See Updates in Daily Downey (February 1, 2011), ECONOMICS (Jan. 31, 2011), HEALTH/STIGMA (Jan. 30, 2011), POLICY (Jan. 21, 2011), MANAGING OBESITY (Jan. 5, 2011)
February 3, 2011
The FDA’s decision on Contrave has received widespread and largely negative press coverage. Here is the New York Times article by Andrew Pollack which includes my take on the issue. http://www.nytimes.com/2011/02/02/business/02drug.html?scp=5&sq=andrew%20pollack&st=cse
February 1, 2011
See the Daily Downey. Vivus Inc.’s Qnexa, alone, holds on to a hope for approval. In effect, the FDA has stated that basic research on obesity is irrevelant because there will be no drug approved for obesity.
January 31, 2011
The Department of Health and Human Services and the Department of Agriculture have released the Dietary Guidelines for 2011. The video of the announcement, summaries and background can be found at http://www.health.gov/dietaryguidelines/
January 28, 2011
The FDA has given Arena Pharmaceuticals a new laundry list of studies, including a 12 month study of cancer in rats. Arena Pharma: Weight-Loss Drug Woes – TheStreet Meanwhile Orexigen Therapeutics is awaiting an FDA decision on Monday for it’s drug, Contrave®
January 21, 2011
CDC’s MMRW’s Grand Rounds reports a dip in obesity rates for 2-5 year olds but dramatic increase for the 6-19 year olds. Since the 1960s, obesity rates among children have tripled from 5% to 15%. Heavier children continue to get heavier and Hispanic girls and boys are disproportionally affected. CDC Grand Rounds: Childhood Obesity in the United States
Another CDC Report shows average daily kilocalorie intake among US adults exploded in the 70s and 80s but has been generally level since then. See QuickStats: Age-Adjusted Daily Kilocalorie Intake Among Adults Aged 20–74 Years, by Sex — National Health and Nutrition Examination Survey, United States, 1971–2008* See the full study at Products – Data Briefs – Number 49 – November 2010
Vivus Inc. has announced an agreement with the FDA to review databases to find cases of cleft lip/palate caused by topirmate, one of two compounds in the company’s weight loss product, Qnexa. There were 15 live births among subjects taking Qnexa in clinical trials and no birth malformations. VIVUS, Inc. – VIVUS Provides Regulatory Update on QNEXA NDA While Vivus’s stock as taken a hit, it could have been worse. The FDA could have asked for another study. Vivus tumbles as FDA seeks birth-defect data | Reuters
Wal-Mart, the major retailer in the United States, has joined forces with First Lady Michelle Obama in a commitment to lower sugar, salt and trans-fats in its retail offerings. The company also committed to lowering the price of fruits and vegetables. Their plan is to make improvements in the supply chain, rather than force lower prices on farmers. The also plan on improving the nutritional quality of their food offerings. The move will likely have profound impact as suppliers are some of the largest food companies in the U.S. Walmartstores.com: Walmart Launches Major Initiative to Make Food Healthier and Healthier Food More Affordable What the plan does not seem to include is a commitment to lowering calories inproducts or providing more clear calorie labeling on the front of packages on their caloric content and removing products from sale which have little to no nutritional value.
January 5, 2011
Most Americans believe they eat a healthy diet. While this may confound nutritionists, a whopping 90% of Americans in a Consumers Union Health poll said that they consume somewhat, a very, or extremely healthy diet. 59% said they were either careful or strict about their food intake. Only 23% said they pretty much ate whatever they wanted. A large number were also confused as to whether they were overweight or obese or normal weight. Healthy Diet – Consumer Reports Health Polls such as this one have implications for policy makers who want Americans to eat better when most Americans think they already do and it’s someone else who isn’t.
January 3, 2011
The National Prevention, Health Promotion and Public Health Council (National Prevention Council) was created by the Affordable Care Act and is in the process of developing a first-ever National Prevention Strategy. http://www.healthcare.gov/center/councils/nphpphc/draft_recommendations.pdf
Draft Recommendations, which are overarching priorities with a focus on communities, have been posted online for public comment at: http://www.hhs.gov/news/reports/nphps.html
Comments will be accepted until January 13, 2011.
