NEW ORLEANS – Evolocumab (Repatha) reduced the risk of a first major cardiovascular (CV) event in patients with diabetes, but found no atherosclerosis in a study of the Vesalius-CV trial.
The PCSK9 inhibitor reduced the relative risk by 31% compared with placebo, whether looking at the combination 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 similar overall plus ischemia-driven arterial revascularization (7.6% vs. 10.5%, P=0.001).
In secondary findings, evolocumab reduced mortality by 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. American College of Cardiology annual meeting.
The findings, which were published simultaneously Jama, Add the primary trial results to a broader primary prevention population of patients with atherosclerosis or high-risk diabetes, in which the risk of composite endpoints was shown to be 19-25% lower without mortality benefit.
The researchers concluded, “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 diabetes.”
Philip Greenland, MD, and Donald M. Lloyd-Jones, MD, both of Northwestern University in Chicago, together agreed. editorial As recommended by current primary prevention guidelines, “clinicians should redouble risk assessment and treatment for all known risk factors.”
However, Marston’s group noted that guidelines recommend moderate-intensity statins for high-risk primary prevention patients, such as patients with diabetes without known atherosclerotic CV disease, “with a class IIa recommendation that a high-intensity statin is appropriate and only a class IIb recommendation that ezetimibe (Zetia) be considered if LDL-C levels remain above 70 mg/dL.” “Addition may be considered. As a result, exacerbations are rare in this population and typically occur only when the patient experiences a cardiac event.”
Greenland and Lloyd-Jones said the new findings “are reassuring that the patients are exactly like those included in the trial and that when LDL-C levels below 90 mg/dL cannot be achieved with those treatments, the sub-study should benefit from adding evolocumab to statins and other lipid-lowering agents.”
However, it is unclear whether low-risk patients or those younger than the trial population with similar risk profiles should receive PCSK9 inhibitors, they argued.
Greenland and Lloyd-Jones wrote, “While overall VESALIUS-CV found no adverse safety signals with evolocumab compared with placebo in the short-term, it is unclear, based on the current evidence, whether PCSK9 inhibition with either agent will be safe in the long-term.” “Given the currently high overall and out-of-pocket costs, significant questions also remain about cost-effectiveness in younger and lower-risk patients.”
The multinational randomized trial included men aged 50–79 years and women aged 55–79 years who had an LDL cholesterol level of 90 mg/dL or higher, a non-HDL cholesterol level of 120 mg/dL or higher, or an apolipoprotein B level of 80 mg/dL or higher despite a stable, optimized lipid-lowering therapy regimen.
While participants could not have a history of MI or stroke, they must have coronary artery disease, atherosclerotic cerebrovascular disease, peripheral artery disease, high-risk diabetes (with ≥10 years’ duration, daily insulin, or microvascular disease), or a combination thereof. They must have at least one additional criterion that places them at higher risk for CV disease, such as being 65 years of age or older, active smoking, excessive lipid levels, or concomitant atherosclerosis and diabetes.
“Thus, while the study was considered a primary prevention study because of the absence of prior myocardial infarction or stroke, all patients were at significantly higher risk,” Greenland and Lloyd-Jones said.
The sub-study looked at only 3,655 participants (29.8% of the overall study) who did not have known significant atherosclerosis as 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 high blood pressure and at least 25% currently smoked. While more than 80% of people were on statins and more than 90% were on some lipid-lowering medication, LDL-C levels averaged 132 mg/dL at baseline, but at 48 weeks fell to an average of 52 mg/dL on evolocumab compared with 111 mg/dL in the placebo group.
Marston and colleagues reported that the low LDL levels achieved with evolocumab were consistent with the 40- to 55-mg/dL target typically reserved for very high-risk secondary prevention, in contrast to the less stringent LDL cholesterol target of less than 70 mg/dL for high-risk primary prevention diabetes in US guidelines.
“In addition to showing clinical benefit from the addition of the PCSK9 inhibitor evolocumab in this population, this study also raises the question of 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 targets in high-risk primary prevention and making the 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.”
Limitations of the study include the fact that not all participants had imaging, so some may have undiagnosed significant atherosclerosis. Furthermore, it was unclear how generalizable the findings would be to individuals in whom imaging confirms no evidence of atherosclerosis.
