Patients With Obesity Get Biggest Benefit from Evolocumab: FOURIER

Using evolocumab (Repatha; Amgen) to treat stable patients with atherosclerotic cardiovascular disease (ASCVD) and obesity results in a larger decrease in major adverse cardiovascular events than it does for such patients when they have a lower body weight, according to an analysis of the FOURIER trial.

Among ASCVD patients with a body mass index (BMI) less than 30 kg/m², evolocumab cut the relative risk of major adverse cardiovascular events by 11%, much lower than the 29% risk reduction among those with class 2 or 3 obesity, which is defined as a BMI of 35 kg/m² or greater.

Yu Mi Kang, MD, PhD (Brigham and Women’s Hospital, Boston, MA), and colleagues report their findings in a paper published online this week in JACC.

“It’s interesting just how much of a gradient of benefit we saw by BMI,” senior investigator Michelle O’Donoghue (Brigham and Women’s Hospital), told TCTMD. “As a consequence, since BMI was also a predictor of risk, it’s quite striking the difference in the absolute risk reduction and number needed to treat [to prevent one clinical event] as you go up in weight.”

From a research perspective, O’Donoghue said it’s necessary to tease out the mechanism of benefit in patients with obesity since baseline LDL cholesterol levels, and the amount of LDL-lowering with evolocumab, were similar across the BMI spectrum. Evolocumab reduced LDL cholesterol by 60.8% in those with a BMI less than 30 kg/m² versus by 56.3% in those with class 2 or 3 obesity.

“This is something that we also saw with evolocumab in patients with autoimmune disease,” she said. “It does raise that question about whether there is something about the inflammatory milieu and whether that helps to identify patients who may benefit from more intensive lipid-lowering.”

In that previous analysis, evolocumab reduced the risk of the primary endpoint—a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization—by 14% in patients without an autoimmune or inflammatory disease and by 42% in patients with these types of diseases, most commonly rheumatoid arthritis or psoriasis.

Largest Absolute Reduction, Lower Number Needed to Treat

FOURIER was the first randomized, controlled trial to demonstrate that a PCSK9 inhibitor could cut the risk of MACE in patients with ASCVD. Published in 2017, the study showed evolocumab reduced the relative risk of the primary endpoint by 15% when compared with placebo over a median follow-up of 2.2 years. The next year, the ODYSSEY Outcomes trial showed that alirocumab (Praluent; Regeneron/Sanofi) provided a similar benefit when used in patients with a recent ACS.

Of the 27,500 patients in FOURIER with BMI information, 42% were overweight (BMI ≥ 25 to < 30 kg/m²) and 40% were obese (BMI ≥ 30 kg/m²). One-third of patients with obesity, or 13% of the total trial population, had class 2 or 3 obesity. These patients were younger on average and more likely to be female, to be enrolled in North America, to have diabetes, and to be treated with a high-intensity statin.

The analysis found an inflection point around 30 kg/m² where the risk of MACE increased. For each 5-unit jump in BMI beyond 30 kg/m², there was a significant 11% higher risk of the primary endpoint and a significant 16% increase in the risk of cardiovascular death, MI, or stroke.

This is something that we also saw with evolocumab in patients with autoimmune disease. Michelle O’Donoghue

When participants were stratified by BMI (< 30, 30 to < 35, and ≥ 35 kg/m²), evolocumab reduced the relative risk of the primary endpoint by 11%, 14%, and 29%, respectively. Across BMI groups, the absolute reductions in risk were 1.4%, 1.8%, and 5.7%, respectively. In those without obesity, 71 patients would need to be treated evolocumab to prevent one primary endpoint. In those with class 2 or 3 obesity, the number needed to treat was just 17 patients.

Regarding the composite endpoint of cardiovascular death, MI, or stroke, evolocumab reduced the relative risk by 18%, 16%, and 33% across the three BMI categories (absolute risk reduction 2.0%, 1.1%, and 4.1%, respectively).   

Researchers also performed an exploratory analysis further stratifying patients by baseline levels of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. Here, evolocumab cut the relative risk of the primary endpoint by 10% in patients without obesity and without high hs-CRP. In contrast, the relative risk was reduced by 25% with evolocumab in the patients with obesity and hs-CRP levels > 3 mg/L.

To TCTMD, O’Donoghue said the interplay between BMI, inflammation, and the effectiveness of evolocumab should be considered hypothesis-generating only at this point.

Right now, there is a lot of focus on the glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of obesity, as well as their ability to reduce cardiovascular risk in patients with overweight or obesity who have preexisting cardiovascular disease. While obesity alone is not an indication for initiating more intensive lipid-lowering therapy, the present analysis raises questions about whether BMI should be considered when thinking about starting or intensifying treatment to lower LDL cholesterol, she said.

Another interesting question the FOURIER analysis raises is whether there’s anything to be gained from combining treatments. Given that evolocumab lowers LDL cholesterol but doesn’t impact body weight, and that the GLP-1 receptor agonists slash weight with only a modest effect on cholesterol, it’s possible that combining the two treatments might lead to an additive benefit when it comes to ASCVD risk reduction, said O’Donoghue. That, however, would need to be investigated in a clinical trial.