Day: 05/15/2012

Adverse Neuropsychiatric Effects of Glucocorticoids.

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Elevated incidence of suicide attempts, depression, mania, and delirium.

Glucocorticoids can have severe adverse neuropsychiatric effects, but the range and community-based population risk of such effects are unclear. In this U.K. study, researchers used a population-based general practice database to identify 370,000 patients with glucocorticoid exposure and compared them with 1.2 million patients with similar diseases (mostly asthma, lower respiratory tract infection, chronic obstructive pulmonary disease, and polymyalgia rheumatica) who had not taken glucocorticoids.

The overall incidence of any adverse neuropsychiatric effects that occurred within 3 months of a glucocorticoid prescription was 22.2 per 100 person-years of exposure. The incidence of adverse effects, adjusted for age, sex, and history of neuropsychiatric disorder, was roughly 3-fold higher for glucocorticoid recipients than for nonrecipients, ranging from roughly 4- to 6-fold higher for suicidal behavior, mania, and delirium or confusion, to about 1.5 times higher for panic disorder and depression. Incidence rose with history of neuropsychiatric disorder and with higher dosage of glucocorticoids, particularly at a prednisone equivalence of 40 mg daily.

Comment: Experienced clinicians often see these neuropsychiatric effects in patients who receive glucocorticoids for self-limited illnesses such as contact dermatitis; this study confirms such observations. Many potential confounders can affect a retrospective cohort study like this, including possible differences in patients with the seemingly same disease who are or are not prescribed glucocorticoids, but these results caution clinicians to consider these risks when prescribing glucocorticoids.

Source: Journal Watch General Medicine

Maintenance Lenalidomide for Multiple Myeloma.

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Lenalidomide improved progression-free survival after first-line induction therapy but increased risk for second cancers.

Response rates and remission durations have improved for patients with multiple myeloma since the advent of more effective induction regimens and autologous stem-cell transplant (ASCT) consolidation. Nonetheless, most patients experience disease progression within 3 to 4 years. To assess the role of maintenance lenalidomide after initial therapy to improve progression-free survival (PFS), investigators conducted three phase III, multicenter, randomized, double-blind, placebo-controlled trials involving previously untreated multiple myeloma patients.

In an industry-supported study by Palumbo and colleagues, 459 patients (aged 65) with newly diagnosed, symptomatic disease who were ineligible for ASCT were randomized to one of three regimens: melphalan plus prednisone followed by placebo (MP), MP plus lenalidomide (Revlimid; 10 mg of on days 1–21 of 28-day cycle) for 9 cycles followed by placebo (MPR), or MPR induction followed by the same dosage of lenalidomide until relapse or unacceptable toxicity (MPR-R). At median follow-up of 30 months, median PFS was longer with MPR-R (31 months) than with MPR (14 months; P<0.001) or MP (13 months; P<0.001); PFS benefit was achieved by patients aged 65 to 75 but not by those older than 75. Overall survival (OS) was not improved with lenalidomide. The rate of grade 4 neutropenia was higher with lenalidomide versus without (32%–35% vs. 8%), as was the 3-year rate of second primary cancers (7% vs. 3%).

In an industry-supported study by Attal and colleagues, 614 patients (aged <65) without disease progression after induction therapy and ASCT were randomized to placebo or lenalidomide (10 mg daily for 3 months, increased to 15 mg if tolerated) until relapse or unacceptable toxicity. At median follow-up of 30 months, the median PFS was longer with lenalidomide than with placebo (41 vs. 23 months; P<0.001). OS was not improved with lenalidomide. At median follow-up of 45 months, the rate of second primary cancers was higher with lenalidomide than with placebo (3.1 vs. 1.2 per 100 person-years; P=0.002).

In a study by McCarthy and colleagues, 460 patients (aged <71) who achieved stable disease or partial or complete remission at 100 days after ASCT were randomized to placebo or lenalidomide (10 mg daily, dose-adjusted to 5–15 mg as tolerated) until relapse. After a planned interim analysis at median follow-up of 18 months showed a benefit for lenalidomide, 86 of the 128 patients remaining on placebo crossed over to lenalidomide. At a median follow-up of 34 months, the median time to disease progression (the primary outcome) was longer with lenalidomide than with placebo (46 vs. 27 months; P<0.001). The rate of OS at 3 years was higher with lenalidomide than with placebo (88% vs. 80%; 2-sided P=0.03). The rate of grade 3 or 4 neutropenia was higher with lenalidomide than with placebo (P<0.001), as was the cumulative incidence of a second primary cancer (P=0.008).

Comment: Each of these trials showed that lenalidomide improved PFS, and one showed that it improved OS. Further analysis and longer follow-up will be important to better assess toxicities (especially the increased risk for second malignancies) and the response to further therapy in patients with disease progression after lenalidomide maintenance. The benefit of lenalidomide maintenance versus lenalidomide therapy at the time of progression is also of interest, especially for patients in complete remission after initial induction. As an editorialist noted, it is necessary to consider the high cost of lenalidomide. In aggregate, these important phase III trials establish maintenance lenalidomide as an option for myeloma patients who respond to first-line induction therapy.

