Anacetrapib lowers the bad stuff, too, new test indicates

ScienceNews.org, November 17, 2010, by Nathan Seppa, CHICAGO — An experimental drug shows the ability to more than double a person’s good cholesterol score, potentially filling a huge gap in cardiovascular care, scientists report. If the findings hold up in a larger trial, the drug, called anacetrapib, stands poised to become the best medication yet for boosting levels of the heart-disease preventer HDL.

“This is a very exciting era we are entering,” said Christopher Cannon, a cardiologist at Harvard Medical School and Brigham and Women’s Hospital in Boston. He presented the findings at a meeting of the American Heart Association on November 17, the same day they appeared online in the New England Journal of Medicine.

“These preliminary data are very promising,” agreed Sidney Smith, a cardiologist at the University of North Carolina at Chapel Hill and a past president of the AHA. “They show dramatic differences in HDL.” High-density lipoprotein, or HDL, ushers low-density bad cholesterol, or LDL, out of the blood. High levels of HDL are closely associated with low risk of heart attack and stroke.

Cannon and his colleagues randomly assigned 1,623 people, average age 63, who had heart disease to receive either anacetrapib or a placebo for 18 months. All were already taking a statin drug to lower LDL. In the anacetrapib group, HDL levels shot up from an average of 41 milligrams per deciliter of blood to 101 mg/dl within the first few weeks of the study and stayed there. Anacetrapib also lowered LDL from an average of 81 mg/dl to around 45 mg/dl. People who received a placebo experienced very slight changes in their HDL and LDL scores.

Only eight people getting anacetrapib — compared with 28 in the placebo group, which was the same size — needed to undergo coronary revascularization during the trial, in which doctors surgically reopen or bypass a blocked artery to restore blood flow to the heart. “We’re very encouraged by this,” Cannon said.

“These were people who were doing fine” at the outset, despite having heart disease, Cannon says. The revascularization data indicate that in some of them, the heart disease was progressing despite being on medication.

But the data in this study are not enough to change medical guidelines, Smith cautioned, and Cannon agreed. Further work will be needed to establish that the higher HDL levels seen in patients taking anacetrapib are truly functional HDL, and that can be established only by a long-term reduction in heart attacks, stroke, angina and other tangible cardiac events. “If it does have a significant benefit on events, then we will have a very valuable potent new therapy to add,” Smith said.

Some people naturally have higher HDL than others. Apart from niacin, which has a side effect of flushed skin, no drug has previously been shown to safely increase HDL substantially. Stopping smoking, losing weight and exercising can add 5 to 10 points to a person’s HDL score, Smith said.

Anacetrapib works by inhibiting CETP, or cholesteryl ester transfer protein, a compound that influences how much LDL and HDL a person carries in the blood at any given moment. A promising drug called torcetrapib had shown the ability to neutralize CETP But research pitting the drug against a placebo was stopped in 2006 when it became clear that people taking torcetrapib were more likely to develop high blood pressure, experience heart problems or die than those getting a statin alone. The result was a blow to the drug’s maker, Pfizer, and left HDL-boosting drug hopes in limbo, although some work is ongoing.

Anacetrapib has now shown “a very potent and impressive change in lipid profiles,” said Thomas Lüscher, a cardiologist at University Hospital Zurich. “And such change occurred without a change in blood pressure.” The number of deaths was roughly the same in the two groups.

But 142 people had their LDL drop so low on anacetrapib plus a statin that they were taken off the experimental drug as a precaution. Scientists will next test anacetrapib, manufactured by Merck, in a trial of 30,000 heart disease patients over four years, paying close attention to that risk and any other that arises, said cardiologist Rory Collins of the University of Oxford.


HealthCare

Merck’s New Drug Could End the Stent Business

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FORBES.com, November 17, 2010, by Robert Langreth  — Millions of heart patients have gotten cardiac stents placed in their arteries to stave off chest pain from angina and open dangerously-clogged arteries. The multibillion dollar business is dominated by companies such as Johnson & Johnson and Boston Scientific.

But if a new drug from Merck lives up to its early promise, it could put much of the stent industry out of business.

