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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IMPROVE-IT Meets Endpoint And Demonstrates Real But Modest Clinical Benefit For Ezetimibe Reply

After all the waiting and all the controversy it turned out to be pretty simple. The IMPROVE-IT trial did what it set out to do and reached its primary endpoint. The benefit wasn’t very big or impressive but it will be enough to put to rest concerns that ezetimibe might have been an expensive placebo or that LDL might not be a reliable surrogate endpoint. The IMPROVE-IT results will also provide comfort to companies developing the next generation of cholesterol drugs, since their approval may have depended on validation of LDL as a surrogate endpoint.

The  Improved Reduction of Outcomes: Vytorin Efficacy International Trial, presented Monday morning at the American Heart Association meeting in Chicago, randomized 18,144 high-risk patients within 10 days of an acute coronary event to either ezetimibe or placebo on top of a statin….

Click here to read the full post on Forbes.

Cannon

At the American Heart Association Meeting You Really Can’t Escape The New Cholesterol Drugs 1

There’s no escaping them. At the American Heart Association in Chicago going on right now Amgen and Sanofi/Regeneron, which are developing competing cholesterol lowering drugs known as PCSK9 inhibitors, have mounted a full scale attack to capture the eyeballs and the brains of cardiologists and any other innocent bystanders who happen to be at the McCormick convention center.

Click here to read the full post on Forbes.

Amgen Door Hanger

 

IMPROVE-IT Trial Paper Won’t Be Published Right Away In The New England Journal Of Medicine 1

The presentation of the eagerly awaited IMPROVE-IT trial, scheduled for Monday at the American Heart Association meeting, won’t be accompanied by a simultaneous publication in the New England Journal of Medicine. Although no one except for a small group of insiders knows for sure, this news may have important implications.

Click here to read the full post on Forbes.

 

Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe Reply

A very large genetic study published in the New England Journal of Medicine offers compelling evidence in support of a central role for LDL cholesterol in coronary heart disease.

In a series of studies analyzing blood samples from nearly 100,000 people, Sekar Kathiresan and colleagues identified 15 rare mutations that block the activity of a single gene — called Niemann-Pick C1-Like 1 (NPC1L1). The mean LDL level was 12 mg/dL lower in mutation carriers than noncarriers. There were just 11 carriers of the mutations among 29,954 people with CHD versus 71 carriers among 83,140 people without known CHD (carrier frequency: 0.04% vs. 0.09%).  This worked out to a 53% reduction in CHD risk for mutation carriers.

Click here to read the full post on Forbes, including comments from James Stein, Sekar Kathiresan, and Harlan Krumholz.

What You Need To Know About IMPROVE-IT Reply

The IMPROVE-IT trial will be big news when its results are finally presented on November 17 during the annual meeting of the American Heart Association. The results of the trial–underway for nearly a decade– have been long and eagerly awaited by everyone interested in cardiovascular medicine.  The trial could impact the future sales of a key Merck drug, ezetimibe, though because it is nearing the end of its patent life the commercial significance is somewhat limited. However, IMPROVE-IT will also have very important implications beyond its specific effect on one drug franchise and could influence the fate of several new drugs now being investigated and may even alter the entire drug development and evaluation process.

Here’s some background information and links to useful resources.

Click here to read the full post on Forbes.

 

Cholesterol Drugs Haunted By Ghosts Of Past, Present, And Future Reply

Cholesterol drugs, both new and old, are in the news again. There’s a lot going on now but the picture won’t really become clear until next month, when the results of a decade-old trial will finally be revealed. Briefly, here’s what’s happening:

  • Two new trials presented fresh evidence that PCSK9s, the much discussed new class of cholesterol drugs, have powerful LDL-lowering properties.
  • A new drug from Esperion, the phoenix of biotech companies, also showed promising results. The drug, ETC-1002, is a few years behind the PCSK9s in development but has some important theoretical advantages that may prove very important down the road.
  • At the annual meeting of the American Heart Association in November the results of the IMPROVE-IT trial will be presented. The results of this trial, as I have argued in the past, may have a broad if not decisive impact on the future of the PCSK9s and ETC-1002.

 …

Click here to read the full post on Forbes.

 

Early Hint At Cardiovascular Outcomes With Sanofi’s and Regeneron’s Rapidly Advancing Cholesterol Drug Reply

Amid a slew of new data demonstrating yet again that PCSK9 inhibitors lower LDL cholesterol– drastically and in a wide variety of different patient populations– data from one trial offers the first suggestion that the drugs may in fact improve cardiovascular outcomes. But the analysis, the authors cautioned, is a post-hoc analysis of a trial neither designed nor powered to study outcomes, so should be considered preliminary and speculative at best.

