From Centers for Disease Control and Prevention (CDC): Expert Commentary
Kimberly Workowski, MD
Infectious Diseases Specialist in the Division of STD Prevention at the Centers for Disease Control and Prevention and lead author of the recently-released 2010 STD Treatment guidelines
Over the next few minutes, I will highlight new information from the 2010 STD guidelines. These guidelines are intended to assist the clinician with the management of persons who have, or are at risk for, sexually transmitted diseases. Although these guidelines emphasize treatment, prevention strategies and diagnostic evaluation are also discussed.
Some of the key changes include the prevention and treatment of HPV, gonorrhea, and lymphogranuloma venereum proctocolitis.
These guidelines highlight expanded prevention recommendations for sexually transmitted infections, including preexposure vaccination for human papillomavirus virus (HPV).Preexposure vaccination is one of the most effective methods to prevent transmission of HPV. There are 2 HPV vaccines licensed for females aged 9 through 26 years to prevent cervical precancer and cancer: the quadrivalent HPV vaccine Gardasil® and the bivalent HPV vaccine Cervarix®. Gardasil will also prevent genital warts. Routine vaccination of females aged 11 or 12 years is recommended with either vaccine, as is the catch-up vaccination for females aged 13 through 26 years. Gardasil may also be given to males aged 9 through 26 years to prevent genital warts.
Neisseria gonorrhoeae, or GC, has developed resistance to many classes of antimicrobials recommended for treatment. Quinolone-resistant Neisseria gonorrhoeae strains are now widely disseminated throughout the United States and the world, and as a result, quinolones are not recommended for the treatment of gonorrhea. Although currently recommended regimens are effective for gonorrhea within the United States, the susceptibility of gonococcal isolates to cephalosporins has been decreasing and treatment failures with oral cephalosporins have been documented in Southeast Asia. Based on prior experience with quinolone-resistant N gonorrhoeae, it is probable that such isolates may spread to the Unites States.
Due to these reports, ceftriaxone 250 mg intramuscularly or cefixime 400 mg orally are recommended for urogenital infection.
Since many with gonorrhea are coinfected with chlamydia, therapy with azithromycin or doxycycline is recommended.
Lymphogranuloma venereum proctocolitis (LGV) is being increasingly recognized especially among HIV-positive men who have sex with men. In persons with painful perianal ulcers or those detected on anoscopy, presumptive therapy should include treatment for LGV, which is doxycycline 100 mg twice daily for 21 days.
A new patient-applied treatment for genital warts is available. The treatment of 15% sinecatechins ointment should be applied by the patient 3 times daily until complete clearance of the warts.
There is also a new alternative treatment for bacterial vaginosis: 2 g of tinidazole taken daily for 3 days or 1 g taken daily for 5 days. For episodic outbreaks of herpes simplex virus, an additional treatment option is 500 mg of famciclovir followed by 2 days of 250 mg taken twice daily. There are also some data that moxifloxacin -- 400 mg daily for 7 days -- is effective in nongonococcal urethritis treatment failures due to Mycoplasma genitalium.
The complete treatment guidelines can be viewed and downloaded at cdc.gov/std/treatment/2010.
Wednesday, December 29, 2010
Tuesday, December 28, 2010
Little Screening of Kids for Obesity Complications
From Reuters Health Information
By Frederik Joelving
NEW YORK (Reuters Health) Dec 23 - Only a minority of obese youths are screened for diabetes, liver problems and high cholesterol, electronic medical records from an Ohio healthcare system show.
Researchers say the findings are a call for action, since such complications could be part of the reason why heavy kids appear to have shorter lives.
Other experts, however, say there is no proof that stepping up routine screening tests will improve the prospects for the more than one in six American youngsters who are obese.
The new study, published online December9th in Obesity, found that among nearly 70,000 children and adolescents with data on height and weight, 13% were obese. But among those with a diagnosis of obesity, only 30% had liver function tests, 41% had their cholesterol and other lipids checked, and 52% had blood glucose tests. Only 22% were screened for all three obesity-related conditions
The numbers did climb over the past decade, the researchers found, but appeared to level off around 2004 and may even be declining.
"Lack of knowledge of current guidelines likely contributes to underscreening, as guidelines have varied throughout the study period, beginning with vague recommendations in 1998 to more complete guidelines published in 2005 and 2007," Dr. Lacey Benson, of the Denver Children's Hospital, and her colleagues write.
"After an obese child is diagnosed with obesity, diagnosis should be followed by an assessment for obesity-related conditions that may require treatment or further intervention," they add.
But not all guidelines agree.
The U.S. Preventive Services Task Force recommends screening for obesity itself and suggests targeting diet and physical activity to help kids lose weight.
But according to the task force, there aren't enough data to show that benefits of further screening tests outweigh the harms -- or are worth the extra cost, for that matter. The drugs used to correct potential problems all have side effects, for instance, such as the muscle pain and occasional liver damage caused by statins.
"There is so much uncertainty about the long-term impacts -- benefits and harms -- of putting kids on statins for decades," said Dr. David Grossman, a member of the USPSTF.
"We do know that you can have some impact on lipid levels, but whether or not that improves outcomes and quality of life, or whether or not you could wait until later to start treatment, that is unclear," he added. "Some people are willing to make that assumption, but our standard is such that we need to prove it."
In the meantime, Dr. Grossman said, the decision to do lab tests should be an individual one, taking into consideration each person's symptoms as well as disease among close relatives.
SOURCE: http://link.reuters.com/vac92r
Obesity 2010.
By Frederik Joelving
NEW YORK (Reuters Health) Dec 23 - Only a minority of obese youths are screened for diabetes, liver problems and high cholesterol, electronic medical records from an Ohio healthcare system show.
Researchers say the findings are a call for action, since such complications could be part of the reason why heavy kids appear to have shorter lives.
Other experts, however, say there is no proof that stepping up routine screening tests will improve the prospects for the more than one in six American youngsters who are obese.
The new study, published online December9th in Obesity, found that among nearly 70,000 children and adolescents with data on height and weight, 13% were obese. But among those with a diagnosis of obesity, only 30% had liver function tests, 41% had their cholesterol and other lipids checked, and 52% had blood glucose tests. Only 22% were screened for all three obesity-related conditions
The numbers did climb over the past decade, the researchers found, but appeared to level off around 2004 and may even be declining.
"Lack of knowledge of current guidelines likely contributes to underscreening, as guidelines have varied throughout the study period, beginning with vague recommendations in 1998 to more complete guidelines published in 2005 and 2007," Dr. Lacey Benson, of the Denver Children's Hospital, and her colleagues write.
"After an obese child is diagnosed with obesity, diagnosis should be followed by an assessment for obesity-related conditions that may require treatment or further intervention," they add.
But not all guidelines agree.
The U.S. Preventive Services Task Force recommends screening for obesity itself and suggests targeting diet and physical activity to help kids lose weight.
But according to the task force, there aren't enough data to show that benefits of further screening tests outweigh the harms -- or are worth the extra cost, for that matter. The drugs used to correct potential problems all have side effects, for instance, such as the muscle pain and occasional liver damage caused by statins.
"There is so much uncertainty about the long-term impacts -- benefits and harms -- of putting kids on statins for decades," said Dr. David Grossman, a member of the USPSTF.
"We do know that you can have some impact on lipid levels, but whether or not that improves outcomes and quality of life, or whether or not you could wait until later to start treatment, that is unclear," he added. "Some people are willing to make that assumption, but our standard is such that we need to prove it."
In the meantime, Dr. Grossman said, the decision to do lab tests should be an individual one, taking into consideration each person's symptoms as well as disease among close relatives.
SOURCE: http://link.reuters.com/vac92r
Obesity 2010.
Wednesday, December 22, 2010
Weight Loss Drugs: What Works?
From Medscape Diabetes & Endocrinology
Laura A. Stokowski, RN, MS
Posted: 12/13/2010
Wanted: A Pill That Melts Fat
As Americans become more obese and the associated health problems reach epidemic proportions, the need for a safe and effective weight loss drug has become urgent. Over the years, this quest has been marked with short-lived triumphs and many defeats, leaving patients and clinicians with less than ideal weapons in the fight against obesity.
The few drugs that have actually reached the market in recent years promote weight loss either by boosting the body's basal metabolic rate, blocking the absorption of dietary fat, or suppressing appetite.People who take these drugs typically lose weight for the first 6 months until they reach a plateau that can't be surpassed without increasing exercise or caloric restriction.The problems with many of these agents have been a lack of proven long-term safety, and the fact that when such drugs are stopped, the weight is usually regained.
Most clinicians are aware that pharmacotherapy is not indicated as a first-line therapy for obesity, and should not be initiated until all nonpharmacologic attempts at weight loss (diet, exercise) have failed.[1] It is also important to evaluate other medications that the patient may already be taking, as some may promote weight gain (eg, sulfonylureas, thiazolidinediones, and insulin), thereby negating the effects of anti-obesity drugs.[2]
The decision to prescribe a weight-loss drug involves a careful assessment of the risks and benefits.[3] As a general rule, an effective regimen should help patients lose at least 4 pounds in the first 4 weeks, or 5% of baseline weight in the first 3 months on therapy.
As researchers continue searching for an ideal weight-loss agent, clinicians must work with available therapies while awaiting newer drugs in the pipeline.
Currently on the Market
Two classes of weight-loss agents are currently available by prescription: noradrenergic agents for short-term weight loss and a lipase inhibitor for long-term weight loss.
Phentermine
Phentermine is US Food and Drug Administration (FDA)-approved for short-term (up to 12 weeks) treatment of obesity and is the most widely prescribed weight-loss drug in the United States.[4] Phentermine is an adrenergic reuptake inhibitor,[5] stimulating the sympathetic nervous system to release norepinephrine, one of the neurotransmitters involved in modulating food intake. Phentermine suppresses appetite and induces satiety much like amphetamines, but has little effect on dopamine transmission, mitigating its abuse potential.[1] Because its effects last about 12 hours, phentermine should be taken in the morning. When used in combination with diet and exercise, phentermine has produced an average 3.6 kg greater weight loss than placebo.[6]
Phentermine is the relatively "safe half" of the formerly popular (but no longer on the market) weight-loss drug phentermine-fenfluramine (phen-fen). Fenfluramine (but not phentermine) was linked to pulmonary hypertension and valvular heart disease. Phentermine alone was found to be an effective anorectic, and it is still available as a prescription drug in 15 mg to 37.5 mg strengths[7] (although many manufacturers discontinued it).
Adverse effects include irritability, nervousness, restlessness, dry mouth, insomnia, constipation, and headache, but it has also been associated with hypertension, tachycardia, and palpitations, so it should not be taken by patients with cardiovascular disease or significant hypertension. Blood pressure should be monitored during therapy.
Diethylpropion
Like phentermine, diethylpropion is a noradrenergic agent with a similar mechanism of action (releasing and inhibiting the uptake of neurotransmitters norepinephrine and dopamine). Diethylpropion is available in 25-mg standard or 75-mg extended-release formulations, and is approved for short-term treatment of obesity.
In a recent study, 69 obese healthy adults were treated with diet and diethylpropion or diet and placebo.[8] After 6 months, the diethylpropion group lost an average of 9.8% of initial body weight vs 3.2% in the placebo group (P < .0001). In 1 year, the mean weight loss in patients taking diethylpropion was 10.6%. Dry mouth and insomnia were the most frequent adverse events.[8]
Benzphetamine and Phendimetrazine
Two other sympathomimetic drugs benzphetamine and phendimetrazine are still available by prescription for short-term weight loss. These drugs also act centrally, releasing dopamine and norepinephrine, resulting in appetite suppression, increased blood pressure, and increased heart rate. As schedule III drugs, however, benzphetamine and phendimetrazine have more potential for addiction and therefore are prescribed less often.[9]
All sympathomimetic drugs stimulate the central nervous system, and can increase blood pressure and heart rate, while releasing glycerol and free fatty acids.[9] Still, in a recent survey of obesity specialists in the United States, these were among the most frequently prescribed drugs in the clinical treatment of obesity. Most respondents (97%) reported prescribing phentermine, 64% prescribed diethylpropion, and 60% prescribed phendimetrazine.[4]
Orlistat
A gastrointestinal and pancreatic lipase inhibitor, orlistat was approved in 1999 as the first in a new class of anti-obesity agents. In the gastrointestinal tract, orlistat binds to gastric and pancreatic lipases, preventing these enzymes from hydrolyzing dietary fat into absorbable free fatty acids.[1] When not absorbed, triglycerides are excreted in the feces, along with cholesterol and fat-soluble vitamins. Taken with meals, orlistat can block the absorption of 30% of ingested fat.[5] In this manner, orlistat reduces caloric intake and may have additional benefits.
A Cochrane meta-analysis[10] of 11 randomized controlled trials of orlistat found that overweight and obese individuals who took orlistat had a mean weight loss of 2.9 kg (2.9%) more than those who took placebo. Compared with placebo, orlistat also significantly reduced waist circumference, body mass index (BMI), blood pressure, fasting glucose, and hemoglobin A1c concentrations in patients with diabetes, as well as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations.[2]
Adverse effects of orlistat are fairly common, affecting 15%-30% of patients and considered unpleasant and unacceptable by some patients.[2] These include steatorrhea, bloating, fecal urgency, fecal incontinence, and oily stools.[5] Orlistat might also interfere with the absorption of fat-soluble vitamins, including vitamins A, D, E, and K, so it has been suggested that patients taking orlistat should also take a multivitamin supplement containing these micronutrients, at least 2 hours before or after the administration of orlistat.
