PCSK9 Drug Prevents First Heart Events in Diabetes Patients Without Atherosclerosis

NEW ORLEANS — Evolocumab (Repatha) reduced risk of a first major cardiovascular (CV) event in patients with diabetes but no known atherosclerosis in a substudy of the VESALIUS-CV trial.

The PCSK9 inhibitor cut relative risk by 31% compared with placebo whether looking at the composite of death from coronary heart disease, myocardial infarction (MI), or ischemic stroke (5-year Kaplan-Meier estimate 5.0% vs 7.1%, P=0.009) or the same composite plus ischemia-driven arterial revascularization (7.6% vs 10.5%, P=0.001).

In secondary findings, evolocumab cut mortality by a relative 24% more than placebo (5-year Kaplan-Meier estimate 7.8% vs 10.1%, HR 0.76, 95% CI 0.61-0.95), reported Nicholas A. Marston, MD, MPH, of Brigham and Women’s Hospital in Boston, at the American College of Cardiology annual meeting.

The findings, which were simultaneously published in JAMA, add to the primary trial results in the broader primary prevention population of patients with atherosclerosis or high-risk diabetes, which had shown a 19-25% reduced risk of the composite endpoints without a mortality benefit.

“These data show the value of intensification of lipid-lowering therapy with the PCSK9 inhibitor evolocumab earlier in the disease process in a high-risk population without known significant atherosclerosis and with diabetes,” the researchers concluded.

Philip Greenland, MD, and Donald M. Lloyd-Jones, MD, both of Northwestern University in Chicago, agreed in an accompanying editorial that “clinicians should double down on risk assessment and treatment of all known risk factors, as recommended by existing primary prevention guidelines.”

Marston’s group pointed out, though, that guidelines for high-risk primary prevention patients, such as those with diabetes without known atherosclerotic CV disease, have recommended a moderate-intensity statin, “with a class IIa recommendation that a high-intensity statin is reasonable and only a class IIb recommendation that one might consider the addition of ezetimibe [Zetia] if the LDL-C level remained above 70 mg/dL. As a result, intensification of therapy in this population is infrequent and typically only occurs if the patient goes on to experience a cardiovascular event.”

Greenland and Lloyd-Jones said that the new findings “provide assurance that patients exactly like those in the trial and the substudy should benefit from the addition of evolocumab to statins and other lipid-lowering agents when LDL-C levels below 90 mg/dL cannot be achieved with those treatments.”

However, it’s not clear that lower-risk patients or those who are younger than the trial population with similar risk profiles should get a PCSK9 inhibitor, they argued.

“While VESALIUS-CV overall found no adverse safety signal with evolocumab compared with placebo in the short term, it is unclear based on existing evidence whether PCSK9 inhibition, with any agent, would be safe in the long term,” Greenland and Lloyd-Jones wrote. “Significant questions also persist about cost-effectiveness in younger and lower-risk patients, given currently high overall and out-of-pocket costs.”

The multinational randomized trial included males, ages 50-79, and females, ages 55-79, who had an LDL cholesterol level 90 mg/dL or greater, a non-HDL cholesterol level 120 mg/dL or greater, or an apolipoprotein B level 80 mg/dL or greater despite a stable, optimized lipid-lowering therapy regimen.

While participants could not have a history of MI or stroke, they had to have coronary artery disease, atherosclerotic cerebrovascular disease, peripheral artery disease, high-risk diabetes (≥10 years’ duration, daily insulin, or with microvascular disease), or a combination thereof. They also had to have at least one additional criterion that placed them at higher risk for CV disease, such as age 65 or older, active smoking, extreme lipid levels, or concomitant atherosclerosis and diabetes.

“Thus, while considered a primary prevention study due to absence of prior myocardial infarction or stroke, the patients were all at quite high risk,” Greenland and Lloyd-Jones noted.

The substudy looked only at the 3,655 participants (29.8% of the overall study) without known significant atherosclerosis, defined by no prior arterial revascularization, no known arterial stenosis ≥50%, and no known coronary artery calcium score ≥100 Agatston units.

In this subgroup, more than 80% had hypertension and at least 25% currently smoked. While more than 80% were on a statin and over 90% were on some lipid-lowering drug, LDL-C levels at baseline averaged 132 mg/dL at baseline but dropped to a median of 52 mg/dL on evolocumab versus 111 mg/dL in the placebo group at 48 weeks.

Those low LDL levels achieved with evolocumab were more in line with the 40- to 55-mg/dL target typically reserved for very high-risk secondary prevention in contrast to the less strict LDL cholesterol target of less than 70 mg/dL for high-risk primary prevention diabetes in U.S. guidelines, Marston and colleagues noted.

“Beyond showing clinical benefit with the addition of the PCSK9 inhibitor evolocumab in this population, this study also raises the question as to whether our LDL-C targets are low enough for high-risk primary prevention patients,” they wrote. “Lowering LDL-C to these levels resulted in large reductions in the risk of cardiovascular events, supporting lower LDL-C goals in high-risk primary prevention and making a case for a single LDL-C target for all high-risk individuals, regardless of where they are in the continuum of their atherosclerotic cardiovascular disease course.”

Study limitations included the fact that not all participants had imaging, so some may have had undiagnosed significant atherosclerosis. Also, it was unclear how generalizable the findings would be to individuals in whom imaging affirms no evidence of atherosclerosis.