HDL Raising Drugs Probably Won’t Work But This Might 1

A new study offers important new insights into the protective role of HDL cholesterol (the “good” cholesterol) against cardiovascular disease. Earlier studies with drugs that increase HDL levels, including niacin and CETP inhibitors, have not shown benefit. The new study suggests that simply increasing HDL levels isn’t the way to go. Instead, cholesterol efflux, the ability of HDL to remove cholesterol from cells, part of the process called reverse cholesterol transport, appears to be the key. The results were presented today by Anand Rohatgi at the American Heart Association meeting in Chicago and published simultaneously in the New England Journal of Medicine.

The investigators followed 2,416 people participating in the Dallas Heart Study who were free of cardiovascular disease at the start for 9.4 years….

Click here to read the full post on Forbes.

 

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Cigna Sues Embattled HDL Laboratory For $84 Million Reply

The Cigna Health and Life Insurance company is suing Health Diagnostic Laboratory Inc. for $84 million.  As reported previously, the embattled lab company is the subject of an ongoing Federal investigation concerning kickbacks and fraudulent billing.

The charges against HDL in the suit filed last week in federal court closely echo the earlier allegations against the company.

Click here to read the full post on Forbes.

 

Previous Stories About HDL:

Doctor: You’re Going To Have A Heart Attack! Patient: Your Tests Results Are Giving Me A Heart Attack! Reply

Last month I wrote a series of articles (starting here) about HDL, a laboratory company under investigation by the DOJ for giving kickbacks to physicians who use their tests. I reported additional allegations of serious misconduct based on questionable sales, marketing, and billing practices involving unnecessary testing. In response to those articles I’ve received emails from several individuals, including a patient and a health care provider, whose stories appear to confirm and provide additional perspective about the allegations in the earlier articles.

“Your test results are giving me a heart attack!”

Click here to read the full post on Forbes.

 

Beyond Kickbacks: More Questions About Unnecessary Cardiovascular Tests Reply

On the front page of the Wall Street Journal today is an important story about a fast-growing company accused of giving kickbacks to physicians who order the company’s tests measuring a wide variety of cardiovascular biomarker tests. But the article leaves one major question unasked: even if the company played fully by the rules, are most of the tests medically necessary?

In their story John Carreyrou and Tom McGinty write about a government investigation into Health Diagnostic Laboratory Inc. (HDL), which was started in 2008 and had $383 million in revenue last year. HDL sells tests that measure cardiovascular biomarkers and “bundles together up to 28 tests it performs on a vial of blood, receiving Medicare payments of $1,000 or more for some bundles.”

Click here to read the full post on Forbes.

 

New Evidence Fuels Concerns About The Safety Of Niacin Reply

The string of failures– for HDL therapies in general and for niacin in particular– continues unabated.  The publication of the main results of the HPS2-THRIVE trial, along with new information from the AIM-HIGH trial, provide no evidence of a beneficial effect for niacin but do fuel concerns that it may cause serious adverse effects.

Click here to read the full post on Forbes.

 

 

Large Genetic Studies May Help Unravel The Triglyceride Problem 1

The precise role of triglycerides in heart disease has been very difficult to determine. To help untangle the knotty problem two research groups studied large populations and identified rare variations in a gene (APOC3) that encodes for apolipoprotein C3, which is known to increase triglyceride levels.

The two studies have received a lot of attention in the media, including, most notably, great stories with lots of details and perspective by Gina Kolata on the front page of the New York Times and Matt Herper in Forbes. Both stories provide lots of background on these studies and present a wide variety of opinions about their significance. In general, though, they suggest that triglycerides and HDL are ready to trade roles: triglycerides are now ready for prime time as HDL fades into the background.

Click here to read the full story on Forbes.

 

Another Failed HDL Therapy Trial Reply

Despite robust epidemiological evidence suggesting that HDL has a strong protective effect against cardiovascular disease, there has been no good evidence showing that HDL-based therapies are beneficial. Large trials of drugs that raise HDL levels, including niacin and CETP-inhibitors, have failed to demonstrate improvements in outcome. Some observers gleaned hope from several small studies of drugs that mimic HDL activity but these studies have been too small to offer convincing evidence. Now a new study– the largest to ever study an HDL mimetic– has failed to find even a glimmer of benefit.

Results of the CHI-SQUARE (Can HDL Infusions Significantly QUicken Atherosclerosis Regression) study were published online in the European Heart Journal.

Click here to read the full post on Forbes, with extensive comments from PK Shah and William Boden.