Concerns about a link between orlistat and colon cancer, as well as possible liver damage, are currently being investigated.[11] Orlistat may also interfere with the absorption, and therefore the effectiveness, of other drugs the patient is taking, such as amiodarone and cyclosporine, and through its effect on vitamin K, it can prolong bleeding in patients taking warfarin.[11] This class of drug should probably be avoided in patients with gastrointestinal disease or malabsorption syndromes.[2]
Orlistat is currently available as a prescription drug (Xenical® 120 mg) or an over-the-counter weight loss supplement (Alli® 60 mg). Although it is approved for long-term weight loss, orlistat's somewhat low tolerability and high cost may limit its long-term use.
Withdrawn or Awaiting Approval
The fall of 2010 was a discouraging time for those who are desperate for a new obesity treatment, including patients who say they would be willing to accept some risk if they were able to lose weight. Hopes were raised and then dashed as promising therapies slipped off the horizon in October, just after an established drug was withdrawn from the market. But companies touting the new therapies are continuing to collect safety information that they hope will satisfy regulators and ultimately allow them to sell their products.
Sibutramine
Abbott, maker of the sibutramine product Meridia®, issued a voluntary product recall in October upon being asked by the FDA to stop marketing Meridia in the United States; this followed reports of an increased risk for heart attack and stroke in Meridia users. Meridia had already been recalled earlier in Canada and Europe.
Sibutramine hydrochloride is a centrally acting monoamine reuptake inhibitor, affecting primarily serotoninand norepinephrine, and to a lesser extent, dopamine.[1] Originally used to treat depression, patients taking sibutramine experienced weight loss as an unexpected effect. Although diminished hunger and increased satiety are the most likely mechanisms of weight loss, sibutramine may also increase thermogenesis, thus increasing energy expenditure by increasing metabolism.[1]
The Sibutramine Cardiovascular OUTcomes (SCOUT) trial was a 6-year study of 10,000 patients, conducted to assess cardiovascular safety in high-risk patients. It showed that, after 5 years (the end of the trial), the average difference in body weight between patients taking Meridia and those taking a placebo was about 2.5%. On long-term follow-up, a 16% increased risk for nonfatal heart attacks and nonfatal strokes was seen in patients with pre-existing cardiovascular risk factors.[12] This was considered by some to be an unacceptable benefit to risk ratio. However, the manufacturer asserts that the increased cardiovascular events occurred primarily in patients with underlying cardiovascular disease, a patient population in whom Meridia is contraindicated according to enhanced labeling initiated earlier this year.[13]
Lorcaserin
Lorcaserin is an anti-obesity drug of the 5-HT2C agonist class. The stimulation of specific central serotonin receptors suppresses appetite and induces a feeling of satiety. Lorcaserin is highly selective for the 5-HT2C receptor, which modulates fat and caloric intake.[14] Signaling through the 5-HT2A and 5-HT2B receptors (found on cardiac valves), however, is minimal.[2]
In a large trial (3182 patients), those who took lorcaserin lost an average of 5.8% of their baseline body weight compared with 2.2% in those who took placebo (P < .001).[15] Nearly half of the patients taking lorcaserin lost 5% or more of their baseline body weight, compared with 20% of those taking placebo, and more of the lorcaserin patients maintained their weight loss after the study had ended. Very few patients in the lorcaserin group failed to lose weight.
Other improvements associated with lorcaserin were: reduced BMI and waist circumference; lower fasting glucose, insulin, and A1c levels; and lower total cholesterol, LDL cholesterol, and triglycerides. However, despite beneficial effects on risk for cardiovascular disease (reduced C-reactive protein, fibrinogen level, systolic and diastolic blood pressure, and heart rate), the FDA voted against approval of lorcaserin in October, citing concerns about lorcaserin-induced valvular heart disease (as well as brain and breast tumors) in declining to recommend lorcaserin for the treatment of obesity.[16]
The agency requested additional data about lorcaserin from drug maker Arena Pharmaceuticals, and the company says it will meet with the FDA before the end of the year, partly to discuss new, "encouraging" data regarding lorcaserin's effects on obese patients with diabetes.
Phentermine/Topiramate
Qnexa® (made by Vivus, Inc.) combines low-dose phentermine with a controlled-release form of topiramate, an antiepileptic drug often used for the prevention of migraine headache. Topiramate inhibits excitatory neurotransmissions by blocking voltage-gated sodium channels,[17] and is sometimes prescribed as monotherapy for weight loss.[4] Topiramate reduces hunger and promotes weight loss in a dose-dependent fashion, but the peripheral and central nervous system effects (parasthesias, memory impairment, taste disturbance) are significant and intolerable in some patients.[18] Topiramate has the added advantage of having mood-stabilizing properties.[5]
Harnessing the effects of the 2 different but complementary mechanisms of phentermine and topiramate allows the use of lower doses of each agent, which should increase safety.[19] This drug combination reportedly induces substantial weight loss, an average of about 10% after 1 year, and significantly reduces systolic blood pressure. Patients taking lower doses of the drug combination lose less weight, but that is still more than those taking placebo.
Despite evidence of effectiveness in phase 3 trials extending to 1 year, the FDA voted against approval of Qnexa in October, expressing concerns about adverse effects associated with its use, including cognitive disorders, metabolic acidosis, increased heart rate, and birth defects, suggesting possible teratogenicity.
Before Qnexa can be approved, the FDA has requested further evidence of its safety.[19] If approved, it would be a schedule IV drug due to the phentermine component.
Naltrexone/Bupropion
Contrave®, another new dual anti-obesity agent, is the combination of the antidepressant bupropion and sustained-release (SR) naltrexone, a drug used to treat alcoholism and other addictions. Bupropion, approved for both depression and smoking cessation, also increases dopamine levels at specific receptors in the brain, which is believed to be responsible for its appetite-reducing effects.[20] These 2 drugs work on the brain reward system and the hunger centers in the hypothalamus, and are believed to be synergistic in reducing food intake.[21]
If approved, this combination therapy could be useful for patients who have issues with food craving. When used with a mild hypocaloric diet and with exercise instruction in overweight or obese patients, it is associated with greater weight loss and greater improvement in several cardiometabolic risk factors compared with placebo.[22] Combination treatment was generally well tolerated; adverse effects included insomnia, nausea, headache, dry mouth, and a small and transient increase in systolic and diastolic blood pressure.[22]
Contrave has not yet been reviewed by the FDA, but phase 3 clinical trials have been completed. The manufacturer, Orexigen, reports that Contrave met all of its primary endpoints for weight loss in these trials, even in patients with diabetes, it also was associated with improvements in cardiometabolic risk markers such as waist circumference, HDL-C levels, and triglyceride levels.[23] Contrave is up for review by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.[23]
The fate of this anti-obesity agent will not be known until sometime in 2011.
In the Pipeline
Zonisamide/Bupropion
In clinical trials for the relatively new antiepileptic zonisamide, an unanticipated effect was weight loss. It has, therefore, been studied for its potential as a weight-loss agent, either in monotherapy or in combination with other agents such as bupropion. Zonisamide has sodium and calcium channel blocking activity, as well as dose-dependent biphasic dopaminergic and serotonergic activity. Empatic™ (made by Orexigen) is a fixed-dose combination of a proprietary formulation of zonisamide SR and bupropion SR.
In trials at Duke University, zonisamide alone with a hypocaloric diet was shown to be more effective in reducing weight than placebo.[24] The same investigators have conducted a short-term, open-label trial of treatment with zonisamide and bupropion, finding that the combination resulted in more weight loss than zonisamide alone.[25] Fatigue, drowsiness, sedation, nausea, and cognitive impairments (difficulty concentrating, memory problems, speech and language difficulties) have all been reported with zonisamide use.[25]
The manufacturer of Empatic recently reported that in phase 2b trials, patients who took the drug for 24 weeks lost 9.9% of their baseline body weight compared with 1.7% for patients taking placebo, without evidence of a plateau. Improvements in waist circumference, triglycerides, fasting insulin, and blood pressure were also reported.[23] Phase 3 trials are now planned.
Tesofensine
Tesofensine (made by NeuroSearch) is a triple monoamine reuptake inhibitor that blocks the presynaptic uptake of norepinephrine, dopamine, and serotonin.[17] Originally being studied for neurodegenerative conditions such as Parkinson and Alzheimer diseases, unintended weight loss was observed in individuals treated with the drug.[26]
The mechanisms through which tesofensine leads to weight loss are a pronounced effect on appetite suppression and increased energy expenditure.[27] In phase 2 clinical trials with tesofensine in obese patients, dose-related reductions in body weight, body fat, and waist circumference, as well as improvements in other obesity-related measures, were observed. Minor adverse events included elevations in heart rate and significant increases in blood pressure only at the highest tested dose.[28] The drug is soon to be tested in phase 3 clinical trials.[26]
Cetilistat
Cetilistat is a new lipase-inhibitor with a similar mode of action to orlistat, inhibiting pancreatic lipase and blocking digestion and absorption of dietary fat, so that it can be eliminated unchanged with the stool. Cetilistat has completed a 12-week phase 2b trial in obese patients, demonstrating weight loss consistent with other obesity medications and significant improvements in other obesity-related parameters.[29] Unpleasant adverse effects, including flatus with discharge and oily spotting, were reported by fewer than 3% of patients using cetilistat.
It is probable that, like orlistat, cetilistat will also block the absorption of fat-soluble vitamins, and this possibility was raised by the FDA in 2009, cautioning that cetilistat could "lead to malabsorption of nutrients and vitamin deficiency."[30] Cetilistat has now been cleared to conduct phase 3 trials in patients with obesity.
Pramlintide/Metreleptin
The combination of these 2 agents represents a novel integrated neurohormonal approach to obesity.[31] Pramlintide is an analogue of amylin, a hormone secreted by pancreatic beta cells along with insulin. Exogenous amylin can increase the absorption of glucose, slow gastric emptying, and by binding to hypothalamic receptors, promote satiety, reduce food intake and elicit weight loss. Metreleptin is recombinant methionine human leptin. Leptin is a neurohormone secreted by adipocytes that also binds to receptors in the hypothalamus to promote satiety. When someone reduces dietary intake to lose weight, leptin levels drop, and this triggers a host of counter-regulatory responses aimed at maintaining body weight. Administration of metreleptin restores leptin concentrations and attenuates the effects of counter-regulation.[31]
Pramlintide is already an approved drug in the treatment of diabetes. Metreleptin has been tested as monotherapy for obesity/weight loss, but failed because of the development of leptin resistance. However, these 2 hormones are believed to act synergistically to reduce food intake and body weight.
Mildly and moderately obese patients (without diabetes) who took this combination lost about 13% of baseline body weight in 24 weeks with no weight-loss plateau, significantly more than was seen with either drug administered as a single agent. Patients who continued treatment with pramlintide/metreleptin for a total of 52 weeks exhibited sustained weight loss, whereas those who received placebo during the extension study regained almost all of their lost weight. The combination therapy appeared to be generally well tolerated. The most common adverse effect was nausea.[31]
Pramlintide/metreleptin combination is an injectable therapy, which may limit its application in the general obese population.
Potential Future Therapies
ZGN-433, a methionine aminopeptidase inhibitor, targets the adipose tissue rather than the central nervous system. This class of medication essentially works by restoring control of adipose tissue lipolysis, ketogenesis, food intake, and fat synthesis. ZGN-433 is believed to stimulate adipose tissue to convert stored triglycerides into free fatty acids that can be used for energy.[32]
ZGN-433 is still in the early stages of development but has shown promise in rodent studies. A safety and tolerability study in humans is in progress.
Another novel therapy that may have a role in weight loss is ezlopitant, a neurokinin receptor-1 (NK1R) antagonist. The NK1R system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; recent evidence from rodent studies suggests that ezlopitant reduces the appetite for sucrose as well, thus decreasing the consumption of sweetened foods and drinks.[33] It has been suggested that sweet foods and drinks can be addictive in the same way as alcohol, explaining the suppressant effects of ezlopitant.
The antidiabetes drugs represent another possible drug class to mine for potential weight-loss effects and for possible development as dual diabetes/obesity agents. Metformin, a biguanide approved for the treatment of type 2 diabetes, causes weight loss by reducing hepatic glucose production and intestinal absorption from the gastrointestinal tract, and enhancing insulin sensitivity.[34]
Liraglutide (Victoza®), another drug that is already approved for the treatment of type 2 diabetes, induces moderate weight loss of approximately 2-3 kg.[35] The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide are newer medications for diabetes that have favorable effects not only on glycemic control but also on weight loss.[3] Although some of these agents might not induce enough weight loss to qualify as anti-obesity agents, they could prove useful for overweight individuals who have diabetes.[34]
Final Thoughts on Anti-Obesity Pharmacotherapy
Obesity is a chronic, relapsing, biologic condition that may well require long-term pharmacotherapy, in the same manner as hypertension and diabetes. To date, however, the average amount of weight lost with most pharmacologic agents has been modest at best, and the typical patient will most likely remain overweight or obese even with ongoing treatment.[12]
Weight-loss drugs are expensive; neither Medicare nor most insurance plans cover them. In addition, most are associated with adverse effects. Therefore, meeting efficacy criteria for weight loss is not good enough for anti-obesity agents that will be taken by millions of people for many years. The benefits of any weight-loss drug must outweigh the risks, and safety is the overriding consideration.
It is too early to tell whether some of the novel weight loss drugs still in development will offer greater efficacy and safety. What is certain is that drug developers will continue to search for the Holy Grail of anti-obesity drugs as the world's girth continues to expand.
