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 Both Triglyceride and LDL-C

ANGPTL3 Antagonist: Evinacumab

Angiopoietin-related protein 3 (ANGPTL3) is a protein secreted by the liver that is primarily expressed in the liver. ANGPTL3 inhibits LPL and endothelial lipase, resulting in increases in TG and HDL-C levels. Together, ANGPTL3 enhances insulin resistance and decreases serum free fatty acids.[165] Genetic studies have shown that LOF mutations in ANGPTL3 were associated with reductions in LDL-C, TG, and HDL-C levels. The magnitude of the reductions showed an increasing trend in the number of mutations.[166,167] The mechanism of reduction in LDL-C levels was assumed to be due to reduced secretion and increased uptake of apoB-containing lipoproteins.[168] Moreover, the presence of the mutations, having 9% lower LDL-C levels, 27% lower TG levels, and 4% lower HDL-C levels, associated with a 41% lower CAD risk that appears to be comparable with another study (34%).[166,169] Although impaired HDL functionality was reported to be associated with LOF mutations in ANGPTL3,[170] the clinical significance has so far been unclear. The beneficial effects on TG and LDL-C levels suggest the potential of ANGPTL3 inhibition to prevent ASCVD.

Two different therapeutic approaches to ANGPTL3 are currently in clinical trials, i.e., mAb and ASO (IONIS-ANGPTL3-LRX).[165] Evinacumab, a mAb to ANGPTL3, was administered subcutaneously or intravenously to healthy volunteers with elevated TG (150 ≤ TG ≤ 450 mg/dl) and/or LDL-C (≥ 100 mg/dl) in a phase 1 trial.[166] The single-dose administration demonstrated dose-dependent reductions in TG levels up to 76% (day 4), LDL-C levels up to 23% (day 15), and HDL-C levels up to 18% (day 15), with a generally good safety profile. This was followed by a phase 2 trial in HoFH patients receiving maximally tolerated LLTs, demonstrating similar lipid-lowering effects.[171] In particular, it is noteworthy that the incremental LDL-C lowering was greater than that of PCSK9 mAbs in HoFH patients on stable LLTs (− 49% vs. ≈ − 20%).[57,58] This promising drug is being assessed in a phase 2 trial in 252 patients with LDL-C ≥ 100 mg/dl despite maximally tolerated LLTs.[172]

Gemcabene Calcium: Gemcabene

Gemcabene is a small molecule that consists of a fraudulent fatty acid with two terminal gem-dimethyl carboxylate moieties.[173] Gemcabene reduces hepatic production of cholesterol and TG and hepatic gene expression of apoC-III, which leads to enhanced uptake of VLDL remnants.[174] These mechanisms are attributed to reductions in LDL-C and TG levels. An LDLR-independent mechanism was also reported in an animal study using LDLR knockout mice.[175] Furthermore, gemcabene lowers CRP levels. A recent study demonstrated that gemcabene reduces CCAAT/enhancer-binding protein-β (C/EBP-β) and nuclear factor kB (NF-kB)–mediated CRP and suppresses the production of CRP induced by interleukin-6 (IL-6) and IL-1β.[176]

A TG-lowering effect was observed in the first randomized trial of this drug, dependent on the baseline TG levels and the doses.[177] In patients with elevated TG levels (≥ 200 mg/dl), gemcabene reduced TG levels by up to 38% in the 300-mg/day group. On the other hand, significant LDL-C reductions, by 15–25%, were found only with higher dosages of gemcabene (600 and 900 mg/day) irrespective of baseline TG level. In the early 2000s, efficacy was tested in a phase 2 trial with hypercholesterolemic patients on stable statin therapy.[175] At week 8, the combination of gemcabene (300 mg/day or 900 mg/day) with statin showed greater LDL-C reductions compared to statin alone (up to 27.7% vs. 6.2%). Of clinical interest, a significant lowering of CRP levels was observed with the combination therapy (statin alone vs. statin + 300 mg/day gemcabene vs. statin + 900 mg/day gemcabene: 11.1% vs. 26.1% vs. 53.9%), although those differences in TG levels were insignificant. This study showed good tolerance and safety profile. However, the baseline LDL-C levels (≥ 130 mg/dl) were quite high compared to the current clinical trial design. Furthermore, the intensity of statin treatment was relatively low (HIST 18.2%). Further trials are being conducted to examine the efficacy of gemcabene in various clinical conditions. The beneficial effect on CRP is also of considerable interest given the result of the CANTOS trial, as mentioned above. This anti-inflammatory property of gemcabene may pronounce incremental benefits in ASCVD patients in addition to LDL-C–lowering effects.