Exenatide (Byetta) gains first line indication from FDA, but also kidney and pancreas warnings (updated) Reply

Update-November 2- The FDA today updated its web page information for exenatide and issued its own press release about the revised label for Byetta. In sharp contrast to the Lilly/Amylin press statement (below), which emphasized the new first line monotherapy indication, the FDA focused on the renal warnings:

“Health care professionals and patients taking Byetta should pay close attention to any signs or symptoms of kidney problems,” said Amy Egan, M.D. M.P.H., of the Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research. “Patients also should be aware that problems with kidney function could lead to changes in urine color, frequency of urination or the amount of urine, unexplained swelling of the hands or feet, fatigue, changes in appetite or digestion, or dull ache in mid to lower back.”

Later Monday afternoon Amylin and Lilly issued the following statement in response to the FDA’s update:

“The FDA update issued today aligns with the BYETTA label approved last week. The current label reflects our understanding of post-marketing reports of renal events and provides physicians with updated guidance about appropriate use in patients with renal conditions. There is no evidence from preclinical and clinical studies that BYETTA has any direct toxic effect on the kidney,” said Orville G. Kolterman, M.D., senior vice president of research and development, Amylin Pharmaceuticals. “Post-marketing reports of serious changes in renal function have been rare and usually complicated by other factors that could have contributed to the kidney problems. It is also important to note that diabetes is the leading cause of kidney failure. Information about use of BYETTA in patients with impaired renal function was included in the initial product label in 2005 and was updated in 2007. We remain committed to working closely with the FDA to ensure that physicians and patients are provided with accurate information about any potential risks associated with the use of our products.” (Click here to read the full statement.)

October 30- Amylin Pharmaceuticals and Eli Lilly and Company announced on Friday that Byetta (exenatide) had received an expanded indication and is now approved for first line monotherapy to help type 2 diabetics achieve glycemic control. The good news for the company was at least partially offset by a prominent placement in the new labeling that a history of pancreatitis represents an important limitation of use of the drug. The warnings and precautions section also includes a strong warning about the drug’s use in patients with renal impairment, as well as a statement that “there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug.”
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Beta blockers for noncardiac surgery deemphasized in revised ACC/AHA guidelines Reply

Following the presentation of the POISE study nearly two years ago, and subsequent publication in the Lancet, clinicians have been uncertain about the precise role of beta blockers to reduce the high rate of cardiac complications surrounding noncardiac surgery. Now a focused update of guidelines from the ACC and AHA may help these clinicians.
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ARBITER-6: Wall Street chorus predicts outcome, publication, and editorials (updated) Reply

November 2 Update: CardioBrief has learned from a reliable source that ARBITER-6 and accompanying editorials will in fact be published in the New England Journal of Medicine.

October 29: Wall Street analysts, in a growing chorus, are confidently predicting that niacin will enjoy a decisive victory over ezetimibe in ARBITER 6, the much discussed trial headed by Allen Taylor that is scheduled to be presented next month at the AHA.

In addition, one analyst, Tim Anderson of Sanford Bernstein, said that he expects the trial to be published concurrently in “a major medical journal” along with– note the plural form– “some interesting editorials.”
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Halloween trick: don’t TREAT diabetes with ESAs 3

In the first adequately powered trial of an erythropoiesis-stimulating agent (ESA), darbepoetin alfa (Aranesp, Amgen) failed to reduce major clinical events and was associated with an increased risk of stroke in a population of type 2 diabetics with chronic kidney disease.

The much-anticipated TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) was presented by Marc Pfeffer as a late-breaking clinical trial as part of Renal Week in San Diego, and published simultaneously in the New England Journal of Medicine. The trial randomized 4038 diabetic patients with CKD and anemia to darbepoetin alfa (target hemoglobin level of about 13 g/dl) or placebo (with rescue darbepoetin alfa when hemoglobin dropped below 9 g/dl).
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Halloween to arrive early this year with presentation of TREAT Reply

Trick or Treat? On Friday night, only hours before Halloween, the much-anticipated TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) will be presented by Marc Pfeffer as a late-breaking clinical trial as part of Renal Week in San Diego. CardioBrief will have full coverage of the trial at 8:40 PM.