Laura A. Stokowski, RN, MS
Posted: 12/13/2010
Wanted: A Pill That Melts Fat
As Americans become more obese and the associated health problems reach epidemic proportions, the need for a safe and effective weight loss drug has become urgent. Over the years, this quest has been marked with short-lived triumphs and many defeats, leaving patients and clinicians with less than ideal weapons in the fight against obesity.
The few drugs that have actually reached the market in recent years promote weight loss either by boosting the body's basal metabolic rate, blocking the absorption of dietary fat, or suppressing appetite.People who take these drugs typically lose weight for the first 6 months until they reach a plateau that can't be surpassed without increasing exercise or caloric restriction.The problems with many of these agents have been a lack of proven long-term safety, and the fact that when such drugs are stopped, the weight is usually regained.
Most clinicians are aware that pharmacotherapy is not indicated as a first-line therapy for obesity, and should not be initiated until all nonpharmacologic attempts at weight loss (diet, exercise) have failed.[1] It is also important to evaluate other medications that the patient may already be taking, as some may promote weight gain (eg, sulfonylureas, thiazolidinediones, and insulin), thereby negating the effects of anti-obesity drugs.[2]
The decision to prescribe a weight-loss drug involves a careful assessment of the risks and benefits.[3] As a general rule, an effective regimen should help patients lose at least 4 pounds in the first 4 weeks, or 5% of baseline weight in the first 3 months on therapy.
As researchers continue searching for an ideal weight-loss agent, clinicians must work with available therapies while awaiting newer drugs in the pipeline.
Currently on the Market
Two classes of weight-loss agents are currently available by prescription: noradrenergic agents for short-term weight loss and a lipase inhibitor for long-term weight loss.
Phentermine
Phentermine is US Food and Drug Administration (FDA)-approved for short-term (up to 12 weeks) treatment of obesity and is the most widely prescribed weight-loss drug in the United States.[4] Phentermine is an adrenergic reuptake inhibitor,[5] stimulating the sympathetic nervous system to release norepinephrine, one of the neurotransmitters involved in modulating food intake. Phentermine suppresses appetite and induces satiety much like amphetamines, but has little effect on dopamine transmission, mitigating its abuse potential.[1] Because its effects last about 12 hours, phentermine should be taken in the morning. When used in combination with diet and exercise, phentermine has produced an average 3.6 kg greater weight loss than placebo.[6]
Phentermine is the relatively "safe half" of the formerly popular (but no longer on the market) weight-loss drug phentermine-fenfluramine (phen-fen). Fenfluramine (but not phentermine) was linked to pulmonary hypertension and valvular heart disease. Phentermine alone was found to be an effective anorectic, and it is still available as a prescription drug in 15 mg to 37.5 mg strengths[7] (although many manufacturers discontinued it).
Adverse effects include irritability, nervousness, restlessness, dry mouth, insomnia, constipation, and headache, but it has also been associated with hypertension, tachycardia, and palpitations, so it should not be taken by patients with cardiovascular disease or significant hypertension. Blood pressure should be monitored during therapy.
Diethylpropion
Like phentermine, diethylpropion is a noradrenergic agent with a similar mechanism of action (releasing and inhibiting the uptake of neurotransmitters norepinephrine and dopamine). Diethylpropion is available in 25-mg standard or 75-mg extended-release formulations, and is approved for short-term treatment of obesity.
In a recent study, 69 obese healthy adults were treated with diet and diethylpropion or diet and placebo.[8] After 6 months, the diethylpropion group lost an average of 9.8% of initial body weight vs 3.2% in the placebo group (P < .0001). In 1 year, the mean weight loss in patients taking diethylpropion was 10.6%. Dry mouth and insomnia were the most frequent adverse events.[8]
Benzphetamine and Phendimetrazine
Two other sympathomimetic drugs benzphetamine and phendimetrazine are still available by prescription for short-term weight loss. These drugs also act centrally, releasing dopamine and norepinephrine, resulting in appetite suppression, increased blood pressure, and increased heart rate. As schedule III drugs, however, benzphetamine and phendimetrazine have more potential for addiction and therefore are prescribed less often.[9]
All sympathomimetic drugs stimulate the central nervous system, and can increase blood pressure and heart rate, while releasing glycerol and free fatty acids.[9] Still, in a recent survey of obesity specialists in the United States, these were among the most frequently prescribed drugs in the clinical treatment of obesity. Most respondents (97%) reported prescribing phentermine, 64% prescribed diethylpropion, and 60% prescribed phendimetrazine.[4]
Orlistat
A gastrointestinal and pancreatic lipase inhibitor, orlistat was approved in 1999 as the first in a new class of anti-obesity agents. In the gastrointestinal tract, orlistat binds to gastric and pancreatic lipases, preventing these enzymes from hydrolyzing dietary fat into absorbable free fatty acids.[1] When not absorbed, triglycerides are excreted in the feces, along with cholesterol and fat-soluble vitamins. Taken with meals, orlistat can block the absorption of 30% of ingested fat.[5] In this manner, orlistat reduces caloric intake and may have additional benefits.
A Cochrane meta-analysis[10] of 11 randomized controlled trials of orlistat found that overweight and obese individuals who took orlistat had a mean weight loss of 2.9 kg (2.9%) more than those who took placebo. Compared with placebo, orlistat also significantly reduced waist circumference, body mass index (BMI), blood pressure, fasting glucose, and hemoglobin A1c concentrations in patients with diabetes, as well as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations.[2]
Adverse effects of orlistat are fairly common, affecting 15%-30% of patients and considered unpleasant and unacceptable by some patients.[2] These include steatorrhea, bloating, fecal urgency, fecal incontinence, and oily stools.[5] Orlistat might also interfere with the absorption of fat-soluble vitamins, including vitamins A, D, E, and K, so it has been suggested that patients taking orlistat should also take a multivitamin supplement containing these micronutrients, at least 2 hours before or after the administration of orlistat.
Concerns about a link between orlistat and colon cancer, as well as possible liver damage, are currently being investigated.[11] Orlistat may also interfere with the absorption, and therefore the effectiveness, of other drugs the patient is taking, such as amiodarone and cyclosporine, and through its effect on vitamin K, it can prolong bleeding in patients taking warfarin.[11] This class of drug should probably be avoided in patients with gastrointestinal disease or malabsorption syndromes.[2]
Orlistat is currently available as a prescription drug (Xenical® 120 mg) or an over-the-counter weight loss supplement (Alli® 60 mg). Although it is approved for long-term weight loss, orlistat's somewhat low tolerability and high cost may limit its long-term use.
Withdrawn or Awaiting Approval
The fall of 2010 was a discouraging time for those who are desperate for a new obesity treatment, including patients who say they would be willing to accept some risk if they were able to lose weight. Hopes were raised and then dashed as promising therapies slipped off the horizon in October, just after an established drug was withdrawn from the market. But companies touting the new therapies are continuing to collect safety information that they hope will satisfy regulators and ultimately allow them to sell their products.
Sibutramine
Abbott, maker of the sibutramine product Meridia®, issued a voluntary product recall in October upon being asked by the FDA to stop marketing Meridia in the United States; this followed reports of an increased risk for heart attack and stroke in Meridia users. Meridia had already been recalled earlier in Canada and Europe.
Sibutramine hydrochloride is a centrally acting monoamine reuptake inhibitor, affecting primarily serotoninand norepinephrine, and to a lesser extent, dopamine.[1] Originally used to treat depression, patients taking sibutramine experienced weight loss as an unexpected effect. Although diminished hunger and increased satiety are the most likely mechanisms of weight loss, sibutramine may also increase thermogenesis, thus increasing energy expenditure by increasing metabolism.[1]
The Sibutramine Cardiovascular OUTcomes (SCOUT) trial was a 6-year study of 10,000 patients, conducted to assess cardiovascular safety in high-risk patients. It showed that, after 5 years (the end of the trial), the average difference in body weight between patients taking Meridia and those taking a placebo was about 2.5%. On long-term follow-up, a 16% increased risk for nonfatal heart attacks and nonfatal strokes was seen in patients with pre-existing cardiovascular risk factors.[12] This was considered by some to be an unacceptable benefit to risk ratio. However, the manufacturer asserts that the increased cardiovascular events occurred primarily in patients with underlying cardiovascular disease, a patient population in whom Meridia is contraindicated according to enhanced labeling initiated earlier this year.[13]
Lorcaserin
Lorcaserin is an anti-obesity drug of the 5-HT2C agonist class. The stimulation of specific central serotonin receptors suppresses appetite and induces a feeling of satiety. Lorcaserin is highly selective for the 5-HT2C receptor, which modulates fat and caloric intake.[14] Signaling through the 5-HT2A and 5-HT2B receptors (found on cardiac valves), however, is minimal.[2]
In a large trial (3182 patients), those who took lorcaserin lost an average of 5.8% of their baseline body weight compared with 2.2% in those who took placebo (P < .001).[15] Nearly half of the patients taking lorcaserin lost 5% or more of their baseline body weight, compared with 20% of those taking placebo, and more of the lorcaserin patients maintained their weight loss after the study had ended. Very few patients in the lorcaserin group failed to lose weight.
Other improvements associated with lorcaserin were: reduced BMI and waist circumference; lower fasting glucose, insulin, and A1c levels; and lower total cholesterol, LDL cholesterol, and triglycerides. However, despite beneficial effects on risk for cardiovascular disease (reduced C-reactive protein, fibrinogen level, systolic and diastolic blood pressure, and heart rate), the FDA voted against approval of lorcaserin in October, citing concerns about lorcaserin-induced valvular heart disease (as well as brain and breast tumors) in declining to recommend lorcaserin for the treatment of obesity.[16]
The agency requested additional data about lorcaserin from drug maker Arena Pharmaceuticals, and the company says it will meet with the FDA before the end of the year, partly to discuss new, "encouraging" data regarding lorcaserin's effects on obese patients with diabetes.
Phentermine/Topiramate
Qnexa® (made by Vivus, Inc.) combines low-dose phentermine with a controlled-release form of topiramate, an antiepileptic drug often used for the prevention of migraine headache. Topiramate inhibits excitatory neurotransmissions by blocking voltage-gated sodium channels,[17] and is sometimes prescribed as monotherapy for weight loss.[4] Topiramate reduces hunger and promotes weight loss in a dose-dependent fashion, but the peripheral and central nervous system effects (parasthesias, memory impairment, taste disturbance) are significant and intolerable in some patients.[18] Topiramate has the added advantage of having mood-stabilizing properties.[5]
Harnessing the effects of the 2 different but complementary mechanisms of phentermine and topiramate allows the use of lower doses of each agent, which should increase safety.[19] This drug combination reportedly induces substantial weight loss, an average of about 10% after 1 year, and significantly reduces systolic blood pressure. Patients taking lower doses of the drug combination lose less weight, but that is still more than those taking placebo.
Despite evidence of effectiveness in phase 3 trials extending to 1 year, the FDA voted against approval of Qnexa in October, expressing concerns about adverse effects associated with its use, including cognitive disorders, metabolic acidosis, increased heart rate, and birth defects, suggesting possible teratogenicity.
Before Qnexa can be approved, the FDA has requested further evidence of its safety.[19] If approved, it would be a schedule IV drug due to the phentermine component.
Naltrexone/Bupropion
Contrave®, another new dual anti-obesity agent, is the combination of the antidepressant bupropion and sustained-release (SR) naltrexone, a drug used to treat alcoholism and other addictions. Bupropion, approved for both depression and smoking cessation, also increases dopamine levels at specific receptors in the brain, which is believed to be responsible for its appetite-reducing effects.[20] These 2 drugs work on the brain reward system and the hunger centers in the hypothalamus, and are believed to be synergistic in reducing food intake.[21]
If approved, this combination therapy could be useful for patients who have issues with food craving. When used with a mild hypocaloric diet and with exercise instruction in overweight or obese patients, it is associated with greater weight loss and greater improvement in several cardiometabolic risk factors compared with placebo.[22] Combination treatment was generally well tolerated; adverse effects included insomnia, nausea, headache, dry mouth, and a small and transient increase in systolic and diastolic blood pressure.[22]
Contrave has not yet been reviewed by the FDA, but phase 3 clinical trials have been completed. The manufacturer, Orexigen, reports that Contrave met all of its primary endpoints for weight loss in these trials, even in patients with diabetes, it also was associated with improvements in cardiometabolic risk markers such as waist circumference, HDL-C levels, and triglyceride levels.[23] Contrave is up for review by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.[23]
The fate of this anti-obesity agent will not be known until sometime in 2011.
In the Pipeline
Zonisamide/Bupropion
In clinical trials for the relatively new antiepileptic zonisamide, an unanticipated effect was weight loss. It has, therefore, been studied for its potential as a weight-loss agent, either in monotherapy or in combination with other agents such as bupropion. Zonisamide has sodium and calcium channel blocking activity, as well as dose-dependent biphasic dopaminergic and serotonergic activity. Empatic™ (made by Orexigen) is a fixed-dose combination of a proprietary formulation of zonisamide SR and bupropion SR.
In trials at Duke University, zonisamide alone with a hypocaloric diet was shown to be more effective in reducing weight than placebo.[24] The same investigators have conducted a short-term, open-label trial of treatment with zonisamide and bupropion, finding that the combination resulted in more weight loss than zonisamide alone.[25] Fatigue, drowsiness, sedation, nausea, and cognitive impairments (difficulty concentrating, memory problems, speech and language difficulties) have all been reported with zonisamide use.[25]
The manufacturer of Empatic recently reported that in phase 2b trials, patients who took the drug for 24 weeks lost 9.9% of their baseline body weight compared with 1.7% for patients taking placebo, without evidence of a plateau. Improvements in waist circumference, triglycerides, fasting insulin, and blood pressure were also reported.[23] Phase 3 trials are now planned.
