Evidence varies for nonstatin lipid-lowering therapies

PHILADELPHIA — The current evidence for PCSK9 inhibitors reducing CV events in high-risk patients is strong, but other questions surrounding nonstatin lipid-lowering therapies remain unanswered, a speaker said during the National Lipid Association Scientific Sessions.

Developing evidence for nonstatin lipid-lowering therapies is essential because “when you consider all the statin trials, look at the burden of residual [CV] risk that remains,” Dean A. Bramlet, MD, FACC, FAHA, FNLA, assistant consulting professor of medicine at Duke University and the Heart and Lipid Institute of Florida, St. Petersburg, said during a presentation. “The forgotten majority of patients that go on to have CV events is probably where we need to focus our attention.”

The most favorable evidence has been developed for PCSK9 inhibitors, he said, starting with the ODYSSEY LONG-TERM study of alirocumab (Praluent, Sanofi/Regeneron) vs. placebo added to statin therapy. Although not an outcomes trial, ODYSSEY LONG-TERM had a post hoc analysis indicating alirocumab was associated with a reduction in major adverse CV events vs. placebo.

Dean A. Bramlet

Meta-analyses of clinical data from PCSK9-inhibitor trials suggested the same thing, but only the CV outcome trials — FOURIER for evolocumab (Repatha, Amgen), ODYSSEY OUTCOMES for alirocumab and SPIRE I and II for bococizumab (Pfizer) — were likely to change practice, Bramlet said.

ODYSSEY OUTCOMES is ongoing. The SPIRE trial was discontinued, among other reasons, after antidrug antibody production occurred in many patients, but “I don’t think we should let the baggage of that trial spill over onto the other trials because [bococizumab] was not a fully human protein, it was a humanized monoclonal antibody, and one would anticipate a greater reaction based on what we know from previous studies of other monoclonal humanized antibodies,” he said.

FOURIER, however, produced “clear, statistically significant positive outcomes,” Bramlet said. Although alirocumab was not associated with reduction in CV death, “it is not really unusual for trials to not show a reduction in CV death but still have remarkably good endpoints, driven by hard events such as statistically significant reduction of MI and stroke. It may simply be that these LDL levels require many more patients to demonstrate [a difference in CV death]. I don’t think that should dissuade us from considering utilization in appropriate patients. Lower [LDL] does seem to be better.”

Current evidence suggests reducing LDL to extremely low levels is safe, according to Bramlet. “The data we have suggest that [cognitive effects potentially linked to very low LDL are] more of a psychological impact on the patient.”

However, he said, there are fewer evidence-based solutions for hypertriglyceridemia, which can lead to pancreatitis and adverse CV outcomes if not controlled.

Statins do not eliminate CV risk associated with triglycerides, and “something about low HDL and high triglycerides predicts further CV risk and might be important to the high residual CV risk that patients have despite being on statin therapy,” Bramlet said.

Subgroup analyses of trials of omega-3 fatty acids suggest they may reduce CV events in patients with high triglycerides and low HDL, but these findings will need to be confirmed by the REDUCE-IT and STRENGTH trials, the first CV outcomes trials that specifically recruited patients with high triglycerides, he said.

Thus, it remains unclear whether it is justified to treat patients with triglycerides between 200 mg/dL and 500 mg/dL, “but we have lifestyle modifications that are the cornerstone for management of high triglycerides,” he said. “Weight loss in obese patients, diet modification and controlling of diabetes, reduced alcohol consumption and increased physical activity have a dramatic effect of lowering triglycerides far more than you see with LDL lowering.”

He told Cardiology Today that “while we don’t have definitive data on treating triglycerides 200 mg/dL to 499 mg/dL, I generally do on an individual basis, given the level of evidence that exists.”

In the real world, not every question will be answered by a randomized controlled trial, so “we have to use the totality of evidence to treat the patient in front of us,” Bramlet said during the presentation. “Be honest with your patient about what we know, what we don’t know and what we think we know.” – by Erik Swain

Reference:

Bramlet DA. Back to the future: Clinical experience with and access to lipid-lowering agents of the past, present and future. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Bramlet reports speaking and consulting for Amarin, Astelas, Kowa and Sanofi/Regeneron.