Treatment options to reduce CVD risk by lowering Lp(a) levels
Future Directions to Establish Lipoprotein(a) as a Treatment for Atherosclerotic Cardiovascular Disease
Stein EA, Raal F.
Cardiovasc Drugs Ther. 2016 Feb 9. [Epub ahead of print]
The number of kringle 4 repeats in the apo(a) moiety of lipoprotein(a) [Lp(a)] determines its size, which is inversely correlated to its plasma concentration. The length of the apo(a) moiety is largely genetically determined, and the effect of diet, food intake or exercise on Lp(a) is minimal.
Oestrogen may influence Lp(a) levels, as lower Lp(a) levels were seen in premenopausal women as compared with postmenopausal women. Hormonal replacement therapy containing oestrogen has also been shown to lower Lp(a) levels, as did androgens including testosterone. The Lp(a)-lowering effects of these hormones have not resulted in a decrease in CV events.
Lp(a) do fluctuate with stress, infections and injury. It was long thought to be an acute phase reactant, but conflicting data have been published on increased or decreased Lp(a) levels after injury and during inflammation. More recently, evidence seems to point in the direction that it is a negative acute phase reactant.
This (summary of a) review article discusses potential therapeutic options to lower Lp(a), as a treatment for atherosclerotic disease.
* Thyroid hormone and thyroid hormone analogues
Hypothyroidism is associated with elevated Lp(a) and similarly, lower levels are seen in hyperthyroidism, which return to normal when patients return to euthyroidism. Thyroid hormone replacement therapy lowers Lp(a) levels. These effects appear to be mediated via the beta isoform thyroid receptor. Studies with the thyroid hormone beta-receptor analogue eprotirome have been terminated because elevations of liver enzymes were seen in subjects in clinical trials.
Statins increase clearance of LDL-c and apoB-containing lipoproteins, by upregulating synthesis of LDL-receptors. But since Lp(a) was not reduced by statin therapy in well-controlled trials, it seems that the LDL-receptor does not contribute much to Lp(a) clearance.
Conflicting data have been shown on the effect of statins on Lp(a). Thus, the available evidence to date does not support a significant effect of statins on Lp(a) levels, although statins have been shown to reduce the added CVD risk associated with elevated Lp(a) levels.
Ezetimibe blocks the Nieman-Pick C1-like protein, which inhibits dietary and biliary cholesterol absorption from the intestine. It is effective at lowering LDL-c by about 20%. Lp(a)-lowering effects have been reported, but not consistently.
* Bile acid sequestrants
Bile acids downregulate LPA-gene expression. Also biliary obstruction is associated with very low Lp(a) levels, which increase when the obstruction is resolved. Based on these observations, it could be expected that bile acid sequestrants increase Lp(a), but this has not been consistently reported.
* Niacin and niacin analogues
Niacin has a long-standing reputation as an effective treatment to lower Lp(a). Randomised trials evaluating statins with or without immediate release niacin showed about 10-20% reductions in Lp(a) that was attributable to niacin treatment. Later studies with extended release (ER) formulations of niacin also showed effective reductions of Lp(a).
Combination therapies have also been evaluated. ER-niacin plus neomycin, or etofibrate, a combination of niacin and clofibrate, appeared to yield greater reductions in Lp(a) than niacin alone. A combination treatment with omega-3 fatty acids did not produce consistent effects on Lp(a).
* ApoB antisense
Antisense oligonucleotides (ASO) selectively target mRNA to prevent the subsequent translation into protein. Mipomersen is an ASO directed against apoB100 that inhibits all apoB-containing lipoproteins including Lp(a). Indeed, in phase II studies in subjects with primary hypercholesterolaemia, 13 weeks of weekly mipomersen injections resulted in reductions in the range of 30-50%. The Lp(a)-lowering effect was confirmed in four phase III trials of 26 weeks and the effect has been shown to persist for 2 years. The use of mipomersen is, however, limited by side-effects.
* Microsomal Triglyceride Transfer Protein (MTP) inhibitors
Subjects with a genetic deficiency of Microsomal Triglyceride Transfer Protein (MTP) have very low levels of apoB-containing lipoproteins, as a result of lower hepatic synthesis. Thus it was hypothesised that pharmaceutical inhibition of MTP would have the same effect. Indeed, reductions of about 16% have been demonstrated with the MTP inhibitor lomitapide, alone or in combination with ezetimibe in a 12 week trial. However, in a phase III open-label trial, reductions seen at week 26 and 56 were not sustained at week 78.
Nowadays, apheresis treatment consists of selective removal of apoB-containing lipoproteins, including Lp(a). Lp(a) levels can be reduced by 70% immediately after an apheresis session, but they ‘rebound’ before the next treatment session. Despite the variations in levels, patients with elevated Lp(a) and CVD showed lower CVD event rates after initiation of apheresis treatment as compared with before. It should be noted that LDL-c levels were also reduced, so the effects cannot be entirely disentangled, but it is suggested that Lp(a) contributed to the CVD benefit.
* Cholesterol ester transfer protein (CETP) inhibition
Some studies evaluating CETP inhibition (with anacetrapib, evacetrapib and the more potent TA8995) have reported robust and sustained Lp(a) reductions of about 30%, with or without statins. The mechanism via which CETP inhibition may affect Lp(a) is unknown.
* PCSK9 inhibition
Unexpectedly based on its mechanism of action, PCSK9 inhibition with alirocumab resulted in robust Lp(a) reductions, ranging from 15-43% in a small dosing study. This effect was confirmed in a pooled analysis of data of 1359 patients from four phase II trials, and in later studies of the ODYSSEY program, in a dose-responsive manner. Lp(a) reductions of about 25% have also been reported with evolocumab.
The mechanism of Lp(a)-lowering as a consequence of PCSK9 inhibition remains to be elucidated. Recent data suggest that increased Lp(a) clearance may occur via the LDL-receptor, in the presence of low LDL-c levels.
* Specific (a) antisense
Apo(a) mRNA can also be targeted with ASO. In mice, treatment with an apo(a) ASO lowered apo(a) and Lp(a) by 86%, and also in cynomolgous monkeys treatment with ISIS-APO(a)Rx diminished plasma Lp(a) by >80%. Single doses had no effect in human healthy volunteers, but multiple dose trials showed about 40%, 60% and almost 80% with 100 mg, 200 mg and 300 mg respectively. Longer trials are needed and these may shed light on whether specifically lowering Lp(a) in patients with optimal LDL-c lowering treatment will reduce CVD events.
Find this article online at Cardiovasc Drugs Ther