Long-Awaited Torcetrapib Will Not Be Released, Too Risky
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Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, has been in development by Pfizer for nearly 15 years. The drug has been shown to elevate HDL levels while reducing LDL levels, prompting hopes that torcetrapib would be the first in a new class of important cholesterol medications. In December, Pfizer abruptly pulled the plug on further development of torcetrapib when the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events trial showed an increase in death from all causes associated with the drug, including an increased rate of cardiovascular events and hypertension. A new study points out a possible mechanism for the lack of cardiovascular benefit. In the international study, 1,188 patients with cardiovascular disease underwent intravascular ultrasonography. They then received atorvastatin and were randomized to receive 60 mg of torcetrapib daily or placebo along with atorvastatin for 24 months. Atorva/torcetrapib resulted in a 61% relative increase in HDL and a 20% further reduction in LDL, resulting in an average HDL higher than LDL. But the drug combination was also associated with an increase in systolic hypertension of 4.6mm Hg, and more importantly an increase in atheroma volume of 0.12%, compared to an increase of 0.19% in the atorvastatin alone group (p = 0.72). The authors conclude that treatment with the CETP torcetrapib was associated with improved lipid endpoints, but was also associated with an increase in blood pressure and no significant decline in coronary atherosclerosis (N Engl J Med. 2007;356:1304-1316.). In an accompanying editorial, Dr Alan Tall holds out hope that other CETP inhibitors may not show the same adverse effects but suggests that further development of this class of drugs needs to proceed with caution (N Engl J Med. 2007;356:1364-1366).
IBS-Drug Treatment Pulled, CV Side Effects
Tegaserod (Zelnorm), Novartis Pharmaceutical's drug for irritable bowel syndrome has been removed from the market by the FDA based on recent findings of increased risk of serious cardiovascular events associated with use of the drug. Tegaserod was approved in 2002 for women with irritable bowel syndrome whose primary symptom was constipation. It was given the additional indication in August 2004 for chronic constipation in men and women under the age of 65. Withdrawal was based on analysis of 29 studies involving more than 18,000 patients that showed a small, but statistically significant increase in the risk of cardiovascular side effects (0.1% serious adverse effects with tegaserod vs 0.01% with placebo). The FDA may allow continued use of the drug in a limited number patients for whom no other treatment options are available and the benefits of tegaserod outweigh the chance of serious side effects. The FDA may consider limited reintroduction of the drug at a later date if the population patients can be identified in whom the benefit of the drug outweighs the risk.
Drug Combo Better for Migraine Treatment
Naprosyn plus sumatriptan is better than either drug alone for the treatment of acute migraine according to a new report. In 2 studies, nearly 3,000 patients with a history of migraine were randomized to sumatriptan 85 mg plus naproxen sodium 500 mg, both drugs alone, or placebo to be used after the onset of a migraine with moderate to severe pain. The primary outcome was headache relief at 2 hours, absence of photophobia, absence of phonophobia, absence of nausea, and sustained pain-free response. Sumatriptan plus naproxen was superior to placebo in all measures and was superior to either drug alone in sustained pain-free response. The incidence of adverse effects was the same for the combination as for the individual medications. The authors conclude that sumatriptan 85 mg plus naproxen 500 mg as a single pill for acute treatment of migraine is more effective than either drug as monotherapy (JAMA.2007; 297:1443-1454.). Pozen Pharmaceuticals/ GlaxoSmithKline is developing the combination pill, which is expected to be approved later this year under the trade name Trexima.
Pergolide Off the Market, Heart Disease Risk
Pergolide (Permax) is being withdrawn from the market after reports of serious valvular heart disease associated with the drug. Pergolide is a dopamine agonist used for the treatment of Parkinson's disease, hyperprolactinemia and pituitary tumor (?). The action was prompted by 2 reports in the January 4, 2007, New England Journal of Medicine that showed increased rates of valvular dysfunction in Parkinson's patients who were taking the drug. These findings coupled with the availability of other dopamine agonists prompted the FDA's action. Valeant Pharmaceuticals is removing Permax brand pergolide as are all generic manufacturers.
Hormone Treatment, Does Timing Matter?
Further analysis of the Women's Health Initiative suggests that the timing of the initiation of hormone therapy may have an effect on the risk of cardiovascular disease. The analysis looked at postmenopausal women who had undergone a hysterectomy and were randomized to conjugated estrogen or placebo and women who had not had a hysterectomy who were randomized to conjugated estrogen plus medroxyprogesterone or placebo. The main outcomes were coronary heart disease (CHD) and stroke. Women who initiated hormone therapy within 10 years of menopause had a lower incidence of CHD (HR 0.76 [95% CI, 0.50-1.16 ]), which equates to 6 fewer events per 10,000 person-years. For women who initiated therapy 10-19 years after menopause the hazard ratio was 1.10 (95% CI, 0.84-1.45), and for women who initiated therapy 20 years after menopause the hazard ration was 1.28 (95% CI, 1.03-1.58) or 12 excess events per 10,000 person years. CHD risk increased when patients were stratified by age as well. Hormone therapy increased the risk of stroke with no significant difference based on time since menopause or age. There was a nonsignificant trend for improved overall mortality in younger women. The authors conclude that women who initiated hormone therapy closer to menopause had a reduced risk of CHD, with an increase risk among women more distant from menopause although the trends did not meet their criteria for statistical significance (JAMA. 2007:297;1465-1477.).
FDA Actions
The FDA has approved Cangene's immune globulin to prevent reinfection with the hepatitis B virus in certain liver transplant patients. The product was previously approved for preventing hepatitis B infection after exposure in 2006. It is marketed as HepaGam B.
The FDA has banned rectal suppositories that contain trimethobenzamide due to lack of efficacy in preventing nausea and vomiting. The popular suppositories have been marketed under various trade names including Tigan, Tebamide, T-Gen and others. The drug will still be available as oral and injectable preparations. The evaluation which eventually led to the withdrawal is part of the FDA's ongoing Drug Efficacy Study Implementation (DESI) which evaluates older drugs previously approved based on safety data to make sure that they are also effective.
The FDA has approved Merck's combination diabetes drug Janumet, which combines sitagliptin with metformin. Sitagliptin, which is a dipeptidyl peptidase-4 inhibitor, has been marketed by Merck since last October under the trade name "Januvia." The combination is approved for the treatment of patients with type 2 diabetes; it should be dosed twice daily with meals with gradual dose escalation.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5431. E-mail: [email protected].
IBS-Drug Treatment Pulled, CV Side Effects; Drug Combo Better for Migraine Treatment; Pergolide Off the Market, Heart Disease Risk; Hormone Treatment, Does Timing Matter?; FDA ActionsYou have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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