Multiple lines of evidence, including epidemiologic, clinical, and genetic, support a causal role for triglycerides (TGs) in the development of cardiovascular (CV) disease.1,2 Elevated TGs are associated with elevated TG-rich lipoproteins, which may contribute to atherosclerosis by a variety of mechanisms, including inflammation, coagulation, endothelial dysfunction, foam cell formation, and plaque formation/progression (see Proposed mechanisms of TG-rich lipoprotein particles in atherosclerosis).3-6 Epidemiologic studies have identified a direct relationship between serum TGs and risk of CV events or mortality that may be independent of other CV risk factors.7,8 Meta-analyses of prospective population-based studies have similarly found an association between elevated TGs and CV disease.9-11 In addition, there is a growing body of genetic data that places TGs in the atherosclerosis causal pathway.12-18
Maximally tolerated statin therapy is the cornerstone of lipid management and improves CV outcomes in primary and secondary prevention. However, even among some patients who achieve optimal low-density lipoprotein cholesterol (LDL-C) levels, residual CV risk remains.19 Residual CV risk is defined as the risk of CV events that persists despite achievement of treatment goals for LDL-C, BP, and glycemic control.19 Patients at such risk include those who have achieved LDL-C goals but still have elevated TGs and non-high-density lipoprotein cholesterol (non-HDL-C) levels. The clinical challenge of managing this residual CV risk is exacerbated by the pandemics of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM).19 Therapy, in addition to statins, may address this residual risk. Support for this concept was provided by the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), which found that addition of ezetimibe to simvastatin significantly reduced major vascular events in patients with recent acute coronary syndromes despite LDL-C levels under 70 mg/dL with simvastatin alone.20 This concept is most recently supported by the Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial of evolucumab (a PCSK9 inhibitor), which met its primary endpoint of a composite of CV death and other CV events in patients treated with statins.21
The accruing evidence for a causal role for TGs in CV disease, coupled with the fact that patients who are treated with statins still have residual CV risk despite optimal LDL-C control, has renewed interest in targeting TGs to improve CV outcomes. To date, CV outcomes studies of TG-lowering agents have had inconsistent findings; however, several new outcomes studies of TG-lowering treatments are ongoing and focus on patients with elevated TGs and residual CV risk who are also treated with statins.22-42 This overview discusses approved TG-lowering treatments with a focus on completed as well as ongoing CV outcomes studies.
FDA-approved TG-lowering agents
Treatments that are FDA-approved and specifically target TGs include fibrates, niacin products, and prescription omega-3 fatty acids (OM3s); all are indicated as adjuncts to diet to reduce TGs in adults with severe (500 mg/dL or higher) hypertriglyceridemia (see Key features of TG-lowering agents).43-48 Therapy with TG-lowering agents in addition to statins is recommended in guidelines for patients with high TGs (200 to 499 mg/dL) who are unable to achieve target non-HDL-C levels with statin treatment alone.49,50 Of note, wording regarding concomitant use with statins has been removed from the labels of fibrates and niacin due to lack of consistent evidence from outcomes studies.47,48 Past wording in fenofibric acid labeling stated that it could be taken at the same time as a statin and that coadministration with the maximum dose of a statin has not been evaluated in clinical studies and should be avoided unless the benefits are expected to outweigh the risks.51 Current fenofibric acid labeling no longer includes a statement that it may be taken with a statin and includes a Limitations of Use statement that fenofibrate at a dose equivalent to 135 mg of fenofibric acid did not reduce coronary heart disease morbidity and mortality in patients with T2DM.48 Similarly, past niacin labeling included a statement that niacin could be used in combination with simvastatin or lovastatin to treat primary hyperlipidemia and mixed dyslipidemia when treatment with niacin, simvastatin, or lovastatin monotherapy is considered inadequate. The current niacin labeling does not include an indication for concomitant use with statins and includes a Limitations of Use statement that the addition of niacin did not reduce CV morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial.47,52
As noted in current labeling, an important safety concern associated with use of fibrates and niacin is the risk of myopathy and rhabdomyolysis, which is increased in certain patient subgroups, including patients taking concomitant statins.47,48 In addition, these agents may increase hepatic transaminase levels; therefore, monitoring of liver enzymes is recommended. Gastrointestinal adverse events are common (reported in at least 3% and at least 5% of patients treated with fibrates and niacin, respectively). Flushing is an especially challenging tolerability issue with niacin (reported in more than 50% of patients) and has limited its use in clinical practice.47 Notably, niacin may increase serum glucose levels, and monitoring is recommended in patients with or at risk for diabetes.47 Fenofibrate use can raise serum creatinine levels and lower several measures of renal function; therefore, monitoring of renal function in patients with renal insufficiency is required, which raises questions as to potential renal harm.48,53 Other considerations of fibrates include risk of cholelithiasis due to increased cholesterol excretion into the bile and the potential to attenuate the beneficial effects of statins on LDL-C, particularly in patients with atherogenic dyslipidemia.48,54
