New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs.

Norata GD, Ballantyne CM, Catapano AL
Eur Heart J. 2013 Mar 18

Dyslipidaemias are a key factor in determining cardiovascular disease (CVD). Lowering LDL-C by statins is effective at reducing CV risk. However, other lipoprotein classes also play important roles in determining CV risk. Furthermore, some high-risk patients fail to reach recommended LDL-C levels despite statin treatment.
We here summarise new therapeutic strategies aimed at modulating lipoprotein levels that are currently being evaluated in clinical trials, as discussed in this review article by Norata et al.

Therapeutic agents lowering LDL-C

Statins promote LDL-receptor activity, following the inhibition of HMG-CoA reductase activity. It would be most efficient if new LDL-C lowering agents would form an add-on therapy to statins, by integrating their mechanism of action with that of statins. This can be reached by two strategies:

1. Agents interfering with lipoprotein synthesis such as apolipoprotein B (apoB) production or microsomal triglyceride transfer protein (MTP) inhibitors,
2. Those promoting lipoprotein catabolism such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

ApoB and the chaperone protein MTP are crucial for hepatic production of very low-density lipoprotein (VLDL). Interfering with lipoprotein assembly is an attractive approach for reducing lipoprotein production and subsequently plasma LDL-C concentration.

Apolipoprotein B production inhibitors

Protein synthesis can be prevented by blocking translation at the level of mRNA: antisense oligonucleotides (ASOs) can induce mRNA degradation. ASOs are rapidly distributed to the liver.
ASOs directed at apoB are quite effective in mice at reducing apoB mRNA, with subsequent reductions in LDL-C, LDL particle number, circulating TG and lipoprotein (a) (Lp(a)).
Mipomersen is an ASO targeting apoB, which shows a dose-dependent reduction in apoB and total cholesterol in clinical trials, but adverse effects (mostly injection site reactions) also increase with dose. Liver fat accumulation has also been observed, which is expected based on the mechanism of action of the drug. Further studies will need to shed more light on potential inflammatory responses in the liver. Results of clinical trials in patients mild-to-moderate hyperlipidaemia, familial hypercholesterolaemie (FH) and statin-intolerant patients are discussed in detail.
In January 2013 mipomersen has been approved by the FDA for use in homozygous FH with a warning for the possible clinical consequences of the liver fat accumulation. EMA on the other hand issued a negative opinion on mipomersen based on safety issues, thus further assessment is awaited.

Microsomal triglyceride transfer protein (MTP) inhibitors

MTP mediates the formation of apoB-containing lipoproteins in the liver and the intestine. A genetic disease arising from a mutation in the MTP gene suggested that inhibiting MTP may reduce circulating concentrations of cholesterol and apoB-containing lipoproteins.
Lomitapide is an MTP inhibitor, which has completed phase III testing. Either by itself or in combination with conventional lipid-lowering therapy in homozygous FH or in patients with hypercholesterolaemia, lomitapide lowered LDL-C, apoB, non-HDL-C and Lp(a) levels. Adverse effects were seen, namely a dose-dependent increase of aminotransferase levels and accumulation of hepatic fat, as well as potentially drug-related gastrointestinal side-effects. These adverse effects may restrict the patient population. However, for patients with homozygous FH that do not obtain sufficient effect with conventional lipid-lowering therapy, MTP inhibition may prove beneficial.
Lomitapide has been approved by the FDA in December 2012, for treatment of patients with homozygous FH. Approval from EMA is pending.
Liver fat accumulation may vary greatly between patients, thus requires careful monitoring and further investigation. No cases of suspected drug-induced liver injury have been observed, but longer-term follow-up should definitely exclude progression to fibrosis and cirrhosis.

Promoting lipoprotein catabolism

LDL-receptor (LDLR) levels determine the uptake of circulating apoB-containing lipoproteins, by binding for example LDL and internalising the receptor-LDL complex into the hepatocyte. More receptors on the hepatocyte surface means higher LDL turnover and lower plasma cholesterol levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that promotes degradation of the LDLR. Mutations in the PCSK9 gene which were associated with lower LDL-C levels, hinted at a potential beneficial effect of inhibiting PCSK9.
At least five monoclonal antibodies (mAbs) and three gene-silencing approaches are currently under development. Promising results have been obtained in phase II trials with mAbs; PCSK9 antibodies are effective at lowering LDL-C, with limited adverse effects. However, studies performed to date have been short in duration, so longer-term safety and efficacy remains to be determined. (for more information read our introduction into the therapeutic potential of monoclonal antibodies in the treatment of CVD),
Other approaches to inhibit PCSK9 activity include nucleic-acid-based strategies, which silence gene translation. Efforts using a locked nucleic-acid-based inhibitor or an antisense RNA therapy were terminated during phase I clinical trials, but preliminary data on the use of an RNA interference molecule are promising regarding both efficacy and safety.

Other agents designed to reduce LDL-cholesterol levels include:

• Ezetimibe decreases cholesterol absorption in the intestine, increases cholesterol synthesis and increases the expression of LDL receptors, which can cause a further reduction in LDL-C after statin therapy.
• ETC-1002 is a dual modulator of AMP-kinase and ATP-citrate lyase, which modulates the cholesterol, carbohydrate and fatty acid metabolism. Initial data show a reduction in LDL-C and good tolerance.
• Cholesteryl ester transfer protein (CETP) inhibitors have been designed to improve HDL plasma levels, by decreasing flux of cholesterol into apoB-containing lipoproteins from HDL. They also appear to reduce VLDL and LDL plasma levels, through an as yet unknown mechanism. CETP inhibitors anacetrapib and evacetrapib are currently being tested in phase III endpoint clinical trials, after having shown promising results in phase II trials. Both agents were well-tolerated with no adverse effects on blood pressure and mineralocorticoid levels.

Lipoprotein(a)-lowering drugs

Several lines of evidence point at a causal role Lp(a) levels in the development of CVD. It is unclear whether this is the result of proatherogenic mechanisms or of enhanced coagulation or both. Lp(a) is relatively refractory to lifestyle and drug intervention, although statins have a mild Lp(a)-lowering effect in patients with heterozygous FH. Contradicting results on a Lp(a)-reducing effect of niacin exist. Some other agents also exist that mildly lower Lp(a), but controlled intervention trials with selective reduction in plasma Lp(a) levels aimed to reduce CVD risk are still needed.
Proper lipidation of apoB is a prerequisite for Lp(a) synthesis and secretion into plasma, thus it was not surprising that mipomersen and lomitapide caused a Lp(a) reduction. Another approach might be to inhibit apo(a) gene expression with ASOs. Better understanding of the Lp(a) metabolism may provide new therapeutic targets.

Conclusion

Since some patients do not reach sufficiently low LDL-C levels with statins, or some patients do not tolerate high-dose statin therapy, they remain at an unacceptably high risk for CVD. Genetic and mechanistic insights have provided us with new therapeutic approaches.  A combination of statins and newly developed agents may improve therapeutic outcome by lowering LDL-C more effectively. Lp(a) may furthermore prove to be an attractive target, but novel therapeutic approaches are needed. Until then, lowering LDL-C in high-risk individuals remains the central focus in decreasing cardiovascular risk. 

For more information on monoclonal antibodies in the treatment of CVD read our introduction into the therapeutic potential of monoclonal antibodies.

Abstract

Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach.