LDL Cholesterol Lowering and CV Risk

Deepak L. Bhatt, MD, MPH: Dr Budoff, I wonder if you could tell us a little bit about the underlying pathophysiology of cardiovascular disease, in particular as it pertains to dyslipidemia and what’s driving that?

Matthew J. Budoff, MD: Thank you, Dr Bhatt. When we think about dyslipidemia and how it impacts our coronary tree, we have to remember that it starts with LDL [low-density lipoprotein] cholesterol itself. And as it gets incorporated into macrophages and those macrophages turn into foam cells, that’s the biological basis for development of atherosclerosis. And it’s impacted by a lot of things that Dr Navar talked about, concomitant risk factors and certainly inflammation. Oxidation is very important.

But when we think about how we can take something as commonplace as a cholesterol molecule and end up with an atherosclerotic plaque, it requires a lot of different factors. I think the LDL and the smaller, denser LDL becomes easier to penetrate the endothelium, get into the underlying blood vessel, and then turn that macrophage into a malignant foam cell that can cause atherosclerosis and develop our plaque that grows over time, incorporates more lipids. And eventually, unfortunately when it ruptures it can lead to a macrovascular event such as a heart attack, stroke, or cardiovascular death.

Deepak L. Bhatt, MD, MPH: That’s a nice play-by-play of exactly how dyslipidemia can cause so much trouble. Maybe I can turn back to Dr Navar for a second. What are your thoughts in terms of targeting that risk with aggressive LDL lowering? How useful is that as a strategy to reduce cardiovascular risk? And how low should you go? What is the right target? Is it still less than 100 [mg/dL]? Is it that 70 to 100 [mg/dL] range? Is it less than 70 [mg/dL]? Is it even lower than that? The guidelines do give us some guidance, but there are lots of guidelines out there and a number of them have different points.

I think physicians like numbers. What do you think about LDL lowering as being a strategy for risk reduction? And, how low to go?

Ann Marie Navar, MD, PhD: This is a really important question and one that’s changed over time. If you look back to the early studies of cholesterol lowering in patients with coronary heart disease, the lipid levels were what we would now consider completely unacceptable—LDLs of 160 [mg/dL] and above.

As we’ve continued trials, we’ve seen a progressive lowering in the inclusion criteria and the LDL levels of those who are receiving treatment. We have yet to find a group with LDL cholesterols that do not benefit from LDL lowering. I think the best data from this come from meta-analyses from the cholesterol treatment trialists that show us that the benefit of LDL lowering therapies has nothing to do with what your starting LDL is. It has to do with how much LDL you reduce on treatment. So for statins, the amount of benefit is directly proportional to the amount of LDL lowering.

We also see from secondary analyses that coronary and cardiovascular risk is lower when your LDL is lower, even down to levels well below 50 mg/dL. We see almost a linear reduction in cardiovascular risk going down to levels of 30 [mg/dL] or even lower.

We used to have what we would consider targets. But really, the guidelines are now making of us think more in terms of triggers. So, what level of LDL confers the potential for a reasonable amount of LDL reduction below which you would actually see a reduction in cardiovascular events? The new US guidelines recommend thinking about adding lipid lowering therapy and secondary prevention for those with LDL levels over [70 mg/dL]. But 70 [mg/dL] isn’t our goal. It’s not a target. It’s really a trigger to say, if you’re over 70 [mg/dL], you probably have substantial room for improvement in regard to lowering LDL cholesterol.

That needle has shifted pretty dramatically. The European guidelines actually go further. In the highest-risk patients, they are recommending trying to get patients to less than 55 mg/dL. I would argue that is pretty in line with what the US guidelines recommend. If you think of the US guidelines as using 70 [mg/dL] as a trigger for therapy, and the European guidelines using less than 55 [mg/dL] as a target, then we think, if you’re looking at the US guidelines and you’re intensifying therapy at 70 mg/dL you’re going to get most of your patients down to 50 mg/dL. That’s a level where some studies have shown if you can get LDLs to 50 [mg/dL] and below, you can start to see not just plaque stabilization but a regression of atherosclerotic plaque.

Deepak L. Bhatt, MD, MPH: That’s a nice way of tying together the epidemiology with the underlying biology with some insights from imaging studies from the past. I’ll add that LDL is a critically important risk factor. Now we know lower is better. You can get there safely through a variety of different medications. Obviously diet and lifestyle modification is an important foundation, but for many at-risk patients, pharmacotherapy will also be needed.

In recent years, I think we’ve discovered, or perhaps it’s fair to say we’ve rediscovered that triglycerides are also important in determining cardiovascular risk. And they seem to be an independent risk factor.

And it seems like there, too, even levels of triglycerides that we used to call normal are, at a minimum, associated with excess cardiovascular risk. This is something we can no longer ignore when evaluating patients, but we’ll come back to that a little bit later in our discussion.