**8. Selective medication for hyper-Lp(a)**

Another current possibility is medication with nicotinic acid or derivatives thereof. Nicotinic acid (niacin), its amide or different retard compounds were, for a long time, in the markets of numerous countries because of their HDL-raising properties. In addition, these compounds reportedly reduce plasma Lp(a) by some 30% [31]. In recent studies, we succeeded to uncover the mode of action of this drug at a molecular level: the *APOA* promoter contains several cAMP response elements that impact the apo(a) transcription [32]. Nicotinic acid interferes in liver with the binding activity of cAMP to these elements and reduces the biosynthesis of apo(a)

**Figure 2.** Influence of nicotinic acid on apo(a) biosynthesis: Proposed mode of action. cAMP regulates apo(a) biosyn‐ thesis by binding to specific cAMP response elements in the *APOA* promoter. Nicotinic acid inhibits adenylate cyclase, the key enzyme of cAMP biosynthesis in the liver and in turn lowers its intracellular concentration, leading to a lower expression of the *APOA* gene. With permission of the Medical University of Graz (copyrights held by the MUG Graz,

A major side effect of nicotinic acid is the activation of prostaglandin D2, particularly in the skin, which causes the dilatation of blood vessels by binding to DP1 (PGD2 receptors) and in turn causing skin flushing (red face). Thus, nicotinic acid is not very well appreciated by most patients and, as a consequence, it was removed from the market in most countries. Another drawback for nicotinic acid was the outcome of the HPS2-THRIVE study (http:// www.nejm.org/doi/full/10.1056/NEJMoa1300955). In this trial, 25,673 patients were treated with a standard statin background therapy plus a nicotinic acid supplement consisting of 2 g extended-release niacin + 400 mg of the DP1 antagonist laropiprant or a matching placebo. As it turned out, the supplement nicotinic acid-laropiprant therapy did not reduce CHD risk but

increased the incidence of serious adverse events.

(see cartoon in Fig. 2).

144 Lipoproteins - From Bench to Bedside

Austria).

In our study cited in ref. [10], we actually found that patients suffering from extrahepatic cholestasis exhibited very low Lp(a) plasma concentrations. After treating these patients and curing them from cholestasis, Lp(a) levels vent up significantly. In this study, we succeeded in pinpointing FXR as the most important repressor for apo(a) biosynthesis (see also Fig. 2). Unfortunately, FXR is a pluripotent nuclear receptor that plays eminent roles not only in bile acid and glucose metabolism but also influences the activity of LXR, the master regulator of cellular cholesterol metabolism. There exist negative feedback loops not only between FXR and LXR but also between FXR and other transcription factors, cytokines and interleukins. Thus, the application of FXR activation must be done with great caution and may be not feasible at all for prolonged applications. Nevertheless, such FXR agonists are in development and are currently being tested for their action on the plasma levels of Lp(a). Phenex, a SME that specializes on the development of antagonists and agonists of nuclear receptors, has the FXR agonist Px-102® in clinical trials (http://www.phenex-pharma.com/pdf/PR-Phenex-Phase %20I%20finished\_5%20M%20Euros\_engl.pdf). Px-102® significantly affects plasma choles‐ terol levels in laboratory animals and is also tested for its potential effect on liver tumors. No data has been released so far on its potential effect on Lp(a).

Other selective Lp(a)-lowering agents are currently under investigation. They comprise mostly drugs that were originally drafted to lower LDL cholesterol or increase HDL cholesterol. Among them, inhibitors of PCSK-9, CETP, MTP and thyromimetica are worth noting.