December 16, 2010
The Food and Drug Administration has sent warning letters to makers of dietary supplements concerning the use of drug agents in such products. Weight loss supplements are specifically mentioned, including Slimming Beauty, Solo Slim, Slim-30 and others. See FDA: Tainted products marketed as dietary supplements potentially dangerous
December 14, 2010
Dr. Arya Sharma comments on an intriguing new study linking weight discrimination to poor glycemic control Does Weight Discrimination Affect Glucose Control? | Dr. Sharma’s Obesity Notes
VIVUS Inc. has announced that it will be meeting with the FDA in late January to discuss issues around Qnexa © for obesity. Qnexa is more effective than Contrave which won a positive vote for approval from an FDA advisory committee on December 7th. However, issues around birth malformations and cardiovascular risks remain to be resolved. VIVUS, Inc. – VIVUS Submits Briefing Document to FDA, Announces Follow-up Meeting to Discuss QNEXA®
In a surprise vote, the FDA Advisory Committee voted to approve Orexigen Therapeutics obesity drug, Contrave. The vote was 13 to 7. This is the first obesity drug to win approval since 1999. The FDA will make the final decision but they usually follow the recommendations of their advisory committees. This opens the door for Vivus to obtain approval since their drug, Qnexa, had a superior efficacy finding. It probably also helps Arena’s lorcaserin to obtain a more favorable decision by the FDA. See F.D.A. Panel Backs New Diet Pill – NYTimes.com
December 3, 2010
An FDA Advisory Committee has approved by a vote of 8-2 the lowering of the BMI threshold for Lap-Band(c) surgery from a BMI of 35 or greater with comorbid conditions to 30 with cormorbid conditions. The votes of an Advisory Committee are not binding on the FDA but the FDA usually follows their judgments.
November 6, 2010
Look who is making the US obese…The Government. Michael Moss of the New York Times writes today about the federal government programs…successful programs…in increase consumption of cheese which is a leading contributor to obesity in the United States. While Warning About Fat, U.S. Pushes Sales of Cheese – NYTimes.com
November 1, 2010
The New York Times has picked up the story, including my observations, on how the FDA is reviewing drugs for obesity Qnexa, a Diet Drug, Is Rejected by the F.D.A. – NYTimes.com
October 23, 2010
The Los Angels Times has picked up our press release on the FDA decision on lorcaserin. FDA shoots down another weight-loss drug – latimes.com and the Baltimore Sun FDA shoots down another weight-loss drug – baltimoresun.com. See the Daily Downey .
October 21, 2010
A new paper in Nature Genetics has confirmed 14 genes involved in body weight regulation and another 18 new ones, opening the door for potential new intervention targets. Association analyses of 249,796 individuals reveal… [Nat Genet. 2010] – PubMed result
A new paper asserts that previous work has seriously underestimated the medical costs of obesity. The researchers have used a method called Instrumental Variables which uses genetic information to identify cases where obesity is the likely cause with data from the Medical Expenditure Panel Survey. As an example, obesity was associated with $676. 00 in higher annual medical costs but the IV results raises that to $2,826. This would make the annual costs of treating obesity in US adults $168.4 billion or 16.5% of national spending on medical care. A higher annual cost for treating persons with obesity could change the risk-to-benefit ratio. The abstract is available at the National Bureau of Economic Research The Medical Care Costs of Obesity: An Instrumental Variables Approach
October 17, 2010
The Equal Employment Opportunities Commission (EEOC) has filed a discrimination lawsuit against a non-profit company which fired an employee who had severe obesity. The employee worked with children of mothers who were undergoing treatment for addiction. The suit alleges that the employer wrongfully assumed the employee was unable to perform her duties. EEOC Sues Resources for Human Development, Inc. for Disability Discrimination
October 14, 2010
A new study has found evidence of the presence of antibodies to a common virus being more common in obese than non-obese children. This is the latest in a number of studies appearing to confirm the role of the virus in the spread of obesity. If cause and effect is established (which is nearly impossible in humans) a new pathway to prevention and treatment could be established. Adenovirus 36 and obesity in children and adolesce… [Pediatrics. 2010] – PubMed result
October 8, 2010