Tesofensine
Tesofensine (made by NeuroSearch) is a triple monoamine reuptake inhibitor that blocks the presynaptic uptake of norepinephrine, dopamine, and serotonin.[17] Originally being studied for neurodegenerative conditions such as Parkinson and Alzheimer diseases, unintended weight loss was observed in individuals treated with the drug.[26]
The mechanisms through which tesofensine leads to weight loss are a pronounced effect on appetite suppression and increased energy expenditure.[27] In phase 2 clinical trials with tesofensine in obese patients, dose-related reductions in body weight, body fat, and waist circumference, as well as improvements in other obesity-related measures, were observed. Minor adverse events included elevations in heart rate and significant increases in blood pressure only at the highest tested dose.[28] The drug is soon to be tested in phase 3 clinical trials.[26]
Cetilistat
Cetilistat is a new lipase-inhibitor with a similar mode of action to orlistat, inhibiting pancreatic lipase and blocking digestion and absorption of dietary fat, so that it can be eliminated unchanged with the stool. Cetilistat has completed a 12-week phase 2b trial in obese patients, demonstrating weight loss consistent with other obesity medications and significant improvements in other obesity-related parameters.[29] Unpleasant adverse effects, including flatus with discharge and oily spotting, were reported by fewer than 3% of patients using cetilistat.
It is probable that, like orlistat, cetilistat will also block the absorption of fat-soluble vitamins, and this possibility was raised by the FDA in 2009, cautioning that cetilistat could "lead to malabsorption of nutrients and vitamin deficiency."[30] Cetilistat has now been cleared to conduct phase 3 trials in patients with obesity.
Pramlintide/Metreleptin
The combination of these 2 agents represents a novel integrated neurohormonal approach to obesity.[31] Pramlintide is an analogue of amylin, a hormone secreted by pancreatic beta cells along with insulin. Exogenous amylin can increase the absorption of glucose, slow gastric emptying, and by binding to hypothalamic receptors, promote satiety, reduce food intake and elicit weight loss. Metreleptin is recombinant methionine human leptin. Leptin is a neurohormone secreted by adipocytes that also binds to receptors in the hypothalamus to promote satiety. When someone reduces dietary intake to lose weight, leptin levels drop, and this triggers a host of counter-regulatory responses aimed at maintaining body weight. Administration of metreleptin restores leptin concentrations and attenuates the effects of counter-regulation.[31]
Pramlintide is already an approved drug in the treatment of diabetes. Metreleptin has been tested as monotherapy for obesity/weight loss, but failed because of the development of leptin resistance. However, these 2 hormones are believed to act synergistically to reduce food intake and body weight.
Mildly and moderately obese patients (without diabetes) who took this combination lost about 13% of baseline body weight in 24 weeks with no weight-loss plateau, significantly more than was seen with either drug administered as a single agent. Patients who continued treatment with pramlintide/metreleptin for a total of 52 weeks exhibited sustained weight loss, whereas those who received placebo during the extension study regained almost all of their lost weight. The combination therapy appeared to be generally well tolerated. The most common adverse effect was nausea.[31]
Pramlintide/metreleptin combination is an injectable therapy, which may limit its application in the general obese population.
Potential Future Therapies
ZGN-433, a methionine aminopeptidase inhibitor, targets the adipose tissue rather than the central nervous system. This class of medication essentially works by restoring control of adipose tissue lipolysis, ketogenesis, food intake, and fat synthesis. ZGN-433 is believed to stimulate adipose tissue to convert stored triglycerides into free fatty acids that can be used for energy.[32]
ZGN-433 is still in the early stages of development but has shown promise in rodent studies. A safety and tolerability study in humans is in progress.
Another novel therapy that may have a role in weight loss is ezlopitant, a neurokinin receptor-1 (NK1R) antagonist. The NK1R system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; recent evidence from rodent studies suggests that ezlopitant reduces the appetite for sucrose as well, thus decreasing the consumption of sweetened foods and drinks.[33] It has been suggested that sweet foods and drinks can be addictive in the same way as alcohol, explaining the suppressant effects of ezlopitant.
The antidiabetes drugs represent another possible drug class to mine for potential weight-loss effects and for possible development as dual diabetes/obesity agents. Metformin, a biguanide approved for the treatment of type 2 diabetes, causes weight loss by reducing hepatic glucose production and intestinal absorption from the gastrointestinal tract, and enhancing insulin sensitivity.[34]
Liraglutide (Victoza®), another drug that is already approved for the treatment of type 2 diabetes, induces moderate weight loss of approximately 2-3 kg.[35] The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide are newer medications for diabetes that have favorable effects not only on glycemic control but also on weight loss.[3] Although some of these agents might not induce enough weight loss to qualify as anti-obesity agents, they could prove useful for overweight individuals who have diabetes.[34]
Final Thoughts on Anti-Obesity Pharmacotherapy
Obesity is a chronic, relapsing, biologic condition that may well require long-term pharmacotherapy, in the same manner as hypertension and diabetes. To date, however, the average amount of weight lost with most pharmacologic agents has been modest at best, and the typical patient will most likely remain overweight or obese even with ongoing treatment.[12]
Weight-loss drugs are expensive; neither Medicare nor most insurance plans cover them. In addition, most are associated with adverse effects. Therefore, meeting efficacy criteria for weight loss is not good enough for anti-obesity agents that will be taken by millions of people for many years. The benefits of any weight-loss drug must outweigh the risks, and safety is the overriding consideration.
It is too early to tell whether some of the novel weight loss drugs still in development will offer greater efficacy and safety. What is certain is that drug developers will continue to search for the Holy Grail of anti-obesity drugs as the world's girth continues to expand.
Monday, December 20, 2010
Starting Dialysis Too Early Linked to Increased Mortality Risk
From MedscapeCME Clinical Briefs
Laurie Barclay, MD
Désirée Lie, MD, MSEd
December 7, 2010 — Starting dialysis too early is linked to an increased mortality risk, according to the results of a study reported online December 6 in the Canadian Medical Association Journal.
"Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate [GFR]) and an association between early initiation and increased risk of death," write William F. Clark, MD, from the University of Western Ontario, London, Canada, and colleagues. "We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis."
Using the Canadian Organ Replacement Register from 2001 to 2007, the investigators identified an analytic cohort of 25,910 patients 18 years or older who began hemodialysis. Dialysis was defined as beginning early if the estimated GFR (eGFR) exceeded 10.5 mL/minute/1.73 m2. To compare mortality risk between patients who started dialysis early vs late, the investigators fitted time-dependent proportional-hazards Cox models.
At initiation of dialysis, mean eGFR increased from 9.3 ± 5.2 mL/minute/1.73 m2 in 2001 to 10.2 ± 7.1 mL/minute/1.73 m2 in 2007 (P < .001). During the same period, the proportion of early dialysis initiations increased from 28% (95% confidence interval [CI], 27% - 30%) to 36% (95% CI, 34% - 37%). Among those starting dialysis early, mean GFR at initiation was 15.5 ± 7.7 mL/minute/1.73 m2 vs 7.1 ± 2.0 mL/minute/1.73 m2 among those who started dialysis late.
For early vs late initiation of dialysis, the unadjusted hazard ratio (HR) for death was 1.48 (95% CI, 1.43 - 1.54). After adjustment for demographic factors, serum albumin, primary cause of end-stage renal disease, type of vascular access, comorbid conditions, late referral, and transplant status, the HR for death decreased to 1.18 (95% CI, 1.13 - 1.23). Difference in mortality per 1000 patient-years between starting dialysis early vs late decreased after 1 year of follow-up but persisted and began increasing again after 24 months of follow-up, with significant differences at 6, 12, 30, and 36 months.
"In Canada, dialysis is being initiated at increasingly higher levels of ...GFR," the study authors write. "A higher GFR at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics."
Limitations of this study include biases related to observational design, those associated with the use of registry data, and potential confounding by indication.
"The consistent absence of a survival benefit with early initiation of dialysis across a variety of study designs, populations and health care delivery systems supports the conclusion that early initiation confers no survival benefit, and argues against pre-emptive initiation of dialysis in asymptomatic patients," the study authors conclude. "In contrast to early initiation of dialysis, early referral to a nephrologist is consistently associated with better survival. Further research is needed to determine the objective signs, symptoms and laboratory test results associated with increased mortality and decreased quality of life among patients with advanced renal failure."
CMAJ. Published online December 6, 2010.
Clinical Context
Examination of dialysis registers has shown that the procedure is being initiated earlier at increasingly higher levels of eGFR. In the United States, the National Kidney Foundation has suggested that initiation of dialysis be considered before stage V chronic kidney disease (eGFR < 15 mL/minute/1.73 m²). However, studies have suggested no survival benefit in patients with early initiation of hemodialysis.
This is a cohort study of Canadian patients who initiated hemodialysis early vs late to examine recent trends in timing of initiation and the association with mortality risk.
Laurie Barclay, MD
Désirée Lie, MD, MSEd
December 7, 2010 — Starting dialysis too early is linked to an increased mortality risk, according to the results of a study reported online December 6 in the Canadian Medical Association Journal.
"Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate [GFR]) and an association between early initiation and increased risk of death," write William F. Clark, MD, from the University of Western Ontario, London, Canada, and colleagues. "We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis."
Using the Canadian Organ Replacement Register from 2001 to 2007, the investigators identified an analytic cohort of 25,910 patients 18 years or older who began hemodialysis. Dialysis was defined as beginning early if the estimated GFR (eGFR) exceeded 10.5 mL/minute/1.73 m2. To compare mortality risk between patients who started dialysis early vs late, the investigators fitted time-dependent proportional-hazards Cox models.
At initiation of dialysis, mean eGFR increased from 9.3 ± 5.2 mL/minute/1.73 m2 in 2001 to 10.2 ± 7.1 mL/minute/1.73 m2 in 2007 (P < .001). During the same period, the proportion of early dialysis initiations increased from 28% (95% confidence interval [CI], 27% - 30%) to 36% (95% CI, 34% - 37%). Among those starting dialysis early, mean GFR at initiation was 15.5 ± 7.7 mL/minute/1.73 m2 vs 7.1 ± 2.0 mL/minute/1.73 m2 among those who started dialysis late.
For early vs late initiation of dialysis, the unadjusted hazard ratio (HR) for death was 1.48 (95% CI, 1.43 - 1.54). After adjustment for demographic factors, serum albumin, primary cause of end-stage renal disease, type of vascular access, comorbid conditions, late referral, and transplant status, the HR for death decreased to 1.18 (95% CI, 1.13 - 1.23). Difference in mortality per 1000 patient-years between starting dialysis early vs late decreased after 1 year of follow-up but persisted and began increasing again after 24 months of follow-up, with significant differences at 6, 12, 30, and 36 months.
"In Canada, dialysis is being initiated at increasingly higher levels of ...GFR," the study authors write. "A higher GFR at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics."
Limitations of this study include biases related to observational design, those associated with the use of registry data, and potential confounding by indication.
"The consistent absence of a survival benefit with early initiation of dialysis across a variety of study designs, populations and health care delivery systems supports the conclusion that early initiation confers no survival benefit, and argues against pre-emptive initiation of dialysis in asymptomatic patients," the study authors conclude. "In contrast to early initiation of dialysis, early referral to a nephrologist is consistently associated with better survival. Further research is needed to determine the objective signs, symptoms and laboratory test results associated with increased mortality and decreased quality of life among patients with advanced renal failure."
CMAJ. Published online December 6, 2010.
Clinical Context
Examination of dialysis registers has shown that the procedure is being initiated earlier at increasingly higher levels of eGFR. In the United States, the National Kidney Foundation has suggested that initiation of dialysis be considered before stage V chronic kidney disease (eGFR < 15 mL/minute/1.73 m²). However, studies have suggested no survival benefit in patients with early initiation of hemodialysis.
This is a cohort study of Canadian patients who initiated hemodialysis early vs late to examine recent trends in timing of initiation and the association with mortality risk.
Alzheimer Disease: Insights Into Advances in Diagnosis and Treatment
From Medscape Education Neurology & Neurosurgery
Samuel Gandy, MD, PhD
Alzheimer disease (AD) is an epidemic of brain failure affecting 5 million Americans, or about half of the population over the age of 85. Clinically, patients with AD exhibit progressive cognitive failure, including changes in personality, loss of the ability to form and retrieve new memories, and loss of the ability to navigate even the most familiar environments. Pathologically, AD is characterized by destruction of hippocampal and neocortical neurons, particularly those involving the cholinergic projections from the basal forebrain to the cerebral cortex.
The cause of the disease is well understood in only roughly 3% of cases, typically those with the rare, early-onset, familial forms of AD that can be attributed to genetic mutations.
The disease was first reported in 1907 by Bavarian psychiatrist Alois Alzheimer, who described a case that was atypical in many ways. The patient was 55 years old when symptoms of paranoia developed, and her young age may explain the long-held misconception that the disease begins in the presenilium. Until fairly recently, physicians were taught that AD was a rare disease that primarily affected people under the age of 65 years. However, the entity we call "common" or "sporadic" AD is the most common disease responsible for what has long been called "senility" in the elderly. Previously, dementia was believed to result from either vascular or degenerative processes. However, most patients with dementia have been found to have concurrent vascular and degenerative pathologies. Indeed, risk factors for stroke likewise increase the risk for AD.
