Cardiology > Atherosclerosis
Who Needs Another LDL Drug Anyway?
Cardiologists look to PCSK9 inhibitors for patients with lipid disorders who require more
Steven Nissen, MD
by Crystal Phend Crystal Phend, Senior Staff Writer, MedPage Today June 23, 2015
This article is a collaboration between MedPage Today® and:
When the FDA advisory committee met this month to consider approvability of two PCSK9 inhibitors, the big question was not lipid-lowering efficacy but which group of patients would get an indication.
The panelists voted in favor of approval of both evolocumab (Repatha) and alirocumab (Praluent) based on a slew of trials in a variety of settings showing that LDL fell by an absolute 30% to 60% from baseline.
Despite the blockbuster success of statins and additive effect of ezetimibe (Zetia), cardiologists told MedPage Today they need the dramatic effect of the PCSK9 monoclonal antibodies for several classes of patients.
Watch MedPage Today's ongoing PCSK9 series video package. This week's topic: Unmet need
The indication proposed for evolocumab was adults with standard lipid disorder -- including patients who are statin-intolerant -- as well as people 12 and older with homozygous familial hypercholesterolemia.
For alirocumab, the proposed indication was adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes. It also included statin-intolerant patients or those "for whom a statin is not considered clinically appropriate."
Inherited Risk
The clearest unmet need that has gotten unanimous support from cardiologists and on the FDA panel is familial hypercholesterolemia (FH).
"The statins just aren't enough to get their cholesterol down to appropriate levels," commented Joseph Alpert, MD, director of the coronary care unit at the University of Arizona in Tuscon.
That was the case for William O'Neill, MD, an interventional cardiologist and trialist at the Henry Ford Hospital in Detroit who also has familial hypercholesterolemia.
After getting on evolocumab as a participant in the OSLER trial, his LDL dropped from around 170 mg/dL down to 14 mg/dL.
"I never thought you could ever get that low," he told MedPage Today. "It's really dramatically controlling my LDL level."
The PCSK9 inhibitors were actually developed from research on the PCSK9 gene, which is turned up by some FH mutations and turned down by rare "loss of function" mutations associated with low heart disease rates.
Heterozygous FH is one of the most common genetic diseases, affecting at least one in 500 overall and one in 250 people of European Caucasian ancestry, which conservatively adds up to a potential 1 million PCSK9 inhibitor users in the U.S.
Atop of that, there are "perhaps several million that don't get adequate LDL reduction despite good treatment with statins and sometimes even with the addition of ezetimibe," noted Steven Nissen, MD, director of cardiovascular medicine at the Cleveland Clinic, who has been involved in both statin and PCSK9 inhibitor research.
Statin Intolerance
About 5% to 15% of patients get myalgias with statins severe enough to be unable to tolerate the drugs, noted Paul Thompson, MD, medical director of cardiology at Connecticut's Hartford Hospital. An editorial in Health Affairs tallied that group to about 1 to 3 million in the U.S. population.
"Ezetimibe alone will probably not be effective in getting them where they need to go," Thompson said.
That drug has a modest effect of only about 20% reduction in LDL cholesterol, explained Daniel Rader, MD, director of the preventive cardiovascular program of the University of Pennsylvania in Philadelphia.
But given its longer track record of safety and proven cardiovascular benefit atop a statin, "if the statin-treated patient has an LDL cholesterol that is within 20% to 30% of where it 'should be' (a difficult call without formal LDL targets), ezetimibe should be considered the preferred next option," Rader suggested.
There are even more partially statin intolerant people too, who can only tolerate a low dose that won't get them to "goal," Nissen noted.
"It's really underdiagnosed," agreed O'Neill. "In my practice, because I'm sensitive to it and ask people, about a third of the people that are on statins have some form of intolerance. It's not an all or none sort of gradation, where some are incredibly sensitive and others have sort of mild aches and pains, but it is a pretty severe side effect. I think that's probably going to generate a lot of interest in the consumers to try to get on those drugs."
Because of their distinct mechanism of action, the PCSK9 inhibitors appear well tolerated in people with statin intolerance, Nissen pointed out.
Despite the unmet need for such patients, whether the FDA will actually include statin intolerance if it does grant an indication to one or both of the drugs is unclear. The FDA advisory panels expressed mixed opinions about it.
Broader Possibilities
An even bigger need is tackling residual cardiovascular risk in secondary prevention overall.
"I feel strongly that we have pushed the antiplatelets as far as we can, and the residual events maybe improved by these drugs," Roxana Mehran, MD, an interventional cardiologist at Mount Sinai Hospital in New York City, told MedPage Today.
However, "this must be proven in the PCI [percutaneous coronary intervention] population and those with acute coronary syndromes who are at high risk for recurrent events," she cautioned.
The IMPROVE-IT trial drove another post in support of the LDL hypothesis suggesting that lower LDL is better for outcomes regardless of how you get there.
If the large clinical outcome trials now ongoing with the PCSK9 inhibitors prove a cardiovascular benefit of getting LDL down to the levels that these drugs do compared with what statins alone achieve, there might well be a rationale for extending those benefits broadly to patients currently considered well controlled, suggested Deepak Bhatt, MD, PhD, of Brigham and Women's Hospital in Boston.
"If this indeed is the case, the PCSK9 inhibitors potentially could become a very commonly used cardiovascular medication," he told MedPage Today.
Thompson agreed that there could be a future indication for driving down LDL to the low double-digit range.
"I think we are going to find with these new agents that by getting folks' cholesterol levels extremely low, we can regress atherosclerosis more rapidly than we could with statins alone," he speculated. "Statins have been shown to regress atherosclerosis, but I think the combination of statins and other agents can get your LDL cholesterol levels so low it may actually lead to egress of cholesterol from these lesions at a rapid rate."
An intravascular ultrasound (IVUS) trial is underway to determine the impact of evolocumab versus placebo on plaque regression.
Although the IVUS results should be out before those of the cardiovascular outcome trials, "the really big indication will have to await the completion of the outcomes trials," Nissen said.
But, he agreed, "if there is an incremental benefit from going to an LDL of 80 to an LDL of 40 [mg/dL], then that opens up the possibility that a lot more people would benefit from these drugs than simply the people that are difficult to treat now."
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
AHA Science News: ACC 2015 : Osler Trials
AHA SS12 : Late-Breaking Clinical Trials: Overview of PCSK9 Inhibition in the Treatment of Hyperlipidemia
O'Neill and Thompson disclosed no relevant relationships with industry.
Nissen disclosed relevant relationships with Novo Nordisk but with all compensation donated to nonprofit organizations.
Bhatt disclosed relevant relationships with Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences, the Boston VA Research Institute, the Society of Cardiovascular Patient Care, the American Heart Association Get With The Guidelines Steering Committee, the Duke Clinical Research Institute, the Harvard Clinical Research Institute, Mayo Clinic, the Population Health Research Institute, the American College of Cardiology, Belvoir Publications, HMP Communications, Slack Publications, WebMD, Clinical Cardiology, the Journal of the American College of Cardiology, Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, sanofi aventis, The Medicines Company, FlowCo, PLx Pharma, and Takeda.
Rader disclosed founding VascularStrategies.
Mehran disclosed relevant relationships with AstraZeneca, Bayer, Behring, Janssen Pharmaceuticals, Merck, Osprey Medical, Regado Biosciences, The Medicines Company, Watermark Consulting, Abbott Laboratories, Boston Scientific, Covidien, and sanofi-aventis.