Four phase 3 trials with the Sanofi and Regeneron PCSK9 inhibitor alirocumab (pronounced “allee rock you mab” by Chris Cannon at a news conference) were presented today at the European Society of Cardiology meeting in Barcelona.

Click here to read the full post on Forbes.

 

IMPROVE-IT Trial Scheduled For Presentation In November Reply

Results of the eagerly-awaited and highly controversial IMPROVE-IT trial are finally going to be revealed. The American Heart Association has announced that the  trial will be presented by Chris Cannon on November 17 at 11:51 AM (central time) in Chicago at the group’s annual scientific sessions . IMPROVE-IT compared the effect on cardiovascular outcomes of the statin simvastatin with Vytorin (the combination of simvastatin and ezetimibe, manufactured by Merck) in more than 18,000 patients with acute coronary syndromes.

Both Vytorin and IMPROVE-IT have been the subject of considerable controversy.

Click here to read the full post on Forbes.

 

12.8 Million More Adults Now Eligible For Statin Therapy Reply

Millions more people are now eligible for statin therapy under the new cholesterol guideline, according to a new estimate published in the New England Journal of Medicine.

There have been many attempts to quantify just how many more people are now eligible for statin therapy under the new guideline. Now in the new paper in NEJM, Michael Pencina and colleagues estimate that the new guideline results in a net increase of 12.8 million people who are now eligible for statins.

Click here to read the full post on Forbes.

 

FDA Sprinkles Some Rain On the PCSK9 Inhibitor Parade Reply

In the last few years the PCSK9 inhibitors have been one of the few bright lights in an otherwise dismal field of new cardiovascular drugs. Now the FDA is raising questions that could dramatically slow down the progress of these new cholesterol-lowering drugs.

Last month Regeneron disclosed that it had been “advised by the FDA that it has become aware of neurocognitive adverse events in the PCSK9 inhibitor class.”

Click here to read the full post on Forbes.

 

Aegerion Warns About Negative Impact Of DOJ Investigation Reply

Earlier this week in its annual report Aegerion Pharmaceuticals provided an update on its ongoing problems with the FDA and the Department of Justice. As previously reported here and on The Street and on CNBC, the company landed in hot water with the FDA last year after its CEO made a series of off-label statements on the CNBC Fast Money show. (The company’s only product, Juxtapid (lomitapide) is a cholesterol-lowering drug indicated for the rare condition of homozygous familial hypercholesterolemia. It sells for $250,000 a year.) Now the company reports that by running “a corrective advertisement on CNBC” and by reviewing additional promotional material  it believes it will be able to resolve its problems with the FDA.

But the DOJ investigation may prove to be a bigger and more serious problem….

Click here to read the full post on Forbes.

 

Pfizer Starts Testing For Over-The-Counter Lipitor Reply

Looking backward to improve its future, Pfizer will once again try to gain FDA approval to market its blockbuster drug, atorvastatin (Lipitor), over-the-counter (OTC). Peter Loftus reports in the Wall Street Journal that the company has started a clinical study to support the application for low-dose atorvastatin (10 mg).

Click here to read the full post on Forbes.

 

Dispatch From The Wild Frontier Of The Statin Wars Reply

The long simmering controversy over the relative benefits and harms of statins has heated to a high boil with the release of the new AHA/ACC US guidelines. But nowhere is the battle more intense right now than in Australia where, according to the National Heart Foundation, a TV show may be the cause of 2,000 heart attacks and strokes over the next five years.

The show was a 2-part documentary  (click here for part 1 and part 2) broadcast in October on the Australian ABC network about dietary fat and cholesterol.

The program, wrote Amy Corderoy, the health editor of the Sydney Morning Herald, “claimed the causal link between saturated fat, cholesterol and heart disease was ‘the biggest myth in medical history’… [and described statins] as toxic and potentially deadly.”

Catalyst delved into a raging debate: has dietary guidance telling us to avoid fats pushed us towards more harmful sugar and carbohydrates instead?

But the program also went a step further, arguing cholesterol was just an innocent bystander in the body’s attempts to deal with the sugar-damage. It was not a big leap to claim statins were dangerous, and the research supporting them fraudulent.

Click here to read the full post on Forbes.

 

Heart of the Matter screen shot

 

 

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.