The drug, called anacetrapib, showed a remarkable ability to prevent the need for stent operations and bypass surgery in a preliminary study  presented today at a big meeting of cardiologists in Chicago. In the 1600 person study, the drug slashed the number of such procedures by an astonishing 70%, with no apparent major safety risks.

The results could revive hopes for a notorious class of drugs that aim to boost good cholesterol particles, which help clear cholesterol out of the arteries.  The Merck compound is in the same class of drugs as a Pfizer drug called torcetrapib that was hailed a few years ago as the next big heart drug. Then it turned out to cause heart attacks and deaths in a giant trial. The colossal failure cast a pall over the good cholesterol field and raised questions over whether doctors  understand how good cholesterol works.

Reassuringly, the Merck drug showed no signs of  raising blood pressure, altering electrolytes, or interfering with the hormone aldosterone, top cardiologists said–problems that occurred with the Pfizer drug. Patients on the drug showed a tendency towards a slightly lower rate of heart attacks and unstable angina, although this was not statistically significant.

“It is very reassuring and very encouraging,” said Harvard cardiologist Christopher Cannon, who led the Merck-sponsored trial. Merck plans to move into a definitive larger trial based on the result.

Overall, Merck and Harvard researchers calculated that they could rule out with 95% certainty the possibility that anacetrapib could cause  the 25% increase in heart attacks and other cardiovascular events seen with torcetrapib. But the current study cannot rule out that the Merck drug increases other causes of death, as the Pfizer drug appeared to do. In the big Pfizer study, there appeared to be higher rates of deaths from both cancer and infections in group of patients who got torcetrapib. It is not clear why this happened, but HDL has been theorized to play a immune system role; interfering with this could cause problems.

In the Merck study, there were 11 deaths in patients on the study drug and 8 deaths among patients who got placebo. This difference was not statistically meaningful.

In the trial, the Merck drug caused a remarkable 138% increase in good cholesterol, pushing people up into supernormal levels above 100. A typical level is more like 50 or 60. “It is just off the charts HDL levels,” said Harvard’s Cannon, a cardiologist at Harvard’s Brigham and Women’s Hospital. “Lots of people are trying to work on raising good cholesterol, but this drug is way more potent than anything we have seen.” Other companies testing good cholesterol drugs include Roche (which has a directly competing medicine in final trials), and tiny Resverlogix, which is working on a totally different mechanism to  alter good cholesterol.

Based on the study Merck said it will move ahead with a massive 30,000 patient study led by Oxford University to prove that anacetrapib can lower heart risk without causing other adverse effects. This will take around five years and will likely cost hundreds of millions of dollars.

“It is a sizable risk that Merck is taking,” said Merck vice president Yale Mitchel. “We are confident we are not going to see the same types of problems that were seen with torcetrapib. But we don’t know whether the drug will work or not.” Only by doing the giant trial can it get an answer.

There have been questions raised whether torcetrapib-style drugs make larger amounts of defective good cholesterol particles that can’t do the job properly.  Cannon noted that recent lab studies appear to indicate that anacetrapib makes “big and puffy” HDL particles that seemed to function properly in removing cholesterol from the arteries.

Today’s Merck study was also published in the New England Journal of Medicine.

Medscape Medical News from the:   American Heart Association (AHA) 2010 Scientific Sessions

Erin Michos, MD

Medscape.com, by Susan Jeffrey, November 15, 2010 (Chicago)—Vitamin D deficiency is associated with an increased risk of fatal stroke in whites but not in blacks, a new study shows.

Although blacks had higher rates of both fatal stroke and vitamin D deficiency, racial differences did not explain the excess risk in blacks compared with whites, said lead author Erin Michos, MD, MHS, assistant professor of medicine at Johns Hopkins University School of Medicine in Baltimore.

In whites, vitamin D deficiency was associated with a two-fold increase in fatal stroke after adjustment for other risk factors.

