The addition of evolocumab to statin therapy in individuals with angiographic coronary disease appeared to encourage coronary atherosclerosis regression, as demonstrated in the GLAGOV* trial presented at the Scientific Sessions of the American Heart Association (AHA 2016) held in New Orleans, Louisiana, US.

In comparison with patients on statin alone who experienced a nonsignificant 0.05 percent increase in percent atheroma volume (PAV), those on combined therapy of statin and evolocumab had a 0.95 percent reduction in PAV (difference, -1.0 percent, 95 percent confidence interval [CI], -1.8 to -0.64 percent; p<0.001). Normalized total atheroma volume (TAV) decreased by 0.9 mm³ (nonsignificant) in those on statin alone compared with 5.8 mm³ in those on statin and evolocumab (difference, -4.9 mm³, 95 percent CI, -7.3 to -2.5; p<0.001). [AHA 2016, LBCT 03; JAMA 2016;doi:10.1001/jama.2016.16951]

Plaque regression occurred in a greater number of patients on evolocumab and statin compared with those on statin alone (64.3 percent vs 47.3 percent; difference, 17.0 percent, 95 percent CI, 10.4 to 23.6 percent; p<0.001 for PAV and 61.5 percent vs 48.9 percent; difference, 12.5 percent, 95 percent CI, 5.9 to 19.2 percent; p<0.001 for TAV).

“We are really reducing plaque burden in the coronaries if we can get [low-density lipoprotein cholesterol (LDL-C)] down to these very low levels,” said study chair Dr Steven Nissen from the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings. “It turns out that a little bit of change in plaque volume translates into a very big change in plaque behaviour.”

“[These findings] suggest a new era in lipid management,” said discussant Dr Raul Santos from the University of São Paulo, Brazil.

Evolocumab appeared to be well tolerated with comparable incidences of injection site reactions (0.4 percent vs 0 percent), myalgia (7.0 percent vs 5.8 percent), neurocognitive events (1.4 percent vs 1.2 percent), and new onset diabetes (3.6 percent vs 3.7 percent) for evolocumab plus statin vs statin monotherapy, respectively.

In this double-blind, placebo-controlled, multicentre trial, participants (n=968, mean age 59.8 years; 72 percent male) with angiographic coronary disease, LDL-C levels ≥80 mg/dL or 60–80 mg/dL with additional high-risk features, and on stable statin therapy were randomized to receive monthly subcutaneous injections of the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab (420 mg) or placebo for 76 weeks. After angiography, participants underwent intravascular ultrasound (IVUS) of the same artery at baseline and at week 78.

“Both the primary and secondary IVUS efficacy measures showed atherosclerosis regression … in patients treated with the combination of evolocumab and statins and absence of regression in patients treated with a statin alone,” said study lead investigator Dr Steven Nicholls, also from the Cleveland Clinic. “These findings provide evidence that PCSK9 inhibition produces incremental benefits on coronary disease progression in statin-treated patients.”

“Over the last 4 decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL,” said Nissen, who acknowledged the limitations of the trial such as the small number of patients and short treatment period. “IVUS is a useful measure of disease activity, but the critical determination of benefit and risk will require completion of large outcome trials currently underway,” he said.

Other factors that could potentially influence disease progression in the setting of very low LDL-C levels also need to be investigated, said Nicholls.

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