Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs

Kohei Takata; Stephen J. Nicholls


Am J Cardiovasc Drugs. 2019;19(2):113-131. 

In This Article

Novel Drugs Targeting Triglyceride

Current therapeutic guidelines recommend LDL-C-lowering therapies for preventing ASCVD.[4,94] However, ongoing CV risks despite achieving target low LDL-C levels suggest the need to identify additional therapeutic targets. Triglyceride-rich lipoproteins (TRLs), such as very low-density lipoprotein (VLDL) and chylomicrons, mainly carry circulating TG. TRLs have pro-atherogenic effects on the endothelium, including inflammation, thrombus formation, and endothelial dysfunction.[95] Although clinical studies have shown that hypertriglyceridemia is an independent risk factor for ASCVD irrespective of fasting state,[95] the mechanisms underlying TRLs and ASCVD risk are not fully understood. Recent genetic studies have provided evidence for the causal role of TRLs in ASCVD.[96] These observations have reinforced the importance of developing TRL-targeted therapies.

New Omega-3 Fish Oils: Icosapent Ethyl (Vascepa®), Omega-3 Carboxylic Acids (Epanova®)

The marine omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to reduce hepatic VLDL production and secretion and increase TRLs clearance, with good safety profiles.[97] Beyond TG lowering, omega-3 fatty acids (OM3FAs) possess pleiotropic effects, including lowering blood pressure, decreases in platelet aggregation, suppression of inflammation, and improvement of endothelial function.[98] Lipid guidelines and scientific statements have recommended OM3FAs in hypertriglyceridemic patients for the prevention of ASCVD,[94,99,100] whereas recent evidence has raised questions about their beneficial effect on ASCVD, from earlier studies showing risk reductions and later studies showing no CV benefits.[101–104] However, the 2017 American Heart Association scientific advisory still recommends omega-3 supplementation for patients with prevalent coronary heart disease (CHD) on the basis of a ≈ 10% reduction in CHD mortality.[105] It noted a concern about insufficient dosage (≈ 1 g/day) in previously published RCTs of omega-3 supplementation. Indeed, the most recently reported negative CVOT of OMFAs, the ASCEND (A Study of Cardiovascular Events in Diabetes) study, was also conducted using a low dosage (< 1 g/day), in diabetic patients without established CV disease.[106] Given these issues, phase 3 RCTs of icosapent ethyl and Epanova were designed with higher dosages of omega-3 supplementation (2 or 4 g/day): REDUCE-IT (Reduction of Cardiovascular Events with EPA–Intervention Trial) trial with Vascepa® [107] and the STRENGTH (Statin Residual Risk Reduction with Epanova in High CV Risk Patients with Hypertriglyceridemia) trial with Epanova®.[108] In particular, these trials were designed to enroll specifically TG-targeted subjects with LDL-C < 100 mg/dl and 150/180 ≤ TG < 500 mg/dl receiving statins, to assess whether TG-lowering reduces CV outcomes (Table 2). Both Vascepa® (icosapent ethyl) and Epanova® (omega-3 carboxylic acids) are the FDA-approved omega-3 in free fatty acid form for severe hypertriglyceridemia (≥ 500 mg/dl). Vascepa® contains only the purified EPA ethyl ester, while Epanova® contains 50–60% EPA and 15–25% DHA along with other potentially active OM3FAs.[109] Recently, the results of the REDUCE-IT trial have been reported, in which LDL-C levels were well controlled (median baseline LDL-C 75 mg/dl).[110] After a median follow-up of 4.9 years, icosapent ethyl treatment (4 g/day) demonstrated an approximately 25% relative risk reduction for CV events, with an acceptable safety profile in the population described above. This result could reconfirm the concern about the insufficient dosage of OM3FAs. In addition, the consistently observed benefits in patients with attained TG levels of < 150 or ≥ 150 mg/dl suggested an involvement of some biological effects of icosapent ethyl other than lowering TG levels. The inconsistent association between the observed reductions of median TG levels (45 mg/dl in the icosapent arm) and those of relative CV risk (25%) in the trial could support involvement of other factors, given recent findings by Mendelian randomization studies: a 200 mg/dl or greater TG reduction is required to generate comparable benefits on CV outcomes to those of a 38.7 mg/dl LDL-C reduction.[111] The baseline TG levels in the REDUCE-IT trial (median 216 mg/dl) should be noted given the current indication of icosapent ethyl: severe hypertriglyceridemia (≥ 500 mg/dl). The results of the REDUCE-IT trial may have the potential to expand the indication. In addition, the incremental benefits on top of statins in the REDUCE-IT trial strongly highlight the importance of OM3FAs, given the magnitude of CV risk reductions. This could change clinical practice in this field. Meanwhile, the results of the STRENGTH trial are keenly awaited.