The clinicopathologic syndrome, when complete, includes:
* an appropriate clinical syndrome (late life-onset amnesia, disorders of executive function [eg, organization, working memory], a psychiatric syndrome, or some combination of these);
* accumulation of abnormal proteinaceous structures; and
* neuronal and synaptic loss.
The molecular pathology of AD is defined by parenchymal and cerebrovascular amyloidosis resulting from an accumulation of amyloid-beta (A-beta), intraneuronal neurofibrillary tangles resulting from a buildup of altered tau protein, and acetylcholine deficiency. The cholinergic neurons that project diffusely from the basal forebrain to the cortex are among the earliest neurons to fail, and loss of acetylcholine content correlates well with the severity of the initial amnestic syndrome. Eventually, virtually all transmitter systems are involved to some degree and all cortical function is lost, leading to a persistent vegetative state.
Clinical Diagnosis of AD
Until very recently, the diagnosis of AD depended on careful clinical interview and mental status tests, with definitive diagnosis only available postmortem. Indeed, neuropsychological testing remains the most sensitive means of making an early clinical diagnosis. Formal testing by a neuropsychometrist is typical at research centers, but far more informal tools are used by most practitioners.
One of the most important distinctions in the diagnosis of AD is differentiating dementia and delirium (often related to metabolic dysfunction or toxic ingestion) or depressive pseudodementia. During the last decade, the concept of mild cognitive impairment (MCI) has become widely accepted. The operational definition of MCI involves demonstrable deficits in 1 domain (typically memory) or multiple cognitive domains, without a clinically important impact on the patient's function. Because patients are not functionally impaired, this level of cognitive impairment is not recognized by the US Food and Drug Administration (FDA) and no medications have been approved for use in patients with MCI. The amnestic form of MCI is the more typical harbinger of eventual progression to AD.[5]
Diagnosis begins by excluding treatable causes of cognitive dysfunction, including endocrine and metabolic disorders, vitamin deficiencies, and hydrocephalus, among others. Complete blood count, serum chemistries including liver and renal function tests, tests for syphilis, and tests of thyroid function have long been established tools in the physician's armamentarium. Computerized tomography and/or magnetic resonance imaging have become more widely used in the last decade, and CSF examination is frequently performed by neurologists, although this is by no means universal.
Biomarkers of Diagnosis and Progression
The emergence of CSF and neuroimaging biomarkers is rapidly changing the approach to dementia diagnosis. Among the most promising developments are the following:
* CSF A-beta 42 and tau levels[6,7]
o A-beta 42 levels typically fall and tau levels rise as disease progresses
o May predict which patients with amnestic MCI will progress to AD
* Fluorodeoxyglucose-positron emission tomography (FDG PET) for distinguishing frontotemporal dementia from AD[8]
o Approved by the Centers for Medicare and Medicaid Services under some circumstances
* Pittsburgh compound B (PiB) PET, AV-45, and/or radiotracer 18F-FDDNP PET for imaging the neuropathologic burden of A-beta plaques and neurofibrillary tangles during life[9,10]
Apolipoprotein E (APOE) genotyping is typically performed for clinical trials and other research studies in the setting of pregenetic and postgenetic counseling. Neither the National Institute on Aging nor the Alzheimer's Association favors routine APOE genotyping because the outcome of testing positive is uncertain.[11] A patient may have an APOE epsilon 4 allele and still escape dementia, and those who lack the APOE epsilon 4 alleles are still at risk for dementia.[12]
Treatment of AD
Currently, the primary benefit of early diagnosis of AD is that it enables the patient to organize his or her affairs and participate in the planning of his or her care. The hope is that research will eventually enable the presymptomatic diagnosis of the presence of AD pathology so that those who are diagnosed can begin disease-modifying treatments to prevent or significantly delay the clinical presentation. Without an effective disease-modifying intervention, this remains an unattained goal and something of a speculation. The growing consensus in this direction is part of the driving force behind the pressure for earlier diagnosis.
Several strategies can improve quality of life at this early stage and forestall other health-related complications or risk factors such as cardiovascular disease and diabetes. Although a diet rich in a variety of vitamins and minerals and low in saturated fats (eg, the Mediterranean diet) has not been shown conclusively to improve cognitive function, such a diet will improve health by addressing obesity, lowering blood pressure, and improving glycemic control. Moreover, physical and mental activities may also mitigate cognitive decline or at the least enhance quality of life.[13] Finally, early diagnosis enables patients and their families to establish supervision and a supportive environment to maximize independence and, thus, quality of life.
Once diagnosed, the most commonly prescribed medications for AD are the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. All are approved for treatment of mild to moderate stages of AD, and donepezil is indicated for severe AD. These drugs have no direct neuroactivity but provide benefit by blocking the degradation of synaptic acetylcholine, thereby sustaining neurotransmission at the presynaptic cholinergic neuron. However, as neurodegeneration progresses and those neurons fail and die, benefit from the cholinesterase inhibitors wears off. Memantine, an N-methyl-D-aspartate receptor antagonist, is believed to reduce abnormal activity in the brain by blocking the glutamatergic N-methyl-D-aspartate receptor, thus protecting against excitotoxic destruction of cholinergic neurons. Memantine is associated with modest reductions in clinical deterioration in patients with moderate to severe AD. Combining acetylcholinesterase inhibitors and memantine has been shown to slow decline and improve behavior to a greater extent than monotherapy or no therapy.[14,15]
Although meta-analyses have shown that the use of cholinesterase inhibitors and memantine in patients with dementia has resulted in only marginal clinical improvements,[16] patients and their families and caregivers do appear to have experienced meaningful benefit from them, particularly regarding quality of life and resource utilization. Moreover, anecdotal reports have described dramatic improvements with cholinesterase inhibitors. A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians, "Current Pharmacologic Treatment of Dementia,"[17] recommends that the decision to use cholinesterase inhibitors and/or memantine should be based on individualized assessments, and that tolerability, adverse effect profile, ease of use, and cost of the medication should guide the choice of agent. Because side effects of these agents are relatively benign, many clinicians will choose to prescribe them, but they must be prepared to manage the expectations of patients and families who will eventually be faced with the reality of a permanently altered life. In July, 2010, the FDA approved high-dose (23 mg) donepezil for patients with moderate to severe AD who have been established on 10 mg for at least 3 months. This approval was based on a study[18] that showed some cognitive benefit from the high dose compared with the standard dose, particularly in patients with advanced disease.
Investigational Agents
Investigational therapies target several different pathways, such as inhibition or modulation of beta- and gamma-secretases involved in A-beta formation, prevention of A-beta aggregation, and through the use of immunotherapy. Strategies to target hyperphosphorylated tau are also under investigation.
The anti-amyloid aggregation agent tramiprosate and the gamma-secretase modulator tarenflurbil were examined in trials that included no central nervous system amyloid endpoint, thus preventing any conclusions about the amyloid hypothesis.[19,20] The immunotherapeutic bapineuzumab, when infused for approximately 80 weeks, lowered brain burden of PiB-positive amyloid by 25% but was associated with no cognitive benefit.[21] Questions remain regarding whether the duration was long enough, whether initiation was early enough, and/or whether brain levels of toxic A-beta oligomer were reduced.[22] A gamma-secretase inhibitor trial was terminated because of complications characterized as an increased rate of both cognitive decline and skin cancers, both apparently attributable to the gamma-secretase inhibitor.[23] Because of the failure and complications of this high visibility trial, gamma-secretase inhibitors are somewhat out of favor, and attention has turned toward gamma-secretase modulators, alpha-secretase activation, beta-secretase inhibitors, and amyloid immunotherapeutics.
Other novel targets include those that affect mitochondrial function, serotonin receptors, receptors for advanced glycation end products, and nerve growth factor, among other pathways. Many of these targeted agents are in phase 2 or 3 clinical development, bringing hope for further development.[24]
The A-Beta Oligomer Hypothesis of AD: Potential New Targets?
Decades of bench science are now providing insights that may result in new avenues of treatment. As mentioned, the neurodegenerative process in AD is characterized by the accumulation of interstitial A-beta plaques and cerebrovascular amyloid. A-beta 40 is the predominantly produced species; only a trace amount of A-beta 42 is produced, in a ratio of approximately 99 to 1. A-beta 42 spontaneously aggregates, making this peptide more likely to form small "n" aggregates (known collectively as oligomers or A-beta-derived diffusible ligands).[25]
A popular current concept regarding the pathogenesis of cognitive failure in AD is that A-beta oligomers are especially neurotoxic. This formulation contrasts with the traditional concept that the key toxins are the highly structured A-beta fibrils that comprise amyloid plaques. Further, the current formulation is that the oligomer pathway and the amyloid fibril pathway are separate and distinct. The advent of amyloid imaging with PiB has confirmed neuropathologic reports that many healthy adults accumulate numerous A-beta deposits with few signs of contemporaneous dementia.[9]
The amyloid precursor protein (APP) is a transmembrane protein that contains 3 sites for cleavage by proteinases, designated alpha, beta, and gamma secretases. The alpha-secretase pathway is nonamyloidogenic. The most compelling line of evidence linking A-beta to AD is genetic, because rare mutations in either APP or gamma-secretase can cause hereditary forms of AD that are clinically and pathologically indistinguishable from the more common, so-called sporadic form of the disease. These mutations apparently exert their actions by modulating APP processing. Some mutations cause quantitative or qualitative changes in the cleavages that generate A-beta. Other mutations are localized within the A-beta sequence of APP and cause generation of A-beta peptides that bear enhanced inherent predisposition toward oligomerization.[25]
Several approaches have converged to implicate soluble oligomeric A-beta in AD. One such approach has employed a well-known electrophysiologic correlate to learning and memory known as hippocampal long-term potentiation (LTP). Several studies have shown that hippocampal LTP can be inhibited by both synthetic and naturally secreted human A-beta oligomers. Some investigators have reported that the oligomeric A-beta levels needed to disrupt LTP correlate well with the amounts observed in cerebrospinal fluid in patients with AD. Furthermore, the effects of A-beta oligomers on LTP can be reduced through application of anti-A-beta antibodies in vivo.[26-29] New mouse models have shown that A-beta oligomers are sufficient to cause behavioral deficits, even in the absence of amyloid plaques.[30]
Defining the importance of A-beta oligomers is critical because oligomers cannot be visualized by PiB PET scans. In addition, there is some surprising evidence from laboratory mouse models that converting oligomers to fibrils and plaques might even be beneficial.[31] Obviously, oligomer research is still in its early days, but if fibrils and plaques prove to be inert or even beneficial, the goals of much amyloid research would be upended.
Conclusion
The future of AD diagnosis and management appears significantly brighter than the past. Nonetheless, early recognition and lifestyle interventions including healthier diet and exercise regimens, creation of a supportive environment, and medications including cholinesterase inhibitors and memantine can enhance quality of life. Investigational agents may improve outcomes by providing interventions at multiple pathophysiologic pathways. The seeds of basic science are bearing fruit and may provide new therapeutic targets through novel insights into the neural mechanisms underlying this fascinating, devastating disease.
Supported by an independent educational grant from Forest.
Samuel Gandy, MD, PhD
Alzheimer disease (AD) is an epidemic of brain failure affecting 5 million Americans, or about half of the population over the age of 85. Clinically, patients with AD exhibit progressive cognitive failure, including changes in personality, loss of the ability to form and retrieve new memories, and loss of the ability to navigate even the most familiar environments. Pathologically, AD is characterized by destruction of hippocampal and neocortical neurons, particularly those involving the cholinergic projections from the basal forebrain to the cerebral cortex.
The cause of the disease is well understood in only roughly 3% of cases, typically those with the rare, early-onset, familial forms of AD that can be attributed to genetic mutations.
The disease was first reported in 1907 by Bavarian psychiatrist Alois Alzheimer, who described a case that was atypical in many ways. The patient was 55 years old when symptoms of paranoia developed, and her young age may explain the long-held misconception that the disease begins in the presenilium. Until fairly recently, physicians were taught that AD was a rare disease that primarily affected people under the age of 65 years. However, the entity we call "common" or "sporadic" AD is the most common disease responsible for what has long been called "senility" in the elderly. Previously, dementia was believed to result from either vascular or degenerative processes. However, most patients with dementia have been found to have concurrent vascular and degenerative pathologies. Indeed, risk factors for stroke likewise increase the risk for AD.
The clinicopathologic syndrome, when complete, includes:
* an appropriate clinical syndrome (late life-onset amnesia, disorders of executive function [eg, organization, working memory], a psychiatric syndrome, or some combination of these);
* accumulation of abnormal proteinaceous structures; and
* neuronal and synaptic loss.
The molecular pathology of AD is defined by parenchymal and cerebrovascular amyloidosis resulting from an accumulation of amyloid-beta (A-beta), intraneuronal neurofibrillary tangles resulting from a buildup of altered tau protein, and acetylcholine deficiency. The cholinergic neurons that project diffusely from the basal forebrain to the cortex are among the earliest neurons to fail, and loss of acetylcholine content correlates well with the severity of the initial amnestic syndrome. Eventually, virtually all transmitter systems are involved to some degree and all cortical function is lost, leading to a persistent vegetative state.
Clinical Diagnosis of AD
Until very recently, the diagnosis of AD depended on careful clinical interview and mental status tests, with definitive diagnosis only available postmortem. Indeed, neuropsychological testing remains the most sensitive means of making an early clinical diagnosis. Formal testing by a neuropsychometrist is typical at research centers, but far more informal tools are used by most practitioners.
