the B complex, essential for governing the oxidation-reduction processes of cellular metabolism and DNA repair. It also acts as a cofactor in the synthesis of steroid hormones, among many other effects. Its deficiency causes pellagra, and its main pharmacological use today is as part of multivitamin complexes. However, at high doses, niacin influences various aspects of lipid metabolism, inflammation, and endothelial function. The main effects on lipoprotein metabolism include increased HDL cholesterol and decreased triglycerides and, to a lesser extent, LDL cholesterol and Lp(a). Niacin increases the synthesis of Apo A-I and the transfer of cholesterol from macrophages to nascent HDL particles, in addition to a potent antilipolytic effect in adipose tissue and a reduced supply of free fatty acids for VLDL synthesis.¹⁰

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health (AIM-HIGH) study¹¹ focused on evaluating the effect of niacin in patients with established cardiovascular disease, hypertriglyceridemia, and low HDL cholesterol levels. In both study arms, patients received simvastatin and ezetimibe as needed to maintain LDL cholesterol levels between 40 and 80 mg/dL. The addition of sustained-release niacin to simvastatin did not provide any benefit in reducing cardiovascular events and showed a non-significant trend toward a higher incidence of ischaemic stroke. The trial was stopped for futility 3 years after its start, but a large group of participants was followed for an additional year, during which the only change was the rate of niacin discontinuation due to tolerance issues.

In a subsequent attempt, using a formulation that included laropiprant to try to minimise common side effects such as facial flushing, The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE¹² also failed to demonstrate any benefit from adding niacin to high-risk patients on simvastatin, and was compounded by a significant increase in myopathy and rhabdomyolysis in patients of Asian origin, leading to its global withdrawal and ending the initial enthusiasm for this therapeutic option.

Omega-3 fatty acids

Long-chain omega-3 polyunsaturated fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in high concentrations in fatty fish and certain concentrated supplements obtained from the processing of fatty oil from oily fish. It should be emphasised that these supplements can be found over-the-counter in multiple formulations without the control or monitoring of regulatory agencies (FDA, EMA) and can be obtained in supermarkets and other physical or virtual distribution chains. These products, which will not be discussed in this review, may contain varying amounts of saturated and/or oxidised fatty acids and various organic and mineral contaminants.¹³

The role of omega-3 s in cardiovascular health has been the subject of numerous studies that have sought beneficial effects based on the reduction of TG levels, their anti-inflammatory effects, and the improvement of endothelial function, among other tentative pleiotropic mechanisms. However, traditional prescription formulations (dispensed in pharmacies), which are more purified and concentrated and mix both fatty acids (EPA and DHA) in different proportions at significantly higher concentrations than supplements, have not consistently demonstrated cardiovascular benefits in multiple placebo-controlled trials at various doses (which may be a bias for meta-analyses), as has purified EPA, an aspect that will be analysed in another article in this issue.¹⁴

Table 1 details the main studies combining EPA + DHA compared with the REDUCE-IT study¹⁵ and the JELIS study¹⁶ with purified EPA, which did demonstrate a significant reduction in major cardiovascular events, independently of the reduction in plasma TG levels.

Table 1.

Main results of clinical trials with Omega-3.

Brand name	Omega-3	Study	n	Primary endpoint	RRR	NNT	Cardiovascular death	Total mortality
Vazkepa®	EPA 4 g/day	REDUCE-IT®^15	8,179	Cardiovascular death, acute myocardial infarction, stroke, revascularization, angina	25%	21	20%	NS
Epadel®	EPA 1.8 g/day	JELIS^16	18,645	Sudden death, acute myocardial infarction, angina, angioplasty, stent, bypass	19%	14,5	NS	NS
Omacor®	EPA + DHA	ORIGIN^17	12,611	Cardiovascular death, acute myocardial infarction, stroke Sudden death	NS	–	NS	NS
Omacor®	EPA + DHA	OMEGA^18	3,851	Sudden death	NS	–	N/A	NS
Omacor®	EPA + DHA	ASCEND^19	15,480	Cardiovascular death, acute myocardial infarction, stroke, transient ischemic attack	NS	–	18%	NS
Omacor®	EPA + DHA	VITAL^20	25,871	Cardiovascular death, acute myocardial infarction, stroke	NS	–	NS	NS
Epanova®	EPA + DHA	STRENGTH^21	13,078	Cardiovascular death, acute myocardial infarction, stroke, revascularization, angina	NS	–	NS	NS

ASCEND: A Study of Cardiovascular Events in Diabetes; N/A: not available; NNT: number needed to treat; NS: not significant; OMEGA: Randomized, Placebo-Controlled Trial to Test the Effect of Highly Purified Omega-3 Fatty Acids on Top of Modern Guideline-Adjusted Therapy After Myocardial Infarction; ORIGIN: Outcome Reduction with an Initial Glargine Intervention; REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention; RRR: relative risk reduction; STRENGTH: Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia; Trial JELIS: Japan EPA Lipid Intervention Study; VITAL: Vitamin D and Omega-3 Trial.

The Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) trial²¹ was the first omega-3 combination (EPA + DHA) study using higher doses of EPA, randomising 13,078 high-risk patients with hypertriglyceridaemia (more than half in secondary prevention) to receive either 4 g of omega-3 (880 mg DHA + 2,200 mg EPA daily) or placebo (corn oil) with an effect on triglycerides comparable to REDUCE-IT15. The STRENGTH trial was terminated prematurely due to the lack of significant differences between the two arms in the primary endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina) in an interim analysis with a mean follow-up of 42 months. This contrasts with the REDUCE-IT trial, which, using the same endpoints and a population with comparable characteristics, demonstrated a significant reduction in events using high doses of IPE (4 g of EPA per day) versus placebo (paraffin oil). These results were consistent with the JELIS¹⁶ study, which also used purified EPA without DHA. Plasma EPA levels were higher in both studies, and these levels were inversely correlated with cardiovascular events, which was not the case in the STRENGTH trial. This leads to the hypothesis that DHA could somehow impede the benefit of EPA, given that there are no trials or evidence to date of the effect of DHA alone on the risk of cardiovascular events.

Conclusions

With the exception of high doses of icosapent ethyl, as demonstrated by the REDUCE-IT study,¹⁵ no treatment for hypertriglyceridaemia (fibrates, niacin, or omega-3 blends) has consistently shown cardiovascular benefit. In patients at high cardiovascular risk with hypertriglyceridaemia, statins are the treatment of choice, demonstrating the highest level of evidence and recommendation, as stated in the European Societies of Cardiology and Atherosclerosis Guidelines for cardiovascular risk reduction through the management of dyslipidemia.²² Treatment with high-dose EPA in the form of icosapent ethyl is recommended in these guidelines for high- or very high-risk patients if, despite statin treatment, TG levels remain between 135 and 499 mg/dL. With a lower level of evidence, treatment with fenofibrate or bezafibrate in combination with statins is assumed for primary prevention or in high-risk situations.

Funding

This study was sponsored by the Spanish Society of Arteriosclerosis with funding from Amarin, which did not participate in the design or preparation of this manuscript.

Supplement information

This article is part of the supplement entitled “Reduction of cardiovascular events in patients with hypertriglyceridaemia,” which was sponsored by the Spanish Society of Atherosclerosis, with funding from Amarin.