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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 9  |  Issue : 1  |  Page : 12-18

Hypertriglyceridemia: A new paradigm


Head of the Department and Sr.Consultant of Diabetology, Podiatry, Obesity, Lakeshore Hospital, Kochi, Kerala, India

Date of Web Publication2-Apr-2018

Correspondence Address:
Dr. Johny J Kannampilly
Lakeshore Hospital, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_22_17

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  Abstract 


Low-density lipoprotein cholesterol (LDL-C) has been proven time and again to be independently associated with the risk of cardiovascular diseases (CVD). However, triglycerides (TG) are now also emerging as an important as well as independent risk factor for CVD. International lipid guidelines recommend statins as first-line drugs. However, there always remains a residual risk with statins, especially in the high-risk diabetes subset of patients. The most important reason cited for increased residual CV risk with statins is the non-high density lipoprotein cholesterol component, of which high TGs are an integral part. Several large epidemiological, Mendelian randomisation, population-based and genetic studies are emerging which are pointing towards the fact that high TG leads to CV morbidity and mortality. Pathophysiological basis of hypertriglyceridemia associated with increased CV risk has been attributed to increase circulating chylomicron and TG-rich lipoprotein remnants, increased small dense LDL, heightened risk of endothelial dysfunction and plaque formation. Recent international guidelines recommend TG lowering therapy at TG >200 mg/dl when not controlled by optimal statin therapy. TG levels more than 500 mg/dl, however, require non-statin lipid-lowering agents as primary agents to reduce the risk of acute pancreatitis. Fibrates, niacin and omega 3 fatty acids are recommended as TG-lowering drugs. However, they are not without their share of adverse events. Saroglitazar is a novel dual peroxisome proliferator-activated enzyme agent which has been found to be free of many such adverse events and also adequate in providing dual control over hypertriglyceridemia along with significant glycaemic control.

Keywords: Cardiovascular disease, hypertriglyceridemia, low-density lipoprotein cholesterol


How to cite this article:
Kannampilly JJ. Hypertriglyceridemia: A new paradigm. J Diabetol 2018;9:12-8

How to cite this URL:
Kannampilly JJ. Hypertriglyceridemia: A new paradigm. J Diabetol [serial online] 2018 [cited 2018 Dec 15];9:12-8. Available from: http://www.journalofdiabetology.org/text.asp?2018/9/1/12/229007




  Introduction Top


There is no dispute to the fact that elevated low-density lipoprotein cholesterol (LDL-C) levels have been independently associated with adverse cardiovascular (CV) events. Another class of lipid particles, triglycerides (TG), has also been found in atherosclerotic plaques. Recent studies have demonstrated an association between elevated TG levels and increased risk of future CV events. With this knowledge, the management of TG is currently undergoing a renaissance with the development of new drugs to address hypertriglyceridemia. Unfortunately, no randomised, controlled clinical trials have managed to prove till date that lowering TG with drugs will reduce CV events. In this review, we highlight some of the evidences that led to this stage where hypertriglyceridemia is being considered as an important CV risk factor and give the reader insight on what the most recent lipid guidelines state about clinical TG management. We also discuss the current data on the pharmacologic intervention of TG levels and the effect on clinical outcomes. Finally, we highlight safe and effective lowering of TG levels with lifestyle modification.


  International Lipid Guidelines Recommend Statins As first-Line Drugs Top


In the last National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III cholesterol guidelines,[1] blood LDL-C levels were the main target of lipid-lowering therapy for the prevention of CV diseases (CVD). To lower cholesterol, HMG-CoA reductase inhibitors or statin drugs, one of the best-studied classes of pharmaceuticals and the most prescribed of all time, are drugs of choice. According to ATP III, patients were categorised by risk categories and there were LDL-C target recommendations to be achieved.

The American College of Cardiology (ACC) and American Heart Association (AHA) released their guidelines in 2013 for the treatment of blood cholesterol to help reduce atherosclerotic CV risk in adults.[2] The international body elected a task force to ensure the use of evidence by maintaining strict adherence to randomised control trial (RCT) studies, systematic reviews and meta-analyses of RCTs to formulate all recommendations aiming to provide the strongest possible evidence for the treatment of cholesterol for primary and secondary reduction of atherosclerotic CVD (ASCVD). These guidelines represented a monumental shift in the approach to lowering cholesterol from target levels of LDL-C and non-high density lipoprotein cholesterol (HDL-C) to a focus on statin intensity and there were four high-risk groups created based on age, ASCVD history and 10-year risk, diabetes status and LDL-C levels. Apart from having no 'treat to target' LDL-C goals, another important aspect of this guideline was a marked reduced emphasis on non-statin therapies since no recommendations were provided for the treatment of TG. These guidelines, though path-breaking, however, met with controversy wherein it was claimed that there are some significant limitations with the potential to both over-treat and under-treat patients depending on the clinical scenario.[3]

Irrespective of having LDL-C targets or not, it is of universal acceptance that statin drugs are the most effective, evidence-based agents to prevent and treat hypercholesterolemia, and they have a central role in the management and are therefore primarily advised as per all international published lipid guidelines.


