Recent trials advance lipidology knowledge base

PHILADELPHIA — Numerous important trials in clinical lipidology have been reported over the last year, according to a presentation at the National Lipid Association Scientific Sessions.

Kevin C. Maki, PhD , CLS, FNLA , FTOS, FACN , from the Midwest Biomedical Research Center for Metabolic and Cardiovascular Health and the department of food science and nutrition at the Illinois Institute of Technology, Chicago, said the trials have shed light on PCSK9 inhibitors, cholesterol ester transfer protein inhibitors, statins, diabetes drugs and other therapies.

ACCELERATE

The ACCELERATE trial of the CETP inhibitor evacetrapib (Eli Lilly), presented at the American College of Cardiology Scientific Session in 2016 and published recently in The New England Journal of Medicine, were disappointing, Maki said.

For the primary efficacy endpoint of first occurrence of death from CV causes, MI, stroke, coronary revascularization or hospitalization for unstable angina in time-to-event analysis, the lines in the Kaplan-Meier curve were identical and there was no evidence of benefit or harm relating to CV events, despite evacetrapib being associated with a significant increase in HDL and a significant decrease in LDL vs. placebo, he said.

In addition, evacetrapib was associated with an approximately 20% reduction in apolipoprotein B and a 22% reduction in lipoprotein(a) compared with placebo, he noted.

According to Maki, there is more to learn about why CV benefits aren’t occurring with favorable lipid changes resulting from CETP inhibitors.

FOURIER

In the FOURIER trial of patients with atherosclerotic CVD on background statin therapy, Maki said, the PCSK9 inhibitor evolocumab (Repatha, Amgen) was associated with a 15% reduction in the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization and a 20% reduction in the key secondary outcome of CV death, MI or stroke.

According to Maki, the improvement in CV outcomes associated with evolocumab provides further evidence that “lower is better: for LDL.

EBBINGHAUS

The EBBINGHAUS substudy looked at the cognitive health in a subset of patients enrolled in FOURIER.

Maki said that EBBINGHAUS showed for the first time that cholesterol lowering, using a sensitive test, did not reduce any degree of cognitive function.

IVUS studies

The GLAGOV study showed evolocumab reduced percent atheroma volume as measured by IVUS compared with placebo, Maki said, noting that a post-hoc analysis demonstrated a linear relationship between achieved LDL and percent atheroma volume progression.

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A pooled analysis of nine IVUS studies of 4,957 patients with CAD indicated the relationship between change in percent atheroma volume and non-HDL appears to be stronger than that between percent atheroma volume and LDL, Maki said, noting that the curves for major adverse CV events separated earlier in patients stratified by non-HDL than in patients stratified by LDL.

In addition, lower non-HDL was associated with greater percent atheroma volume regression compared with higher non-HDL, regardless of LDL level, he said.

USAGE Survey

The USAGE survey was a survey of approximately 10,000 current and former statin users with at least one component of metabolic syndrome, who were asked whether they experienced new or worsening muscle symptoms while taking a statin and whether they stopped statin therapy due to muscle symptoms.

Originally, the survey was conducted to study the link between metabolic syndrome and the likelihood of muscle symptoms while on a statin, however, a recently published analysis showed that the relationship between metabolic syndrome and statin-associated muscle symptoms is primarily driven by self-reported elevated triglycerides and low HDL levels, Maki said.

“This is an interesting finding,” he said. “It’s hypothesis-generating and we are hopeful that this will lead to additional research evaluating the associations of these lipid impairments or changes with the likelihood of having statin-associated muscle symptoms”

GAUSS-3

Another study dealing with statin-associated muscle symptoms was the GAUSS-3 trial, a two-stage randomized clinical trial including patients with uncontrolled LDL and a history of intolerance to two or more statins.

The first stage of the study included a 24-week crossover re-challenge with atorvastatin or placebo conducted to identify patients who had symptoms.

The second stage was a 24-week randomized parallel comparison of ezetimibe vs. evolocumab; 218 of the 491 patients qualified for it.

At 24 weeks, the mean LDL change was –16.7% with ezetimibe and –54.5% with evolocumab, indicating that PCSK9 inhibitors may be appropriate for patients with statin intolerance, Maki said.

LEADER and SUSTAIN-6

The LEADER and SUSTAIN-6 trials demonstrated CV benefits of two diabetes drugs, Maki said.

In LEADER, patients with diabetes assigned the glucagon-like peptide-1 receptor agonist liraglutide (Victoza, Novo Nordisk) had lower risk for CV death, nonfatal MI or nonfatal stroke vs. those assigned placebo, and in SUSTAIN-6, those assigned the novel glucagon-like peptide-1 analog semaglutide (Novo Nordisk) had lower risk for CV death, nonfatal MI or nonfatal stroke vs. those assigned placebo, he said.

"This is exciting that we now have multiple classes of hypoglycemic agents that seem to be associated with reduced CVD risk and, I think will lead to ... more cross-pollination and interaction in efforts to prevent CVD among those involved with etiology and those involved in diabetology,” Maki said. – by Dave Quaile

Reference:

Maki KC. Recent Developments in Clinical Lipidology. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Maki reports consulting for, serving on an advisory board for or receiving research grants from ACH Food Companies, AstraZeneca, DSM, DuPont Nutrition and Health, FMC Corp., Global Organization for EPA and DHA, Matinas BioPharma Inc., Pharmavite LLC, Sancilio & Co. and Shaklee.