Although OM3FAs have been shown to reduce TG levels markedly, there is some suggestion that DHA-containing OM3FAs may increase LDL-C levels, the clinical implications of which are uncertain.[112] Indeed, icosapent does not appear to increase LDL-C. In substudies of the MARINE (Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension) trial in 177 non–statin-treated patients with severe TG levels (500 ≤ TG ≤ 2000 mg/dl) and the ANCHOR trial in 427 statin-treated patients with high TG levels (200 ≤ TG < 500 mg/dl), icosapent demonstrated dose-dependent and significant reductions in TG (MARINE up to − 26%; ANCHOR − 18%) without significant increases in LDL-C (MARINE up to − 7%; ANCHOR + 2%) at week 12.[113,114] The latter study additionally reported that icosapent increased LDL-P size (+ 0.5% vs. 0.0%, P < 0.05) and decreased LDL-P concentration (− 3.8% vs. − 11.9%, P < 0.05) compared to placebo. An animal study suggested that DHA treatment downregulates LDLR, but EPA does not.[115] Hence, icosapent has the potential to enhance the clearance of LDL-P, which may relate to the observed reductions in LDL-C levels in the REDUCE-IT trial.[110]

In contrast, Epanova® was associated with elevating LDL-C (TG up to − 31%; LDL-C up to + 19%) at week 12 in the EVOLVE (Epanova® for Lowering Very High Triglycerides) trial, consisting of 399 patients with severe TG levels (500 ≤ TG < 2000 mg/dl).[116] Inconsistent with the ANCHOR trial, there was no difference in LDL-P concentration between Epanova® and placebo in a substudy of the ESPRINT (Epanova Combined with a Statin in Patients with Hypertriglyceridemia to Reduce non-HDL cholesterol) trial (+ 3% vs. + 2%).[117] As noted, the downregulated LDLR with DHA treatment could account for the observation regarding LDL-C levels. Nonetheless, Epanova® showed greater bioavailability and better absorption than other approved omega-3-acid ethyl esters (Lovaza®) in the ECLIPSE (Epanova® Compared to Lovaza® in a Pharmacokinetic Single-Dose Evaluation) study.[118] Epanova® does not rely on pancreatic lipase hydrolysis, and is independent of dietary intake unlike other OM3FAs.[119]

Interestingly, both icosapent and Epanova® have been shown to be associated with a reduction in apolipoprotein C-III (apoC-III).[109,120] This is consistent with previous OM3FA studies in statin-treated patients. Additional treatments with OM3FAs showed greater apoC-III reductions, by 11–13%, compared to statin alone.[121,122] The mechanisms of apoC-III reduction by OM3FAs are still unclear. However, the involvement of peroxisome proliferator-activated receptor α (PPARα) activation has been proposed.[121] Given the pro-atherogenic role of apoC-III in ASCVD, apoC-III reduction of these agents may have an incremental impact on CV outcomes. Future studies are needed to elucidate this relationship.

Antisense Molecules Targeting ApoC3: Volanesorsen (ISIS 304801), APOCIII-LRX

ApoC-III is a small apolipoprotein (79 amino acid residues) present on the surface of TRLs and high-density lipoprotein (HDL), and has been known to be a central regulator of TG levels via both lipoprotein lipase (LPL)-dependent and LPL-independent pathways.[123] LPL is an enzyme involved in hydrolysis of TRLs. Reduced catabolism of TRLs was confirmed by kinetic studies, which showed a delayed clearance of apoB-containing lipoproteins that contain apoC-III.[124] In addition to the effect on TRL metabolism, proatherogenic properties of apoC-III have been demonstrated, including endothelial function, inflammation, and HDL functionality.[125–127]

Epidemiological studies have demonstrated positive associations between apoC-III levels and ASCVD risk.[128–131] Mendelian randomization studies have also shown that LOF mutations in APOC3, encoding to inhibit LPL and enhance VLDL production in the liver, showed ≈ 40% reductions in TG levels, and were associated with a ≈ 40% reduced ASCVD risk.[132,133] Furthermore, a positive association between apoC-III levels and subclinical atherosclerotic risk was independent of statin use, indicating the potential of apoC-III to predict ASCVD risk in statin-treated patients as a biomarker of the residual risk.[134] Consequently, apoC-III has attracted considerable interest for the management of ASCVD.

ApoC-III–targeting ASO, targeting apoC-III mRNA in the liver, is the most developed approach among several therapeutic approaches. A phase 1 trial of volanesorsen (ISIS 304801) showed its dose- and time-dependent reductions of apoC-III, and concomitant lowering of TG levels in healthy volunteers.[135] Comparable lowering effects of once-weekly subcutaneous-administered volanesorsen on apoC-III and TG levels were confirmed in a phase 2 trial, comprising hypertriglyceridemic patients with or without fibrate (with fibrate: apoC-III up to − 72%, TG up to − 64%; without fibrate: apoC-III up to − 80%, TG up to − 71%). Although increases in HDL-C levels were reported irrespective of concomitant fibrate use (with fibrate + 49%; without fibrate + 46%), the clinical significance is uncertain.[136] Moreover, similar reductions of apoC-III and TG were obtained in three patients with familial chylomicronemia syndrome (FCS).[137] Given a lack of functional LPL activity in FCS, this result supports the involvement of an LPL-independent pathway in TRL metabolism. Importantly, volanesorsen was well-tolerated and safe in all these early clinical trials. This agent is now being tested in ongoing phase 3 trials in patients with several backgrounds, including FCS, severe hypertriglyceridemia, and familial partial lipodystrophy.[138] Both APPROACH (A Study of Volanesorsen in Patients with Familial Chylomicronemia Syndrome) and COMPASS (A Study of Volanesorsen in Patients with Hypertriglyceridemia) studies have so far shown significant TG reductions (APPROACH − 77%; COMPASS − 73%), in addition to reductions in the recurrence of pancreatitis.[139,140] A reduction in platelet count has been observed in some treated patients, the mechanism and clinical implications of which are unknown.