  Residual Cardiovascular Risk for Patients on Statin Therapy Top


Outcome trials of statins have proved conclusively that lowering LDL-C results in significant improvement in cardiovascular morbidity and mortality.

However, even with low LDL levels, the residual risk for subsets of high-risk patients on statins continues to be elevated. In the Treating to New Targets trial, patients taking atorvastatin 80 mg (mean LDL-C 77 mg/dL) had a 28% cardiovascular event rate compared with a 33% event rate for patients taking atorvastatin 10 mg (mean LDL-C 101 mg/dL), a 22% relative risk reduction.[4] Therefore, approximately 70% of the events were not avoided despite significant LDL-C reduction. The 80 mg atorvastatin therapy also was associated with a slightly elevated rate of increased transaminase levels. Therefore, an important clinical challenge remains to further reduce the residual CV risk in patients taking optimal statin therapy without adversely affecting patient safety.

Analyses of statin outcome trials done post hoc and with pre-specified criteria demonstrate higher CVD event rates for patients with additional risk factors. Of the modifiable risk factors, the presence of diabetes mellitus, cigarette smoking, the metabolic syndrome and elevated high-sensitivity C-reactive protein predicts a high residual risk. In accordance to this, the NCEP ATP III guideline update recommends a LDL-C goal of 70 mg/dL and a non-HDL goal of 100 mg/dL for patients at very high risk wherein the definition of 'very high risk' includes patients of CVD with diabetes, cigarette smoking or factors associated with the metabolic syndrome.[5]

In the Heart Protection Study (HPS), statin therapy (simvastatin 40 mg/day) resulted in highly significant reductions in coronary mortality rate (18%), an incidence rate of first non-fatal myocardial infarction (38%), stroke incidence (25%) and incidence of coronary revascularisation (30%),[6] but patients with diabetes who had CVD and who were receiving statin therapy had a higher event rate as compared with event rates in non-diabetic patients with CVD. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial, intensive (atorvastatin 80 mg/dL) versus moderate (pravastatin 40 mg/dL) lipid-lowering resulted in greater reductions in LDL-C to mean levels of 78.9 and 110.4 mg/dL, respectively (P = 0.001). In addition, intensive lipid-lowering intervention resulted in a significantly lower progression rate in the percent change in atheroma volume (P = 0.02).[7] However, in this study as well, the diabetic subset taking aggressive lipid-lowering therapy of atorvastatin 80 mg continued to have marked progression of atheroma volume. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2 trial, the diabetic subset also continued to have progression of intima-media thickness despite statin therapy.[8] The results of the Yellow trial suggest that though lipid-core content regress rapidly with intensive statin therapy in a short time period, its subgroup analysis reflected that even after aggressive statin usage the lipid core content is still high in diabetic patients.[9] Other statin event trials also further establish that patients with diabetes demonstrate a greater elevated rate of residual events even with statin treatment when compared to their non-diabetic counterparts.[10],[11],[12],[13]

Therefore, even with an LDL–C of 70 mg/dL, a patient with CVD who has diabetes is likely to have a high recurrent event rate.

The most important reason for increased residual CV risk seen in high-risk diabetes subset of patients on statin therapy is the non-HDL-C component, of which high TGs are an integral part.[14],[15] Therefore, it becomes pertinent to address hypertriglyceridemia in high-risk patients on optimal statins to reduce the residual risk of CVD.


  Hypertriglyceridemia and Increased Cardiovascular Disease Risk Top


The association of CVD with LDL-C has been well established since decades. However, the other lipid counterpart, hypertriglyceridemia and its association with CVD have been debated. Enough evidences are now mounting which clearly points towards the fact that high TG should not be neglected as it does increase CV risk which is independent to the risk caused by high LDL-C.