One of the most important distinctions in the diagnosis of AD is differentiating dementia and delirium (often related to metabolic dysfunction or toxic ingestion) or depressive pseudodementia. During the last decade, the concept of mild cognitive impairment (MCI) has become widely accepted. The operational definition of MCI involves demonstrable deficits in 1 domain (typically memory) or multiple cognitive domains, without a clinically important impact on the patient's function. Because patients are not functionally impaired, this level of cognitive impairment is not recognized by the US Food and Drug Administration (FDA) and no medications have been approved for use in patients with MCI. The amnestic form of MCI is the more typical harbinger of eventual progression to AD.[5]
Diagnosis begins by excluding treatable causes of cognitive dysfunction, including endocrine and metabolic disorders, vitamin deficiencies, and hydrocephalus, among others. Complete blood count, serum chemistries including liver and renal function tests, tests for syphilis, and tests of thyroid function have long been established tools in the physician's armamentarium. Computerized tomography and/or magnetic resonance imaging have become more widely used in the last decade, and CSF examination is frequently performed by neurologists, although this is by no means universal.
Biomarkers of Diagnosis and Progression
The emergence of CSF and neuroimaging biomarkers is rapidly changing the approach to dementia diagnosis. Among the most promising developments are the following:
* CSF A-beta 42 and tau levels[6,7]
o A-beta 42 levels typically fall and tau levels rise as disease progresses
o May predict which patients with amnestic MCI will progress to AD
* Fluorodeoxyglucose-positron emission tomography (FDG PET) for distinguishing frontotemporal dementia from AD[8]
o Approved by the Centers for Medicare and Medicaid Services under some circumstances
* Pittsburgh compound B (PiB) PET, AV-45, and/or radiotracer 18F-FDDNP PET for imaging the neuropathologic burden of A-beta plaques and neurofibrillary tangles during life[9,10]
Apolipoprotein E (APOE) genotyping is typically performed for clinical trials and other research studies in the setting of pregenetic and postgenetic counseling. Neither the National Institute on Aging nor the Alzheimer's Association favors routine APOE genotyping because the outcome of testing positive is uncertain.[11] A patient may have an APOE epsilon 4 allele and still escape dementia, and those who lack the APOE epsilon 4 alleles are still at risk for dementia.[12]
Treatment of AD
Currently, the primary benefit of early diagnosis of AD is that it enables the patient to organize his or her affairs and participate in the planning of his or her care. The hope is that research will eventually enable the presymptomatic diagnosis of the presence of AD pathology so that those who are diagnosed can begin disease-modifying treatments to prevent or significantly delay the clinical presentation. Without an effective disease-modifying intervention, this remains an unattained goal and something of a speculation. The growing consensus in this direction is part of the driving force behind the pressure for earlier diagnosis.
Several strategies can improve quality of life at this early stage and forestall other health-related complications or risk factors such as cardiovascular disease and diabetes. Although a diet rich in a variety of vitamins and minerals and low in saturated fats (eg, the Mediterranean diet) has not been shown conclusively to improve cognitive function, such a diet will improve health by addressing obesity, lowering blood pressure, and improving glycemic control. Moreover, physical and mental activities may also mitigate cognitive decline or at the least enhance quality of life.[13] Finally, early diagnosis enables patients and their families to establish supervision and a supportive environment to maximize independence and, thus, quality of life.
Once diagnosed, the most commonly prescribed medications for AD are the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. All are approved for treatment of mild to moderate stages of AD, and donepezil is indicated for severe AD. These drugs have no direct neuroactivity but provide benefit by blocking the degradation of synaptic acetylcholine, thereby sustaining neurotransmission at the presynaptic cholinergic neuron. However, as neurodegeneration progresses and those neurons fail and die, benefit from the cholinesterase inhibitors wears off. Memantine, an N-methyl-D-aspartate receptor antagonist, is believed to reduce abnormal activity in the brain by blocking the glutamatergic N-methyl-D-aspartate receptor, thus protecting against excitotoxic destruction of cholinergic neurons. Memantine is associated with modest reductions in clinical deterioration in patients with moderate to severe AD. Combining acetylcholinesterase inhibitors and memantine has been shown to slow decline and improve behavior to a greater extent than monotherapy or no therapy.[14,15]
Although meta-analyses have shown that the use of cholinesterase inhibitors and memantine in patients with dementia has resulted in only marginal clinical improvements,[16] patients and their families and caregivers do appear to have experienced meaningful benefit from them, particularly regarding quality of life and resource utilization. Moreover, anecdotal reports have described dramatic improvements with cholinesterase inhibitors. A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians, "Current Pharmacologic Treatment of Dementia,"[17] recommends that the decision to use cholinesterase inhibitors and/or memantine should be based on individualized assessments, and that tolerability, adverse effect profile, ease of use, and cost of the medication should guide the choice of agent. Because side effects of these agents are relatively benign, many clinicians will choose to prescribe them, but they must be prepared to manage the expectations of patients and families who will eventually be faced with the reality of a permanently altered life. In July, 2010, the FDA approved high-dose (23 mg) donepezil for patients with moderate to severe AD who have been established on 10 mg for at least 3 months. This approval was based on a study[18] that showed some cognitive benefit from the high dose compared with the standard dose, particularly in patients with advanced disease.
Investigational Agents
Investigational therapies target several different pathways, such as inhibition or modulation of beta- and gamma-secretases involved in A-beta formation, prevention of A-beta aggregation, and through the use of immunotherapy. Strategies to target hyperphosphorylated tau are also under investigation.
The anti-amyloid aggregation agent tramiprosate and the gamma-secretase modulator tarenflurbil were examined in trials that included no central nervous system amyloid endpoint, thus preventing any conclusions about the amyloid hypothesis.[19,20] The immunotherapeutic bapineuzumab, when infused for approximately 80 weeks, lowered brain burden of PiB-positive amyloid by 25% but was associated with no cognitive benefit.[21] Questions remain regarding whether the duration was long enough, whether initiation was early enough, and/or whether brain levels of toxic A-beta oligomer were reduced.[22] A gamma-secretase inhibitor trial was terminated because of complications characterized as an increased rate of both cognitive decline and skin cancers, both apparently attributable to the gamma-secretase inhibitor.[23] Because of the failure and complications of this high visibility trial, gamma-secretase inhibitors are somewhat out of favor, and attention has turned toward gamma-secretase modulators, alpha-secretase activation, beta-secretase inhibitors, and amyloid immunotherapeutics.
Other novel targets include those that affect mitochondrial function, serotonin receptors, receptors for advanced glycation end products, and nerve growth factor, among other pathways. Many of these targeted agents are in phase 2 or 3 clinical development, bringing hope for further development.[24]
The A-Beta Oligomer Hypothesis of AD: Potential New Targets?
Decades of bench science are now providing insights that may result in new avenues of treatment. As mentioned, the neurodegenerative process in AD is characterized by the accumulation of interstitial A-beta plaques and cerebrovascular amyloid. A-beta 40 is the predominantly produced species; only a trace amount of A-beta 42 is produced, in a ratio of approximately 99 to 1. A-beta 42 spontaneously aggregates, making this peptide more likely to form small "n" aggregates (known collectively as oligomers or A-beta-derived diffusible ligands).[25]
A popular current concept regarding the pathogenesis of cognitive failure in AD is that A-beta oligomers are especially neurotoxic. This formulation contrasts with the traditional concept that the key toxins are the highly structured A-beta fibrils that comprise amyloid plaques. Further, the current formulation is that the oligomer pathway and the amyloid fibril pathway are separate and distinct. The advent of amyloid imaging with PiB has confirmed neuropathologic reports that many healthy adults accumulate numerous A-beta deposits with few signs of contemporaneous dementia.[9]
The amyloid precursor protein (APP) is a transmembrane protein that contains 3 sites for cleavage by proteinases, designated alpha, beta, and gamma secretases. The alpha-secretase pathway is nonamyloidogenic. The most compelling line of evidence linking A-beta to AD is genetic, because rare mutations in either APP or gamma-secretase can cause hereditary forms of AD that are clinically and pathologically indistinguishable from the more common, so-called sporadic form of the disease. These mutations apparently exert their actions by modulating APP processing. Some mutations cause quantitative or qualitative changes in the cleavages that generate A-beta. Other mutations are localized within the A-beta sequence of APP and cause generation of A-beta peptides that bear enhanced inherent predisposition toward oligomerization.[25]
Several approaches have converged to implicate soluble oligomeric A-beta in AD. One such approach has employed a well-known electrophysiologic correlate to learning and memory known as hippocampal long-term potentiation (LTP). Several studies have shown that hippocampal LTP can be inhibited by both synthetic and naturally secreted human A-beta oligomers. Some investigators have reported that the oligomeric A-beta levels needed to disrupt LTP correlate well with the amounts observed in cerebrospinal fluid in patients with AD. Furthermore, the effects of A-beta oligomers on LTP can be reduced through application of anti-A-beta antibodies in vivo.[26-29] New mouse models have shown that A-beta oligomers are sufficient to cause behavioral deficits, even in the absence of amyloid plaques.[30]
Defining the importance of A-beta oligomers is critical because oligomers cannot be visualized by PiB PET scans. In addition, there is some surprising evidence from laboratory mouse models that converting oligomers to fibrils and plaques might even be beneficial.[31] Obviously, oligomer research is still in its early days, but if fibrils and plaques prove to be inert or even beneficial, the goals of much amyloid research would be upended.
Conclusion
The future of AD diagnosis and management appears significantly brighter than the past. Nonetheless, early recognition and lifestyle interventions including healthier diet and exercise regimens, creation of a supportive environment, and medications including cholinesterase inhibitors and memantine can enhance quality of life. Investigational agents may improve outcomes by providing interventions at multiple pathophysiologic pathways. The seeds of basic science are bearing fruit and may provide new therapeutic targets through novel insights into the neural mechanisms underlying this fascinating, devastating disease.
Supported by an independent educational grant from Forest.
Many US Adults Had Tough Childhoods: CDC Report
From Medscape Medical News > Psychiatry
Megan Brooks
December 20, 2010 — More than half of US adults have a history of at least 1 adverse childhood experience (ACE), such as abuse (verbal, physical, or sexual) or family dysfunction (domestic violence, divorce, or a family member who is mentally ill, incarcerated, or abusing drugs).
That's according to a report from the Centers for Disease Control and Prevention (CDC) appearing in the December 17 issue of the Morbidity and Mortality Weekly Report.
The findings are based on data from the 2009 ACE module of the Behavioral Risk Factor Surveillance System (BRFSS), an ongoing state-based telephone health survey of US adults.
"State-based surveillance of ACEs can provide guidance for the allocation of maltreatment prevention strategies and trauma-related intervention services," the CDC notes.
Among 26,229 adults from 5 states (Arkansas, Louisiana, New Mexico, Tennessee, and Washington), roughly 59% reported 1 or more ACEs.
Approximately one-quarter (25.9%) of respondents reported experiencing verbal abuse as a child, 14.8% reported physical abuse, and 12.2% reported sexual abuse; 29.1% reported household substance abuse, whereas 7.2% reported an incarcerated family member.
For ACEs measuring family dysfunction, 26.6% reported separated or divorced parents; 19.4% reported that they had lived with someone who was depressed, mentally ill, or suicidal; and 16.3% reported witnessing domestic violence.
Men and women reported similar prevalence rates for each ACE, with the exception of sexual abuse (17.2% for women and 6.7% for men; P < .05), living with a mentally ill household member (22.0% for women and 16.7% for men; P < .05), and living with a substance-abusing family member (30.6% for women and 27.5% for men; P < .05).
Younger respondents more often reported living with an incarcerated and/or mentally ill household member (P < .05).
Non-Hispanic black respondents reported the lowest prevalence of each ACE category among all racial/ethnic groups (P < .05), with the exception of having had an incarcerated family member, parental separation or divorce, and witnessing domestic violence.
Hispanics reported a higher prevalence than non-Hispanic whites of physical abuse, witnessing domestic violence, and having an incarcerated family member (P < .05 for all).
Adults with less than a high school education compared with those with more than a high school education had a greater prevalence of physical abuse, an incarcerated family member, substance abuse, and separation or divorce (P < .05 for all). There was little variation among the 5 states.
The CDC notes that adverse events experienced in childhood have been linked to a range of problems in adulthood, including substance abuse, depression, cardiovascular disease, diabetes, cancer, and premature death.
For each ACE, a sharp decrease was observed in prevalence reported by adults 55 years and older. For example, the prevalence of reported physical abuse was 16.9% among adults aged 18 to 24 years compared with 9.6% among those 55 years and older. These findings, they say, suggest that “a higher number of ACEs were associated with premature mortality (up to 20 years of life lost).”
These survey data have several limitations, the CDC notes. Because BRFSS excludes persons in institutions and hospitals who might have experienced ACEs disproportionately, the data might underestimate the true prevalence of ACEs.
Furthermore, the 18-year to 35-year age group might be underrepresented given that the BRFSS also excludes persons who rely on cellular telephones as their only telephone service. The study only covered 5 states and so may not be generalizable to the entire US adult population, and the BRFSS response rates were low, which increases the risk for response bias, the researchers point out.
"More research," the CDC concludes, "is needed to disentangle the specific role each ACE plays in the development of health problems later in life. As it currently exists, the ACE total captures the cumulative risk associated with child maltreatment and family dysfunction but could be further refined to address issues of unequal severity."
MMWR Morb Mortal Wkly Rep. 2010;59:1609-1613.
