NEW ORLEANS: Cleveland Clinic researchers have found that adding the injectable cholesterol-lowering drug evolocumab (Repatha) to full doses of statin drugs reversed the buildup of cholesterol plaques in the coronary artery walls after 18 months of treatment.
Patients receiving the combination of evolocumab and a statin achieved an average level of LDL (“bad cholesterol”) of just 36.6 mg/dL, the lowest level ever studied in a major trial of cholesterol-lowering drugs.
The study – directed by Steven Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic and Stephen Nicholls, M.B.B.S, Ph.D., a professor at the South Australian Health and Medical Research Institute and cardiologist at Royal Adelaide Hospital – was presented today by Dr. Nissen at the American Heart Association Scientific Sessions and simultaneously published in the Journal of the American Medical Association.
The study, known as the GLAGOV Trial, randomly assigned 968 participants to a statin alone or the combination of a statin and a monthly self-injection of 420 mg of evolocumab, a drug that belongs to a new class of cholesterol-lowering treatments known as PCSK9 inhibitors. The statin-only patients achieved an average LDL level of 93 mg/dL, while the group receiving combination therapy reduced LDL by an additional 60 percent to reach 36.6 mg/dL, on average.
The study employed a technique known as intravascular ultrasound (IVUS) that uses a tiny ultrasound probe to directly measure coronary plaques. For the primary measure of efficacy, IVUS showed a 0.05 percent increase plaque with a statin alone and a 0.95 percent decrease with combination therapy. For those taking a statin alone, less than half of patients experienced plaque regression (47 percent), whereas 64 percent of those taking both drugs showed reduction in plaque.
“Statins are already the gold standard for lowering cholesterol, but we wanted to find out if we could do better,” said Dr. Nissen. “These findings demonstrate significant regression of coronary disease can be achieved by adding a PCSK9 inhibitor to statins to drive cholesterol to incredibly low levels never previously studied.”
For patients who started the study already at LDL levels below the recommendations of any current global guideline (<70 mg/dL), there was additional benefit for combination therapy, with 81 perecnt of patients showing regression of coronary plaque. Analysis of trial results showed incremental benefits down to LDL levels as low as 20 mg/dL. No safety issues arose for patients treated to these very low LDL levels.
“These findings suggest that the large clinical outcome trials currently underway are likely to show major benefits from combination therapy using a PCSK9 inhibitor and a statin compared with a statin alone,” Dr. Nicholls said. “However, it is important to keep mind that this combination therapy may not be for everybody, and in this study we only looked at high-risk heart patients.”
Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is an injectable non-statin cholesterol-lowering drug self-administered by the patients once per month. It was approved by the FDA in August 2015, the second in this class to be approved. The first, alirocumab, was approved in July 2015. The drugs work by inactivating the protein PCSK9. Blocking the protein allows more receptors to be available to remove LDL from the bloodstream, lowering LDL cholesterol levels.
The study was funded by Amgen. Dr. Nissen has served as a consultant for many pharmaceutical companies and has overseen clinical trials for Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda and Pfizer. However, he does not accept honoraria, consulting fees or other compensation from commercial entities. Five of the study’s co-authors are employed at Amgen. Amgen participated in study design, development of protocol and provided logistical support and monitoring. After completion of the trial, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical research, where statistical analyses were performed by an independent statistician.
For more information about the GLAGOV trial, please see the following “Frequently Asked Questions:”
What is a PCSK9 inhibitor?
A PCSK9 inhibitor is a newer type of cholesterol-lowering medication that is not a statin. It is an injectable medication that is self-administered by patients. The drugs work by inactivating the protein PCSK9. PCSK9 reduces LDL-removing receptors on the liver. Blocking the protein allows more receptors to be available to remove LDL from the bloodstream, lowering LDL cholesterol levels.
When were PCSK9 inhibitors approved?
The first PCSK9 inhibitor alirocumab, (Praluent), was approved in July 2015. Evolocumab (Repatha), the drug studied in this trial, was approved in August 2015.
Why would someone need a PCSK9 inhibitor?
Currently, statins (which lower cholesterol) are some of the most widely prescribed drugs in the US. However, they don’t work effectively for everyone – and some people can’t tolerate them due to side effects. The GAUSS 3 trial, published earlier this year, demonstrates that PCSK9 inhibitors are effective at lowering cholesterol in this population and well tolerated with less than 1% of patients unable to tolerate evolocumab. In addition, PSCK9 inhibitors can be effective for those with genetically high cholesterol (familial hypercholesterolemia) and for those whose cholesterol levels aren’t lowered enough by statins.
What did GLAGOV study?
The GLAGOV(GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound) trial studied the effects of adding a PCSK9 inhibitor to an optimized statin dose on LDL and coronary plaque burden. The study employed a technique known as intravascular ultrasound (IVUS) that uses a tiny ultrasound probe to directly measure coronary plaques. Prior intravascular ultrasound (IVUS) trials have shown that statins slow progression or induce regression of coronary disease in proportion to the magnitude of LDL-C reduction. No other LDL-lowering therapy has shown plaque regression in an IVUS trial.
How was the trial designed?
The trial randomly assigned 968 participants with symptomatic coronary artery disease or other high-risk features to a statin alone or the combination of a statin and a monthly self-injection of 420 mg of evolocumab (a PCSK9 inhibitor).
What were the findings?
The statin-only patients achieved an average LDL level of 93 mg/dL, while the group receiving combination therapy reduced LDL by an additional 60% to reach the average level of 36.6 mg/dL, the lowest level ever studied in a major clinical trial.
IVUS showed a 0.05 percent increase in plaque burden with a statin alone and a 0.95 percent decrease with combination therapy. In addition, for a statin alone, less than half of patients experienced plaque regression (47%), whereas 64% of those taking both drugs showed reduction in total plaque burden.
Furthermore, the investigators looked at patients who started the study with already low LDL levels (less than 70 mg/dl, which is below any current global guideline for LDL) to see if there would be incremental benefits. Of these patients, those who had combination therapy, 81% of patients showed regression of coronary plaque. Analysis of trial results showed incremental benefits down to LDL levels as low as 20 mg/dL.
Is it safe to have LDL levels this low?
During the trial, no safety issues arose for patients treated to these very low LDL levels. However, the sample size of the trial was modest, providing limited power for safety assessments.
What were the limitations of the trial?
The GLAGOV trial assessed a select group of patients with coronary disease presenting for a clinically-indicated angiogram treated for only 18 months. Effects in other populations and longer term treatment need further study. Another limitation is that 13% of trial participants did not have a follow-up examination. Lastly, while IVUS is a useful measure of disease activity, the critical determination of benefit and risk will require completion of large outcomes trials currently underway.
What does GLAGOV tell us about optimal LDL levels?
LDL cholesterol is now universally accepted as the major driver of atherosclerosis, however, the question of how far to reduce lipid levels has remained a moving target. This study adds to evidence that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved.
Should more heart patients be on PCSK9 inhibitors or combination therapy? Patients should talk to their doctor about their optimal treatment plan. This study was a modest size and only looked at a population with symptomatic coronary artery disease or high-risk features. Furthermore, large outcomes trials studying PCSK9 inhibitors are underway and will give a better picture of the benefits and risks.