Prescription OM3s are high-purity formulations that have generally favorable tolerability profiles. Among the FDA-approved OM3s, several products contain both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and one formulation contains the ethyl ester of EPA (icosapent ethyl).43-46 Gastrointestinal adverse events are common with DHA-containing products (reported in at least 3% of patients), whereas arthralgia was the only adverse event with icosapent ethyl reported in greater than 2% of patients and occurring more frequently than with placebo.43-46 While all prescription OM3s produce robust reductions in TGs, a clinically important difference between products is that DHA-containing OM3s have been associated with increased LDL-C; in contrast, the EPA-only product has not been associated with such increases.55-61 Thus, only the labeling of DHA-containing products recommends periodic monitoring of LDL-C, while the EPA-only product does not require this monitoring.44-46
Beyond TG-lowering effects, EPA may have beneficial effects on atherosclerosis through additional cellular and molecular mechanisms (for example, reducing inflammation and inhibiting plaque development, rupture, and thrombus formation), which was the subject of a recent comprehensive review.62
CV outcomes studies with TG-lowering agents
An overview of major CV outcomes studies that involved TG-lowering agents is provided in Large CV outcomes studies.22-42,63,64 These studies have recently been reviewed in detail.1
Fibrates have been shown to reduce cardiac endpoints in some, but not all, studies to date.22,23 The inconsistencies have been attributed to multiple factors, including study design, statin use, endpoint selection, and baseline TGs. Notably, in the trials that did not demonstrate improved CV outcomes, subgroup analyses showed or suggested reduced CV events in patients with elevated TGs.24-26 Consistent with these findings, a meta-analysis of fibrate CV outcomes studies reported that in patients with elevated TGs (204 mg/dL or higher) and low HDL-C (34 mg/dL or lower), fibrates significantly reduced the odds of coronary heart disease by 35% (95% confidence interval [CI], 22-46).65 Prominent CV outcomes studies of extended-release niacin did not demonstrate a significant reduction in major vascular events; however, a subgroup analysis of patients with high TGs and low HDL-C at baseline in one of these studies showed that addition of niacin to statins reduced major vascular events by 36% versus statin monotherapy (hazard ratio [HR], 0.64; P = 0.032).27-29 However, these hypothesis-generating results with fibrates and niacin in dyslipidemic groups need to be confirmed in large, prospective, randomized trials that examine the use of these agents in addition to statin treatment.
Similarly, OM3s have been shown to reduce cardiac endpoints in some but not all outcomes studies to date.30-32,34-39 There are several potential contributing factors to the mixed findings, including differences in patient populations, disease conditions, variations in dietary fish intake, differences in whether statins were available and/or how they were used, changes in standard of care/advances in treatment for CV disease, and use of composite CV outcomes.66-68 In addition, doses of OM3s in these studies were much lower (ranging from less than 1.0 to 2.4 g/day) than currently recommended prescription OM3 doses (4 g/day), and study patients were not required to have elevated TGs (mean or median baseline TGs were 150 mg/dL or lower in most studies). Given the differences between DHA-containing OM3 products and the EPA-only OM3 product noted earlier, the type of OM3 being investigated may also influence CV outcomes. Of note, the Japan EPA Lipid Intervention Study (JELIS) was the only one of the OM3 CV outcomes studies to date that assessed EPA alone, and a notable beneficial impact was found.32 JELIS compared EPA ethyl ester 1.8 g/day plus low-dose statin with statin monotherapy in patients with hypercholesterolemia (cholesterol 250 mg/dL or higher; LDL-C 170 mg/dL or higher).32 In the overall study population, EPA significantly reduced the risk of major coronary events by 19% compared with statin therapy alone (HR: 0.81; 95% CI: 0.69-0.95; P = 0.011).32 Although the daily dose of EPA used in JELIS (1.8 g) was less than that of the U.S. FDA-approved daily dose of the prescription EPA-only product (4 g), Japanese patients in JELIS had higher baseline serum and tissue levels of OM3s due to high dietary intake from fish; the EPA levels attained in JELIS were similar to those seen with 4 g/day of icosapent ethyl in a U.S. population.69 Also, the observed TG reductions were modest in JELIS, suggesting that the decreased CV risk may have been due in part to the pleiotropic effects of EPA beyond TG lowering. Similar clinical benefits of EPA as a statin adjunct were also seen in a more recent Japanese study, albeit in a small sample of subjects, where TG reductions were also minimal.70 In a subgroup analysis of JELIS, it was demonstrated that in patients with TGs 150 mg/dL or higher and HDL-C under 40 mg/dL, EPA achieved a more pronounced risk reduction of 53% (HR: 0.47; 95% CI: 0.23-0.98; P = 0.043).33 This finding supports the concept that targeting treatments to appropriate patient populations will enhance the potential for benefit.