Source:  Journal Watch Oncology and Hematology

 

Contrary To Medical Advice, High-Fat Diets Lower Blood Sugar, Improve Blood Lipids.

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People with Type 2 diabetes are usually advised to keep a low-fat diet. Now, a study at Linkoping University shows that food with a lot of fat and few carbohydrates could have a better effect on blood sugar levels and blood lipids.

The results of a two-year dietary study led by Hans Guldbrand, general practitioner, and Fredrik Nystrom, professor of Internal Medicine, are being published in the prestigious journal Diabetologia. 61 patients were included in the study of Type 2, or adult-onset diabetes. They were randomized into two groups, where they followed either a low-carbohydrate (high fat) diet or a low-fat diet.

In both groups, the participants lost approximately 4 kg on average. In addition, a clear improvement in the glycaemic control was seen in the low-carbohydrate group after six months. Their average blood sugar level dropped from 58.5 to 53.7 mmol/mol (the unit for average blood glucose). This means that the intensity of the treatment for diabetes could also be reduced, and the amounts of insulin were lowered by 30%.

Despite the increased fat intake with a larger portion of saturated fatty acids, their lipoproteins did not get worse. Quite the contrary — the HDL, or ‘good’ cholesterol, content increased on the high fat diet.

No statistically certain improvements, either of the glycaemic controls or the lipoproteins, were seen in the low-fat group, despite the weight loss.

“You could ask yourself if it really is good to recommend a low-fat diet to patients with diabetes, if despite their weight loss they get neither better lipoproteins nor blood glucose levels,” Nystrom says.

In the low-carbohydrate diet, 50% of the energy came from fat, 20% from carbohydrates, and 30% from protein. For the low-fat group the distribution was 30% from fat, 55-60% from carbohydrates, and 10-15% from protein, which corresponds to the diet recommended by the Swedish National Food Agency.

The participants were recruited from two primary health care centres and met for four group meetings during the first year of the study. All 61 participants remained in the study for the follow-up.

“In contrast to most other studies of this type, we lost no patients at all, which vouches for the good quality of our data,” Guldbrand says.

Source:Diet

 

Wireless startup LightSquared files for bankruptcy.

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LightSquared Inc., which hoped to create an independent wireless broadband network in the U.S., filed for bankruptcy protection on Monday.

Regulators blocked its plan this winter because of concerns that its transmissions would interfere with GPS navigation.

LightSquared hasn’t given up. Chief Finacial Officer Marc Montagner said in a statement that the bankruptcy filing is intended to gain the company “breathing room” while it continues to work through its regulatory issues.

It has said that it has invested more than $4 billion in the network. LightSquared listed assets and liabilities of more than $1 billion each in the filing Monday with the U.S. Bankruptcy Court for the Southern District of New York.

The company, which is based in Reston, Va., is owned by Harbinger Capital Partners, a private-equity firm that made billions betting against subprime mortgages ahead of the collapse of the housing market.

Harbinger bought SkyTerra, a provider of satellite communications services to businesses, in 2010. It then lobbied the Federal Communications Commission to allow it to use the spectrum set aside for SkyTerra for ground-based communications – essentially, a conventional wireless broadband network, rather than a satellite-based one.

But SkyTerra’s licenses were for spectrum adjacent to a band used by GPS satellites. On the ground, GPS units had no problem filtering out transmissions from SkyTerra’s satellites, but regulators determined that they could be disrupted by strong, ground-based signals.

LightSquared’s CEO, telecom veteran Sanjiv Ahuja, resigned in February.

The company’s largest creditors are Boeing Satellite Systems Inc., owed $7.5 million, and telecom equipment maker Alcatel-Lucent, owed $7.3 million, according to the filing.

Source:The Associated Press.

 

Antiepileptic Drug Comparison: More Details.

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A post hoc analysis of the focal epilepsy arm in the SANAD trial reveals outcome predictors for patients receiving specific AED treatments.

In the Standard and New Antiepileptic Drug (SANAD) trial (JW Gen Med Apr 10 2007), 1721 patients with suspected focal epilepsy were randomized equally to carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate, to compare outcomes with the newer medications versus the older medication (carbamazepine). Now, researchers have conducted a post hoc analysis of the data to determine clinical factors that affect the probabilities of treatment failure and of achieving 12-month remission. Time to treatment failure was divided into failure caused by inadequate seizure control or by unacceptable adverse effects.