The FDA as pressured Abbott Laboratories to take sibutarmine (Meridia) off the market. The FDA has not explained why Avandia should stay on the market with a worse safety profile than Meridia. Abbott to Voluntarily Withdraw Meridia® (Sibutramine) in the U.S.: October 8, 2010
USA Today has done a nice video on the rising costs to hospitals for equipment for larger Americans. You can catch me commenting on how the costs will be absorbed by the health care system. Videos: News, Sports, Entertainment, Technology & More – USATODAY.com#/The+rising+costs+of+obesity/628086759001
October 7, 2010
Who gets a diagnosis obesity? The question is important because many health care decisions are premised on having an accurate diagnosis. A study of who gets a diagnosis of obesity was conducted by researchers at the Bloomberg School of Public Health at Johns Hopkins. They found only 7.7% of members of a health plan had a diagnosis of obesity and they were largely female, below age 44, over a BMI of 35, hypertensive and dyslipidemic. Variation in Provider Identification of Obesity by… [J Obes. 2010] – PubMed result Another study from the Bloomberg School group found physicians were likely to assume their overweight patients would be less likely to adhere to their medications than normal weight patients. Disparity in physician perception of patients’ adh… [Obesity (Silver Spring). 2010] – PubMed result In yet a third paper from this prolific group, they found a majority of patients reported regular exercise (55.6%) and efforts to lose weight by eating less (63.1%). However, their physicians perceived only a third of their patients as engaging in such activities. Physicians were less likely to perceive obese patients as engaging in these activities although they were more likely to exercise and try to eat less than their non-obese patients. Patient use of weight-management activities: a com… [Patient Educ Couns. 2010] – PubMed result
Mayor Mike Bloomberg has asked the US Department of Agriculture for permission to ban food stamp recipients from using them to purchase sugar-sweetened beverages. A Push to Ban Soda Purchases With Food Stamps – NYTimes.com
Vivus’s obesity treatment Qnexa holds on by a thread at the Food and Drug Administration. Now, a single-subject case report on phentermine (one of the two components of Qnexa) as a cause of pulmonary hypertension may be just enough (which is say very little) to derail Qnexa’s approval by the FDA. See article in Yonsei Medical journal Pulmonary hypertension associated with use of phen… [Yonsei Med J. 2010] – PubMed result
Public education campaigns on obesity prevention almost always entail pleas for eating “healthy foods.” A newly published survey from Switzerland found widespread misconceptions in the general public over healthy eating which was associated with lower consumption of healthy foods. Consumers’ knowledge of healthy diets and its corr… [J Hum Nutr Diet. 2010] – PubMed result
A new study just published in Obesity by Bollealli and colleagues at the University of Cincinnati School of Medicine shows a significant association of a variant of the FTO gene with obesity in African-Americans. Another variant was found significant for non-Hispanic whites. This study confirms the association of the FTO gene in childhood obesity. See Association of FTO Gene Variants With Adiposity in… [Obesity (Silver Spring). 2010] – PubMed result
September 24, 2010
Researchers at the World Health Organization have found an enormous increase in childhood obesity around the world. In 2010, 43 million children were estimated to be overweight and obese, 92 million at risk for overweight. Worldwide prevalence increased from 4.2% in 1990 to 6.7% in 2010. The trend is expected to reach 9.1% or 60 million in 2020. Global prevalence and trends of overweight and obe… [Am J Clin Nutr. 2010] – PubMed result. Increased adiposity has been shown to increase C-reactive protein, a marker for inflammation which contributes to increased risk for chronic diseases, such as atherosclerosis and rheumatoid arthritis. Predictors of inflammation in U.S. children aged 3… [Am J Prev Med. 2010] – PubMed result
New research confirms that physical activity can be very helpful in overcoming genetic predisposition to obesity. PLoS Medicine: Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study
September 23, 2010
The prestigious OECD, the Organization for the Economic Cooperation and Development which usually forecasts economic trends in the leading economies, released a new report which forecasts obesity trends predicting that 75% of the US population will be obese in ten years. They found that obesity reduced lifespan by 8-10 years compared to a normal weight person. See the report at Health: OECD says governments must fight fat.
