The PCSK9 inhibitor evolocumab reduced the risk of a first major cardiovascular event in patients with diabetes without known significant atherosclerosis, according to a prespecified subgroup analysis of the VESALIUS-CV trial, presented during a Late-Breaking Clinical Trial session at ACC.26 in New Orleans and simultaneously published in JAMA.

The double-blind VESALIUS-CV trial randomized 12,257 patients with qualifying atherosclerosis or high-risk diabetes, without a prior myocardial infarction (MI) or stroke, and LDL-C ≥90 mg/dL 1:1 to either 140 mg evolocumab every two weeks or matching placebo added to optimally tolerated statin therapy.

This present analysis examined outcomes in 3,655 patients with diabetes and without known atherosclerosis, defined as no prior arterial revascularization, arterial stenosis ≥50% or elevated coronary calcium (coronary artery calcium ≥100 Agatston units). Of them, 1,849 had been randomized to evolocumab and 1,806 to placebo. Their median age was 65 years, 57% were women and 93% were White; BMI was 31.4 kg/m2 and median baseline LDL-C was 132 mg/dL. At baseline, 89% were on lipid-lowering therapy, including 64% receiving high-intensity statin therapy; more than 80% had hypertension, and at least 25% in each group were smokers.

Results showed that at 48 weeks, LDL-C levels fell to 52 mg/dL with evolocumab vs. 111 mg/dL with placebo (p<0.001) During a median 4.8-year follow-up, 83 evolocumab patients vs. 117 placebo patients experienced a first primary endpoint event, a composite of coronary heart disease death, MI or ischemic stroke (3-P MACE) (hazard ratio [HR], 0.69; p=0.009). Additionally, 127 evolocumab patients vs. 178 placebo patients experienced the second primary endpoint, 3-P MACE plus ischemia-driven revascularization (IDR) (HR, 0.69; p=0.009), with a 2.9% between-group difference.

Investigators note that this effect became apparent after one year, with 41% and 39% reductions in risk in 3-P MACE and 4-P MACE in the years that followed.

The evolocumab arm also saw lower mortality rates – both cardiovascular (44 vs. 63 deaths; HR, 0.68) and all-cause (136 vs. 172 deaths; HR, 0.76), although these results should be considered exploratory.

A consistent benefit was seen with evolocumab vs. placebo for prespecified secondary endpoints: 34% reduction in MI, stroke or IDR; 31% reduction in coronary heart death, MI or IDR; and a 32% reduction cardiovascular death, MI or ischemic stroke. The benefit was consistent across subgroups too.

“These data support intensification beyond statins in such patients earlier in the atherosclerotic cardiovascular disease process and targeting LDL-C goals typically reserved for very high-risk secondary prevention patients,” write the authors.

“I think this study changes the paradigm,” said Nicholas Marston, MD, MPH, the study’s lead author. “In current practice, PCSK9 inhibitors are largely reserved for patients who have had a prior heart attack or stroke, but here we see a benefit of using evolocumab not only to treat patients without a history of heart attack or stroke, but without known significant atherosclerosis. It’s a message to physicians and patients that we don’t have to wait until someone has atherosclerosis to treat them intensively. We can – and should – be much more proactive.”

In an accompanying editorial comment, Philip Greenland, MD, FACC, and Donald M. Lloyd-Jones, MD, FACC, write that the trial results, “show the benefit of evolocumab in a high-risk primary prevention patient population, specifically with long-standing diabetes and other risk factors, many of whom undoubtedly had significant, although unmeasured, ASCVD burden,” but raise additional questions about long-term results, cost-effectiveness and age of treatment in younger, lower risk patients.

Clinical Topics: Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: ACC Annual Scientific Session, ACC26, New Orleans, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ischemic Stroke, PCSK9 Inhibitors, Myocardial Infarction, Atherosclerosis, Hypertension, Ischemia, Diabetes Mellitus