However, CardioBrief readers may be interested to learn that some of the major results were released by Amgen in their third-quarter conference call on October 21. Here is the relevant paragraph from the company’s press release:
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Study suggests statins may prevent flu deaths 1

People on statins are less likely to die of the flu, according to a new observational study to be presented on Friday in Philadelphia at the Annual Meeting of the Infectious Diseases Society of America.

Meredith Vandermeer (Oregon Public Health Division) and colleagues studied 2,921 patients hospitalized with lab-confirmed influenza, 26% of whom were taking statins. The researchers found that older patients and patients with cardiovascular disease had an increased risk of death, while patients on statins enjoyed a protective effect.
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UK’s NICE allows limited use of prasugrel 1

The UK’s National Institute for Health and Clinical Excellence (NICE) has recommended prasugrel (Efient) for use in the National Health Service, but only under limited conditions. Specifically, the guidance document specified that prasugrel should only be used during PCI for ACS only when emergent PCI is required for a STEMI, for stent thrombosis in patients treated with clopidogrel, or when a patient has diabetes.
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Review article highlights differences between European and North American STEMI guidelines Reply

Differences between recently published updated STEMI guidelines from the ACC/AHA and the ESC are partly the result of conflicting interpretations of the data, according to a review article in the American Heart Journal by Deepak Thomas and Robert Giugliano. Other differences may be due to the availability of new data between the publications, though on most major issues the guidelines are in accord.
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Medicare advisory committee delivers mixed review for AF catheter ablation 2

Catheter ablation for atrial fibrillation received mixed reviews from MedCAC (the Medicare Evidence Development and Coverage Advisory Committee), according to a report in the Gray Sheet. The advisory committee met on October 21 to “discuss the adequacy of the available evidence for the use of catheter ablative techniques to treat patients with atrial fibrillation,” according to the committee website.
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Senator queries NIH about Ballantyne and other NIH grantees who took Vytorin money 2

Following the detailed disclosure of the vast sums of money spent on academic institutions and individual physicians for Vytorin CME and consulting, Senator Grassley is now raising additional concerns about conflicts of interest involving 5 physicians who were also recipients of NIH grants.

In his letter to Francis Collins, the new NIH director, Grassley highlighted the case of Baylor’s Christie Ballantyne. The letter states that Ballantyne
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Women and MI: increasing incidence but improved survival Reply

Two new studies provide important new details about the complex situation regarding women and MI. On the one hand, middle-aged women over the last 20 years have developed an increased risk of MI. (The trend for men of the same age has been improving, by contrast, though men still have a higher absolute risk than women.) On the other hand, women who do have an MI have achieved larger larger gains in mortality than men.
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FDA advisory committee to review primary prevention indication for Crestor (rosuvastatin) Reply

On December 15 the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will evaluate AstraZeneca’s application for a primary prevention indication for rosuvastatin (Crestor). The application is based on the results of JUPITER. Click here for the FDA announcement.
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Duke cardiologist to be new president of Gladstone Institutes Reply

Roberts Sanders “Sandy” Williams will be the next president of the Gladstone Institutes, the Institutes announced yesterday. Sanders, a Duke Univeristy cardiologist, most recently served as the senior vice chancellor for academic affairs at Duke University Medical Center. Williams succeeds the Gladstone’s founding director and president, Robert Mahley, who is stepping down after 30 years, according to the announcement, “to pursue his research into the biology of apolipoprotein E in heart disease and Alzheimer’s disease.”
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Lancet: liraglutide shows considerable promise in weight loss trial 1

Can liraglutide go where rimonabant couldn’t? Can it safely and effectively help to mitigate the effects of the obesity and metabolic syndrome pandemic? Results of a new trial with liraglutide may well help restart speculation and refuel the rumor mill. But the chief limitations to liraglutide are the current absence of robust long term data and the fact that because it is a peptide it can only be given as an injection.

According to a new study from Europe appearing in the Lancet, liraglutide is more effective than both placebo and orlistat in reducing weight and improving risk factors. The startling results prompted George Bray, in an accompanying comment, to  say of liraglutide and other  GLP-1 analogs that he is “optimistic that their promise for the treatment of obesity will be fulfilled.”