September 22, 2010
The International Journal of Obesity (IJO) features an on-line article using NHANES data showing a continuing increase in obesity and abdominal obesity (the more dangerous type) in men and abdominal obesity in women from 1999 to 2008. Access : Trends in obesity and abdominal obesity among adults in the United States from 1999|[ndash]|2008 : International Journal of Obesity Another study has found an increase in American’s cholesterol levels over the last 30 years. Rising obesity rates are seen as offsetting drug treatments to lower cholesterol. 30-Year Trends in Serum Lipids Among United States… [Am J Cardiol. 2010] – PubMed result
Studies throw doubts on dietary supplements for weight loss. See An Evidence-Based Review of Fat Modifying Supplemental Weight Loss Products and Experience (mostly negative) with the use of sympa… [J Obes. 2011] – PubMed result
September 22, 2010
The International Journal of Obesity (IJO) features an on-line article using NHANES data showing a continuing increase in obesity and abdominal obesity (the more dangerous type) in men and abdominal obesity in women from 1999 to 2008. Access : Trends in obesity and abdominal obesity among adults in the United States from 1999|[ndash]|2008 : International Journal of Obesity
September 22, 2010
A new study adds to a growing body of research on the role of a virus in the spread of obesity. The focus is on a common virus, Adenovirus -36. The virus was found more common in overweight children who were significantly heavier than children not showing the presence of the virus. See, Obesity In Children Linked To Common Cold Virus – Science News
September 21, 2010
George Washington University study shows individual costs of overweight, obesity. First-Ever Report on the Individual Cost of Obesity Unveiled — WASHINGTON, Sept. 21 /PRNewswire-USNewswire/ –
September 17, 2010
You would think that fighting childhood obesity with exhortations to “health eating” would be a pretty non-partisan issue. Think again. It appears a number of ‘right-wing’ voices see this as part of plan for bigger, more intrusive government. See Right-wing media attack Michelle Obama for fighting childhood obesity | Media Matters for America
September 16, 2010
The FDA advisory committee voted 9 to 5 against approval of Areana Pharmaceuticals’ obesity drug, lorcaserin. The committee, in shooting down the thrid obesity drug this year, cited the drug”s moderate weight loss efficacy and uncertaininty raised by pre-clinical studies showing cancer growth in rats and mice. The FDA can approve the drug but the negative vote of the advisory committee makes that unlikely. At the end of the meeting, the lead FDA staffer, Dr. Eric Coleman apologized to the committee for “putting you through this.” He said that at least the committee members didn’t ‘have to do this every day,’ presumably as he does.
September 15, 2010
At 4:05 PM today, obesity pharmacology went on life support. The FDA Advisory Committee reviewing Abbott Laboratories sibutarmine (Meridia) split on what to do. There were 8 votes in favor of taking Meridia off the market and 8 votes in favor of two different alternives to changing the label or restricting distribution. Much of the Advisory Committee’s discussion focused on trying to find the benefits of weight loss in general and in the SCOUT trial in particular. (See below for my comments on the SCOUT trial.) The coup d’grace was delivered by Dr. Eric Coleman, Deputy Director of the Division of Metabolism and Endocrinology, who presented a cartoon at the end of the day and his presentation. The cartoon, titled “CV Disease Continuum” depicted a man on Monday for whom sibutramine was appropriate who has a heart attack in the second frame and on Tuesday sibutramine is contraindicated. He indicated he was perplexed how this could be. Dr. Arya Sharma, a leading researcher on the SCOUT trial, responded with some obvious dismay that this “continuum” was exactly the same as one with see with physical activity being recommened one day and discontinued after a heart attack. To no avail, however.
It is hard to read just how this sets up tomorrow’s review of Arena Pharmaceutical’s compound, lorcaserin, but it can’t be good.
At the same time, the Brookings Institution issued a study detailing the costs of obesity in terms of direct medical costs, productivity losses, transportation and human capital costs. See The Economic Impact of Obesity in the United States – Brookings Institution Total annual costs: $215 billion.
September 12, 2010
Obesity likely to increase colon cancer. The BBC reports on a European study predicting a 50% increase in cases of colon cancer due to obesity. BBC News – Colon cancer cases ‘may rise 50%’
September 10, 2010
The Food and Drug Administration plays a critical role in the nation’s fight against obesity. This year is a crucial one as the FDA is reviewing three drugs and an expansion of the BMI levels for bariatric surgery. In July, the FDA advisory committee voted against approving Vivus Inc. drug Qnexa. Next week the FDA will review sibutramine (on the market as Meridia) and Arena Pharmaceutical Inc.’s lorcaserin.. Later in the year, Orexigen’s product, Contrave, will be reviewed. Below is the written statement we filed addressing the myths which dominate the FDA’s thinking, going back to the fen-phen controversy, the uncertainities around the sibutramine, and the FDA’s failed risk-benefit calculus.
Watch this space for reports on next week’s hearings.
Statement of Morgan Downey
Before the Endocrinologic and Metabolic Drugs Advisory Committee
Food and Drug Administration
September 15 & 16, 2010
Good afternoon and thank you for allowing me to testify.
