Stephen Nicholls, MD, professor of cardiology at Monash University in Melbourne, added in an interview that “the precedent has been to conditionally approve LDL cholesterol–lowering drugs at this stage of development, based on the large body of evidence demonstrating that LDL cholesterol–lowering consistently produces clinical benefit.”
Mitchel L. Zoler/MDedge News
Dr. Stephen Nicholls
To gain more confidence that treatment with bempedoic acid exerts a benefit to patients prior to availability of clinical-outcome results, the developing company sponsored a genetic and epidemiologic study that looked at the association between naturally occurring mutations that dampen the activity of ATP citrate lyase, an enzyme that metabolically sits just upstream from HMG CoA reductase, the enzyme that statins target. Dr. Nicholls, Dr. Ray, and several other collaborators devised “genetic scores” that took into account variants of the gene that codes for ATP citrate lyase, and a separate score for HMG CoA reductase variants. Each score estimated a person’s activity for each of these enzymes. The researchers then used the scores to classify enzymatic activity in more than 650,000 people in several different databases, including more than 100,000 people with a history of major cardiovascular events.
The results showed that “genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level,” the investigators said in an article published concurrently with the CLEAR Harmony results (N Engl J Med. 2019 March 14;380[11]:1033-42).
Dr. Steven E. Nissen
This finding “strengthens the likelihood that an outcome trial will show benefits,” Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, and a lead investigator in the bempedoic acid outcomes trial, CLEAR Outcomes, said in an interview.
Dr. Nicholls noted that, on the basis of the genetic study’s results “it would seem very reasonable to extrapolate and expect that bempedoic acid should reduce cardiovascular events.”
The data reported by Dr. Ray and his associates from the CLEAR Harmony trial showed that overall, the adverse-event rates associated with bempedoic acid treatment were similar to the rates seen in patients who received placebo. But Michael V. Holmes, MD, who wrote an editorial that accompanied both reports, highlighted a few differences in the adverse event rates that concerned him. These were a statistically significant higher rate of gout and blood uric acid levels on bempedoic acid treatment compared with controls, a significantly higher rate of discontinuations because of adverse events, and nominally higher rates of death, cardiovascular death, and heart failure hospitalization, said Dr. Holmes, an epidemiologist at the University of Oxford, England.
But Dr. Nissen said that “the safety ‘signals’ involve very small numbers of patients and do not raise major concerns. The increases in gout and uric acid are worth noting, but are less weighty than the disease the drug is intended to treat: major cardiovascular events.”
Dr. Nichols added that “the large cardiovascular outcome trial will provide the opportunity to further study safety and potential side effects. I’m hesitant to overinterpret event data from a relatively small clinical trial that primarily focused on the lipid effects.”
Despite recent success of the PCSK9 inhibitors as an add-on or substitute for statin treatment of elevated LDL cholesterol, the cost of the drugs in this class has made the cardiovascular disease community eager for another alternative to statins.
“The PCSK9 inhibitors are extremely effective, but uptake has been slow due to their cost and formulary restrictions,” said Dr. Ballantyne. “Many high-risk patients continue to have persistently elevated levels of LDL cholesterol.” Bempedoic acid is “a new therapy that can help people who continue to have elevations of LDL cholesterol despite current therapies.”
CLEAR Harmony and the genetic study were sponsored by Esperion, the company developing bempedoic acid. Dr. Ray has been a consultant to several drug companies but had no other financial relationship to Esperion. Dr. Ballantyne and Dr. Nicholls have been consultants to and have received research funding from Esperion and from several other companies. Dr. Nissen is leading an Esperion-sponsored study but has no financial relationships with the company or with other companies.
SOURCEs: N Engl J Med. 2019 Mar 14;380[11]:1022-32 and 1033-42.