Megan Brooks
December 20, 2010 — More than half of US adults have a history of at least 1 adverse childhood experience (ACE), such as abuse (verbal, physical, or sexual) or family dysfunction (domestic violence, divorce, or a family member who is mentally ill, incarcerated, or abusing drugs).
That's according to a report from the Centers for Disease Control and Prevention (CDC) appearing in the December 17 issue of the Morbidity and Mortality Weekly Report.
The findings are based on data from the 2009 ACE module of the Behavioral Risk Factor Surveillance System (BRFSS), an ongoing state-based telephone health survey of US adults.
"State-based surveillance of ACEs can provide guidance for the allocation of maltreatment prevention strategies and trauma-related intervention services," the CDC notes.
Among 26,229 adults from 5 states (Arkansas, Louisiana, New Mexico, Tennessee, and Washington), roughly 59% reported 1 or more ACEs.
Approximately one-quarter (25.9%) of respondents reported experiencing verbal abuse as a child, 14.8% reported physical abuse, and 12.2% reported sexual abuse; 29.1% reported household substance abuse, whereas 7.2% reported an incarcerated family member.
For ACEs measuring family dysfunction, 26.6% reported separated or divorced parents; 19.4% reported that they had lived with someone who was depressed, mentally ill, or suicidal; and 16.3% reported witnessing domestic violence.
Men and women reported similar prevalence rates for each ACE, with the exception of sexual abuse (17.2% for women and 6.7% for men; P < .05), living with a mentally ill household member (22.0% for women and 16.7% for men; P < .05), and living with a substance-abusing family member (30.6% for women and 27.5% for men; P < .05).
Younger respondents more often reported living with an incarcerated and/or mentally ill household member (P < .05).
Non-Hispanic black respondents reported the lowest prevalence of each ACE category among all racial/ethnic groups (P < .05), with the exception of having had an incarcerated family member, parental separation or divorce, and witnessing domestic violence.
Hispanics reported a higher prevalence than non-Hispanic whites of physical abuse, witnessing domestic violence, and having an incarcerated family member (P < .05 for all).
Adults with less than a high school education compared with those with more than a high school education had a greater prevalence of physical abuse, an incarcerated family member, substance abuse, and separation or divorce (P < .05 for all). There was little variation among the 5 states.
The CDC notes that adverse events experienced in childhood have been linked to a range of problems in adulthood, including substance abuse, depression, cardiovascular disease, diabetes, cancer, and premature death.
For each ACE, a sharp decrease was observed in prevalence reported by adults 55 years and older. For example, the prevalence of reported physical abuse was 16.9% among adults aged 18 to 24 years compared with 9.6% among those 55 years and older. These findings, they say, suggest that “a higher number of ACEs were associated with premature mortality (up to 20 years of life lost).”
These survey data have several limitations, the CDC notes. Because BRFSS excludes persons in institutions and hospitals who might have experienced ACEs disproportionately, the data might underestimate the true prevalence of ACEs.
Furthermore, the 18-year to 35-year age group might be underrepresented given that the BRFSS also excludes persons who rely on cellular telephones as their only telephone service. The study only covered 5 states and so may not be generalizable to the entire US adult population, and the BRFSS response rates were low, which increases the risk for response bias, the researchers point out.
"More research," the CDC concludes, "is needed to disentangle the specific role each ACE plays in the development of health problems later in life. As it currently exists, the ACE total captures the cumulative risk associated with child maltreatment and family dysfunction but could be further refined to address issues of unequal severity."
MMWR Morb Mortal Wkly Rep. 2010;59:1609-1613.
Lifestyle Changes May Avert Age-Related Macular Degeneration
From Medscape Medical News
Nancy Fowler Larson
December 20, 2010 — Eating a healthy diet, exercising, and abstaining from smoking may reduce the risk for early age-related macular degeneration (AMD), according to a study published online December 13 in the Archives of Ophthalmology.
The macula, a portion of the retina responsible for central vision, degenerates with age. The progression can result in AMD, a deterioration of the macula's photoreceptors. Treatment is limited and costly, and the cumulative cost will grow as the population ages.
Those affected by AMD experience a substantial decline in independent function.
"The loss of central vision associated with advanced AMD diminishes the ability to see and recognize other people's faces and to read fine print such as that in newspapers and on pill bottles and food packages," write Julie A. Mares, PhD, from the Departments of Ophthalmology and Visual Sciences, at the University of Wisconsin, in Madison, and colleagues.
Smoking is associated with an increased risk, and chronic conditions including cardiovascular disease, diabetes, hypertension, and obesity, all of which can be managed through diet and other lifestyle adjustments, seem more common in patients with AMD. Adopting healthier habits has been linked to a reduced incidence of AMD.
To further explore those relationships, the investigators used data from the Carotenoids in Age-Related Eye Disease Study (CAREDS), part of the 1994-1998 Women's Health Initiative Observational Study. The 1313 participants ranged in age from 55 to 74 years.
The participants' answers to a food frequency questionnaire were used to produce scores on a modified 2005 Healthy Eating Index. Requirements for a healthy daily diet included 3.5 servings of fruit and vegetables; 2.3 servings of dairy; 2.7 ounces of meat, poultry, fish, beans, or eggs; and 3.5 serving of grain, including 1 whole-grain item.
Exercise habits and lifelong smoking history were also recorded. The presence of AMD in 202 participants, 94% of whom had early-stage degeneration, was determined an average of 6 years later through stereoscopic fundus photographs.
Overall Healthier Lifestyle May Reduce AMD Risk 3-Fold
The results demonstrated a significant association between early AMD and diet, exercise, and overall healthy habits, as follows:
* With use of multivariate models, women with highest-quintile 2005 Healthy Eating Index diet scores vs those with the lowest quintile showed a 46% reduction in the odds for early AMD (multivariate-adjusted odds ratio [OR], 0.54; 95% confidence interval [CI], 0.33 - 0.88).
* Those in the highest quintile for physical activity demonstrated a 2-fold decrease in multivariate-adjusted odds for AMD (OR, 0.46; 95% CI, 0.27 - 0.78; P for trend = .002).
* Smoking for long or short intervals had only a slight positive association with AMD (P = .07).
* Nonsmokers who also ate the healthiest diets and were the most active (5% of participants) reduced their odds for AMD by 71% vs those with high-risk scores (P < .001).
"Adopting these healthy habits may markedly lower the prevalence of early AMD, the number of people who develop advanced AMD in their lifetime, and health care costs associated with treatment for this condition," the study authors write.
Several limitations to the study were noted:
* The primarily white, female population hinders the generalization of findings to men and to those of Hispanic, African, and Asian ethnicities.
* Interrelated habits were not independently evaluated.
* Consideration was not given to high-risk genotypes for AMD.
"In our study, having a family history of AMD did not modify the association of a healthy diet or lifestyle to AMD, but genotyping will better characterize a person's susceptibility for the disease and improve the ability to examine the possibility that diet and lifestyle modify genetic risk," the study authors write.
Arch Ophthalmol. Published online December 13, 2010. Abstract
Nancy Fowler Larson
December 20, 2010 — Eating a healthy diet, exercising, and abstaining from smoking may reduce the risk for early age-related macular degeneration (AMD), according to a study published online December 13 in the Archives of Ophthalmology.
The macula, a portion of the retina responsible for central vision, degenerates with age. The progression can result in AMD, a deterioration of the macula's photoreceptors. Treatment is limited and costly, and the cumulative cost will grow as the population ages.
Those affected by AMD experience a substantial decline in independent function.
"The loss of central vision associated with advanced AMD diminishes the ability to see and recognize other people's faces and to read fine print such as that in newspapers and on pill bottles and food packages," write Julie A. Mares, PhD, from the Departments of Ophthalmology and Visual Sciences, at the University of Wisconsin, in Madison, and colleagues.
Smoking is associated with an increased risk, and chronic conditions including cardiovascular disease, diabetes, hypertension, and obesity, all of which can be managed through diet and other lifestyle adjustments, seem more common in patients with AMD. Adopting healthier habits has been linked to a reduced incidence of AMD.
To further explore those relationships, the investigators used data from the Carotenoids in Age-Related Eye Disease Study (CAREDS), part of the 1994-1998 Women's Health Initiative Observational Study. The 1313 participants ranged in age from 55 to 74 years.
The participants' answers to a food frequency questionnaire were used to produce scores on a modified 2005 Healthy Eating Index. Requirements for a healthy daily diet included 3.5 servings of fruit and vegetables; 2.3 servings of dairy; 2.7 ounces of meat, poultry, fish, beans, or eggs; and 3.5 serving of grain, including 1 whole-grain item.
Exercise habits and lifelong smoking history were also recorded. The presence of AMD in 202 participants, 94% of whom had early-stage degeneration, was determined an average of 6 years later through stereoscopic fundus photographs.
Overall Healthier Lifestyle May Reduce AMD Risk 3-Fold
The results demonstrated a significant association between early AMD and diet, exercise, and overall healthy habits, as follows:
* With use of multivariate models, women with highest-quintile 2005 Healthy Eating Index diet scores vs those with the lowest quintile showed a 46% reduction in the odds for early AMD (multivariate-adjusted odds ratio [OR], 0.54; 95% confidence interval [CI], 0.33 - 0.88).
* Those in the highest quintile for physical activity demonstrated a 2-fold decrease in multivariate-adjusted odds for AMD (OR, 0.46; 95% CI, 0.27 - 0.78; P for trend = .002).
* Smoking for long or short intervals had only a slight positive association with AMD (P = .07).
* Nonsmokers who also ate the healthiest diets and were the most active (5% of participants) reduced their odds for AMD by 71% vs those with high-risk scores (P < .001).
"Adopting these healthy habits may markedly lower the prevalence of early AMD, the number of people who develop advanced AMD in their lifetime, and health care costs associated with treatment for this condition," the study authors write.
Several limitations to the study were noted:
* The primarily white, female population hinders the generalization of findings to men and to those of Hispanic, African, and Asian ethnicities.
* Interrelated habits were not independently evaluated.
* Consideration was not given to high-risk genotypes for AMD.
"In our study, having a family history of AMD did not modify the association of a healthy diet or lifestyle to AMD, but genotyping will better characterize a person's susceptibility for the disease and improve the ability to examine the possibility that diet and lifestyle modify genetic risk," the study authors write.
Arch Ophthalmol. Published online December 13, 2010. Abstract
Lunch in Front of a Computer Leads to Higher Calorie Intake
From Reuters Health Information
By Amy Norton
NEW YORK (Reuters Health) Dec 16 - Many of us eat lunch parked in front of a computer, but that habit might be boosting our appetite for dessert, a small study suggests.
In a lab study of 44 men and women, researchers found that those who ate lunch while playing a computer game ended up eating more cookies 30 minutes later than those who'd had their lunch with no distractions.
The reason? Researchers say the computer users had a fuzzier memory of their lunch and felt less full afterward compared with the computer-free lunch group.
This suggests, they say, that distractions like computers and TV muddy our memories of mealtime, which in turn may have real effects on appetite.
"We think that memory for recent meals influences the amount of food that we select and then consume at a subsequent meal," researcher Jeffrey M. Brunstrom, of the University of Bristol in the UK, told Reuters Health in an e-mail.
"When our memory is poor," he said, "then at a subsequent meal we tend to select and consume a greater amount of food."
Past research has suggested that people are prone to eat more when they dine in front of a TV instead of at the kitchen table -- possibly because they are paying more attention to the screen than to what their stomachs are telling them.
"We know from several studies that distraction can increase the amount that people consume in a meal," Brunstrom said. "Here, we extend this finding to show that the effects of distraction last beyond a meal."
The study, published online December 8th in the American Journal of Clinical Nutrition, involved 44 volunteers who were assigned to one of two groups. In one, participants ate a set lunch while playing solitaire on a computer; those in the other group had the same meal with no distractions.
Thirty minutes after the meal, both groups took a cookie "taste test," in which they could sample as many of the sweet treats as they wanted. They were also asked to recall all nine items they'd eaten at lunch, and the order in which the foods were served.
On average, the researchers found, the computer group ate roughly 250 calories' worth of cookies, while their counterparts ate only half as much.
In addition, the computer group had more difficulty remembering the order in which their lunchtime fare was served, and typically reported feeling less full after lunch.
The findings suggest that effects on memory might account for the greater cookie craving in the computer group, according to Brunstrom's team.
The study was, of course, conducted under controlled lab conditions. Whether the findings hold true in the real world -- where many factors could affect what and how much we eat -- is unknown.
Brunstrom said he and his colleagues plan to study that question in the future.
For now, he said, "one implication is that we should avoid eating while distracted, which means eating away from our computer screens and TV sets."
And what about non-technological distractions, like having a conversation during dinner or reading the newspaper at breakfast?
There's some evidence they could thwart your diet, too. One lab study found that both eating while watching TV and eating with friends boosted calorie intake to a similar degree, versus eating distraction-free. (Eating with strangers did not, however.) Another found that people ate more when they listened to a recorded story during their meal.
Brunstrom and his colleagues say their findings are particularly relevant in today's technology-driven, "multi-tasking" world, where people are increasingly dining in front of a screen. And that includes children, they note; one U.S. study found that up to a quarter of kids' calorie intake occurs in front of a TV.
Am J Clin Nutr. Posted online December 8, 2010. Abstract
By Amy Norton
NEW YORK (Reuters Health) Dec 16 - Many of us eat lunch parked in front of a computer, but that habit might be boosting our appetite for dessert, a small study suggests.