The Fate Of New Cholesterol Drugs Depends On IMPROVE-IT Reply

Prospects for the highly anticipated new class of cholesterol-lowering drugs, the PCSK9 inhibitors, took a wild roller coaster ride this week. The publication of new lipid guidelines by the American Heart Association and the American College of Cardiology led many observers to think that the promising new drugs under development by Regeneron (in partnership with Sanofi), Amgen, and Pfizer might suffer significant delays.

The guidelines delivered a strong statement questioning the increasingly controversial theory that LDL lowering by itself is beneficial. “We found that non-statin therapies really didn’t provide an acceptable risk reduction benefit compared to their potential for adverse effects in the routine prevention of heart attack and stroke,” said the co-chair of the guideline. This led many observers to think that the FDA would likely require the developers of PCSK9 inhibitors to complete cardiovascular outcome trials before getting US approval. This decision would delay approval for several years.

Then, on Thursday, the companies developing PCSK9 inhibitors received some apparent good news. Bloomberg News reported that an FDA official said that the drugs “will only have to meet the U.S. Food and Drug Administration’s existing standards for clearance, including whether they cut cholesterol and reduce blood pressure or inflammation.”

But then the FDA added one other very important caveat. Here’s how they phrased it to me:

Click here to read the full post on Forbes.

 

After Long Wait, Updated US Cardiovascular Guidelines Now Emphasize Risk Instead Of Targets 1

Updated cardiovascular health guidelines were released today by  the American Heart Association (AHA) and the American College of Cardiology (ACC). The guidelines are designed to provide primary care physicians with evidence-based expert guidance on cholesterol, obesity, risk assessment, and healthy lifestyle.

The new guidelines reinforce many of the same messages from previous guidelines, but also represent a sharp change in philosophy. That change is most evident in the new lipid guidelines, in which the focus has shifted away from setting numerical targets for cholesterol levels in favor of treatment decisions based on individual risk status.

“This guideline represents a departure from previous guidelines because it doesn’t focus on specific target levels of low-density lipoprotein cholesterol, commonly known as LDL, or ‘bad cholesterol,’ although the definition of optimal LDL cholesterol has not changed,” said Neil J. Stone, chair of the lipid expert panel that wrote the new guideline. “Instead, it focuses on defining groups for whom LDL lowering is proven to be most beneficial.”

The long-awaited and often controversial guidelines are the successors to the extremely influential NHLBI guidelines, including the Adult Treatment Panel (ATP) series of guidelines that brought cholesterol to the consciousness of millions of people. Earlier this year the NHLBI announced that it would no longer issue guidelines but would, instead, provide support for guidelines produced by other organizations. Following the NHLBI announcement, the AHA and the ACC said that they would take over publication of the guidelines.

Statins Indicated for Four Broad Groups

Click here to read the full post on Forbes.

Guideline Maze

Original illustration by Max Husten

 

Prevalence Of Cardiovascular Disease Likely To Increase Despite Gains In Treatment Reply

It is the best of times and the worst of times in the battle against cardiovascular disease. On the one hand, mortality rates from cardiovascular disease in the US have dropped by more than half in the last 30 years, likely due in large part to improvements in treatment for elevated blood pressure and cholesterol levels and big declines in smoking. On the other hand, it is uncertain whether these gains will continue, and many experts think that cardiovascular disease may well be on the rise once again, largely due to the aging of the population and to increases in obesity and diabetes.

In an article in Health Affairs, Ankur Pandya and colleagues (including cardiologist Thomas Gaziano of the Brigham and Women’s Hospital) forecast cardiovascular disease trends through the year 2030 using data from the National Health and Nutrition Examination Survey. They project that although the age-adjusted risk for cardiovascular disease is likely to continue to decline through 2030, because of an aging population and the increase in obesity the overall incidence of cardiovascular disease will increase.

Click here to read the full story on Forbes.

 

 

 

The Guidelines Are Dead. Long Live The Guidelines. Reply

Following last month’s surprising announcement that the National Heart, Lung, and Blood Institute would no longer issue guidelines, leaders of the American Heart Association and the American College of Cardiology have now announced that are “officially assuming the joint governance, management and public distribution” of the enormously influential cardiovascular prevention guidelines, including the much-delayed and much-anticipated hypertension and cholesterol guidelines (formerly known as JNC 8 and ATP IV). The ACC and AHA will also assume responsibility for guidelines on cardiovascular risk assessment, cardiovascular lifestyle interventions and obesity.

In an editorial published in Circulation and the Journal of the American College of Cardiology, leaders of the NHLBI, AHA, and ACC provide a little more information on how the new model will work. One important announcement, that “all chairs and members of the current writing panels have been invited to continue to work together with the ACC and AHA to finalize the guidelines,” might indicate that the hypertension and cholesterol guidelines could see the light of day in the not-too-far-distant future. In June the NHLBI’s Michael Lauer expressed confidence that these guidelines would appear in less than a year, but the AHA said that no timeline had yet been established.

