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Managing CV risk evolves with new research
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More research has been conducted that affects the diagnosis and treatment of patients with CVD, yet issues involving access and the need for more information on the mechanics of LDL and triglycerides remain, according to a webinar hosted by Amarin Corp.
“The proposition that we’ve conquered cardiovascular disease is, frankly, absurd, not even close,” Peter W. Toth, MD, PhD, director of preventive cardiology at CGH Medical Center in Sterling, Illinois, and professor of clinical family and community medicine at the University of Illinois College of Medicine in Chicago, said in the webinar. “We can see in the ongoing secondary prevention trials that despite patients being on an extraordinarily intensive background of known drugs that reduce event rates and then adding an agent that is being tested, that despite very intensive therapy addressing blood pressure, lipids [and] diabetes ... event rates remain relatively high.”
MI and stroke remain the two leading causes of death in the United States and surpasses the rate of death for all cancers put together, Craig B. Granowitz, MD, PhD, senior vice president and chief medical officer of Amarin and facilitator of the panel discussion, said in the webinar. Although the total number of deaths for CVD dropped during a 20-year period, it started to increase between 2011 and 2015. The American Heart Association estimates that by 2035, more than 130 million Americans will have CVD.
“Not only have we not conquered cardiovascular disease, but cardiovascular disease still remains the No. 1 killer of Americans, and that’s something that has been lost a little bit in the dialogue,” Granowitz said.
Prevention, treatment
Regarding primary and primordial prevention, the debate continues on when to screen for lipids and at what age to begin statin therapy. One in five patients have plaque that is at least 70% obstructive, Toth said.
“Disease is out there in young people, but people get uncomfortable with the idea at starting medication at a young age, especially when they have no signs or symptoms of illness,” Toth said in the webinar.
Even once patients are on medications, sometimes they are on anywhere between seven and nine drugs, including antihypertensive medications and therapies for dyslipidemia and diabetes, yet they are still having events, Toth said.
Additional issues that persist include identifying unstable, underlying plaque and how to stabilize it.
“A particular interest of mine is being able to do a better job of engaging in primordial and primary prevention, providing patients with better information, better clinical trials, convincing them that early initiation of therapy is a good idea because so often, we wait until people have disease and then initiate therapy,” Toth said in the webinar.
Recent data from studies such as IMPROVE-IT and FOURIER has shown that lower LDL is better and leads to incremental risk reduction. Meta-analyses have also shown that the relationship between LDL and the risk for acute CV events is linear. Another meta-analysis by S. Matthijs Boekholdt, MD, PhD, of the department of cardiology at the Academic Medical Center in Amsterdam, and colleagues found the relationship between LDL and the risk for ischemic heart disease was a straight line between 20 mg/dL and 200 mg/dL.
Residual risk does not just consist of LDL, but also smoking, inactivity, obesity, remnant lipoproteins and uncontrolled BP and diabetes. The CANTOS trial showed that a heightened inflammatory tone also contributes to residual risk.
“What is interesting about remnants and triglycerides is the fact that remnants not only potentiate atherogenesis, but they also heighten levels of systemic inflammatory tone,” Toth said in the webinar. “They give you a double whammy because not only do the remnants add lipid to the vessel wall, but they also augment the inclination toward atherogenesis because they induce inflammation.”
Although there is evidence that lowering LDL reduces the risk for CV events, there are some misconceptions about lowering it aggressively, including hormone interference and an increased risk for hemorrhagic strokes, which have all been shown to be false, he said. The FDA has informed clinicians to be aware of inducing dementia or cognitive impairment when reducing LDL to very low levels, although the EBBINGHAUS, the Heart Protection and PROSPER trials showed that they are not connected.
Even with lowering LDL to very low levels, patients still have substantial LDL particle numbers.
“You’re never really getting LDL down to zero,” Toth said in the webinar. “There’s always going to be plenty of LDL around, but what is clear is when you get it down to very low levels, you also appear to knock risk down substantially.”
People in hunter-gatherer populations have LDLs between 35 mg/dL and 50 mg/dL. At birth, LDL is around 32 mg/dL.
“We were never meant to have the LDLs that we currently have,” Toth said. “We’ve outstripped natural selection and evolution, and if were meant to have the LDLs that we currently have, we wouldn’t be running around developing atherosclerotic disease.”
Effects of obesity, diabetes
With obesity on the rise, the incidence of metabolic syndrome and diabetes is also increasing. Patients with these conditions often have heightened inflammation, high triglycerides, high remnant lipoproteins and low HDL. Age also contributes to the increased risk for atherosclerotic disease and diabetes. It is important to focus efforts on identifying and treating these patients appropriately, Toth said.
Patients who have diabetes, insulin resistance and metabolic syndrome have difficulty metabolizing VLDL particles, a parent lipoprotein secreted by the liver that is highly enriched in triglycerides. This leads to increased triglyceride levels and an accumulation of remnant lipoproteins.
“Because these particles are so enriched in triglyceride and the triglyceride is accumulating in the serum, there has to be sort of a safety valve to offload this because it can’t continue indefinitely,” Toth said. “Biologically, we don’t want heavy cream to comprise our plasma.”
Inhibiting cholesteryl ester transfer protein (CETP), as seen in the REVEAL trial, may help stop the accumulation of triglycerides and effect risk for CV events.
“In patients with high triglycerides, CETP is actually an important enzyme because it helps to offload triglycerides from these triglyceride-rich lipoproteins into HDL or LDL, but there’s a price to pay for that,” Toth said. “If you do that, you’re going to promote HDL catabolism or break down and you’re going to induce the formation of large numbers of small dense LDL particles, which makes them even more atherogenic.”
Remnant lipoproteins predict risk for future CV events, according to the Framingham Offspring study and Jackson Heart Study. New data from prospective longitudinal cohorts show that triglycerides can also predict risk.
More research is focused on novel therapies, but the cost of these therapies is preventing patients from accessing them.
“I am aware of the fact that we are reaching some sort of limit on what society will pay for, and I think that’s very clear,” Toth said.
Even with the roadblocks, innovation is still necessary in the field.
“We will forever need innovation in novel therapies,” Toth said. “If we don’t have innovation, we’re not going to have progress.” – by Darlene Dobkowski
References:
Boekholdt SM, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.02.615.
Toth PP, et al. Reaching a turning point in defining and managing CV risk. Digital Media Briefing. Accessed Sept. 6, 2017.
Disclosures: Toth reports he is consultant and speaker for Amgen and Regeneron, and has a relationship with Amarin, Kowa and Merck. Granowitz is an employee of Amarin.