Emerging approaches for the treatment of hypertriglyceridemia

Abstract

Hypertriglyceridemia is frequent in diabetic and obese subjects, who are at increased risk for cardiovascular diseases (CVD). Increased triglycerides (TG) are a hallmark of atherogenic dyslipidemia, representing a marker of atherogenic small dense low-density lipoproteins (sdlDL). Importantly, non-fasting/postprandial TG measurements tend to be emphasized in clinical practice for the prediction of CVD, and TG-lowering agents (primarily fibrates) have a beneficial effect on atherogenic dyslipidemia, reducing TG-rich particles and ultimately lowering the production of sdlDL. The combination of omega-3 fatty acids and statins is also recommended, and widely used in clinical practice for subjects with hypertriglyceridemia. However, a consensus on the optimal clinical use of these pharmacological agents is not fully established yet, and additional large clinical studies are needed. It seems that there is a favorable association between fish consumption and mortality from CVD, but it remains to be confirmed by future trials. Finally, there are a number of novel therapies, such as those targeting microsomal transport protein and its inhibitors, which represent new promising option for treating subjects with hypertriglyceridemia.

Keywords::

• cardiovascular diseases
• hypertriglyceridemia
• triglyceride-lowering agents
• triglycerides

1. Introduction

Since cardiovascular disease (CVD) is still the leading cause of death worldwide, there is a need for new treatments and identification of novel biomarkers of CV risk. In this view, the predominance of small, dense low-density lipoproteins (sdlDL) has been suggested as a novel marker for the prediction of future vascular events [1]. In addition, a European panel of experts has recently highlighted the role of post-prandial hypertriglyceridemia for CV risk [2], suggesting that measurement of fasting triglycerides (TG) levels may be replaced by non-fasting TG levels for the evaluation of CVD risk [2]. The prevalence of hypertriglyceridemia is higher in subjects with obesity and diabetes; further elevations in TG are correlated with increased levels of atherogenic lipoproteins, and these conditions additionally enhance the risk for CVD. Trials in monotherapy with fibrates suggest some benefit in reducing CV events, mostly based on evidence derived from older studies; however, endpoint trials of adding fenofibrate to statins have not shown any benefit, except possibly in patients with an increased atherogenic index (TG: high-density lipoprotein cholesterol (HDL-C) ratio), or have been underpowered [3].

Indeed, hypertriglyceridemia is also due to an accumulation of atherogenic remnant lipoproteins in the very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), and these conditions are usually associated with the presence of sdlDL particles. The combination of elevated TG, reduced HDL and increased sdlDL is known as ‘lipid triad' or ‘atherogenic lipoprotein phenotype', since the increase in TG levels is followed by strong changes in the composition of both LDL and HDL particles: LDL and HDL can become TG-enriched and then processed by lipases and by exchange of cholesteryl esters with TG.

It should be emphasized that LDL cholesterol (LDL-C) lowering remains the primary goal of lipid-lowering treatment. However, a considerable residual risk exists even with LDL-C levels within treatment goals. This can be explained at least in part by the atherogenic lipid profile [4].

2. Treatment options for hypertriglyceridemia

The initial treatment of hypertriglyceridemia should be focused on lifestyle, including nutritional factors, physical activity, cigarette smoking and alcohol consumption. In addition, gender, genetic polymorphisms and obesity play a role, thus, aggressive lifestyle modification can be useful [2]. Current approaches to lower TG include therapy with statin, fibrates, niacin and omega-3 fatty acids [3]. Fibrates have a major impact on TG metabolism and significantly modulate the distribution of LDL subclasses, towards larger more buoyant and less atherogenic LDL particles [5]. For instance, we have reported that gemfibrozil (at a dose of 1200 mg/day) reduced TG and LDL-cholesterol (LDL-C) concentrations, and increased HDL-C; yet, the greatest reduction in lipoproteins was in the largest and intermediate-sized VLDL particles [6]. In this latter study, gemfibrozil induced greater reductions in sdlDL in normolipidemic subjects with a predominance of small LDL (classified as having LDL pattern B) compared with those with a predominance of larger or medium sized LDL (LDL pattern A). In addition, subjects with the LDL pattern B had significantly greater postprandial TG reduction in response to gemfibrozil compared with those with LDL pattern A [6].

On the other hand, adding either niacin or fenofibrate to statins have not shown significant benefit in reducing CVD events (except in subjects with an increased TG : HDL-C ratio) and further investigations are required [3], while use of statin–niacin and statin–fibrate combinations are limited by numerous adverse events. Omega-3 polyunsaturated fatty acids have favorable effects on hypertriglyceridemia either as monotherapy or in combination with other lipid-lowering agents, such as statins or fibrates [7]. However, a recent systematic review and meta-analysis have highlighted that omega-3 fatty acids supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction or stroke based on relative and absolute measures of association [8].