 

Slouching Toward Phase 3: Progress Report On New Cholesterol Drugs At The AHA Reply

The American Heart Association meeting in Dallas this year brought new phase 2 data about several promising new cholesterol drugs. But before jumping on any bandwagons it would be good to remember that even for the drugs most far along in development we still haven’t seen any phase 3 data. In addition, it bears repeating that the FDA may well be raising the entry bar for new cholesterol medications. As I wrote not too long ago, there is a good chance that the FDA will require completed outcomes studies for new cholesterol drugs. There’s good reason to be interested in these drugs but any predictions at this point would be hopelessly speculative.

One Year Results For Amgen’s PCSK-9 Inhibitor 

HDL Drug From CSL Limited

Esperion’s Novel Agent

Click here to read the full story on Forbes.

More Bad News For HDL Therapies: ASSURE Trial Misses Primary Endpoint Reply

The string of bad news for HDL-related therapies continues. Resverlogix yesterday announced that the ASSURE clinical trial had failed to meet its primary endpoint. RVX-208, the drug being studied in the trial, is a novel small molecule that increases production of ApoA-1, which raises HDL levels and is thought to enhance reverse cholesterol transport.

Click here to read the full story on Forbes.

Steve Nissen

WSJ Article Fails To Raise Key Questions About Cardiovascular Risk In Children Reply

There’s probably no greater public health issue than the long-term  consequences of the childhood obesity epidemic. So the Wall Street Journal should be commended for digging into some of the important science behind this problem in a feature article in today’s paper. The author, Ron Winslow, is widely regarded as the best working journalist who regularly covers cardiovascular medicine. But I’m afraid the article fails to raise several key questions about the topic and therefore misses an opportunity to educate people about its complexities.

The article deals with the “growing concerns about the cardiovascular health of millions of children in the U.S. who are considered obese or overweight” and then focuses on one recent study published in Pediatrics that “suggests there is a simple way to assess a child’s arterial health with a calculation based on an often-overlooked component of cholesterol: triglycerides.” Winslow faithfully reports the main finding of the study, which is that the triglyceride to HDL ratio corresponds closely with arterial stiffness. A stiff vessel is a sign of “accelerated aging” and “likely raises the risk of dangerous outcomes relatively early in adult life,” writes Winslow.

Winslow notes that an NHLBI panel now recommends universal cholesterol screening for children between 9 and 11, but there is no mention that some experts disagree with this recommendation.  Further, these screening tests focus on the measurement of LDL cholesterol. Winslow doesn’t discuss whether  LDL would be equally effective as triglycerides and HDL at identifying children with stiff arteries. Winslow writes, reasonably, that high triglycerides and low HDL “are a hallmark reflection of the poor diets and sedentary lifestyles that researchers say are behind the wide prevalence of obesity among both children and adults,” but there’s a big gap between that association and concrete recommendations to measure HDL and triglycerides in children and, more importantly, to take actions based on these measurements.

Click here to read the full story on Forbes.

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Merck Starts To Suspend Worldwide Availability Of Tredaptive Reply

In the wake of the negative HPS2-THRIVE study announced last month, Merck said today that it was beginning to suspend the worldwide availability of Tredaptive, its combination of extended-release niacin and laropiprant.

Click here to read the full story on Forbes.

Should Niacin Still Be Prescribed? William Boden Versus Harlan Krumholz 1

In the wake of HPS2-THRIVE many have argued that there is no longer any reason to prescribe niacin. William Boden, the lead investigator of AIM-HIGH and COURAGE, thinks there were enough flaws in the design of the niacin trials to justify the cautious use of niacin in certain circumstances. Says Boden:

“There is evidence of clinical outcome improvement (i.e., CHD death/MI reduction) from VA-HIT for gemfibrozil; there is similar clinical outcome improvement for niacin from the Coronary Drug Project. Numerous studies show niacin’s benefit on surrogate outcome measures (i.e., quantitative coronary angiography, IVUS, cIMT, etc.). What more evidence do you need?”

” I have not given up on niacin.”

Harlan Krumholz  disagrees:

“We have to face the facts about the trials. They have failed to be supportive, and despite concerns about their flaws, they were developed by some of the best minds in our profession (including yours) and had millions of dollars devoted to them. I just feel that we cannot justify millions of people being prescribed a drug that has failed in two recent, large, prominent trials, which actually had signals of harm…”

Read the entire fascinating discussion over on CardioExchange.

