ReviewRecent advances in pharmacotherapy for hypertriglyceridemia
Section snippets
Classification, etiology and clinical significance of hypertriglyceridemia
Hypertriglyceridemia refers to a fasting plasma triglyceride (TG) concentration above the 95th percentile for age and sex in a population, with most international guidelines defining it at a threshold of ⩾1.7 mmol/L (Table 1). These guidelines generally recognize elevated plasma TG as being mild, moderate, severe and very severe [1], [2], [3], [4], [5].
Elevated plasma TG is emerging as an independent risk factor for Type 2 diabetes, metabolic syndrome and atherosclerotic cardiovascular disease
Metabolic mechanisms underlying hypertriglyceridemia: the role of insulin resistance
Hypertriglyceridemia arises as a consequence of dysregulated metabolism of TRLs (including VLDL, chylomicron and their remnants) [25], the underlying cause of which is insulin resistance. Insulin resistance promotes VLDL production and secretion through a series of events that includes increased flux of FFAs (derived from visceral TG lipolysis) to the liver, thereby providing substrate for hepatic TG biosynthesis; enhancement of hepatic de novo lipogenesis through activation of forkhead box O1
Mechanisms underlying the atherothrombotic properties of TRLs
Although TRLs contain pro-atherogenic components (such as cholesteryl esters, apoB and apoC-III), their atherogenicity has been commonly attributed to their remnant lipoprotein particles (RLPs), which are formed from larger particles by the action of LPL. Like LDL particles, RLPs have been identified in human atherosclerotic lesions [37], and can directly promote foam cell formation [38], up-regulate the expression of pro-inflammatory cytokines [39], induce cell apoptosis in the arterial wall,
Therapeutic principles and targets
Mild hypertriglyceridemia (1.7 < TG ⩽ 2.3 mmol/L) is usually treated by excluding secondary causes (Table 1) and introducing lifestyle modifications [46]. These include restricting dietary saturated fat and carbohydrate intake (particularly simple sugars, such as sucrose and fructose); increasing dietary intake of plant-based proteins, unsaturated fat and soluble fiber; increasing aerobic physical activity; weight loss; moderation of alcohol intake, and smoking cessation. Moreover, improved glycemic
Fibrates
Fibrates activate peroxisome proliferator-activated receptor-α (PPAR-α), resulting in increased β-oxidation of fatty acids in the mitochondria and peroxisomes, which decreases hepatic biosynthesis of TG and VLDL secretion [49]. Fibrates can also decrease plasma TG by stimulating LPL activity and down-regulating apoC-III, leading to enhanced lipolysis of TRLs [50]. In addition, fibrates increase the catabolism of apoB-48 and apoB-100 in chylomicrons and VLDLs, and increase the expression of
n-3 PUFAs
Treatment with n-3 PUFAs, primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), at high dose (2–4 g/day) can lower plasma TG in subjects with isolated hypertriglyceridemia (26–52% reduction) and mixed dyslipidemia (19–44% reduction) [42]. n-3 PUFAs may also have multiple pleiotropic cardioprotective effects by reducing inflammation [67], arrhythmias [68], atherosclerosis [69], endothelial dysfunction [70], thrombosis [71], and blood pressure [72]. n-3 PUFAs might lower plasma TG
Niacin
Niacin decreases fatty acid flux to the liver by inhibiting adipose tissue TG lipolysis [99], and it also inhibits hepatocyte diacylglycerol acyltransferase (DGAT)-2 activity [100], and enhances TRL apoB-100 and apoB-48 catabolism [101]. The TG-lowering efficacy of niacin is comparable to fibrates, but niacin has additional effects in lowering LDL-C and lipoprotein(a) [Lp(a)], as well as elevating HDL-C and apoA-I [102], [103]. However, niacin use is limited by its side effects, (flushing and
Thiazolidinediones
Thiazolidinediones, also known as glitazones, are agonists of PPAR-γ and regulators of insulin sensitivity, and glucose and lipid metabolism. The widespread use of glitazones in the management of Type 2 diabetes has been limited owing to their serious adverse events. Troglitazone was withdrawn from the market as early as three years following its introduction owing to the reports of hepatotoxicity and acute fulminant liver failure. The use of rosiglitazone has also been withdrawn (in Europe) or
Statins and ezetimibe
Statins remain first-line pharmacotherapy for mixed dyslipidemia because they can decrease both LDL-C and TG, and they have been shown to reduce CVD events in both primary and secondary prevention settings [113], [114], [115], [116], [117], [118], [119], [120]. Statins, particularly the more potent agents such as rosuvastatin and atorvastatin, have been proposed as first-line treatment for patients with fasting plasma TG concentrations of 2.3–5.6 mmol/L [121]. This relates to the potency of
Apheresis
Severe hypertriglyceridemia (TG > 10 mmol/L) increases the risk of life-threatening acute pancreatitis and necessitates urgent treatment with a low-fat diet, correction of secondary causes and fibrate therapy. Acute pancreatitis and chylomicronemia syndrome may require intensive care management, including use of lipoprotein apheresis or plasma exchange. Plasmapheresis is a safe and effective treatment that can reduce plasma TG concentrations by 60–80% [132], and also lower atherogenic
Treatment of hypertriglyceridemia and non-alcoholic fatty liver disease (NAFLD)
