Treatment of hypertriglyceridemia to reduce cardiovascular risk

Cardiovascular diseases continue to be the leading cause of death worldwide.¹ Although Spain has lower adjusted rates of cardiovascular disease than other European countries, it remains the leading cause of death, especially among women.² Dyslipidaemia is one of the risk factors for the development of cardiovascular complications, and significant advances have been made in dietary and pharmacological approaches in recent years.^3,4 However, the most successful clinical trials achieve a relative risk reduction of cardiovascular complications of approximately 25 %–30 %, so even in these studies, a majority of patients do not benefit from the therapeutic action evaluated. The term "residual cardiovascular risk" refers to this circumstance. Perhaps the term "persistent vascular risk" would be more appropriate, as the term "residual" minimises the relevance of the entire trajectory that remains to be taken to complete a comprehensive approach to vascular risk.

Regarding dyslipidaemia, the most significant advances are related to the consolidation of LDL cholesterol as a aetiological agent of atherosclerosis and the success of its intense reduction in the prevention of vascular complications in all areas: coronary, cerebral, and peripheral.⁵ Although we are far from accurately using the available therapeutic arsenal for this therapeutic target, the prospects continue to expand, particularly targeting PCSK9 blockade (whether with small interfering RNAs or small molecules).

Obviously, persistent risk has non-lipid components: aging, inflammation, thrombosis, etc., but the "lipid risk" does not end with LDL cholesterol. HDL cholesterol as a therapeutic target has been called into question both by Mendelian randomisation genetic studies and by the failure of therapeutic interventions targeting it. This is a complex topic stretching beyond the scope of this issue.

Conversely, the importance of elevated triglycerides (TG) as a cardiovascular risk factor is becoming increasingly important, particularly in patients with apparently good control of LDL cholesterol.^6,7 Within endogenous cholesterol metabolism, TG-rich lipoproteins (initially VLDL) are the precursors of low-density lipoproteins (LDL) and share apolipoprotein B as their specific protein component. Mendelian randomisation studies reinforce an aetiological role for elevated TG-rich lipoproteins in the development of arteriosclerosis.⁸ In fact, vascular risk estimates that incorporate TG or Apo B are more accurate than those based solely on LDL cholesterol.⁸ Lipoprotein (a) is a "modified LDL" that incorporates (in addition to Apo B) apolipoprotein A. The relevance of lipoprotein (a) in "persistent lipid risk" and the current approach to this topic have been recently developed in multiple reviews,⁹ and will not be discussed in this issue.

In the first article of this special issue, Dr. López Miranda, addresses in detail the relevance of hypertriglyceridaemia and TG-rich lipoproteins in the development of cardiovascular complications.¹⁰

Therapeutic recommendations for patients with hypertriglyceridaemia from the perspective of cardiovascular prevention have historically been considered secondary, following attempts to control LDL cholesterol, primarily with statins and, occasionally, other additional drugs.¹¹

Drugs primarily targeting hypertriglyceridaemia include fibrates and omega-3 fatty acids, the main studies of which are the subject of the article by Dr. Ovidio Muñiz.¹²

In the post-statin era, several randomised controlled clinical trials with fibrates have failed to reduce cardiovascular complications. Post hoc subgroup analysis, however, suggested that these drugs might be useful in certain patients.¹³ However, recent results from the PROMINENT study have again shown that TG reduction with fibrates does not clearly translate into improved cardiovascular prognosis, and this therapeutic option therefore currently lacks solid support.¹⁴

Globally, omega-3 fatty acids have been shown to be effective in reducing TG, and have therefore been evaluated in various cardiovascular prevention studies, sparking intense scientific controversy. Perhaps the most striking example of this controversy is the simultaneous publication in the New England Journal of Medicine of a negative and a positive cardiovascular prevention study in the same issue.^15,16 Indeed, omega-3 fatty acids share the double bond at carbon 3, but differ in many other characteristics, and it is therefore not surprising that their biological effects are heterogeneous. Currently available omega-3 fatty acids include the combination of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Ethyl icosapent (EPI), on the other hand, is a highly purified (99.99%) composition of EPA. In his article, Dr. Muñiz addresses the evidence on cardiovascular protection of various omega-3 fatty acid formulations, highlighting that EPI is the only compound that has convincingly shown a potent cardiovascular protective effect within this therapeutic group.¹⁵ Following the REDUCE IT study, the European Medicines Agency and the Spanish Agency for International Development (AEMPS) approved the indication for the use of EPI for the reduction of cardiovascular complications in high-risk vascular patients treated with statins and with moderate hypertriglyceridaemia (TG > 150 mg/dl).¹⁷

The protective mechanism of EPI appears to clearly surpass its effect on TG. In his article, Dr. Díaz reviews the special characteristics of EPI's multifactorial action, including its anti-inflammatory and antithrombotic effects.¹⁸ In this regard, he also addresses the subgroups of patients who may especially benefit from EPI treatment, particularly after acute coronary syndrome.

Finally, Dr. Pedro-Botet considers the target population likely to benefit from EPI treatment.¹⁹ Moreover, given the drug's characteristics, he also considers the potential benefits of EPI treatment in other clinical contexts.

To sum up, elevated TG-rich lipoproteins identify patients with increased vascular risk independent of LDL cholesterol levels. The approach to pharmacological treatment of these patients in the post-statin era has been limited by the controversial results obtained with "standard" treatments (niacin, fibrates, and omega-3 fatty acids). EPI provides the most robust therapeutic option for this group of patients. We trust that the articles included in this issue will provide readers with a better understanding of the topic, leading to more appropriate treatment for high-risk vascular patients with hypertriglyceridaemia.

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.