APOCIII-LRX, a same-class but different RNA delivery platform to improve efficiency,[141,142] is currently being investigated in a phase 2 trial in hypertriglyceridemic patients with established ASCVD.[143] Its phase 1 trial confirmed dose-dependent reduction in apoC-III up to 84% and TG up to 71%.[144] Although apoC-III ASO has been expected to be a promising therapeutic approach, large CVOTs are needed to determine whether these drugs can become the cornerstone of TG-lowering therapies.

New PPARα Agonist: Pemafibrate (Parmodia™)

Fibrates, synthetic PPARα agonists, have been used for the treatment of hypertriglyceridemia and mixed dyslipidemia.[145] PPARα activation increases hepatic β-oxidation of fatty acids, reduces hepatic apoC-III production and TG synthesis, and facilitates VLDL clearance through activating LPL. Together, it increases HDL-C levels through enhancing hepatic apoA-I and apoA-II transcriptions.[146] Thus, fibrates effectively lower TG levels, with a modest rise in HDL-C levels. While genetic studies have manifested the causal role of TRLs in ASCVD,[147] RCTs and meta-analyses of fibrates have not been concordant.[4] However, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) LIPID study and some meta-analyses have suggested a potential to reduce CV outcomes in patients with elevated TG and low HDL-C levels,[148–151] indicating an implicit target for PPARα agonists.

Pemafibrate, a novel selective PPARα modulator (SPPARMα), possesses higher PPARα activity and selectivity than currently used fibrates. A preclinical study reported its atheroprotective effects on inflammation and HDL functionality, in addition to lipid metabolism.[152] In a phase 2 trial, 423 hypertriglyceridemic Japanese patients (≥ 200 mg/dl) treated with pemafibrate for 12 weeks had significant reductions in TG (up to − 53%) and apoC-III (up to − 38%) and increases of HDL-C (up to + 20%) without safety issues in combination with statins. LDL-P size had shifted to larger LDL subfractions, combined with lowered TG/HDL-C ratio, up to 57%.[153] Moreover, there is considerable interest as the residual risk during the statin era in the ability of pemafibrate to reduce remnant cholesterol up to 52%, given the causal role of remnant cholesterol in ASCVD.[154,155] A subsequent phase 3 trial, comprising 166 diabetic Japanese patients with hypertriglyceridemia (150 ≤ TG < 1000 mg/dl), showed that treatment with pemafibrate for 24 weeks yielded comparable beneficial effects over 24 weeks on both lipid and lipoprotein profiles, in addition to concomitant improvement in insulin resistance.[156] Concerning safety, pemafibrate was superior to fenofibrate in another phase 3 trial.[157] Accordingly, pemafibrate was approved by the Pharmaceuticals and Medical Device Agency of Japan in July 2017 (Parmodia™), but not yet in the USA and EU. The PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial in 10 000 diabetic patients at high CV risk with elevated TG and low HDL-C levels on background statins will evaluate the impact on CV outcomes[158] (Table 2).

Niacin Mimetics

Niacin or nicotinic acid is known as vitamin B3, and was the first drug approved for dyslipidemia.[159] The mechanisms regarding lipids are unresolved.[160] However, in pharmacological doses, niacin raises HDL-C levels by up to 25% and lowers TG levels by 20–40%, with moderate reductions in LDL-C levels, by 15–18%.[4] Nonetheless, niacin was not commonly used due to its side effect: flushing. Therefore, extended-release (ER) niacin and ER niacin plus laropiprant, a prostaglandin D2 receptor antagonist, were developed to decrease the side effect. However, both CVOTs did not reveal incremental effects of niacin with statins on ASCVD risk reductions even though earlier studies with niacin showed positive results.[161–163] At the same time, much interest in niacin has remained in light of the earlier studies. Several niacin mimetics are currently under development, for example, CAT-2003, a novel conjugate of niacin and EPA that inhibits the maturation of SREBP and the activation of SREBP-target genes including HMGCR and PCSK9. An increase in LPL activity, which is followed by the inhibition of SREBP, reduces TG levels.[160,164] Several phase 2 studies showed significant TG reductions. Additionally, LDL-C levels were modestly lowered in statin-treated patients (11%).[161] CAT-2003 may be a potent therapeutic approach to the management of abnormal lipid metabolism.