**7. Medication of patients with elevated plasma Lp(a)**

Although recent publications might be taken as a clear hint for the causal relationship between elevated Lp(a) and CHD, a final proof might be only obtained from intervention studies with Lp(a)-lowering drugs (see ref. [28]). Unfortunately, there hardly exists any drug that may specifically lower plasma Lp(a). As a consequence of the work cited above, however, intensive efforts have been taken to develop such therapeutic agents. In addition, any new lipid-lowering or HDL-raising drug that is in clinical trials is checked for its potential action on Lp(a). There exist several serious recommendations for the treatment of relevant patients (reviewed in ref. [16]), but many of them are based on anecdotal observations, or are of little practical value or low efficacy. As mentioned above, Lp(a) is hardly bound by the LDL-R and thus specific drugs acting solely by increasing LDL-R activity are mostly inactive in the treatment of hyper-Lp(a) patients. Statins that belong to this sort of drugs are therefore not the drugs of choice—and actually there are reports that statins even may lead to an elevation of Lp(a) [29]. Unfortunately, the pathomechanism of the LDL-raising effect of this observation is unknown.

The only current method that reduces plasma Lp(a) levels to a satisfactory extent is apheresis, and it has been shown that lowering Lp(a) by this method reduced the CHD risk significantly [30]. Apheresis is therefore strongly advised in the secondary prevention of patients with very high plasma Lp(a) (>80 mg/dl).

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) (see cartoon in Fig. 2).

**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, Austria).

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.
