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.

No Evidence That Statins Impact Cognitive Function Reply

In 2012 the FDA revised the label of statins to include a warning about reports that the drugs had been linked to memory loss or confusion. The FDA action appeared to be based largely on case reports. Despite concerns about this topic that have appeared sporadically in recent years, no high-quality review of the topic has appeared until now. In a paper published in Annals of Internal Medicine, Karl Richardson and colleagues report on a systematic review of the literature to assess the effect of statins on cognitive function.

The authors reviewed 25 trials, including randomized, controlled trials and cohort, case-control, and cross-sectional studies, that evaluated cognition in patients taking statins.

Their review found little evidence to support any adverse effect on cognitive function:

Click here t read the full story on Forbes.

 

No Evidence That Statins Impact Cognitive Function Reply

In 2012 the FDA revised the label of statins to include a warning about reports that the drugs had been linked to memory loss or confusion. The FDA action appeared to be based largely on case reports. Despite concerns about this topic that have appeared sporadically in recent years, no high-quality review of the topic has appeared until now. In a paper published in Annals of Internal Medicine, Karl Richardson and colleagues report on a systematic review of the literature to assess the effect of statins on cognitive function.

The authors reviewed 25 trials, including randomized, controlled trials and cohort, case-control, and cross-sectional studies, that evaluated cognition in patients taking statins.

Their review found little evidence to support any adverse effect on cognitive function:

“… low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance in procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment, nor any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception.”

In a second analysis of the FDA post-marketing surveillance databases, the investigators found similar reporting rates for cognitive-related adverse events for statins and two other widely used drugs, losartan and clopidogrel.

The reviewers noted, however, that much of the data were not high quality and, in particular, there was a sparsity of data for high-dose statins, which are increasingly used.

They concluded that the available evidence does not support concerns linking statin use to cognitive impairment. “Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition.”

 

News From Our ‘Statin Civilization': High-Dose Statins Found To Reduce Gum Disease Inflammation Reply

In addition to their well-known benefits in heart disease, high-dose statins appear to reduce gum inflammation caused by periodontal disease, a new report published in the Journal of the American College of Cardiology shows. The findings offer more evidence that heart disease and gum disease may be linked, and also help support the view that statins achieve at least some of their effect not through their cholesterol-lowering effect but through separate inflammation-fighting mechanisms.

Researchers reported findings from 59 patients with cardiovascular disease or at high risk for cardiovascular disease who had evidence  of arterial inflammation on a  PET scan. The patients were randomized to a low (10 mg per day) or high (80 mg per day) dose of atorvastatin. After 12 weeks there was a significant reduction in periodontal inflammation as measured by PET in patients taking high dose atorvastatin. The effect was greatest in those patients who had active periodontal disease. There was evidence of a significant effect as early as 4 weeks. Furthermore, there was a strong correlation between reductions in periodontal inflammation and atherosclerosis, though the authors acknowledged that the precise nature of the association remains undefined.

Click here to read the full story on Forbes.

English: Periodontal bone loss shown in X-Ray ...

Periodontal bone loss shown in X-Ray image. (Photo credit: Wikipedia)

Low Rate Of Problems With Statins In Study Of Quarter Million Patients 1

A very large analysis of previously published studies finds that statins are generally safe and well tolerated, but helps confirm previous links to a small increased risk for diabetes and elevation of liver enzymes. Some statins were better tolerated than other statins and lower-dose statins were better tolerated than high dose statins.

In a paper published in Circulation: Cardiovascular Quality and OutcomesHuseyin Naci and colleagues report their findings from a systematic review of clinical trials with statins for both primary and secondary prevention. The data from 55 placebo controlled trials and 80 trials included nearly 250,000 subjects comparing statins to placebo or to other statins. Previous analyses of available data have generally confirmed the overall benign profile of statins, but have not explored in depth the differences between statins and the effect of different doses of individual statins.

The new study found no differences between statins and placebos in the rate of discontinuations due to myalgia, CK elevation and cancer, but statins were associated with a higher risk for diabetes (OR 1.09, CI 1.02-1.16) and transaminase elevations (OR 1.51, CI 1.24-1.84).

Click here to read the full post on Forbes.