Ongoing CV outcomes studies with TG-lowering agents
New CV outcomes studies have been initiated to help clarify the role of TG-lowering agents in patients with elevated CV risk (see Large CV outcomes studies).40-42,63,64,71 Based on approximations from past large CV outcomes trials including or limited to patients with T2DM, the populations under investigation in some of these new and ongoing studies of patients who are on statins are large: In past studies, roughly 25% to 40% of patients had TG levels of 150 mg/dL or higher and LDL-C levels under 100 mg/dL and roughly 15% to 20% of patients had TG levels of 200 mg/dL or higher and LDL-C levels under 100 mg/dL.26,27,29,72,73
For fibrates, the Pemafibrate to Reduce Cardiovascular OutcOMes by Reducing Triglycerides IN PatiENts with DiabeTes (PROMINENT) study has been designed to evaluate a fibrate agent, pemafibrate, in high-risk patients with diabetes mellitus who are treated with statins and to determine whether lowering TGs and increasing functional HDL can reduce CV risk.40
Several of the new outcomes studies are focused on OM3s. In contrast to previous studies, two of these new studies are using prescription-strength doses and include adults with elevated TGs (200 mg/dL or higher) at high risk for CV events despite statin treatment. The STatin Residual Risk Reduction with EpaNova in HiGh CV Risk PatienTs with Hypertriglyceridemia (STRENGTH) study is evaluating a DHA+EPA combination product (omega-3-carboxylic acids) and the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) is evaluating high-purity EPA (icosapent ethyl); both are global investigations.41,42,71 Another study, the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA), is being conducted in Japan using high-purity EPA and has been designed to confirm the results of JELIS in a secondary prevention population.74 Two additional large OM3 studies are ongoing but are evaluating relatively low doses of OM3 (doses comparable to that of nonprescription dietary supplements): The Vitamin D and Omega-3 Trial (VITAL) is assessing OM3 (DHA+EPA) with vitamin D in the general population, and A Study of Cardiovascular Events in Diabetes (ASCEND) is assessing OM3 (DHA+EPA) with aspirin in patients with diabetes.63,64 REDUCE-IT results are projected to be available in 2018, likely sooner than results for the other high-dose OM3 trial (STRENGTH) and the fibrate trial (PROMINENT).
Residual CV risk remains in some patients despite maximally tolerated statin therapy. Multiple lines of evidence support a causal role of elevated TGs in atherosclerosis and CV risk. The collective experience from CV outcomes studies of TG-lowering agents including niacin, fibrates, and OM3s has been mixed; however, findings from analyses in subgroups of patients with elevated TGs suggest that TG-lowering treatments may be beneficial for patients with elevated TGs and residual CV risk despite statin treatment. Results from several ongoing CV outcomes studies designed to target this patient population will help clarify the role of TG-lowering agents as additional therapy to statins in the setting of residual CV risk
Medical writing assistance was provided by Peloton Advantage, LLC, Parsippany, N.J., USA, and funded by Amarin Pharma Inc., Bedminster, N.J., USA. Medical scientific reference checks and associated assistance were provided by Sephy Philip, RPh, PharmD, and Loree Levine, RPh, MS, MBA, of Amarin Pharma Inc.
Tina Copple serves on speakers bureaus for Abbott, Amarin, Sanofi, Regeneron, and AstraZeneca and has received honorarium as an advisory board member for Becton Dickinson. Nicole A. Ciffone serves on speakers bureaus for Amarin, Amgen, Sanofi, and Regeneron and is a consultant for Akcea Therapeutics.
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