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Future holds promise to address unmet needs in lipid disorders causing CV risk
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PHILADELPHIA — Despite success with therapies that lower LDL, other lipid disorders confer risk for CVD that are not well-controlled, but intensive research efforts may address them in the near future, according to a speaker at the National Lipid Association Scientific Sessions.
“There are still a lot of unmet medical needs in the treatment of lipid disorders with the goal of preventing CVD,” Daniel J. Rader, MD, from Perelman School of Medicine at the University of Pennsylvania, told Cardiology Today. “Human genetics are driving us toward new therapeutic targets in really interesting ways. We have several things in the clinic and on their way, hopefully to be approved, to be used as new therapies orthogonal to and complimentary to the existing LDLlowering therapies like statins and PCSK9 inhibitors.”
Despite evidence that statins, ezetimibe and PCSK9 inhibitors reduce risk for CV events by lowering LDL, “we need to get better at figuring out who goes on to have recurrent CV events despite having well-controlled LDL,” Rader told Cardiology Today. Clearly, there are a lot of people who still have events even their LDLs are 60 mg/dL or lower. We need to figure out who those people are, what’s going on with them, and how we can use additional orthogonal therapies to lower that event rate.”
The challenge for lipidologists is to identify whether other lipid targets play a role in this risk, and if so, how to address them, he said during the presentation.
Genetic studies “are identifying additional targets that will help us address the remaining unmet medical need in treating dyslipidemia to reduce CV risk,” he said.
Some of the most interesting research concerns triglycerides and lipoprotein(a), he said.
Triglycerides have been shown to predict recurrent risk for CV events even when LDL is controlled, according to Rader. “The data have come in quite beautifully using DNA to assess causality,” he said. “Genetic variants that affect triglycerides and triglyceride-rich lipoproteins also themselves are directly related to and associated with coronary disease.”
Triglycerides also appear to play a major role in the relationship between apolipoprotein C-III and elevated CAD risk, he said.
Researchers have also discovered that loss-of-function mutations of APOC3 lower plasma triglycerides and are linked to reduced risk for CAD, Rader said.
These developments have confirmed apolipoprotein C-III (ApoC-III) as a target and helped lead to the development of volanesorsen (Akcea Therapeutics) an antisense inhibitor of ApoC-III for treatment of patients with familial chylomicronemia syndrome, he said, noting it may also be studied in patients with hypertriglyceridemia.
Another target is ANGPTL3, a secreted protein that inhibits lipoprotein lipase, he said, noting that genetic research showed that ANGPTL3 loss-of-function mutations protect humans from CAD.
“The human genetics point to this as a really interesting potential target, and in fact, an antibody, evinacumab (Regeneron), is being studied in humans, and has been shown to, in a dose-dependent way, reduce triglyceride levels, consistent with the genetic information and suggesting a very substantial effect,” he said.
Researchers have also discovered that ANGPTL4 inhibits lipoprotein lipase and increases risk for coronary disease, and apolipoprotein A-V activates lipoprotein lipase and protects against CAD, with loss-of-function mutations increasing risk for CAD, Rader said.
Another important target is Lp(a), he said. “The epidemiology and the human genetics strongly support Lp(a) as not just associated, but as a causal risk factor for coronary disease. The data are very strong that when you look at genetic variants that raise Lp(a), those genetic variants are also associated with increased risk for coronary disease. Even in people with LDL 50 mg/dL, Lp(a) is still a risk factor. Maybe some of these patients who go on to have events despite a low LDL have elevated Lp(a).”
An antisense oligonucleotide (IONIS-APO(a)LRx, Ionis Pharmaceuticals/Akcea Therapeutics) targeting the APOA protein, which is the major protein component of Lp(a), is in development, he said. “This suggests that for the first time, we have an intervention that quite substantially reduces Lp(a),” he said. “It has the potential to make a major dent in our residual risk.” – by Erik Swain
Reference:
Rader D. 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: Rader reports consulting for Alnylam, Dalcor, Novartis and Pfizer and co-founding Staten Biotech and VascularStrategies.