Hypertriglyceridemia is the most common type of lipid abnormality in patients with NAFLD and non-alcoholic steatohepatitis (NASH). Although several insulin-sensitizing and lipid-modifying agents have been evaluated for the treatment of NAFLD, there is no evidence as yet for the efficacy of such agents in reducing NAFLD-associated morbidities or clinical endpoints [134], [135]. Statins, fibrates, n-3 PUFAs and ezetimibe have all been tested in patients with NAFLD and dyslipidemia, and have been
LPL gene replacement therapy
Alipogene tiparvovec (Glybera®) is the first approved gene therapy product (European Medicines Agency 2013) indicated for the treatment of LPL deficiency (LPLD). This is an inherited autosomal recessive disorder characterized by severe hypertriglyceridemia, related to impaired clearance of chylomicrons and large TRLs, which markedly increases the risk of acute pancreatitis [147], [148]. Alipogene tiparvovec contains the coding sequence of a natural human gain-of-function variant of the LPL gene
Dual PPAR-α/δ agonists
Although PPAR-α and PPAR-γ agonists are well-known for their hypotriglyceridemic and insulin-sensitizing effects, respectively, less is known about PPAR-δ. Recently, it has been revealed that induction of PPAR-δ receptors has a TG-lowering effect, which is most probably due to a decrease in apoCIII expression [154], but may also involve fatty acid oxidation [155], [156], [157] and improvement in insulin sensitivity [156], [158], [159], [160].
In a small trial of healthy subjects, treatment with
Balanced PPAR-α/γ agonists
Dual PPAR-α/γ agonists, also known as glitazars, aim to combine the lipid-modifying properties of fibrates (PPAR-α) with the insulin-sensitizing effects of thiazolidinediones (PPAR-γ). These agents were intended as effective treatments for metabolic syndrome and related disorders, but balanced activation of PPARs α and γ receptors was required to avoid the toxicities seen with the first-generation agents, such as muraglitazar and tesaglitazar [164], [165].
The only balanced dual PPAR-α/γ agonist
Incretin mimetics
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is secreted by the intestinal L-cells in response to meal intake [169]. It has multiple physiological actions relevant to the management of diabetes, including stimulation of pancreatic insulin secretion, inhibition of glucagon release, prolongation of gastric emptying time and reduction of food intake [169]. GLP-1 has a very short plasma half-life (<2 min) because of rapid inactivation by dipeptidyl peptidase-4 (DPP-4) [170], hence its
MTTP inhibitors
MTTP is an enzyme, predominantly expressed in hepatocytes and enterocytes, that is involved in the synthesis of apoB-containing lipoproteins. Its main functions are to transfer TG, phospholipids and cholesteryl esters to the nascent apoB, and mediate the assembly of VLDL and chylomicrons in liver and intestine, respectively [191]. Inhibition of MTTP, accordingly, results in decreased lipidation of apoB, and inhibition of the assembly and secretion of VLDLs and chylomicrons [192], [193]. MTTP
Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) inhibitors
DGAT is an enzyme that catalyzes the final step in TG biosynthesis in either the glycerol phosphate or monoacylglycerol pathway. DGAT exists in two isoforms: DGAT-1 (expressed ubiquitously) and DGAT-2 (expressed primarily in the liver, intestine and white adipose tissue). While DGAT-2 deficiency is lethal [202], [203], experimental DGAT-1-deficient phenotypes are viable and have intermediate (heterozygous) or complete (homozygous) resistance to diet-induced obesity, insulin resistance and
CETP inhibitors
CETP is an enzyme that catalyzes the hetero-exchange of TG and cholesteryl ester between plasma lipoproteins [209]. The net effect of CETP action is transfer of cholesteryl ester from HDLs to TRLs, and TG from TRLs to HDLs and, to a lesser extent, LDLs, resulting in enrichment of apoB-containing lipoproteins by cholesterol, which increases the number of LDL particles and the risk of atherogenesis.
CETP inhibitors can lower plasma TG by enhancing TRL-apoB-100 catabolism and decreasing TRL-apoB-48
Angiopoietin-like protein (ANGPTL) inhibitors
LPL is an endothelial-bound enzyme and a member of the TG lipase family (which includes hepatic lipase and endothelial lipase) that is central to the metabolism of lipids and lipoproteins. LPL is involved in the hydrolysis of TG in circulating TRLs, the tissue uptake of chylomicron remnants and other lipoproteins, anchorage of lipoproteins to the vessel wall, and, together with CETP, the exchange of lipids among lipoproteins [222]. Loss-of-function variants of the LPL gene, such as occurs in
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
PCSK9 is a cell surface regulator whose major physiological role is to promote LDLR degradation via the lysosomal pathway, thereby inhibiting its recycling to the hepatic cellular membrane [235], [236]. PCSK9 may also be involved in the regulation of hepatic apoB secretion and TRL receptors, and could therefore have a role in TRL metabolism. There is evidence suggesting that PCSK9 is also involved in the degradation of adipose VLDLR, thereby modulating visceral adipogenesis [237]. Experimental
ApoB-100 antisense oligonucleotides (ASOs)
ApoB is the main structural protein of all atherogenic lipoproteins, including VLDL and its remnants. Inhibition of apoB synthesis in the liver results in reduced synthesis and secretion of VLDL particles, and thereby decreased plasma TG concentrations.
