Inflammation is Key to Reducing Adverse Cardiovascular Events

Haris Riaz, MD

A recent meta-analysis found that lipid-lowering therapies, such as statins and PCSK9 inhibitors, reduce the relative risk of major adverse cardiovascular effects in patients with varying levels of inflammation, but that the therapies did not mitigate the risks associated with higher levels of inflammation.

Haris Riaz, MD, a fellow at Cleveland Clinic in Cleveland, OH, presented results from the study at the American Heart Association Scientific Sessions 2018 in Chicago, IL.

This area of study—the role of inflammation in coronary artery disease—is a brand-new field, according to Milind Desai, MD, also a cardiologist at the Cleveland Clinic and a study author.

Pulling from 13 randomized controlled trials of either statins or PCSK9 inhibitors compared with either placebos or active controls, the investigators analyzed whether either form of lipid-lowering therapy was associated with a reduction in inflammation. Inflammation was measured by levels of high reactivity C reactive protein (hsCRP).

“It turns out that the patients with the least hsCRP derived the most benefit from lipid-lowering therapy, suggesting that the event rate is higher with higher inflammation,” Riaz told MD Magazine®.

However, the meta-analysis found that high-dose statins did not significantly reduce hsCRP compared to placebo or low-dose statins (standard mean difference [SMD], -.016; 95 % confidence interval [CI] -.099, .066; P = .69) despite showing a significant reduction in MACE across all hsCRP levels (HR .81, 95% CI .72-.91; P <.001).

Additionally, PCSK9 inhibitors did not produce differences in hsCRP levels with therapy (SMD = 0; 95% CI -.017-.017; P = 1) despite a significant reduction in MACE (HR .86; 95% CI .81-.92; P < .001).

Looking ahead, the investigators said that research into which patients will benefit most from anti-inflammatory treatment will be a focus. Additionally, Riaz emphasized the need for the development of new anti-inflammatory therapies.

“There is a dire need for further therapies that can reduce this inflammation,” said Riaz.

What were you investigating in this study?

What was the connection between inflammation and MACE risk?

Milind Desai, MD: The overriding big picture is: the study looked at residual inflammatory risk in patients that were enrolled in large lipid-lowering trials.Haris Riaz, MD: Typically speaking, studies have looked at 3 different levels of inflammation. One is folks with high sensitivity C reactive protein of less than 2. The second ones are the folks with high sensitivity C reactive protein between 2 and 3, and the third are the ones with high sensitivity C reactive protein of greater than 3.

Did inflammation differ between groups taking statins and PCSK9 inhibitors?

It turns out that there is a linear relationship between inflammation and cardiovascular endpoints, such that the more inflammation you have the worse off you typically are. I think that would also explain why patients with inflammatory disorders, like rheumatoid arthritis and what have you, tend to have higher cardiovascular events compared to those who have less.Riaz: So, you know what is well known is that statins compared to placebos reduce inflammation—that is well-established. So, that's why we looked at 2 different groups: one is PCSK9 [inhibitors] compared to placebo, and PCSK9 inhibitors have absolutely no effect on inflammation whatsoever, which I think is a very interesting finding in this particular study.

What is the “take-home” message for clinicians?

Desai: It is important, Haris’ point is very crucial. In the general community, the thought process is, “if you lower the lipids as low as you can, it’s all going to be okay.” But there is clearly an increasing understanding that lipids bring a lot more to the table, in terms of pleiotrophic effects especially anti-inflammatory effect. And PCSK9 inhibitors are flat—there is absolutely no impact on the inflammation. So, the concept of “oh, I cannot tolerate the statins, so the higher-power PCSK9 are going to be okay”&mdash;it may not entirely work the way we want it to. I think that's an important message that needs to be conveyed and this data needs to be teased out.Riaz: What we showed was that despite the contemporary lipid-lowering therapy, either in the form of statins or ezetimibe or PCSK9 inhibitors, the inflammation still persists. So, I think the take-home message of this study is that the future studies should look into adding anti-inflammatory therapy on the background of high-intensity lipid-lowering therapy to see if we can mitigate the inflammatory risk.