As was previously reported, compared with carbamazepine, the overall risk for treatment failure was significantly lower with lamotrigine. However, the carbamazepine and lamotrigine groups did not differ in risk for treatment failure specifically caused by inadequate seizure control. Both gabapentin and topiramate were associated with the highest risk for treatment failure — approximately twice that of the other antiepileptic drugs (AEDs). For achieving 12-month remission, none of the newer AEDs was better than carbamazepine. Other factors associated with an increased likelihood of overall treatment failure were (1) younger age (10 years), (2) higher number of seizures before randomization, (3) female sex, (4) presence of electroencephalogram abnormality (epileptiform and nonspecific), (5) partial-onset seizures that do not secondarily generalize, and (6) history of AED treatment.

Comment: The greatest strengths of this study are its prospective design, the inclusion of patients who are typical of those seen in clinical practice, and use of classification (suspected partial vs. generalized epilepsy) that most physicians use in assessment and treatment decisions. Carbamazepine is still as likely as or more likely than newer AEDs to provide the best control of partial-onset seizures, but intolerance of adverse effects can decrease overall effectiveness.

The more frequent and severe the seizure burden, the less likely treatment failure was a result of adverse effects. This might have been predicted, given that adverse effects are common with most AEDs and that most are more a nuisance than intolerable in contrast to frequent and severe seizures. Also, the entire increase in risk for treatment failure in women was attributed to adverse effects. The cause of this apparent gender disparity (whether genetic or pharmacokinetic differences or other) is unclear and worthy of further study, with the goal of optimizing treatment.

Source:  Journal Watch Neurology

 

 

FDA panel gives OK to new drug application for obesity.

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By an 18-4-1 vote, the FDA’s Endocrinologic and Metabolic Drug Advisory Committee approved a new drug application for lorcaserin hydrochloride, a 5HT2c receptor agonist, indicated for weight management in patients who are obese. However, a post-marketing study will evaluate cited concerns on uncertainty of risk for mammary tumor and valvular heart disease associated with the drug.

According to FDA Briefing Documents, the RR of valvular heart disease in patients assigned lorcaserin was 1.07 (95% CI, 0.74-1.55). Other adverse events associated with use of the drug were a higher incidence for depression as well as suicidal ideation.

Arena Pharmaceuticals, Inc., manufacturer of the tablets provided clinical study designs and patient baseline characteristics, efficacy results and clinical perspective, clinical safety results, preclinical studies and preclinical safety as it relates to human risk.

Edward W. Gregg, PhD, chief of epidemiology and statistics branch at the Division of Diabetes Translation at the CDC, who voted for the approval of the drug, said, “the difference here as opposed to a year and a half ago, when we reviewed this, I think that their work basically did a lot to allay the risks that we were concerned about.”

The drug is indicated for use in patients with BMI ≥30 kg/m2, or BMI ≥27 kg/m2 if accompanied by weight-related co-morbidities.

The first sets of studies were conducted in 2002-2004 in support of early clinical trials, and the second was conducted in 2009 in the course of characterizing metabolites of lorcaserin. A 5% weight loss in 47.5% of patients assigned lorcaserin vs. 20.3% of patients assigned placebo was reported in a phase 3 trial, researchers said.

According to data results, approximately one-third of patients lost approximately 11% or 25 lbs after 52 weeks. Additionally, 50% of lorcaserin patients reached HbA1c≤7% at week 52.

Disclosure: Voting member Dr. Daniel Bessesen of the Endocrinologic and Metabolic Drugs Advisory Committee reports consultancy for a competing firm in a magnitude of $0-5,000 per year. All other voters report no relevant financial disclosures.

Perspective

 

George A. Bray

  • The FDA has two weight loss criteria as well as requirements for safety that they implement in evaluating any drug: 1) The drug must produce a weight loss that is 5% below placebo and this must be statistically significant, 2) And/or the drug must have 35% or more of the patients losing more than 5% body weight, and this must be more than twice the placebo response. Lorcaserin met the second criterion better than the first. Its initial problems were related to tumors in animals, and this still caused some concern for the toxicological experts on the panel.

The tumors were one of the major concerns for this drug, and are still of some concern to the toxicology experts on the panel. From what we know of this drug, it does not appear to have effects of cardiac valves as fenfluramine did, nor does it appear to have neuropsychiatric effects.

Currently there is only one medication, orlistat (Xenical) that is approved by the FDA for long term treatment of obesity. This contrasts with many drugs for treatment of diabetes, dyslipidemia and hypertension. To the extent that physicians can induce and maintain weight loss these other conditions may well be ameliorated and require fewer total medications.

In the drug trials with lorcaserin, the potential for developing valvular heart disease was carefully scrutinized and is certainly one of the outcomes that the FDA is going to continue to follow. There are a large number of trials examining effectiveness of this drug in subpopulations which could be valuable, as well as examining how well it works when combined with orlistat or other medications.

    • George A. Bray, MD
    • Boyd Professor, Pennington Center, Louisiana State University
      Endocrine Today Editorial Board member

Source: Endocrine today