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Experts discuss potential benefits of raising HDL
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In the past few years, research has confirmed that lowering LDL and triglyceride levels has a positive effect on reducing the risk for coronary heart disease. Recently, researchers have turned their attention to the effects of raising HDL.
“HDL has been an area of great interest to clinicians over the last few years,” Peter Libby, MD, chief of cardiovascular medicine at Brigham and Women’s Hospital and Mallinckrodt professor of medicine at Harvard Medical School, told Cardiology Today. “We have very good tools at hand to deal with LDL, particularly with the statins. HDL has taken obvious prominence as an unsolved problem because we have decades of very clear evidence that baseline HDL correlates inversely with CV risk.”
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Peter Libby, MD |
Peter Libby, MD, of Brigham and Women’s Hospital and Harvard Medical School, encourages cardiologists and researchers to look to the future for the potential role of HDL.The increasing burden of those with dyslipidemia and the epidemics of obesity, diabetes and metabolic syndrome have also brought the idea of raising HDL to the forefront for cardiologists and researchers, Libby said.
Philip Barter, MD, PhD, director of the Heart Research Institute at University of Sydney, Australia, said, “If we look at 2011, there is one word that covers everything related to HDL: confusion.”
Varying results from AIM-HIGH, ILLUMINATE and other key clinical trials have many cardiologists looking to the future, specifically anticipating data from trials such as dal-OUTCOME, which is examining the effects of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib (Roche), and REVEAL, which is examining the effects of anacetrapib (Merck).
“Unfortunately, we do not yet have good clinical outcome studies that tell us if we raise HDL with niacin or fibrate, for example, that this will reduce the risk for MI or stroke. And, the recent studies have been disappointing,” Roger S. Blumenthal, MD, a Cardiology Today Editorial Board member, said in an interview.
AIM-HIGH
The AIM-HIGH study received a great deal of attention in 2011. In May, the NIH stopped the trial 18 months earlier than planned due to a lack of efficacy in reducing CV events with a combined treatment of niacin and statin compared with statin alone.
Results of AIM-HIGH were presented at the 2011 American Heart Association Scientific Sessions in November. The study included 3,414 patients with a history of CVD who were treated with a combination of high-dose extended-release niacin and statin (n=1,718) or statin therapy alone. Both groups received simvastatin (Zocor, Merck) 40 mg to 80 mg and ezetimibe (Vytorin, Merck/Schering-Plough) 10 mg daily, as needed, to maintain LDL levels between 40 mg/dL and 80 mg/dL.
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During a discussion at the AHA Scientific Sessions, William E. Boden, MD, professor of medicine and public health at the University of Buffalo, said, “The AIM-HIGH study was designed to address the issue of residual risk associated with low levels of HDL in patients with CVD whose CHD risk was presumably optimized with the use of LDL-reduction therapy that consisted of simvastatin and ezetimibe, as needed, to optimally control the LDL.”
Results showed that added niacin to statin therapy had no clinical benefit in this patient population. At 2 years, the primary endpoint of composite death from CHD, nonfatal MI, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization occurred in 16.4% of patients in the niacin plus statin group and 16.2% in the placebo group (HR=1.02; 95% CI, 0.87-1.21). HDL increased in the niacin group from 35 mg/dL to 42 mg/dL; triglyceride levels improved from 164 mg/dL to 122 mg/dL and LDL levels from 74 mg/dL to 62 mg/dL. HDL was also increased in the placebo group, creating only a 4 mg/dL difference between the two groups.
“This trial disturbs me greatly,” Barter said at the AHA Scientific Sessions. “Not because the results are different from all previous niacin trials, because that happens. It disturbs me because the design was such that in no way could attest the hypothesis of raising HDL or the benefit of niacin.”
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In an interview, Barter added, “Now, does that mean that niacin does not, work? Does it mean that raising HDL is ineffective? The answer to both those questions is: No, it doesn’t tell us anything.”
In a commentary published previously by Cardiology Today, Seth S. Martin, MD, cardiology fellow at The John Hopkins Ciccarone Center for the Prevention of Heart Disease, and Blumenthal, professor of medicine and director of the center wrote, “It was clearly a challenge to end the AIM-HIGH trial after a mean follow-up of 3 years. Although AIM-HIGH did not show benefit, this does not mean that the HDL hypothesis is dead. Indeed, several clinical trials of novel agents that raise HDL are undergoing investigation. AIM-HIGH also does not mean that niacin itself should dig an early grave.”
Other drugs being investigated
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Researchers have found CETP to be a promising protein under investigation because it transfers cholesterol from HDL to LDL. According to Barter, “CETP doesn’t exist in most species but is present in humans, nonhuman primates and rabbits. What we’ve discovered over the past 25 years is if you put the gene for CETP into mice or rats that do not have it, they become susceptible to atherosclerosis.”
A number of CETP inhibitors, such as torcetrapib (Pfizer), anacetrapib and dalcetrapib, have been investigated to reduce risks for atherosclerosis and to improve HDL levels. However, none of these drugs are currently approved by the FDA. Even without FDA approval, the study of CETP inhibitors is not over.
Similar to AIM-HIGH, the ILLUMINATE trial was halted early. Results showed that patients with CHD or CHD risk equivalent assigned to torcetrapib and atorvastatin had more CV problems and a higher mortality rate vs. patients assigned to atorvastatin and placebo.
“The ILLUMINATE trial almost killed the idea of inhibiting CETP,” Barter said. “However, with much of the analysis we did after this trial, including a post-hoc analysis and basic preclinical studies, we found that there are many functions of torcetrapib unrelated to the primary action of inhibiting CETP that are sufficient to account for the problem.”