In an article published in a reputed journal, using data from 75,725 participants in two general population studies, it was ascertained that participants with non-fasting TG <90 mg/dL had 60% lesser risk of CV event compared to participants with non-fasting TG >350 mg/dL.[16] In a pre-specified analysis of the dal-OUTCOMES and the atorvastatin group of MIRACL trials, it was further emphasised that the relationship of high TG and CV risk was independent of LDL-C.[17] In a study cohort comprising 15,355 patients who were screened for the Bezafibrate Infarction Prevention trial, the 22-year mortality risk for patients with severe hypertriglyceridemia was increased by 68% when compared with patients with low-normal TG (P < 0.001).[18] Strong Heart Study is an on-going, community-based, prospective cohort study and the results on 3216 patients with a median follow-up of 17.7 years revealed some interesting facts about CV risk in high TG and low HDL patients specifically suffering from diabetes. The study published in diabetes care earlier this year concluded that adults with both high TG and low HDL-C, particularly those with diabetes, have increased risks of incident coronary heart disease (CHD) (hazard ratio: 1.54) and stroke (hazard ratio: 2.13).[19]

High TG and low HDL-C levels have been shown even in the past to singly and collectively boost the risk of CV events independent of conventional risk factors in large cohort studies.[20],[21],[22] High TG and low HDL form an integral part of atherogenic dyslipidemia which is a common form of dyslipidemia characterised by three lipid abnormalities: elevated serum TG, increased small dense LDL (sdLDL) particles and reduced serum HDL-C.[23] This form of dyslipidemic triad is notoriously associated with obese and diabetic individuals and metabolic syndrome, as insulin resistance (IR) directly contributes to such dyslipidemic abnormalities [24],[25]

Several genome-wide association and Mendelian studies recently have identified hypertriglyceridemia as an important link to the causality of CVD. Mutations in the genes coding for lipoprotein lipase (LPL) have been shown to alter the TG levels. In a meta-analysis, carriers of the Gly188Glu substitution mutation in LPL had reduced LPL activity, an average increase in TG levels of 78% and a nearly fivefold increased CHD risk compared with non-carriers.[26] Loss-of-function mutations in ApoC-II, the activating cofactor for LPL, have been reported to cause profound increases in serum TG levels.[27] Mutations in APOC3 have the opposite effect consistent with the inhibitory effect of this apolipoprotein on LPL activity. Studies show that loss-of-function mutations in APOC3 cause lifelong low levels of non-fasting TG.[16] On the other spectrum, gain–of–function mutations in APOC3 leading to high APOCIII levels can also cause severely elevated TG levels.[28]

A Mendelian randomisation trial with data from 10,208 individuals from the Copenhagen City Heart Study found that individuals with a genetically conferred reduction in non-fasting plasma TG levels had reduced all-cause mortality.[29] Furthermore, another study focusing on single nucleotide polymorphisms (SNPs) found a significant association of TG with CV risk along with LDL-C. There has been proof of multiple SNPs associated with high TG and causative CHD even after accounting for LDL-C and HDL-C.[30]

Most recently, angiopoietin-like 4 (ANGPTL4) mutations were shown to be associated with lower TG levels and hence lesser risk of coronary artery disease (CAD).[31],[32] The DiscovEHR human genetics study inferred that carriers of the E40K variant of ANGPTL4 had 13% lower TG levels and 19% lower risk of CAD compared with non-carriers. Another analysis with a large number of participants, 72,868 patients with CAD and 120,770 participants without CAD also proved decreased TG levels and protection from CAD in individuals with ANGPTL4 mutations. These studies specifically reinforce the independent association of TG with CV risk.


  Pathophysiological Mechanism behind Association of Hypertriglyceridemia and Cardiovascular Events Top


Large-sized chylomicrons and very low-density lipoprotein (VLDL) cannot enter arterial lumen owing to their size. However, TG-rich chylomicron and VLDL remnants rapidly penetrate the arterial wall and contribute cholesterol to atherosclerotic lesions.[33] A unique aspect of these remnants compared with LDL particles is that they do not require oxidative modification to be taken up by arterial macrophages and they might also be associated with a greater degree of inflammation.[34] LPL enzyme presents within the subendothelial space hydrolyzes remnant TGs and generates pro-inflammatory mediators including free fatty acids. These increased levels of fatty acids contribute to the development of atherosclerosis by various mechanisms such as induction of pro-inflammatory cytokines, procoagulant factors, inhibition of fibrinolysis and upregulation of endothelial adhesion molecules.[35],[36] In various population studies, TG-associated CVD risk has been associated with Apo C3-containing VLDL particles and their metabolic remnants, sdLDL particles.[37] Long residence time of VLDL in the circulation leads to the formation of smaller and denser LDL particles which are more atherogenic.[38] Hypertriglyceridemia is also associated with higher concentrations of reduced HDL particle and apoA-I concentrations and greater concentrations of apoC-III-containing particles apart from increased sdLDL particles.[39]