Click here to read the full story on Forbes.

English: sm team guidelines logo

Hypertension And Cholesterol Guidelines Delayed Again As NHLBI Gets Out Of The Guidelines Business Reply

The National Heart, Lung, and Blood Institute (NHLBI) will no longer issue guidelines, including the much-delayed and much-anticipated hypertension (JNC 8) and cholesterol (ATP IV) guidelines. Instead, the NHLBI will perform systematic evidence reviews that other organizations, including the American Heart Association and the American College of Cardiology, will use as a resource for their own guidelines.

The exact fate and form of the delayed hypertension and cholesterol guidelines has not yet been decided, though the NHLBI’s Michael Lauer said he was confident that these guidelines would appear in less than a year. But a lot of work remains before the documents can be published. ACC President John Harold said that  “the ACC has not formally agreed to or begun the process of updating” the NHLBI documents, “but we are open to this role and look forward to working out details with NHLBI and the American Heart Association.”

Click here to read the full story on Forbes.

 

NHLBI Director Dr. Gary Gibbons

NHLBI Director Dr. Gary Gibbons

Unconventional Analysis Finds Threshold For LDL Reduction With Statins Reply

Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.

According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume “a constantly increasing or decreasing risk as the exposure increases or decreases.” Linear models, however, can be “misleading,” they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes “flexible” models that can more readily uncover “threshold effects.”

Click here to read the full post on Forbes.

 

Lifelong Statin Sentence Now Includes Furloughs 1

Although the benefits of statins are among the best documented in all of medicine, continuous lifelong statin therapy is not always easy to achieve in clinical practice. Now a new retrospective study suggests that although clinical events causing temporary cessation of statin therapy occur often, most of these patients are later able to resume statin therapy.

In a paper published in Annals of Internal Medicine, researchers analyzed data from 107,835 patients with a statin prescription treated by physicians associated with Massachusetts General Hospital and Brigham and Women’s Hospital. 18,778 of these patients had documented events that were statin related, resulting in 11,124 patients who stopped taking statins. Within a year more than half of these (6,579) were rechallenged with a statin, and most of these (92.2%) were taking a statin a year after the initial statin-related event.

Click here to read the full story on Forbes.

 

 

Large Meta-Analysis Finds No Harm Associated With Eggs 2

No food has had more ups and downs over the last century or so than the common egg. Following a long period in which eggs were ubiquitous and highly regarded, eggs fell from favor with the rise of concerns over cholesterol. Currently the American Heart Association recommends that people restrict dietary cholesterol to 300 mg per day, which effectively limits people to 1 egg per day at most. However, the relationship of dietary cholesterol and serum cholesterol  is, at best, tenuous, and a significant number of experts now believe that egg consumption poses no risk to cardiovascular health.

In a new paper published in BMJ, a group of researchers from China and Boston performed a meta-analysis of 8 studies that included 263 938 participants for coronary heart disease (CHD) and 210 404 participants for stroke and followed them for 8 to 22 years. The authors found no evidence for an association between egg consumption and either coronary heart disease or stroke…

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

Merck’s Combination Of Ezetimibe And Atorvastatin Back On NDA Path 1

English: Logo of the .

A combination tablet containing the cholesterol-lowering drugs ezetimibe and atorvastatin is back on the path to possible FDA approval, according to Merck, which already markets Zetia (ezetimibe) and Vytorin, the combination of ezetimibe and simvastatin. Merck has repeatedly stumbled in its efforts to gain FDA approval of the proposed new drug, which has been dubbed “Son of Vytorin.” The new drug application (NDA) submission was first rejected by the FDA in 2009 and, again, last year.

Merck said yesterday that the FDA had accepted Merck’s resubmission of its NDA, which included additional data provided by Merck in response to the FDA’s rejection of the application last year. Merck said it also planned to pursue approval of the drug in other countries.

Despite its potent cholesterol-lowering effects, the clinical benefits of ezetimibe have never been demonstrated, prompting furious debates about the proper role of surrogate endpoints. Last year the FDA rejected a new indication for Vytorin and  Zetia (ezetimibe alone) in chronic kidney disease patients, as the independent effect of ezetimibe had not been assessed in SHARP, the pivotal study for the indication. Results of the IMPROVE-IT trial, expected this year, may finally resolve the question of whether ezetimibe is beneficial.
Click here to read the Merck press release…