Randomized trials indicate a lipid-lowering agent such as a PCSK9 inhibitor, ezetimibe, inclisiran or bempedoic acid can reduce cardiovascular event risk when added to statin therapy. Most clinical guidelines worldwide appropriately suggest low-density lipoprotein cholesterol (LDL-C) should be as low as possible. Yet randomized trials of adding targeted anti-inflammatory agents to statin therapy have also shown significant benefits for cardiovascular outcomes.
A current debate in cardiology is whether clinicians should choose an anti-inflammatory agent or a second cholesterol-lowering agent for people on statin therapy.
Now, a collaborative analysis of 31,245 participants in three recent randomized trials suggests residual inflammatory risk is more strongly associated with future cardiovascular events than residual cholesterol risk. Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention in the Division of Preventive Medicine at Brigham and Women’s Hospital, and colleagues provide guidance to prescribers in The Lancet.
The researchers analyzed three multinational trials that recruited patients with moderately elevated triglyceride who were on a statin for primary or secondary prevention and received an additional agent:
- PROMINENT, published 2022—Pemafibrate vs. placebo (n=9,988)
- REDUCE-IT, published 2019—Icosapent ethyl vs. mineral oil (n=8,179)
- STRENGTH, published 2020—Omega-3 fatty acids vs. corn oil (n=13,078)
The current analysis was truly collaborative. Each of the three trial coordinating centers was asked to convert data into a standard template and conduct specific statistical analyses. One of the centers performed meta-analyses of the three trials, and each trial group computed risk estimates across four predefined subgroups.
Those subgroups were participants with both residual inflammatory risk and residual cholesterol risk (high-sensitivity C-reactive protein [hsCRP] ≥2 mg/L and LDL-C ≥70 mg/dL), participants with only residual inflammatory risk, participants with only residual cholesterol risk and participants with neither risk.
Outcomes for hsCRP
In all three trials, baseline hsCRP was a significant predictor of incident cardiovascular events:
- Major adverse cardiovascular events (MACE)—HR, 1.20 for the highest high-sensitivity CRP quartile vs. the lowest in PROMINENT, 1.48 in REDUCE-IT, 1.23 in STRENGTH, and 1.31 when combined in a meta-analysis
- Cardiovascular death—HR, 2.55, 2.45, 3.02, and 2.68, respectively
- All-cause death—HR, 2.29, 2.32, 2.69, and 2.42, respectively
Outcomes for LDL-C
In all three trials, the relationships of baseline LDL-C to subsequent cardiovascular event risk were less robust than for hsCRP:
- MACE—HR, 1.11 for the highest LDL-C quartile vs. the lowest in PROMINENT, 1.10 in REDUCE-IT, 1.03 in STRENGTH, and 1.07 when combined
- Cardiovascular death—HR, 1.55, 1.26, 1.15, and 1.27, respectively
- All-cause death—HR, 1.33, 1.11, 1.04, and 1.16, respectively
Opportunities to Improve Care
These results must not be interpreted as diminishing the crucial role of adjunctive lipid lowering beyond statins for patients with persistent or refractory hypercholesterolemia. However, they do suggest targeting LDL-C alone is unlikely to completely reduce atherosclerotic risk.
For general practice, the most applicable anti-inflammatory agent for vascular protection is oral colchicine 0.5 mg/day. This regimen has been associated with relative and absolute risk reductions at least as large as those obtained in trials of adjunctive lipid-lowering agents.
Combining aggressive lipid-lowering and anti-inflammatory therapies may someday be standard care for atherosclerotic disease.