A recent study has shown that high TG, specifically when more than 200 mg/dl, leads to atherosclerotic plaque progression and reducing the TG levels led to invariable regression in the plaques.[40] In the last year, there was a large community-based study which concluded that high TGs are an independent causative factor for endothelial dysfunction which is considered one of the preliminary initiation steps for atherogenesis.[41] Endothelial function was assessed by the measurement of flow-mediated vasodilation (FMD) in this cross-sectional study involving 4887 individuals. Subjects were divided into six groups based on serum TG levels. FMD was significantly decreased with an increase in serum TG levels (P < 0.001) after adjusting for age, sex and other CV risk factors inferring that TG could be a possible independent predictor for endothelial dysfunction, which is the first step of subclinical atherosclerosis.


  At What Levels Triglycerides Should Be Treated With Triglycerides-Lowering Drugs: What Do the Recent International Guidelines Say? Top


Statins are the first-line drugs indicated to treat high LDL-C and are universally recommended by all international guidelines. Over and above statin, the guidelines currently recommend TG lowering drugs when TG levels are >200 mg/dL.

The European Society of Cardiology 2016 guidelines recommends that in high-risk patients with TG >2.3 mmol/L (200 mg/dL) despite statin treatment, TG lowering therapy may be considered in combination with statins.[42] The high-risk group of patients comprised those with documented CVD, diabetes and chronic kidney disease. As per the American Association of Clinical Endocrinologists (AACE) 2017 Diabetes guidelines, TG levels should be part of routine lipid screening: moderate elevations (≥150 mg/dL) may identify individuals at risk for the IR syndrome and levels ≥200 mg/dL may identify individuals at substantially increased ASCVD risk. TG goals of <150 mg/dL are recommended as per the AACE 2017 guidelines.[43] ADA 2017 guidelines recommend that in men with TG >204 mg/dl and HDL <34 mg/dl, TG-lowering therapy can be given. However, for patients with TG >500 mg/dl, TG-lowering therapy is primarily recommended to reduce the risk of acute pancreatitis.[44] However, ACC/AHA 2013 guidelines clearly said that there are no data to show that adding a non-statin drug (s) to high-intensity statin therapy would provide incremental ASCVD risk reduction benefit with an acceptable margin of safety.[2] However, even as per their guidelines, TG levels more than 500 mg/dl should be addressed and evaluated separately, non-statin drugs can be combined with statins in such instances.

TG levels more than 500 mg/dl require non-statin lipid-lowering agents as primary agents to reduce the risk of acute pancreatitis. However, recently published results from two large prospective cohort (n = 116,550)-based Copenhagen studies (Copenhagen General Population Study and Copenhagen City Heart Study) have shown that even mild-to-moderate increase in non-fasting TG levels (above 176 mg/dL) are associated with significant increase in the risk of acute pancreatitis; moreover, the hazard ratio for acute pancreatitis seems to be even higher than the hazard ratio for myocardial infarction.[45]


  Current Pharmacological Intervention for Triglycerides Reduction Top


With the knowledge of increased risk with elevated TG levels and the international guidelines recommending TG-lowering drugs when TG >200 mg/dl, it becomes very important to address TG. Furthermore, hypertriglyceridemia is on the rise all across the world as are its associated diseases and comorbidities such as diabetes, metabolic syndrome and obesity.

Statins are the most important lipid-altering agents at present and are unanimously endorsed by all international guidelines. They reduce LDL-C considerably but their ability to reduce TG levels is not so substantial. The results from the VOYAGER meta-analysis have revealed that almost 50% of patients even with optimal statin doses do not attain target TG levels.[46]

Besides statins, there are currently three pharmacological agents approved globally for TG reduction. In no particular order, these are fibrates, for example, fenofibrate and bezafibrate, nicotinic acid (Niacin) containing agents and n-3 polyunsaturated fatty acids. Unfortunately, clinical trials that evaluated the use of these agents in addition to optimal statin therapy for CV event reduction failed to show additional benefit. The Fenofibrate Intervention and Event Lowering in Diabetes trial assessed the effect of fenofibrate on CVD events in diabetic patients, Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial used fenofibrate in addition to simvastatin, AIM-HIGH trial and HPS-2 trial used simvastatin and niacin or a combination of niacin and laropiprant, respectively.[47],[48],[49],[50] In addition, a large trial studied the effects of n-3 polyunsaturated fatty acids in individuals with multiple CV risk factors and found no improvement in CV morbidity or mortality [51] It is to be noted, however, that pivotal trials with fibrates have been focused on the general population and not individuals with hypertriglyceridemia with baseline TG ranging from 150 to 160 mg/dl.[47],[48]