 

Study Finds More Musculoskeletal Problems In People Who Take Statins Reply

An observational study published in JAMA Internal Medicine provides new evidence suggesting that people who take statins are more likely to develop musculoskeletal problems.

Ishak Mansi and colleagues analyzed data from 6,967 statin users and an equal number of propensity-matched nonusers who were active-duty soldiers, veterans and their families in the San Antonio Military Area. They found that the statin users were more likely to have musculoskeletal problems:

  • All musculoskeletal diseases: Odds Ratio 1.19, CI 1.08-1.3
  • Dislocation/strain/sprain: OR 1.13, CI 1.05-1.21
  • Musculoskeletal pain: OR 1.09, CI 1.02-1.18
  • Osteoarthritis/arthropathy: OR 1.07, CI 0.99-1.16

The authors calculated that between 37 and 58 people would need to be treated with statins to cause one additional person to develop musculoskeletal disease. However, increased exposure did not appear to raise the risk of statin use.

The results, according to the authors, “indicate that the full spectrum of statin AEs [adverse events] has not been fully explored.” They call for more studies on this topic: “the full spectrum of statin AEs will provide more complete data for cost-benefit and cost-effectiveness analyses of statin use.”

The study appears two weeks after a small study published in the Journal of the American College of Cardiology received considerable attention after it was covered in the New York Times. In that study the investigators found that statins appeared to blunt the beneficial effects of aerobic exercise.

 

 

Small Study Suggests Statins May Blunt Benefits Of Exercise 1

A small study is raising big questions about whether statins may blunt the beneficial effects of exercise. The study has been published online in the Journal of the American College of Cardiology and was the subject of a New York Times blog today.

The authors concluded: “Given the strong independent cardio-protective effects of increasing cardiorespiratory fitness or lowering LDL, the benefits and risks of each should be carefully considered when choosing treatment modalities.”

Click here to read the full story on Forbes.

 

John Thyfault

 

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.

 

Blood Sample Mismatch Leads ‘Anguished’ Authors To Retract Three Lipitor Papers 1

Three substudies of the influential TNT (Treating to New Targets) trial have been retracted after the sponsor of the trial, Pfizer, discovered that blood samples from the study had been matched to the wrong participants.

The main results of TNT, published in 2005 in the New England Journal of Medicine, had a major impact on clinical practice and statin prescription patterns. The trial supported the increasingly aggressive use of statins and helped to solidify the enormous commercial success of atorvastatin (Lipitor, Pfizer).

The 3 newly-retracted substudies do not appear to affect the main finding of TNT. Two papers were published in the Journal of the American College of Cardiology. The third was published in the American Heart Journal. (The AHJ retraction notice has not yet been published, but the editors have confirmed the retraction.) Here are the 3 retracted articles:

Click here to read the full story on Forbes:

 

English: A package and pill of atorvastatin 40...

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.

 

 

High Potency Statins Linked To Increased Risk For Acute Kidney Injury Reply

Although the beneficial effects of high-potency statins have been well-characterized in clinical trials, these same trials have lacked the power to illuminate rare but potentially important adverse events. A suggestion of one such area of concern, acute kidney injury, was first raised in the JUPITER trial. Now, a new study published in BMJ provides further information about this area.

Researchers in the Canadian Network for Observational Drug Effect Studies (CNODES) performed a retrospective observational analysis of administrative databases in Canada, the UK and the US containing more than 2 million patients newly treated with statins.  59,636 of the subjects already had chronic kidney disease. One-third of the subjects received high potency statins, defined as ≥10 mg rosuvastatin, ≥20 mg atorvastatin, and ≥40 mg simvastatin.

Within 120 days of starting treatment there were 4691 hospitalizations for acute kidney injury in patients without pre-existing kidney disease and 1896 hospitalizations in patients with pre-existing disease. Patients without pre-existing disease on high potency statins were 34% more likely to be hospitalized with acute kidney injury than patients on other statin regimens. Patients with pre-existing disease did not have a significant increase in risk if they were taking high potency statins.

