What new data can teach cardiologists about statin use and treating inflammation

Ridker said the JUPITER trial, published in 2008, showed that anyone with elevated cholesterol needed to be on a statin, which has been the basis for cardiovascular preventive care for about 30 years. However, he and his team wanted to see if there is anything else cardiologists should be keeping an eye on in addition to cholesterol. To do this, he looked at trial data where the main focus was not low-density lipoprotein (LDL) or CRP. 

He recently ran a trial called PROMINENT, in which he had a deep look into his own database of patients. 

"I was expecting to find both the lipid piece and the CRP piece were going to be similar as it was 25 years ago, well, it wasn't," Ridker explained. "What we found was, among the patients taking stains in the PROMINENT trial, there was a very strong gradient of risk, what I call residual inflammatory risk. So the CRP levels were a very powerful predictor of cardiovascular and all-cause mortality, and the LDL levels were less so."

To confirm this elevated risk, he collaborated with Deepak Bhatt, MD, principal investigator of the REDUCE-IT trial, and Steven Nissen, MD, principal investigator of the STRENGTH trial, to pool their data for analysis in the study presented at ACC.23 and published in the Lancet.[1]
  
"To my surprise, the observation we made in PROMINENT, that CRP was a much stronger risk predictor was exactly the case as well in REDUCE-IT and STRENGTH. That surprised all three of us and it was not what we expected," Ridker said. "This is a very provocative paper because what it says is in contemporary, guideline-directed care on high intensity statins, we have done a very good job of lowering LDL, but we are not really attacking that inflammation in any fundamentally, useful way."

The CANTOS trial in 2017 showed a proof of principle that if the inflammation is targeted, cardiovascular risk can be lowered in a patient, even without changing LDL levels, Ridker said. So the new data showed maybe a bigger focus should be made on targeting inflammation

"The bigger question here with the new data is what are the implications? The data are very clear cut — CRP really matters. And it is really surprising to me how few of my colleagues measure CRP at all. For those colleges I would say you measure LDL so you know what you are doing. You measure blood pressure so you know what you are doing. If you are not measuring CRP, you don't even know who in the clinic has this residual inflammatory risk problem," he explained. "You need to measure CRP just like you measure LDL and blood pressure."

How to treat coronary inflammation 

A second point the data raises is what can be done to treat inflammation. While CANTOS showed proof of concept, Ridker said he would not recommend the drug canakinumab used in the trial for several reasons.

Low-dose colchicine is a good option, Ridker said. Larger randomized trials of the drug have shown reductions in risk. 

"To remind people, colchicine has a 32% reduction in risk. Now PCKS-9 inhibitors only give us a 15-17% reduction in risk and they are very expensive. But colchicine is very inexpensive, but physicians are not using it. So I think physicians should start thinking about using colchicine," Ridker said. 

He said one big issue is colchicine is that it is not good for patients with renal insufficiency. It also has interactions with some anti-fungal medications. 

Other suggestions to reduce inflammation include changes in diet, exercise and smoking cessation. Ridker said those three areas all lower CRP and the body's inflammatory response. He measures CRP to monitor the impacts of following these suggestions and to remind patients that they are not doing what they should to help themselves. 

Drugs that can lower LDL and CRP such as statins and bempedoic acid are very helpful, but he said new drugs that specifically target the inflammation are in development. 

Ziltivekimab targets interleukin-6 inhibitors (IL-6), which has been implicated in atherothrombosis. Ridker said the agent can be used in patients who cannot take colchicine. The ZEUS and HERMES trials are ongoing. 

Other drugs for gout that work in specific inflammation pathways are now being considered for trials in cardiovascular disease, Ridker added.  

Key takeaways from the study

Ridker said targeting LDL is still a primary goal, but the data show cardiologists need to look at the inflammation as well and find ways to lower it if they want to improve outcomes. 

"If we do not attack the inflammation, we just are not going to get the best outcomes for our patients," Ridker said. "We in the cardiology community have done a great job on the LDL side, we just to focus on the other half of the inflammation piece."