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AHA Conference Blog: Tempered enthusiasm for novel approaches to address cholesterol
LOS ANGELES — Some of the most anticipated research in the field of cardiology is being presented at this year's American Heart Association Scientific Sessions. There are about 18,000 registrants, 15,000 of whom are professional members, and a record 27 late-breaking trials are being presented over the course of 3 days.
To expand our coverage, Cardiology Today caught up with several fellows to get their opinions and impressions on this year's conference.
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Parag H. Joshi, MD, on November 5, 2012
The late-morning late-breaking clinical trials session Monday at the American Heart Association Scientific Sessions focused on two fairly new methods to change lipids in patients at risk for CVD. A lot of excitement was generated by several phase 2 PCSK9 inhibitor trials, a novel method to lower LDL particles and LDL cholesterol. This enthusiasm was contrasted by further disappointment in the latest installment of the CETP inhibitor saga.
Parag H. Joshi
Beyond statin therapy, efforts to address residual risk for events by further affecting lipoproteins have thus far been disappointing. Nevertheless, the search for novel ways to address this important part of risk reduction forges on, particularly with therapies designed to inhibit two proteins that are heavily involved in lipoprotein management and metabolism (CETP and PCSK9). The LDL receptor on the surface of the hepatocyte is involved in removing potentially atherogenic LDL particles from the serum through endocytosis into the liver where the particle can be broken down, thus allowing for cholesterol to be removed, incorporated into bile and eventually excreted through the gut. The LDL-receptor molecule then recycles and reincorporates back into the surface of the hepatocyte to repeat the process. PCSK9 exists in serum and binds and blocks the LDL receptor, which leads to endocytosis and subsequent degradation of the LDL receptor so that it cannot reincorporate into the hepatocyte and remove further LDL particles. Inhibition of PCSK9, in theory, would lead to greater presence and activity of the LDL receptor, thus lowering LDL particles in the serum.
Yesterday, researchers announced results of four phase 2 trials of two human monoclonal antibodies designed to inhibit PCSK9. Amgen’s PCSK9 inhibitor, AMG145, was the topic of the first two trials, RUTHERFORD and GAUSS. The degree of LDL and apolipoprotein B reduction were striking in both heterozygous familial hypercholesterolemia patients mostly on statins with baseline LDL levels of 150 mg/dL to 160 mg/dL from the RUTHERFORD trial and in statin-intolerant patients with baseline LDL levels of nearly 200 mg/dL in the GAUSS study. Subcutaneous injections every 4 weeks of the highest dose of AMG145 led to nearly 50% reduction in LDL in both studies, with very little in the way of adverse events over 12 weeks. Finally, Pfizer’s RN316 molecule was tested in patients on maximal statin therapy still not at LDL goal per ATP criteria and IV infusion every 4 weeks again showed an additional 40% to 50% reduction in LDL.
While these results are impressive and exciting, the final trial presented was a sobering reminder that outcomes are the key to any new therapies. The presentation of dal-OUTCOMES, a trial of more than 15,000 patients with recent ACS randomized to the CETP inhibitor dalcetrapib (F. Hoffmann-La Roche) vs. placebo, on top of optimal secondary prevention therapy, was another disappointing addition to the CETP inhibitor tale, as the trial was stopped early for no difference in interim analysis between the two arms. The class of CETP inhibitors lead to impressive increases in HDL (30% improvement with dalcetrapib; 100% increase with anacetrapib), but, thus far, two outcomes trials have been disappointing showing either harm with torcetrapib (attributed to off-target effects on BP) or no difference in the case of dalcetrapib. Healthy skepticism surrounds this mechanism of raising HDL as many experts in the field are more focused on HDL functionality and not simply the amount of cholesterol within the particle. Two large outcomes trials of the CETP inhibitor class are currently enrolling, and hopefully will settle the question of whether simply increasing HDL by this mechanism is an effective way to change outcomes.
In summary, this nicely organized session was an excellent balance of building enthusiasm for a novel way to attack cholesterol while also tempering enthusiasm by reminding us that outcomes trials are the only means to assess the utility of these therapies. I eagerly anticipate the phase 3 trials of the PCSK9 inhibitors, particularly in statin-intolerant patients.
Parag H. Joshi, MD, can be reached at the Johns Hopkins Division of Cardiology, 600 N. Wolfe St./Carnegie 568, Baltimore, MD 21287; his email is pjoshi9@jhmi.edu.
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Posted by Seth S. Martin, MD on November 4, 2012
It was a fantastic Sunday at the AHAScientific Sessions in Los Angeles. Entering the convention hall in the morning, I immediately found myself in the usual sea of suits. Within a few minutes, I ran into a familiar face — a co-fellow, Jose Vargas. Like many other senior cardiology fellows, he recently finished his cardiology boards and told me that he arrived in LA relieved to have the weight of the boards off his shoulders.
Seth S. Martin
This is my first time here at the LA convention center, so I started my day by finding my bearings. As I walked about and registered at the speaker’s resource center, I ran into more familiar, friendly faces. I consider this one of the greatest aspects of these meetings — the opportunity to catch up with many friends and colleagues. I saw Khurram Nasir, a close collaborator and innovative researcher, as he was on his way to put up his poster on the BioImage study. I was also very happy to chat with Victor Dzau, the leader of Duke Health System (where I did my residency) and also the father of a good friend of mine.
After getting a latte, I made my way upstairs to a Core 2 session of interest: the Clinical Lipidology Update. There were a number of great presentations and speakers, including Donald M. Lloyd-Jones, MD, ScM, who discussed state-of-the-art CVD risk assessment. He made many important points and showed evidence that patients substantially overestimate and underestimate their CVD risk, and that physicians are only slightly better at approximating patients’ risk. He concluded that we need risk equations to guide us. The prospect of taking robust risk estimation tools and integrating them into clinical practice more seamlessly via electronic health records is truly exciting for my generation of computer-savvy doctors. This should give a big boost to our move towards more personalized medicine.
Next, I made my way to the poster hall, where things quieted down. I saw more familiar faces and enjoyed perusing some interesting posters. In Core 2, many projects focused on exercise capacity and stress testing. The first poster I came across was by Mihesh Patel, Jarrett Berry and colleagues, which reported a strong, graded, inverse association between midlife fitness and stroke in the Cooper Center Longitudinal Study.
The day wrapped with some disappointing results for personalized antiplatelet therapy from the ARCTIC study and TRILOGY ACS Platelet Function Substudy, although the discussion following the presentations noted that we still need more studies in higher-risk patients. The studies themselves were certainly interesting, but as the presenters flashed their simultaneously published articles in the New England Journal of Medicine and Journal of the American Medical Association, I thought to myself how interesting it is to see the people behind the data at the AHA Scientific Sessions.
As for the upcoming late-breaking clinical trials, as a “lipids guy,” I am especially interested to hear all about the efficacy and tolerability of PCSK9 inhibition from RUTHERFORD and GAUSS and others on Monday. On the lipids front, I am also excited to present some of my own data from the TRIUMPH study on HDL subclasses and mortality after acute MI during a Wednesday morning session.
As for now, I'm getting hungry, and glad it’s about time for dinner with some friends.
Seth S. Martin, MD, can be reached at the Johns Hopkins Division of Cardiology, 600 N. Wolfe St./Carnegie 568, Baltimore, MD 21287; his email is smart100@jhmi.edu.