In a lab study of 44 men and women, researchers found that those who ate lunch while playing a computer game ended up eating more cookies 30 minutes later than those who'd had their lunch with no distractions.
The reason? Researchers say the computer users had a fuzzier memory of their lunch and felt less full afterward compared with the computer-free lunch group.
This suggests, they say, that distractions like computers and TV muddy our memories of mealtime, which in turn may have real effects on appetite.
"We think that memory for recent meals influences the amount of food that we select and then consume at a subsequent meal," researcher Jeffrey M. Brunstrom, of the University of Bristol in the UK, told Reuters Health in an e-mail.
"When our memory is poor," he said, "then at a subsequent meal we tend to select and consume a greater amount of food."
Past research has suggested that people are prone to eat more when they dine in front of a TV instead of at the kitchen table -- possibly because they are paying more attention to the screen than to what their stomachs are telling them.
"We know from several studies that distraction can increase the amount that people consume in a meal," Brunstrom said. "Here, we extend this finding to show that the effects of distraction last beyond a meal."
The study, published online December 8th in the American Journal of Clinical Nutrition, involved 44 volunteers who were assigned to one of two groups. In one, participants ate a set lunch while playing solitaire on a computer; those in the other group had the same meal with no distractions.
Thirty minutes after the meal, both groups took a cookie "taste test," in which they could sample as many of the sweet treats as they wanted. They were also asked to recall all nine items they'd eaten at lunch, and the order in which the foods were served.
On average, the researchers found, the computer group ate roughly 250 calories' worth of cookies, while their counterparts ate only half as much.
In addition, the computer group had more difficulty remembering the order in which their lunchtime fare was served, and typically reported feeling less full after lunch.
The findings suggest that effects on memory might account for the greater cookie craving in the computer group, according to Brunstrom's team.
The study was, of course, conducted under controlled lab conditions. Whether the findings hold true in the real world -- where many factors could affect what and how much we eat -- is unknown.
Brunstrom said he and his colleagues plan to study that question in the future.
For now, he said, "one implication is that we should avoid eating while distracted, which means eating away from our computer screens and TV sets."
And what about non-technological distractions, like having a conversation during dinner or reading the newspaper at breakfast?
There's some evidence they could thwart your diet, too. One lab study found that both eating while watching TV and eating with friends boosted calorie intake to a similar degree, versus eating distraction-free. (Eating with strangers did not, however.) Another found that people ate more when they listened to a recorded story during their meal.
Brunstrom and his colleagues say their findings are particularly relevant in today's technology-driven, "multi-tasking" world, where people are increasingly dining in front of a screen. And that includes children, they note; one U.S. study found that up to a quarter of kids' calorie intake occurs in front of a TV.
Am J Clin Nutr. Posted online December 8, 2010. Abstract
Obesity Linked to Risk for Metastasis and Death in Breast Cancer
From Medscape Medical News > Oncology
Roxanne Nelson
December 17, 2010 — A new study lends further evidence to what has already been suspected: obesity can affect outcomes in breast cancer. In a large, retrospective analysis, Danish researchers found that obesity is an independent prognostic factor for mortality and developing distant metastases after a diagnosis of breast cancer.
In addition, adjuvant therapy appeared to be less effective, on a long-term basis, among obese patients with breast cancer.
Published online November 29 in the Journal of Clinical Oncology, the results showed that after adjusting for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased (by 46%) in patients with a body mass index (BMI) of 30 kg/m2. The risk of dying from breast cancer after 30 years was also significantly increased (by 38%).
"It has become increasingly clear that obesity is associated with increased cancer risk and mortality, and that obesity has the potential to diminish important advances that have been made in the fight against breast and other cancers," according to an accompanying editorial.
Thus, these data have important implications for cancer prevention and treatment, write Frank A. Sinicrope, MD, from the Mayo Clinic in Rochester, Minnesota, and Andrew J. Dannenberg, MD, from Weill Cornell Cancer Center in New York City. They point out that both endocrine and metabolic changes that are associated with obesity are reversible by weight reduction.
Losing at least 10% of body weight has been shown to reduce serum concentrations of estradiol, leptin, and insulin, and losing weight also increases concentrations of sex hormone–binding globulin and adiponectin, they note. In addition, weight reduction in obese individuals leads to a reduction in levels of proinflammatory cytokines.
"Therefore, changes in diet and increased physical activity to achieve a healthier body weight are a cancer-prevention strategy that may also improve the prognosis of patients with curatively resected breast and other cancers," the editorialists write. In addition, as the current study shows that obesity may reduce the efficacy of endocrine therapy, it is possible that weight loss will increase the efficacy of these agents, even in the adjuvant setting.
Add Evidence to Existing Data
The current study adds to the existing evidence that obesity is associated with poor outcomes in breast cancer, Dr. Sinicrope and Dr. Dannenberg conclude. "Accordingly, obese patients with breast cancer should be made aware of the substantial evidence for the adverse impact of obesity on risk and outcome, and should be counseled about the potential importance of lifestyle changes to improve weight control."
As previously reported by Medscape Medical News, factors such as maintaining a healthy weight and getting regular physical exercise may reduce a woman's risk for breast cancer. In addition, obesity, along with alcohol use and smoking, can significantly increase the risk for second primary invasive contralateral breast cancer among breast cancer survivors.
High BMI Increases Risk for Metastasis and Death
In the current study, Marianne Ewertz, MD, DMSc, from the Department of Oncology, Odense University Hospital in Denmark, and colleagues, used the Danish Breast Cancer Cooperative Group to identify 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006. These patients all had complete follow-up information for first events (locoregional recurrences and distant metastases) up to 10 years, and mortality data up to 30 years.
Within this group, information on BMI at diagnosis was available for 18,967 (35%) patients. The cohort was divided into 4 categories, according to BMI: less than 25 kg/m2, 25 to 29 kg/m2, 30+ kg/m2, and unknown.
Patients with a BMI of 30 kg/m2 or greater tended to be older, were more often postmenopausal, had larger tumors, and had both more lymph nodes removed and more positive lymph nodes, but had less invasion into deep fascia (P < .001 for all), compared with those with a BMI of less than 25 kg/m2.
At a median estimated potential follow-up period of 7.1 years, there were 4180 locoregional recurrences and 7278 distant metastases as first events. Although BMI did not seem to influence the risk for locoregional recurrences, risk for distant metastases rose with increasing BMI. At 10 years, the cumulative incidences were
* 20.1% (95% confidence interval [CI], 19.2% - 20. 9%) for patients with a BMI of less than 25 kg/m2,
* 22.4% (95% CI, 21.1% - 23.8%) for patients with a BMI of 25 to 29 kg/m2, and
* 24.3% (95% CI, 22.1% - 26.5%) for patients with a BMI of 30 kg/m2 or more.
The authors noted that among the group of patients whose BMI was unknown, the risk of developing distant metastases throughout the 10 years of follow-up was consistently lower: At 10 years, the cumulative incidence was 16.1% (95% CI, 15.6% - 16.6%).
At a median estimated potential follow-up of 11.4 years, 15,197 patients had died of breast cancer, and 5967 had succumbed to other causes. There was a trend of increasing risk for breast cancer–specific mortality with increasing BMI. At 30 years, the cumulative risks of dying from breast cancer were
* 46.4% (95% CI, 44.8% - 48.0%) for patients with a BMI of less than 25 kg/m2,
* 53.4% (95% CI, 50.5% - 56.2%) for patients with a BMI of 25 to 29 kg/m2, and
* 57.2% (95% CI, 51.8% - 62.2%) for patients with a BMI of 30 kg/m2 or more.
Those with unknown BMI had a consistently lower risk of dying from breast cancer; the cumulative risk at 30 years was 41.1% (95% CI, 40.2% - 42.0%). The risk for death from other causes was also higher among patients with the greatest BMI compared with those in the other weight categories.
The authors also evaluated the efficacy of adjuvant treatment in lean and obese women. Although they did not observe a specific pattern during the first 10 years of follow-up, both chemotherapy and endocrine therapy seemed to be less effective in patients with BMIs of 30 kg/m2 or greater after 10 or more years.
The authors have disclosed no relevant financial relationships.
J Clin Oncol. Published online November 29, 2010.
Roxanne Nelson
December 17, 2010 — A new study lends further evidence to what has already been suspected: obesity can affect outcomes in breast cancer. In a large, retrospective analysis, Danish researchers found that obesity is an independent prognostic factor for mortality and developing distant metastases after a diagnosis of breast cancer.
In addition, adjuvant therapy appeared to be less effective, on a long-term basis, among obese patients with breast cancer.
Published online November 29 in the Journal of Clinical Oncology, the results showed that after adjusting for disease characteristics, the risk of developing distant metastases after 10 years was significantly increased (by 46%) in patients with a body mass index (BMI) of 30 kg/m2. The risk of dying from breast cancer after 30 years was also significantly increased (by 38%).
"It has become increasingly clear that obesity is associated with increased cancer risk and mortality, and that obesity has the potential to diminish important advances that have been made in the fight against breast and other cancers," according to an accompanying editorial.
Thus, these data have important implications for cancer prevention and treatment, write Frank A. Sinicrope, MD, from the Mayo Clinic in Rochester, Minnesota, and Andrew J. Dannenberg, MD, from Weill Cornell Cancer Center in New York City. They point out that both endocrine and metabolic changes that are associated with obesity are reversible by weight reduction.
Losing at least 10% of body weight has been shown to reduce serum concentrations of estradiol, leptin, and insulin, and losing weight also increases concentrations of sex hormone–binding globulin and adiponectin, they note. In addition, weight reduction in obese individuals leads to a reduction in levels of proinflammatory cytokines.
"Therefore, changes in diet and increased physical activity to achieve a healthier body weight are a cancer-prevention strategy that may also improve the prognosis of patients with curatively resected breast and other cancers," the editorialists write. In addition, as the current study shows that obesity may reduce the efficacy of endocrine therapy, it is possible that weight loss will increase the efficacy of these agents, even in the adjuvant setting.
Add Evidence to Existing Data
The current study adds to the existing evidence that obesity is associated with poor outcomes in breast cancer, Dr. Sinicrope and Dr. Dannenberg conclude. "Accordingly, obese patients with breast cancer should be made aware of the substantial evidence for the adverse impact of obesity on risk and outcome, and should be counseled about the potential importance of lifestyle changes to improve weight control."
As previously reported by Medscape Medical News, factors such as maintaining a healthy weight and getting regular physical exercise may reduce a woman's risk for breast cancer. In addition, obesity, along with alcohol use and smoking, can significantly increase the risk for second primary invasive contralateral breast cancer among breast cancer survivors.
High BMI Increases Risk for Metastasis and Death
In the current study, Marianne Ewertz, MD, DMSc, from the Department of Oncology, Odense University Hospital in Denmark, and colleagues, used the Danish Breast Cancer Cooperative Group to identify 53,816 women treated for early-stage breast cancer in Denmark between 1977 and 2006. These patients all had complete follow-up information for first events (locoregional recurrences and distant metastases) up to 10 years, and mortality data up to 30 years.
Within this group, information on BMI at diagnosis was available for 18,967 (35%) patients. The cohort was divided into 4 categories, according to BMI: less than 25 kg/m2, 25 to 29 kg/m2, 30+ kg/m2, and unknown.
Patients with a BMI of 30 kg/m2 or greater tended to be older, were more often postmenopausal, had larger tumors, and had both more lymph nodes removed and more positive lymph nodes, but had less invasion into deep fascia (P < .001 for all), compared with those with a BMI of less than 25 kg/m2.
At a median estimated potential follow-up period of 7.1 years, there were 4180 locoregional recurrences and 7278 distant metastases as first events. Although BMI did not seem to influence the risk for locoregional recurrences, risk for distant metastases rose with increasing BMI. At 10 years, the cumulative incidences were
* 20.1% (95% confidence interval [CI], 19.2% - 20. 9%) for patients with a BMI of less than 25 kg/m2,
* 22.4% (95% CI, 21.1% - 23.8%) for patients with a BMI of 25 to 29 kg/m2, and
* 24.3% (95% CI, 22.1% - 26.5%) for patients with a BMI of 30 kg/m2 or more.
The authors noted that among the group of patients whose BMI was unknown, the risk of developing distant metastases throughout the 10 years of follow-up was consistently lower: At 10 years, the cumulative incidence was 16.1% (95% CI, 15.6% - 16.6%).
At a median estimated potential follow-up of 11.4 years, 15,197 patients had died of breast cancer, and 5967 had succumbed to other causes. There was a trend of increasing risk for breast cancer–specific mortality with increasing BMI. At 30 years, the cumulative risks of dying from breast cancer were
* 46.4% (95% CI, 44.8% - 48.0%) for patients with a BMI of less than 25 kg/m2,
* 53.4% (95% CI, 50.5% - 56.2%) for patients with a BMI of 25 to 29 kg/m2, and
* 57.2% (95% CI, 51.8% - 62.2%) for patients with a BMI of 30 kg/m2 or more.
Those with unknown BMI had a consistently lower risk of dying from breast cancer; the cumulative risk at 30 years was 41.1% (95% CI, 40.2% - 42.0%). The risk for death from other causes was also higher among patients with the greatest BMI compared with those in the other weight categories.
The authors also evaluated the efficacy of adjuvant treatment in lean and obese women. Although they did not observe a specific pattern during the first 10 years of follow-up, both chemotherapy and endocrine therapy seemed to be less effective in patients with BMIs of 30 kg/m2 or greater after 10 or more years.
The authors have disclosed no relevant financial relationships.
J Clin Oncol. Published online November 29, 2010.
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