A randomized placebo-controlled trial, the Vitamin D and Omega-3 Trial (VITAL), funded by the National Institutes of Health and run by Harvard Medical School and Brigham and Women’s Hospital, is currently investigating whether 2000 IU daily vitamin D or fish oil containing about 1 gram of omega-3 fatty acids, reduces incident cancer, heart disease or stroke. Investigators plan to enrol 25% black subjects in that trial. “We certainly await those results before we can strongly endorse widespread screening and treatment programs for vitamin D deficiency,” Dr. Michos concluded. “But while we’re waiting on the clinical trial data, I think there is compelling enough data that I do recommend screening for vitamin D deficiency. It’s very common and doses of 1000 to 2000 IU a day appear safe with little downside, and we know it has good benefit for the bone.”

The findings will be presented Monday here at the American Heart Association Scientific Sessions 2010 but were discussed Sunday at a press conference here.

Independent Risk Factor

Previously, the Johns Hopkins group and others have shown vitamin D deficiency to be a risk factor for cardiovascular disease, myocardial infarction and all-cause and cardiovascular mortality, independent of traditional cardiovascular risk factors, Dr. Michos said. Vitamin D deficiency can be easily screened for through 25-hydroxyvitamin D [25(OH)D] testing, and treated by vitamin D supplementation and modest sunlight exposure, she said.

Previous work has also noted racial differences in 25(OH)D vitamin D levels, that were thought perhaps to explain part some of the excess cardiovascular risk seen in blacks compared to whites, Dr. Michos noted. Vitamin D deficiency is highly prevalent in the US, but particularly so for black populations, since melanin in the skin blocks the UVB synthesis of vitamin D, acting as a natural sunscreen, she said. It’s estimated 80% of blacks in the US have insufficient vitamin D levels.

Prior studies looking at the relationship of vitamin D to stroke have only been done in white populations to date. “Because vitamin D deficiency is more common in blacks and stroke is more common in blacks, we decided to examine whether low vitamin D levels contributes to the excess risk of stroke in blacks compared to whites,” she said.

For this analysis they used the third National Health and Nutrition Examination Survey (NHANES III), a nationally representative cross-sectional sample of US adults. Included were 7981 white and black adults with no history of cardiovascular disease and stroke. Between 1988 and 1994, they answered medical questionnaires, and underwent physical exam and 25(OH)D testing.

NHANES III was linked to the National Death Index in 2006, which was used to identify participants who had died with stroke listed as the cause of death. Over an average 14 years of follow up, there were 176 total stroke deaths, 116 whites and 60 blacks.

“At baseline, as we anticipated that we’d see, blacks had much lower 25(OH)D levels compared to whites,” Dr. Michos said. Vitamin D deficiency, defined as a 25(OH)D of less than 15 ng/ml, was seen in 6.6% of whites vs 32.3% of blacks.

“We confirmed prior work that among whites, whites that were vitamin D deficient had a two-fold increased risk of dying of a fatal stroke compared to whites who had optimal vitamin D levels,” she said. “However, to our surprise, we actually saw no association of vitamin D levels with fatal stroke among blacks.”

Risk of Fatal Stroke Associated with Vitamin D Deficiency (25[OH]D < 15 ng/ml) in White vs Black Participants

Group Hazard Ratio 95% CI P
Whites 2.16 1.04 – 4.49 < .05
Blacks 0.94 0.50 – 1.79 NS

Still, blacks had a higher rate of fatal stroke compared with whites, a 65% increase after adjustment for a variety of risk factors including age, sex, education, income, body mass index, smoking, physical activity, and C-reactive protein among others.

Rate of Fatal Stroke for Blacks vs Whites

Endpoint Hazard Ratio 95% CI
Fatal Stroke 1.65 1.07 – 2.54

She pointed to limitations of their study, including that vitamin D was measured only once at baseline, which may not capture lifetime patterns of vitamin D status. They had only 60 fatal stroke events among blacks, so they may have been underpowered to detect a difference.

In addition, the methodology didn’t allow them to assess nonfatal or silent strokes, or transient ischemic attacks, she said, “but this is an area that our group is going to be actively working on.”

She speculated that it is possible that blacks may have a relative adaptive resistance to the adverse effects of low vitamin D levels; for example, despite lower vitamin D levels, blacks have lower fracture and osteoporosis rates than whites.

Association is Not Causation

During discussion here, Dr. Michos said that while information from the VITAL trial will be valuable, providing evidence-based data to help guide patient management, she is concerned that with a single dose of vitamin D, the trial will not answer the question it has set out to answer.