While there does not seem to be a benefit for a population at large, there was still hope for the benefit of non-statin agents in particular patients. Subgroup analysis of the ACCORD trial showed a possible benefit of combined statin and fibrate therapy in dyslipidemic diabetic patients, with high TG levels >200 mg/dl and low HDL levels <40 mg/dl.[52] Similar observations were made in a subset of participants of the aim-high trial. They found a reduction in CV events in diabetic patients in the highest tertile of TG levels (>198 mg/dl) and the lowest tertile of HDL levels (<33 mg/dl).[53] Unfortunately, the trend failed to show high significance, and it is also pertinent to keep in mind that subgroup analyses are not conclusive. Nevertheless, these findings raise the question if further trials should be conducted that particularly study the possible benefit of combined statin and non-statin lipid therapy in patients with high TG and low HDL levels.

Nevertheless, fibrates are recommended by international guidelines as first-line drugs for TG reduction.

Given that both fibrates and statins are associated with an increased risk of myopathy,[54],[55] the risk of this adverse effect might be increased when these drugs are coadministered, particularly if the statin dose is high. Fibrates also have other limitations such as a reversible increase in serum creatinine, cholelithiasis and increase in liver enzymes.[56] Highly selective peroxisome proliferator-activated enzyme (PPAR)-α agonists (i.e., pemafibrate) are being researched and they might be free of these adverse events.

Saroglitazar is a predominantly PPAR-α agonist with moderate PPPAR-γ agonism available in India approved for the treatment of diabetic dyslipidemia and hypertriglyceridemia in diabetes uncontrolled with statin therapy.

Controlled Phase 3 clinical trials have shown that saroglitazar 4 mg once daily when added to statin, leads to significant decrease in TG (46.7%) and non-HDL-C (32.5%) along with significant decrease in hemoglobin A1c (HbA1c) (0.3%) in addition to lowering of lipid parameters. In these controlled clinical trials, saroglitazar was found to be safe and well tolerated.[57],[58] A post-marketing, observational, multicentre study was conducted in India involving 2804 patients of diabetic dyslipidemia where the use of saroglitazar led to significant reduction in TG (35.8%), LDL-C (16.4%), total cholesterol (19%) and non-HDL-C (23.4%). Addition of saroglitazar to baseline antidiabetic medications showed a significant 0.9% absolute reduction in HbA1c with significant improvement in blood glucose levels.[59]

Saroglitazar has not been associated with weight gain, hepatotoxicity, renal toxicity or muscle-related toxicity when co-prescribed with statin.

Saroglitazar has ongoing trials approved by the FDA for indications of hypertriglyceridemia, non-alcoholic steatohepatitis and primary biliary cholangitis.

Saroglitazar is the only Glitazar approved so far and owing to its dual PPAR action; it convincingly addresses both the lipid and glycaemic aberrations of diabetic dyslipidemia with significant alteration of both these parameters.

Finally, elevated TG levels can be reduced much more effectively than elevated LDL-C levels by lifestyle interventions. Weight loss is one of the most important and effective approaches to lowering elevated TG levels, regardless of the method used to achieve it.[60] Diet and exercise are well known to be safe and effective strategies for reducing elevated TG as well as a host of other morbidities such as IR, diabetes, obesity and hypertension.


  Summary Top


International lipid guidelines recommend statins as first-line antilipid drugs. Statins reduce cholesterol levels significantly and major statin trials have proved its CV benefit potential. However, residual risk remains even after optimal statin therapy which points out that there is a need to reduce the other lipid parameters of which hypertriglyceridemia forms an integral part.

Hypertriglyceridemia has been proved to have a causative role in CVD over and above LDL-C. Recently, the evidences have been accumulating in its favour so much so that the recent international guidelines are recommending treatment of hypertriglyceridemia with TG reducing agents in individuals whose TG levels are over 200 mg/dl despite optimal statin therapy. The effect of statins on TG is only modest; hence, there is a need for additional TG-lowering drugs.

Fibrates are the most preferred TG-lowering agents. However, they are not without their share of adverse events. Saroglitazar is a novel dual PPAR agent which has been found to be free of such adverse events and also effective in controlling hypertriglyceridemia along with significant glycaemic control.

Finally, new treatment options currently in pipeline are forthcoming since most of the TG reducing agents available currently have not managed to show CV benefit in their outcome trials. However, a certain subset of patients having high TG and low HDL, typically found associated with diabetes, also coined diabetic dyslipidemia, have been found to be benefitted the most from TG-reducing agents.

Saroglitazar, specifically indicated for diabetic dyslipidemia, caters to this high-risk population who seem to require TG reduction the most.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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