Prof Julian Halcox, Professor of Cardiology, Swansea University College of Medicine, UK, speaks with Cardio Debate & Radcliffe Cardiology about Advances in the Management of Dyslipidaemia (Part 2 of 3 interviews), during the 2015 Cardiovascular Sciences Research Centre Annual Meeting held at the Royal College of Surgeons of England in London, UK.
What are the latest advances in the treatment of dyslipidemia?
I think that before we talk about some of the positive stories it’s important to reflect on the less salubrious outcomes. Firstly the failure of two really important clinical strategies – the use of niacin and also the use of CETP antagonism.
So niacin, for example, increases HDL cholesterol levels, reduces triglycerides to a certain extent and has a small impact on LDL in total cholesterol. But interestingly we’ve seen in large-scale clinical trials a neutral impact on cardiovascular outcomes in a population of high-risk patients on statins, but also specifically in individuals with low HDL cholesterol in whom one might consider that they would be more likely to derive a beneficial effect from niacin therapy when added on top of a statin by virtue of the increased residual risk seen in these patients. But unfortunately that wasn’t to be the case.
When it comes to the story of the CETP antagonists, three our of four of the agents that have been tested out in large-scale clinical trials have already fallen by the wayside.
The first called Cetapin which failed possibly due to off-target effects, there was an increase in cardiovascular events that seemed to be independent of its effect on lipids. But also with two other agents, dalcetrapib and most recently evacetrapib – these trials were discontinued due to the lack of any beneficial signal being seen at the stage of analysis that they’d got to.
The question really is whether CETP antagonism is a strategy that is going to improve outcomes. Now going back to my initial points on HDL cholesterol levels being associated epidemiologically with outcome, one might confer that having high levels of HDL cholesterol level would be associated with the benefit – actually we see with the CETP antagonists, although they raise HDL cholesterol levels quite substantially, in three studies so far there doesn’t appear to be a beneficial effect.
And that’s perhaps because of the nature of the effect of CETP antagonism. CETP is an agent that facilitates the translocation of cholesterol ester and triglyceride between Apo-B containing proteins and the Apo-A lipoprotein, so it retains the cholesterol ester with the HDL particles and retains triglyceride within the LDL Apo-B containing lipoproteins if its inhibited.
So what we see is more cholesterol within the HDL sub-fraction, which doesn’t necessarily improve its function. It doesn’t necessarily mean that there’s an increase rate of reverse cholesterol transport, it doesn’t necessarily mean that there’s a clinically significant impact on function – perhaps even a deleterious effect on function.
We’re still waiting, of course, for the results of the HPS3 Study which is testing out anacetrapib in a huge population of patients, but we’ll have to wait to see what happens. But judging by the effects seen in the first three studies I’m not holding out any hopes there.
There’s also interest returning to the Omega-3 fatty acid story, which I think is on a positive note. We know that in a couple of fairly large trials conducted recently with low dose supplementations – 1 gram a day, which doesn’t really have much of an appreciable effect on triglyceride and levels of vLDL in the system. There was no significant benefit on outcomes.
However, retrospective analysis of a large study called the GISSI study that looked at just under 2 grams of EPA suggested that there was a beneficial impact on cardiovascular outcomes, particularly in a sub-group analysis of individuals with the low-levels of HDL and high levels of triglyceride, who tend to have more atherogenic lipoproteins – their triglyceride-rich lipoproteins are very abundant which are associated with a greater preponderance of small dense LDL which is more atherogenic, it gets into the vessel wall more easily, it stays in the vessel wall more readily. In these individuals, the higher dose omega-3 intervention with a substantial impact on triglyceride levels and the atherogenic lipoprotein biology, this seemed to have a beneficial effect.
There’s been a couple of new omega-3 agents developed recently. A compound which is a semi-synthetic EPA which is currently marketed in American for treatment of hypertriglyceridemia, called Vascepa. And then a new agent which has just been licensed in the US called Epanova which is a fatty acid preparation rather than an ethyl ester or triglyceride preparation of EPA.
And these agents seem to have fairly profound effects on triglyceride levels, and on the atherogenics of the triglyceride-rich lipoproteins. And these agents are being tested out in large adequately powered outcome trials in high-risk patients.
It may be a little while before they present, but judging by the effects of the GISSI study using higher doses that really have an appreciable effect on the atherogenic lipoprotein biology, I think this could be an interesting thing to look out for.