“I’m a big believer that what matters biologically is having adequate levels of vitamin D as measured by 25-hydroxy vitamin D levels,” she said. “So I’m not sure there’s one fixed dose that everybody should take because your blood levels vary in response to a given dose based on your sun exposure, your genetics, your body mass index. That dose may be too low for someone who’s too vitamin D deficient; on the other hand someone who has adequate vitamin D levels may not need that dose.”

Michelle A. Albert, MD, MPH, from Brigham and Women’s Hospital in Boston, is a coinvestigator on the VITAL trial, and is responsible for the enrolment component for African Americans in the study.

At the press conference here, she agreed that it is difficult to use a single dose of vitamin D to ensure all subjects get to adequate levels. “However, I can tell you the dose was chosen to be one that would be as high as possible and not be toxic to at least be powered to see an effect in the black population.”

Dr. Michos acknowledged that it is the highest dose that’s been used to date in a clinical trial. “By comparison, the Women’s Health Initiative only used 400 IU, so they are to be commended,” she said.

Dr. Albert was more cautious though about recommending vitamin D supplements at this time after negative experience with antioxidant vitamins in the Women’s Health Study. Vitamin D is promising, but she doesn’t advocate vitamin D for her patients, she said, “because we don’t have any evidence, any clinical trial evidence that says that giving vitamin D will reduce your risk.

“We have a lot of epidemiologic data, observational data that suggests that higher levels are associated with lower risk but we have been up that tree before, and we have to be very careful because we’ve failed up that tree before.”

Russell Luepker, MD, MS, Mayo professor at the University of Minnesota School of Public Health, was moderator of the press conference. In an interview, he said that in his view, the data connecting vitamin D levels and cardiovascular disease is too preliminary to have much impact on practice.

“We all got on the vitamin E bandwagon a few years ago until finally somebody did some studies, including Julie Buring and JoAnn Manson and the Brigham group and they couldn’t find anything, in the HOPE trial couldn’t find anything, and I think we need good studies before saying that at least for cardiovascular disease,” Dr. Luepker told Medscape Medical News.

Bone health in adults and bone growth in children is a “good enough reason to put (vitamin D) in the milk, he added, but they tend not to measure vitamin D for their patients at his institution. “As Michelle pointed out, we’ve been led down the pathway where epidemiologists say ‘well there’s an association here, so obviously doing something about it must be the answer.'”

An epidemiologist himself, he still would like to see the results of VITAL and perhaps a confirmatory trial before changing clinical practice based on epidemiologic evidence.

Accumulating Evidence

Other studies that will presented here this week focus on other aspects of the connection between vitamin D and cardiovascular disease.

  • Researchers used data again from NHANES III and found serum vitamin D levels were related to prehypertension. Charumathi Sabanayagam, MD, PhD, a post-doctoral fellow at West Virginia University in Morgantown, conclude that future randomized intervention trials should look at whether supplementation at that stage could prevent or delay onset of hypertension.
  • Charles B. Eaton from Brown University and colleagues looked at 25(OH) levels in 1829 postmenopausal women in the Women’s Health Initiative observational study and control groups followed over 10 years for cardiovascular and all-cause death. They found low vitamin D levels were associated with both mortality measures, but the association was attenuated after adjustment for other traditional risk factors; waist circumference was most prominent.
  • On Tuesday, researchers with lead author Mathew Good, DO, a cardiology fellow at the University of Kansas Medical Center will report results of an observational study using a database of more than 10,000 male and female patients, and found vitamin D deficiency was associated with hypertension, coronary heart disease, cardiomyopathy, diabetes and mortality (odds ratio 2.64 (95% CI 1.901 – 3.662, P < .0001).

Vitamin D supplementation in this cohort was associated with a “substantial survival benefit,” the researchers note, with a hazard ratio of 0.39 (95% CI 0.277 – 0.534, P < .0001). The benefit was particularly evident in those who were deficient, and was independent of aspirin or statin use, they note.

NHANES III is sponsored by the Centers for Disease Control and Prevention and the National Center for Health Statistics. Dr. Michos and colleagues report no conflict of interest.