Arne Astrup and colleagues reported on 564 overweight subjects who were randomized to either open-label orlistat, placebo, or one of four doses of liraglutide. At 20 weeks weight loss was significantly greater in all of the liraglutide dose groups than in the placebo or orlistat groups.

Mean weight loss (kg) % of pts w/ >5% weight loss
Liraglutide 1.2 mg 4.8 52.1
Liraglutide 1.8 mg 5.5 53.3
Liraglutide 2.4 mg 6.3 60.8
Liraglutide 3.0 mg 7.2 76.1
Orlistat 120 mg 4.1 44.2
Placebo 2,8 29.6

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FDA turns down King’s NDA for CorVue (binodenoson) Reply

The FDA has issued a completed response letter in response to King Pharmaceuticals NDA for CorVue (binodenoson). The company has not disclosed the content of the letter. Binodenoson is a pharmacologic stress agent for use as an adjunct in SPECT (single-photon-emission computed tomographic) cardiac imaging.

The FDA response is not entirely unexpected, as the FDA’s cardiorenal advisory panel failed to recommend the agent in July. Here are links to our earlier coverage:
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Hospitals getting with the guidelines are not getting with aldosterone antagonism Reply

Only a third of heart failure patients who have a guideline-based indication for an aldosterone antagonist are actually receiving one, according to a new study appearing in JAMA. Ironically, the observational analysis  of 43,625 heart failure patients took place in  241 hospitals participating in the Get With The Guidelines–HF quality improvement registry.
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Medco launches 14,000 patient head-to-head observational comparison of clopidogrel and prasugrel 2

Medco announced today that it is launching a large head-to-head prospective, observational study comparing clopidogrel (Plavix) and prasugrel (Effient) in more than 14,000 patients. The study, GeCCO (Genotype Guided Comparison of Clopidogrel and Prasugrel Outcomes Study), is designed to assess whether clopidogrel given to patients who are CYP2C19 extensive metabolizers is noninferior to prasugrel on the composite primary endpoint of CV death, nonfatal MI, or nonfatal stroke.
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Telmisartan gets FDA approval for CV prevention in ACE inhibitor-intolerant patients Reply

Update: October 23– Boehringer Ingelheim announced in a press release that CHMP had issued a positive opinion for telmisartan as the first treatment in its class to reduce the risk of cardiovascular morbidity in high CV risk patients.

Telmisartan (Micardis) has received FDA approval for the prevention of MI, stroke, or death from cardiovascular causes in high risk patients who are unable to take ACE inhibitors. Boehringer Ingelheim announced the new indication this morning, as well as approval of aNDA for Twynsta, the combination of telmisartan and amlodipine for the treatment of hypertension alone or in combination with other agents.
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More allegations about ENHANCE fiasco laid out in Vytorin lawsuit complaint 3

A 200+ page complaint filed in the Schering-Plough/ENHANCE lawsuit provides the closest glimpse yet of the inner workings and details of the ENHANCE trial fiasco, at least from the perspective of the company’s critics. The lengthy document provides a detailed chronology of the trial’s history and the interactions of the company and the trial’s academic investigators and consultants.

One potentially explosive new development: the document includes many details based on testimony from several insiders within Schering-Plough, though for now these confidential witnesses remain anonymous, and they have not been deposed or cross-examined by opposing attorneys.

A spokesman for Schering-Plough sent the following response to CardioBrief:

There is nothing new in this filing.  These allegations have been made and responded to before.  We are confident the company will ultimately be vindicated.

Click here for links to the complaint and other resources…

Study raises concerns about trauma treatment in growing population on warfarin Reply

A large observational study raises concerns that the growing population of patients on warfarin is more likely to die because of trauma. The new study, which included 36,000 warfarin users among 1.2 million people in the National Trauma Databank, was presented at the 2009 Clinical Congress of the American College of Surgeons.

The finding is not especially surprising, but it has not been examined previously in a large sample, according to the authors. The growing population of elderly people taking warfarin means this is a potential problem of increasing urgency.
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IOM report: smoking bans cut heart attacks in smokers and nonsmokers Reply

The Institute of Medicine has released a report, Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence, that provides strong evidence to support the effectiveness of smoking bans.

The report found strong evidence that exposure to secondhand smoke increases the risk of coronary heart disease among both men and women. The existing data was not sufficient to estimate the size of the effect, however.
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