Hypertriglyceridemia Therapy: Past, Present and Future Perspectives

Abstract

Hypertriglyceridemia therapy is essential for preventing cardiovascular diseases. Fibrates belong to an important class of lipid-lowering drugs useful for the management of dyslipidaemia. By acting on the peroxisome proliferator-activated receptor (PPAR)-α, these drugs lower serum triglyceride levels and raise high-density lipoprotein cholesterol. Fibrate monotherapy is associated with a risk of myopathy and this risk is enhanced when these agents are administered together with statins. However, whereas gemfibrozil can increase plasma concentrations of statins, fenofibrate has less influence on the pharmacokinetics of statins. Pemafibrate is a new PPAR-α-selective drug considered for therapy, and clinical trials are ongoing. Apart from this class of drugs, new therapies have emerged with different mechanisms of action to reduce triglycerides and the risk of cardiovascular diseases.

Keywords: cardiovascular disease; fibrates; hypertriglyceridemia; lipid-lowering drugs; pharmacotherapy.

Figure 1

Evidence of fenofibrate-induced side effects on skeletal muscle function collected by previous studies [11]. (A) Fenofibrate administered in vivo to rats reduced the resting chloride conductance (gCl) sustained by the ClC-1 chloride channel in the extensor digitorum longus fast-twitch muscle. This effect is responsible for sarcolemma instability. Since ClC-1 is negatively modulated by protein kinase C (PKC), we evaluated the effects of the in vitro application of chelerythrine, an inhibitor of this protein. Chelerythrine did not restore gCl, suggesting that the reduction in gCl is not mediated by PKC activation but is a direct inhibitory effect on the channel. # Significantly different with respect to control (CTRL) value measured in physiological solution (by Student’s t-test) (p < 0.001) [11]. (B) Fenofibrate increased sarcolemma excitability, evidenced by the increase in the maximum number of spikes in rat skeletal muscle fibres [11]. (C) Effect of in vitro application of fenofibric acid on hClC-1 channel expression in cultured HEK293 cells. Whole-cell patch-clamp chloride currents were recorded in the absence and presence of 500 μM of fenofibric acid. Fenofibric acid significantly reduced inward chloride currents, sustaining the direct inhibitory effect on the channel [11]. (D) Effects of fluvastatin and fenofibrate chronic treatment on muscle ClC-1 mRNA expression. Normalized ClC-1 mRNA levels in the extensor digitorum longus muscle of fluvastatin- and fenofibrate-treated rats with respect to control (CTRL) rats were measured by real-time polymerase chain reaction. The levels of ClC-1 were normalized to β-actin, which was constant in all muscle preparations. Both fluvastatin and fenofibrate significantly reduced ClC-1 expression. ** Significantly different with respect to CTRL (p < 0.05, one-way ANOVA test followed by Tukey’s post-test) [11]. Adapted from Ref. [11].

Figure 2

Description of recent therapeutic approaches that are useful for reducing hypertriglyceridemia, a disease that can be responsible for the progression of cardiovascular diseases. The drugs (already used in therapy or in clinical trial evaluations) are classified based on their mechanisms of action. See text for details. ASO: antisense oligonucleotides; MoAb: monoclonal antibody; FGF21: human fibroblast growth factor 21.