Boden

William Boden

Harlan Krumholz

Harlan Krumholz

2012 In Review: A Bad Year For Conventional Wisdom 3

This was a really grim year for anyone who thought we had things pretty well figured out. Time and again conventional wisdom was thrown out the window. 2012 forced the cardiology community to reconsider what it thought it knew about HDL cholesterol, platelet function tests, aspirin resistance, triple therapy, IABP, and more.

One device company, with a lot of help, did just about everything right when it introduced a radical, highly disruptive new technology. Another device company did just about everything wrong in handling a series of crises. The new generation oral anticoagulants continued to make gains– slowly– but also failed to achieve the early blockbuster success that some had thought they might achieve.

And it was another bad year for scientific integrity.

Conventional Wisdom Isn’t

Raising HDL cholesterol had to be great. Then the evidence arrived. Just last week HPS2-THRIVE put the final  nail in the niacin coffin. (I wonder what all the critics of AIM-HIGH have to say now?) And another CETP inhibitor bit the dust. The HDL hypothesis is far from dead, but any claim of benefit due to raising HDL will need to be rigorously demonstrated in a large, well-designed clinical trial.

Platelet function tests just had to be useful in guiding therapy. Then ARCTIC came along and blew a cold wind on the idea.

On a related note, many believed that testing for aspirin resistance might be a good idea. Then a paper in Circulation presented strong evidence that the entire concept of aspirin resistance might be a myth.

Triple therapy for PCI patients already receiving anticoagulation was standard clinical practice, endorsed by the guidelines. Now, after WOEST, we know that what we knew was wrong. Drop the aspirin.

Intraaortic balloon counterpulsation (IABP) has a class 1 recommendation for patients in cardiogenic shock following myocardial infarction for whom early revascularization is planned. Until IABP-SHOCK II was presented at the ESC and published in NEJM.

Depending on your perspective the FREEDOM trial either confirmed or denied conventional wisdom. We now know with near certainty that diabetics with multivessel disease have better outcomes with CABG than with PCI. An important lesson from an important trial.

Conventional wisdom had it that chelation therapy was worthless. The conventional wisdom may still be valid, but the NIH’s TACT trial means the debate will continue. It’s hard to imagine a satisfactory result to this controversy, despite the good intentions of the NIH and at least some of the TACT investigators. In general I support the concept of testing alternative therapies, especially if they gain traction in clinical practice, but it’s not clear yet whether we really learned anything from TACT (except that doing trials like this is extraordinarily hard). A trial like TACT should only be performed if it has a good chance of actually answering the big clinical question. Unfortunately, TACT didn’t do this.

TAVR: Bright Spot in a Dark Year

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Early Look: New Methods To Enhance Cholesterol Efflux Reply

Although clinical trials of HDL-boosting CETP inhibitors have so far failed to produce positive results, many other avenues of HDL-related research remain active.  A glimpse at the very early phases of two intriguing lines of research in this area was offered on Monday at the AHA.

Apo A-1 is thought to be the key HDL component that removes cholesterol from cells. Almost a decade ago a study demonstrating regression of atherosclerosis with apo A-1 Milano caused tremendous excitement, but the recombinant product has not yet undergone further research or commercial development. A somewhat similar approach is now being developed by by CSL Limited with a novel formulation of human apo A-1, known as CSL112. At the AHA, Andreas Gille and colleagues reported giving CSL112 to healthy volunteers and observing dramatic increases in the ability of the HDL in their blood plasma to remove cholesterol from cells.

Gille reported that the increase in cholesterol efflux capacity was higher and occurred faster than any previous therapy, more than doubling within two hours, as opposed to a 2.9% increase after 4 weeks with niacin or 6.8% after 24 months with dalcetrapib. “CSL112 may offer a novel means to rapidly remove cholesterol from plaque following a heart attack,” said Gille. To date two phase 1 studies have demonstrated a favorable safety profile, he reported. A phase 2 study of CSL112 in patients with an acute coronary syndrome is planned.

An even more unusual approach is being explored by Alan Fogelman and his team, who have genetically engineered a tomato to produce a small peptide, 6F, that mimics the action of apo A-1. They then fed the tomatoes to mice with high LDL levels. After consuming the tomatoes along with a high-fat and high-calorie diet, there were a number of signs suggesting a beneficial effect, including significantly lower levels of inflammation, higher levels of the antioxidant paraoxonase, higher HDL levels, and less atherosclerotic plaque.