The authors estimated that 1,700 patients without pre-existing kidney disease would need to be treated with a high potency statin instead of a low potency statin to cause one additional acute kidney injury requiring hospitalization. The findings, according to the authors, are broadly consistent with the JUPITER trial. They write:

Given what is likely to be a small magnitude of incremental cardiovascular benefit of high potency statins over low potency statins in reality, a pressing question is how to identify patients for whom the risk-benefit balance for high potency statin treatment is unfavourable.

In an accompanying editorial, Robert Fassett and Jeff Coombes write that “clinicians should use low potency statins whenever possible to provide cardiovascular benefits without the increased risk of acute kidney injury.” Further, they note, “despite extensive experience with the use of statins over many years, optimization of doses to derive benefit but minimize risk is still evolving.”

HPS2-THRIVE Coming Attraction: First Look At What Went Wrong With Niacin Reply

In a few weeks, on March 9, the main results of the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study will be presented in San Francisco at the annual meeting of the American College of Cardiology. These results have been eagerly awaited since Merck’s brief announcement in December that the trial had not met its primary endpoint and that it would no longer pursue approval of Tredaptive, the combination of extended-release niacin and laropiprant, in the US. The trial was designed to assess whether adding the niacin/laropiprant combination to standard statin therapy in high risk individuals would further reduce vascular events.

Now, serving almost as a coming attraction for the main event at the ACC, an important substudy from HPS2-THRIVE has been published in the European Heart JournalThe paper discusses the trial design, the pre-specified muscle and liver outcomes, and the reasons for stopping treatment during the trial.

Click here to read the full story in Forbes.

European Heart Journal

HPS2-THRIVE: No Benefit, Signal Of Harm For Niacin Therapy 3

The largest-ever study of niacin has failed to show a clinical benefit for niacin and even found a strong signal of harm. Merck announced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared to statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median followup of 3.9 years, the combination of niacin and laropiprant “did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Ball-and-stick model of the niacin molecule, a...

Merck said it was now no longer planning to seek approval of Tredaptive in the United States. The drug’s initial application for approval in the US was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of any evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the US. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s  AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to the string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also impact the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Did the study fail because of niacin or laropiprant?

We will need to decide whether to withdraw patients from niacin.

Update: Here’s a terrific comment posted below from cardiologist John Osborne:

Also don’t forget that this trial did not have a cut-off for HDL, so that patients could have any level of HDL and still get into this trial, not just patients with low HDL where presumptively the greatest benefit would be seen, according to the HDL-raising hypothesis. We will need to see how this sub-group responded, which was a pre-specified sub-group analysis. As far as the vague “excess of non-fatal serious adverse events”, it is no surprise given the known issues with the use of niacin, such as flushing (even occasionally to the point of causing vasodilation resulting in rare syncope), hyperuricemia, gout and gout flares, peptic ulcer disease, and hyperglycemia. If these non-fatal adverse events were higher int the niacin-laropriprant arm, I would not be at all surprised. If, however, we saw an excess of non-fatal strokes, as a tendency was seen in AIM-HIGH, that would be much more concerning. Obviously science and medical care cannot and should not be based on lay press reports and we need to see and digest all the data from this trial when it comes out. Stay by your radios (and Internet feeds), my friends!

Update #2: James Stein sent the following comment:

HPS did not THRIVE!  I am disappointed.  It suggests that in people on a statin with well controlled LDL and non-HDL cholesterol levels, adding niacin may not reduce CVD risk.  I still think niacin is a useful drug for those who can’t reach goals on statins or who can’t take them, and for selected patients with combined dyslipidemia.  However, this may be as much about laropiprant as it is about niacin. I am especially concerned about the increase in non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. You may recall that the idea for using laropiprant was to improve the tolerability of niacin by blocking flushing. However a close look at the laropiprant data for its effectiveness as a flushing blocker showed that at the dose it was being used at, it was not significantly better than adult dose aspirin.

More worrisome, pre-clinical Merck research showed an off-target effect of laropiprant on platelet DP1 receptors. Bleeding times were not prolonged, so the meaning of this off-target effect is unclear, but this is evidence that the drug may affect more than just the DP1 receptor on dermal blood vessels.   We know DP1 receptors also are on neurons and lung tissue, among other places.  We in the lipid world need to be very humble about off target effects – even if we can’t explain them with our current knowledge base.

Click here to read the Merck press release…