Statin Users Show LDL Doesn't Come Close to Telling Whole Story of ASCVD

NEW ORLEANS -- It was inflammation, not cholesterol per se, that was the bigger contributor to residual cardiovascular risk on statin therapy, according to a large meta-analysis of the PROMINENT, REDUCE-IT, and STRENGTH trials.

Statin-treated individuals pooled across these studies had 3- to 5-year clinical outcomes tied more strongly to high-sensitivity C-reactive protein (hsCRP) than LDL cholesterol:

• Major adverse cardiovascular events (MACE) risk was significantly elevated in the top two quartiles of hsCRP and had no relationship with LDL cholesterol
• Cardiovascular mortality risk was higher in the top three quartiles of hsCRP and the top quartile of LDL cholesterol
• All-cause mortality was elevated in the top three quartiles of hsCRP and the top quartile of LDL cholesterol

"In all three trials, individuals with elevated hsCRP were at high cardiovascular risk irrespective of LDL cholesterol level," reported Paul Ridker, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, at the American College of Cardiology (ACC) annual meeting. The full paper was published in The Lancet.

"While these data must not be construed to diminish the proven and crucial role of adjunctive lipid-lowering for those with persistent or refractory hypercholesterolemia, they do suggest that targeting of LDL cholesterol alone is unlikely to completely reduce atherosclerotic risk and that inflammatory pathways have yet to be fully exploited to reduce fatal and nonfatal cardiovascular events," Ridker told the audience.

His suggestion for clinical practice is the introduction of an anti-inflammatory agent instead of another purely LDL-lowering drug for patients on existing statin therapy.

For example, colchicine, previously considered a gout medication, may be considered for those with stable atherosclerosis and normal kidney function based on the COLCOT and LoDoCo2 trials. Those studies used a 0.5-mg dose of colchicine, however, which is not yet FDA approved for the indication of cardiovascular prevention.

Ridker added that concomitant LDL lowering and anti-inflammatory effects may be found in bempedoic acid (Nexletol), GLP-1 receptor agonists, and SGLT2 inhibitors.

A notable late-breaking trial at this year's ACC, CLEAR Outcomes had recently shown that bempedoic acid modestly reduces MACE while cutting LDL cholesterol by approximately 22% and hsCRP by another 22%.

That 22% hsCRP reduction is "pretty good" and "equivalent to a higher-intensity statin," said the investigator Steve Nissen, MD, of Cleveland Clinic, who added that his group is looking to probe how much each LDL and hsCRP contributed to bempedoic acid's reduction of clinical events.

"It is not an either/or situation," Ridker stressed. "In the future, we believe the combined use of aggressive LDL-lowering and inflammation inhibiting therapies will become standard of care for almost all atherosclerotic patients."

"I've argued for years that we should be measuring CRP. If you're not measuring CRP, you have no idea if the patient has this problem," he said. "Physicians need to recognize there's a big chunk of [heart] disease that we are systematically ignoring."

Inflammation-lowering lifestyle habits such as diet, weight loss, exercise, and smoking cessation remain important as well, he added.

Session discussant Kim Williams Sr., MD, of University of Louisville in Kentucky, echoed the sentiment on diet and endorsed plant-based nutrition to reduce LDL and CRP.

"I think that these findings are important because cardiovascular risk is multifactorial. Lipids, although a major contributor, are not the sole cause of CVD. As we look to minimize residual risk clinicians need to be conscious of other risk factors, but we also need to continue to learn more about how to treat them," commented Eric Brandt, MD, MHS, of University of Michigan in Ann Arbor.

PROMINENT, REDUCE-IT, and STRENGTH were three multi-national trials assessing clinical outcomes of triglyceride-lowering therapy in over 31,000 statin-treated individuals.

The pooled cohort had a mean age of 64 and was around 30% women. At enrollment, median LDL cholesterol was around 76 mg/dL and triglycerides 240 mg/dL. Median hsCRP was approximately 2.1 mg/L.

Altogether, around half of participants were on high-intensity statins at baseline, and two-thirds were considered secondary prevention patients. This population was generally on excellent background care, according to Ridker.

"Although the results from this study represent an important step in our understanding of the role of cholesterol and inflammation among patients receiving statin therapy, caution should be exercised in their interpretation," according to Jean-Claude Tardif, MD, and Michelle Samuel, PhD, MPH, both of Montreal Heart Institute.

The pooled analysis had the limitation of leaving room for confounding, according to an accompanying comment.

"High-intensity statin use and diabetes are known confounders for the associations between cholesterol, inflammation, and cardiovascular events; however, the multivariable Cox models did not account for those factors. Effect modification according to the setting of primary prevention versus secondary prevention was also not investigated," Tardif and Samuel cautioned.

Brandt also cited non-HDL and apolipoprotein B as other ways to measure atherogenic lipids that may be more accurate. "I wonder if the impact of atherogenic lipids measured by either of these markers would have had a higher treatment effect," he told MedPage Today.