Researchers found that average blood glucose levels were lower in the torcetrapib and atorvastatin group (7.06%) vs. the statin and placebo group (7.29%), and HDL levels improved 66.8% after 1 year with torcetrapib and atorvastatin vs. a minimal change with statin and placebo.
“The possibility that CETP inhibitors may not only reduce the risk for [MI] and stroke, but may also improve the control of blood sugar in people with diabetes is an exciting prospect that may translate into real health benefits for people with diabetes,” Barter said.
Where the ILLUMINATE trial failed to meet researchers expectations, the DEFINE trial brought promising results for another CETP inhibitor. Among patients randomly assigned to anacetrapib, LDL was reduced by 39.8% and HDL increased 138.1% (P<.001) as compared with placebo. Researchers also reported no change in BP, electrolyte or aldosterone levels through 76 weeks.
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In a previous article published in Cardiology Today, Christopher P. Cannon, MD, of Brigham and Women’s Hospital in Boston and senior investigator of the TIMI study group, said, “We’re very encouraged with these results. This is a moderate-sized safety study, so we have reassurance that we can move forward and really test this [drug].”
A third CETP inhibitor, dalcetrapib, was tested against placebo in both the dal-VESSEL and dal-PLAQUE trials, part of the dal-HEART program. In dal-VESSEL, dalcetrapib did not negatively affect endothelial function or markers of inflammation and oxidative stress while increasing HDL and reducing CETP activity by 31%. In dal-PLAQUE, compared with patients on placebo, fewer adjudicated CV events were experienced among patients on dalcetrapib. MRI measures also showed plaque burden parameters improved after 24 months with dalcetrapib vs. placebo.
In an interview with Cardiology Today, Barter said, while dal-VESSEL and dal-PLAQUE were both interesting and worthwhile, they will not affect clinical practice. “The earliest that they can possibly be approved for use will be after the first of the clinical outcome trials is finished, reported and reviewed by the FDA, the European Association for the Study of Diabetes and all of the other regulators and shown to be beneficial,” he said.
Even without FDA approval, the study of CETP inhibitors is not over. Libby said researchers and physicians should look to the future.
Niacin and extended-release niacin, both alone or combined with statin, are currently approved to lower LDL and triglycerides and to raise HDL levels along with diet and exercise. Beyond statins and other approved lipid-lowering therapies, several other classes are being investigated to raise HDL levels. “One class is called ApoA-1 mimetics. Mainly looked at in animal studies, these are substances that increase the production of the main protein of HDL. Another class of medicines, liver X receptor agonists, are also being looked at in animal studies. We await human data with them,” Blumenthal said in an interview.
Looking ahead
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Experts interviewed by Cardiology Today expressed optimism for the future of HDL research.
“HDL may have suffered a partial setback in 2011 based on results of the AIM-HIGH study. But there are a number of ongoing clinical trials with results that should be available during the next several years that will provide important insight into the role of HDL in offsetting CHD risk,” Michael Miller, MD, professor of the departments of medicine, epidemiology and public health at the University of Maryland School of Medicine and director of the Center for Preventive Cardiology at the University of Maryland Medical Center, told Cardiology Today.
“Epidemiologic studies have consistently demonstrated an inverse association between HDL and CVD risk,” he said. “We now need to provide clinical trial evidence that raising HDL reduces risk for MI and CHD death. Upcoming studies will help us determine whether HDL is directly involved in mediating atheroprotection.”
Researchers and physicians will have to wait until results from ongoing trials are presented (see Table). The DAL HEART program has three studies, dal-OUTCOMES, dal-OUTCOMES 2 and dal-PLAQUE 2, under way to study the effects of dalcetrapib on CV morbidity and mortality and atherosclerotic disease progression. Anacetrapib is another CETP inhibitor that is the focus of other research. The REVEAL HPS-3 TIMI-55 trial will help determine whether anacetrapib can decrease the risk for MI and death from heart disease.
“The bottom line is that I would not diminish the potential importance of raising HDL until data from these ongoing trials dictate otherwise,” Miller said. – by Casey Murphy
For more information:
- Boden WE. N Engl J Med. 2011;365:2255-2267.
- Dalcetrapib phase II studies support the safety profile and potential for slowing of plaque progression in patients at risk of coronary heart disease. Roche Website. www.roche.com/investors/ir_update/inv-update-2011-08-29.htm. Updated Aug. 29, 2011. Accessed Nov. 9, 2011.
- Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification. REVEAL Home Page. www.ctsu.ox.ac.uk/reveal/index.htm. Accessed Nov. 9, 2011.
- Roche announces start of new atherosclerosis study (dal-PLAQUE 2) for dalcetrapib. Roche Website. www.roche.come/investors/ir_update/inv-update-2009-11-18b.htm. Updated Nov. 18, 2009. Accessed Nov. 9, 2011.
- Schwartz GG. Am Heart J. 2009;158:896-901.
- Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE. Clinical Trials: A Service of the US National Institutes of Health. clinicaltrials.gov/ct2/show/NCT00461630. Updated July 19, 2010. Accessed Nov. 9, 2011.
Disclosure: Dr Barter has received research grants from Merck, Pfizer and Roche; honoraria from Abbott, AstraZeneca, Kowa, Merck, Novartis, Pfizer and Roche; and is on the advisory board of Astrazeneca, CSL, Lilly, Merck, Novartis, Pfizer, and Roche. Drs. Blumenthal, Boden and Libby report no relevant financial disclosures. Dr. Cannon has received research grants from Accumetrics, AstraZeneca, GlaxoSmithKline, Merck and Takeda; and received honorarium from AstraZeneca and Pfizer. Dr. Miller received research grants from and is a consultant for Abbott and Roche.