Mipomersen sodium (ISIS 301012) is a second-generation ASO targeted against apoB mRNA that has been approved by the FDA as adjunct therapy to diet and lipid-lowering drugs for the management of homozygous FH in adults. Mipomersen has been shown
ApoC-III ASOs
ApoC-III is a small molecular weight (875 kDa) protein that attaches itself to the surface of chylomicron, VLDL and HDL particles, and plays a pivotal role in the regulation of TG metabolism [130]. ApoC-III enhances the hepatic biogenesis and secretion of VLDL, and decreases plasma TG clearance through inhibition of LPL action and receptor-mediated uptake of VLDL and its remnants [130], [131], [161].
Genetic studies support the important role of apoC-III in the metabolism of TG and associated
ApoE mimetic peptides
ApoE is a structural component of TRLs that mediates the receptor-mediated uptake of apoB-containing particles via hepatic receptors (LDLR and VLDLR), or interaction of TRLs with HSPGs. Further to its important role in the clearance of atherogenic lipoprotein particles, apoE has several lipid-independent atheroprotective effects including anti-inflammatory, antioxidant and anti-platelet actions, inhibition of vascular smooth muscle cell and endothelial cell proliferation, and enhancement of
Selective PPAR modulators (SPPARMs)
Selective PPAR modulators (SPPARMs) were developed with the aim of potentiating the favorable metabolic effects of PPAR activation, whilst minimizing off-target adverse effects [282], [283], [284]. K-877, a SPPARM-α with a 1000-fold greater potency than fenofibrate, has been shown in Phase I and II trials, at dose ranges of 50–400 μg/day for 12 weeks, to have greater efficacy in reducing both fasting and postprandial TG levels (32–42%) than fenofibrate. K-877 has additional anti-atherogenic
New n-3 PUFA formulations
n-3 PUFAs can influence TRL metabolism through diverse mechanisms, which, collectively, result in reduced hepatic secretion and enhanced plasma clearance of TG [86]. Although earlier trials with mixed (EPA + DHA) n-3 PUFA ethyl esters (Lovaza®) showed significant reductions in plasma TG, non-HDL-C and VLDL-C, and an increase in HDL-C in patients with both moderate (2.3 ⩽ TG < 5.6 mmol/L) and severe hypertriglyceridemia (TG ⩾ 5.6 mmol/L) [289], [290], [291], there were concerns related to significant
Curcuminoids
Curcuminoids are naturally occurring polyphenols, whose major components are curcumin (∼77%), demethoxycurcumin (∼17%) and bisdemethoxycurcumin (∼3%). Experimental and human studies using purified curcuminoids have revealed several pharmacological properties, including anti-inflammatory [303], [304], [305], antioxidant [306], [307], anti-cancer [308], [309], [310], neuroprotective [311], chemopreventive [312], anti-arthritic [313], anti-depressant [314] and cardioprotective [315], [316], [317]
CAT-2003
CAT-2003 is a novel small molecule that has been developed by Catabasis Pharmaceuticals Co. to treat severe hypertriglyceridemias. Production of CAT-2003 is based on a patented SMART (safely metabolized and rationally targeted) linker technology. This technology enables conjugation of two drugs (acting at different sites of disease pathogenesis) using a linker that is cleavable by specific intracellular enzymes. The conjugate is inactive in plasma and is taken up by target cells, where it
RNA interference
MicroRNAs (miRs) are short (18–25 nucleotides), non-coding, and double-strand sequences that regulate gene expression at the post-transcriptional level. In most cases, regulation of gene expression by miRs is mediated by binding to the complementary region at the 3′-untranslated region of the target mRNA causing subsequent translational repression or mRNA destabilization and cleavage [336]. Recently, the role of miRNAs in the pathophysiology of CVD has been the subject of increasing attention,
Conclusions
Hypertriglyceridemia has several environmental and genetic etiologies. Obesity, insulin resistance and loss-of-function mutations that control the metabolism of TRLs are frequently implicated. Pure monogenic disorders are very rare and can express clinically as chylomicronemia syndrome. Hypertriglyceridemia in the range of 2–5 mmol/L is associated with the accumulation in plasma of TRL remnants and atherogenic changes in LDL and HDL, collectively resulting in an atherogenic lipoprotein profile.
Conflict of Interest
G.F.W. has received honoraria for lectures and commentaries from Genfit, Pfizer, Astrazeneca, MSD, Novartis, Amgen and Sanofi-Aventis. With respect to the content of the article, G.T.C. has previously received research grant funding from Pfizer and GlaxoSmithKline, and has participated in research sponsored by Laboratories Fournier.
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