LDL cholesterol remains the proven target. Many alternatives have been presented. The possibilities debated involved cholesteryl ester transfer (CETP) protein inhibitors, apolipoprotein B (apoB) mRNA antisense oligonucleotides, microsomal triglyceride transfer protein (MTP) inhibitors and proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies, which one would be better?
Thank you Dr. Mishra for yours considerations, with which I agree. Let's wait for the new studies to establish the behavior improvements .
Dear Paulo
the problem with MTP inhibition/apoB mRNA antisense is the enrichment of lipids within the cells and the risk of developing a fatty liver. Therefore the admission is restricted to a very limited number of patients (e.g. homozygous FH).
In my opinion CETP inhibition is a dead end, what to do gain with the increase of HDL mass but not functionality? Recently several publication showed very nicely that the functionality of HDL in people with CAD is different from healthy controls. If this is true an increase of these HDL can´t work, its only expensive lab cosmetic.
Actually I believe the most promising way will be PCSK9 inhibition.
Dear Paolo,
first a disclaimer - I am not a medical doctor. However, I would say that even before using statins, lifestyle modification should be the first alternative unless there are underlying genetic reasons for the high cholesterol (for example familial hypercholesterolaemia in which case LDL apheresis is still standard of care as far as I know).
In regards to treatment:
1. CETP inhibitors have either caused more deaths (torcetrabib) or not shown any clinical benefit in spite of HDL increases. Two more are still in clinical development, but I agree with Michael, they seem to be a dead end; probably related to the particular subclass of HDL that is beneficial vs the one that transfers cholesterol to VLDL and LDL.
2.Lomitapide (MTTP inhibitor) has gastrointestinal side effects in about 90% of patients as it also inhibits chylomicron formation in the intestine and thus fat and fat solulable vitamin uptake from food. As Michael pointed out, there have been concerns about fat accumulation in liver, but these seem to plateau and are reversible. Also, people with hypobetalipoprotenaemia who have ~20% of normal LDL levels due to ApoB truncation have fatty liver, but do not show hepatosteatosis or fibrosis. With lomitapide, there's also been increases in ALT levels. Anyway, it was approved for homozygous familial hypercholesterolaemia only under a Risk evaluation and mitigation strategy (REMS) in the USA and Europe, but at a cost of £230,000 - 650,000 depending on dose it seems unlikely it will be recommended by NICE here in England.
3. Mipomersen (ApoB antisense oligonucleotide) has only been approved in the USA again under REMS, while the EMA declined it due to concerns over increased cardiovascular events. This could be an artefact of the small study population, but does require careful monitoring.
4. PCSK9 inhibitors certainly seem to be swimming on top, although they will not be effective for LDLR negative familial hypercholesterolaemia as there is not point in inhibiting LDLR recycling if you don't have any in the first place. However, they've shown surprisingly good results in FH patients with at least partially functional LDLR. None of these is approved yet though and big longer term phase III studies are ongoing. There's a lot that still can go wrong.
Of course then there's my work on modulating ApoB splicing to mimic the shortened forms seen in hypobetalipoproteinaemia... except that with the rise in PCSK9 inhibitors we seem to be unable to get funding to take this into pre-clinical work.
In my opinion, herbal treatment options in addition with dietary and life style modifications are better candidates for lowering hyperlipidemia.
Ezetimibe (Zetia) blocks cholesterol uptake from the diet by inhibiting NPC1L1. This may be beneficial in some cases. Also, the PCSK9 inhibitors are showing promise. Along with statins combinations of therapies may be useful when diet and lifestyle changes are not sufficient to reduce risk.
The answer is contingent on the clinical context of the patient's hypercholesterolemia. Specifically, 1 in every 200-500 persons suffers from heterozygous familial hypercholesterolemia (HeFH). Hypercholesterolemia in HeFH is often resistant to statins, or these patients may be intolerant of statins, so your question is quite relevant. Here, combination of high intensity statin therapy with ezetimibe is usually recommended (eg NICE guideline) and has been shown to result in favourable LDL-c reduction. However some studies have shown that this combination versus statin monotherapy did not result in significant difference in intima-media thickness, so while ezetimibe drops LDL-c its clinical efficacy is still questioned. Perhaps PCSK9 inhibitors will be a welcome option.
OK Satish. I agree with you. Let´s hope the new results.
I think that the PCSK9 Inhibitors are the most powerful alternative to statins. Unfortunately they are not yet on the market. For the time being ezetimibe and the new anionexchange resin alone or in combination are probably the only choice in People whopresent a statin intolerability
OK Dr. Riesen, but I think in a few time we will have PCSK9 inhibitors as a strong alternative to patients intolerant to statins.
I agree on PCSK9 Inhibitors. However we must Keep in mind that most studies have been done as add on to statins. But PCSK9 ist certainly a valuable alternative to patients intolerant to statins