“To our knowledge this is the first example of a drug with these properties that has been produced in an edible plant and is biologically active when fed without any isolation or purification of the drug,” Fogelman said in an AHA press release.
Click here to read the press releases from the AHA…

Dalcetrapib: Another HDL-Raising CETP Inhibitor Bites The Dust 1

Another HDL-raising CETP inhibitor has failed to demonstrate cardiovascular benefit in a large clinical trial. With the presentation of the dal-OUTCOMES trial at the American Heart Association in Los Angeles andsimultaneous publication in the New England Journal of Medicine, dalcetrapib joins torceptrapib on the list of once-promising CETP inhibitors.

In dal-OUTCOMES, 15,871 patients with a recent acute coronary syndrome were randomized to dalcetrapib or placebo. At a prespecified interim analysis after a median follow-up of 31 months, the Data and Safety Monitoring Board recommended termination of the trial for futility. The primary endpoint — a composite of death from CHD, nonfatal MI, ischemic stroke, unstable angina, or cardiac arrest with resuscitation — occurred in 8.3% of dalcetrapib recipients and 8.0% of placebo recipients (HR, 1.04; 95% CI, 0.93-1.16; P=0.52).

As expected, dalcetrapib raised HDL (by about 30%) and had little effect on LDL. However, there was no correlation between baseline HDL level and clinical outcome. Furthermore, dalcetrapib treatment resulted in mean increases of 18% in CRP level and of 0.6 mm Hg in systolic blood pressure.

The chair of the trial, Gregory Schwartz, said that the small increases in blood pressure and CRP might explain the results. The discussant for the trial, Alan Tall, said that the decision to stop the trial prematurely was rational. In addition to the changes in blood pressure and CRP, he offered several additional possible reasons for the drug’s failure to improve outcomes:

  • Moderate HDL elevation in patients who are already well treated may have little impact. It is possible that much larger elevations in HDL will be required to alter the course of disease.
  • CETP inhibitors may produce a form of HDL that does not enhance reverse cholesterol transport.
  • Dalcetrapib is only a partial CETP inhibitor. Phase 3 trials of more-potent CETP inhibitors, such as anacetrapib and evacetrapib, may still demonstrate benefit.

You Know Nothing, Dr. Snow: Why Medicine Can’t Be More Like Facebook 3

Medicine can never be like Facebook, despite what Matt Herper argues over at Forbes. Perhaps he was just trolling for hits on a day when everyone is thinking about the Facebook IPO, but Herper proposed, with apparently seriousness, that medicine needs to model itself on the tech world in order to match the kind of progress– and profits– of a Facebook. But the medical news this week provided ample evidence why this will never happen. Biology is much more complex and resistant than the digital world.

For a medical journalist like myself this was a frustrating week. There were a whole bunch of large, major studies on important subjects published in top journals. But the take-away message from these studies, both individually and combined, is that achieving any kind of real progress in medicine is incredibly hard.

Let’s take a quick look at these studies:

1. Coffee in the New England Journal of Medicine: Despite some of the breathless news reports, some of which erroneously claimed that the study proved that drinking coffee can extend your life, this large study added little or nothing new to our knowledge about coffee. Even the editor of the journal, Jeff Drazen, acknowledged the limitations of this sort of study. The simple truth is this: although coffee is ubiquitous and has been the subject of hundreds of different studies of all different types and designs, we will almost certainly never learn to any degree of certainty whether coffee is good or bad for us. An enormous, decades-long randomized controlled clinical trial, which is the only possible way to ascertain the truth about coffee with any degree of certainty, would be nearly impossible to perform, for multiple reasons.

I don’t want to overstate my pessimism here. I think there is a much more limited lesson that can be derived from this NEJM study and the rest of the coffee literature. From the totality of the evidence it seems highly unlikely that coffee has any large effect, either positive or negative, on important outcomes like mortality or cancer. But we’ll never know for sure about small effects, and we will certainly never know if there are small populations or individuals who are particularly likely to derive benefit or harm from coffee.

2. HDL Cholesterol in the Lancet. In some respects the HDL cholesterol story is exactly the opposite of the coffee story. Unlike coffee, the epidemiology of HDL is clear-cut, and therefore the reverse association of HDL with cardiovascular disease is among the best established facts in all of medicine. But association is not causation, and despite more than a generation of intense research we still don’t know how– or even if– HDL works. In fact, as its name implies, high density lipoprotein is not so much a biological entity as an artificial construct of something that we can measure easily.
Click to continue reading…