As the appreciation for TGs as a risk factor for CVD is increasing, a wide array of novel therapeutic modalities is currently in different stages of development. In November 2012, the EMA (European Medicines Agency) for the first time approved human gene therapy, alipogene tiparvovec, for the treatment of severe hypertriglyceridemia in patients with lipoprotein lipase (LPL) deficiency. Other new potential approaches for treating hypertriglyceridemia include the use of microsomal transport protein (MTP) inhibition or Diaglycerol acyltransferase (DGAT) inhibition. DGAT enzymes are responsible for the re-assembly of free fatty acids (FFAs) into TGs. The DGAT1 inhibitor LCQ908 was able to decrease mean fasting TGs in severe hypertriglyceridemic, LPL deficient patients. At present, a randomized, double-blind, placebo-controlled trial is being conducted to further substantiate these findings [9]. MTP is an intracellular lipid-transfer protein responsible for transferring TG onto apolipoprotein B (apoB) as a crucial step in the assembly of VLDL. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. In addition, they may have anti-atherosclerotic and insulin-sensitizing effects [10]. These agents need to be administered at low doses in order to avoid their side effects seen at higher doses [11]. Lomitapide is an MTP inhibitor with promising prospects for the treatment of subjects with dyslipidemia and a risk of CVD [12]. Following the recent trial in patients with familial hypercholesterolemia in which a 50% LDL-C lowering effect was obtained with a concomintat 7.5% increase in liver fat content, this drug has now been approved by both the Food and Drug Administration (FDA) as well as EMA for the treatment of severe, homozygous familial hypercholesterolaemia (FH). In addition, liver steatosis can be avoided by the use of intestine-specific MTP inhibitors [10]. Further studies in combined dyslipidemia have to date not been planned. Many novel therapeutic compounds are being developed for dyslipidemia, including those with the goal of gene therapy, while DGAT1 inhibitors are aimed at reduction of pancreatitis risk [13].

Recent studies suggest that ethyleicosapentaenoic acid + docosahexaenoic acid, a novel omega-3 FFA formulation, has a potential therapeutic advantage in the treatment of hypertriglyceridemia compared with omega-3-acid ethyl esters, since it has been developed to maximize eicosapentenoic acid (EPA) and docosahexenoic acid bioavailability with low-fat diets [14]. However, additional studies are needed to clarify the TG-lowering effects of this agent, as well as the potential CV benefit, particularly in hypertriglyceridemic subjects.

Icosapent ethyl (IPE) is a high-purity prescription form of EPA ethyl ester recently approved to reduce TG levels in subjects with severe hypertriglyceridemia (≥ 500 mg/dl). This drug lowered TG and other atherogenic lipoproteins in two Phase III randomized, placebo-controlled trials, and no adverse effects on renal or hepatic function or glucose has been reported. It seems that IPE has similar effect as statins in preventing CV events in subjects at high risk. Further, in the USA, the FDA has approved EPA as capsules for oral use along with a low-fat and low-cholesterol diet, for severe hypertriglyceridemia. In a randomized, placebo-controlled, double-blind, parallel-group study this drug (at a dosage of 4 g per day) reduced TG, VLDL-C and apoB levels from baseline compared with placebo [15]. However, in a double-blind study no effect of fish oil supplementation (1 g of n-3 fatty acids daily) on CV outcomes in patients with dysglycemia have been reported [16].

Finally, the development of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, as new agents for the treatment of several features of MetS, including hypertriglyceridema, have gained interest. It seems that 11β-HSD1 inhibitors, such as carbenoxolone, lead to a reduction in TG concentration. However, these data are still under investigation [17].

3. Expert opinion

Fibrates target atherogenic dyslipidemia (decreasing TG, increasing HDL and lowering sdlDL particles) as monotherapy or in combination with a statin or other agents, such as ezetimibe and niacin [5]. Yet, strong variations exist among the different fibrate molecules in managing levels of plasma lipids and lipoproteins, and overall fenofibrate seems to be more effective compared to ciprofibrate, bezafibrate and gemfibrozil [18]. Whereas the older trials using fibrates, such as the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) study, did show a beneficial effect on CVD, it should be noted that this trial was performed in the pre-statin era in patients selected for low HDL-C [19]. More recent trials using fibrates in a much broader population, often on top of statin therapy without a clear lipid phenotype at baseline, did not show a benefit of fibrate use on CVD morbidity and mortality [20]. The 2013 American Diabetes Association guidelines do not recommend adding a fibrate or niacin to statin therapy for treatment of dyslipidemia [21]; they recommend treating severe hypertriglyceridemia to prevent pancreatitis, and fibrates are indicated if the serum TGs are 500 mg/dl or higher to prevent pancreatitis. Whereas post-hoc analyses in patients with a marked dyslipidemic phenotype at baseline (TG > 2.4/ HDL < 1.0 mmol) did show a trend towards benefit, routine use of fibrates for CVD prevention is not justified.

Several MTP inhibitors have been investigated or are currently under investigation, and available data indicate that these agents are able to decrease levels of TG, LDL-C and apoB. Yet, the clinical efficacy and safety of the MTP inhibitors still needs to be fully elucidated, since gastrointestinal and hepatic adverse events have been reported [11]. Additional data are also needed for the omega-3 fatty acids: the epidemiological studies and intervention trials investigating the relationship between n-3 polyunsaturated fatty acids consumption and CVD have been recently reviewed, and it is expected that on-going trials would provide further insights into the beneficial effects of fish oil supplementation [7,22]. Although, some negative data have been presented recently [16].

It has been suggested that the TG:HDL cholesterol ratio may be potentially applied in clinical practice for the prediction of subjects with a predominance of sdlDL particles [18]. However, in the last years the main target of treatment of combined dyslipidemia remained LDL-C, although the value of non-HDL-C is increasingly recognized as a second or as an additional therapeutic target. Since the metabolism of TG-rich lipoproteins (mainly VLDL) is intimately linked to that of HDL, the increment of HDL-C may lead to lower cholesterol content in VLDL and LDL particles [23]. This further highlights the role of atherogenic dyslipidemia on CV risk and the need to treat the risk, and not just the cholesterol content [23,24]. However, effective HDL-C raising was not associated with the expected benefits in vascular risk reduction in clinical trials [25].

Outcomes data of ongoing studies as well as further clinical trials may provide important information about the usefulness of novel therapies in both decreasing TG levels and preventing CV events, particularly in subjects at high-risk.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript. Yet, some of the authors have given talks, attended conferences and received research support from various pharmaceutical companies.