I was the CEO of the American Obesity Association from 1997 to 2006 and subsequently Executive Vice President of The Obesity Society until 2008. I am Editor and Publisher of the Downey Obesity Report.com which covers research, health news and public policy regarding obesity. I currently consult with a number of organizations on obesity issues including a health care provider, an anti-obesity coalition as well as both pharmaceutical and device manufacturers. I have attended virtually every meeting of this committee since 1997. As CEO of the American Obesity Association, I organized an industry-wide collaboration in 2003-4 regarding the FDA Guidance for the development of weight loss drugs. This effort involved 13 pharmaceutical companies, Food and Drug Administration officials and the National Institutes of Health. The concerns regarding the FDA processes for approval of weight loss drugs were incorporated into a meeting of this Advisory Committee in 2004 which were adopted in large part in 2007.
Obesity is a fatal, chronic, relapsing, neuro-endocrine disease with multiple causes including genetics, environment and behavior which continues to increase. No other condition combines obesity’s deaths and discrimination, sickness and stigma, disease and disability. According to Humana, one of the nation’s largest insurers, There are more than 122 million overweight and obese Americans between the age of 20 and 65. Every pound in an overweight person adds nearly $20 in health care costs on average. The total additional health care costs are $534 per year for an overweight person, $1,614 for a person with obesity. These costs add up to $127 billion.1
Obesity is now widely recognized as one of the nation’s leading health problems. However, effective long term prevention strategies and intervention strategies remain elusive. Therefore, the putative role of pharmacology in the treatment of obesity is an important one as it may enhance weight loss and encourage additional efforts to fight obesity both on an individual basis and as a society. My statement therefore address three points: the committee’s past assumptions about the use and role of drugs to treat obesity, the analysis of the sibutramine SCOUT study as potential justification for taking one of the few drugs physicians can prescribe for obesity off the market and finally, my thoughts on the FDA’s benefit-risk calculations in deciding approval or withdrawal of obesity medications overall.
PART ONE Assumptions about Pharmacologic Treatment of Obesity
As a close observer of this process, I want to address some of the underlying assumptions which, I believe, affect the advisory committee’s decisions and which arose during the last meeting in July, 2010 in consideration of Qnexa.
Briefly, the assumptions are something like these:
Any obesity drug will be taken by millions of persons for a long period of time, possibly a lifetime. Many users of drug should not be taking it. These drugs are being abused. Wide-spread usage will disclose unforeseen adverse events, such as was the case with the fen-phen combination. This will result in having to take the drug off the market. Since drugs provide modest efficacy at best, they will not reverse the obesity epidemic. This constitutes an unacceptable human experiment.
Let’s examine each component.
1. Obesity drugs will be taken by millions of persons for a long period of time, possibly a lifetime.
There is little doubt that the potential market for anti-obesity agents is very significant. However, that market potential has never been realized. There were reports, at the time of peak usage of fen-phen of 6 million users. A more recent study indicated a smaller but still impressive number of 2.5 million Americans were taking an anti-obesity medications at the peak time. 2 Even at 6 million users, this is only 5% of the affected population. This comports with another study which found that 2% of men and 3% of women were taking diet pills, less than those joining a weight loss program, eating food supplements, skipping meals, eating less fat and eating fewer calories. 3
Cawley and Rizzo examined disparities in use of anti-obesity agents from 1996 to 2001. Using the MEPS database, they found that the percentage of adults using anorectics rose from 0.81 in 1996 to 0.94 in 1997 but fell thereafter in the wake of the fen-phen withdrawal. In no year from 1998 -2001 is the percentage higher than 0.45, less than half its level in 1997.This is still a sizeable number but only a fraction of the population who have a BMI of 27 with comorbidities or greater.
Cawley and Rizzo found use of these drugs was lower among African-Americans and Hispanics than whites, lower in men than in women and decreases with age. Usage is greater among those with health insurance and appears to increase with education. Those meeting the medical criteria are 333% more likely to take anorexigens than those not meeting criteria. Nonetheless, 41% of those taking the drugs do not meet medical criteria. 99% of those meeting the medical criteria do not take the anti-obesity drugs. 4
These findings seem to be borne out in other studies. Bolen et al examined records of approximately 4.2 million persons in two Blue Cross Blue Shield plans and observed a reduction in use of obesity medications from 1% in 2002 to 0.7% in 2005. They also found that the majority of users took the medications for less than 3 months. (However, a minority (14-17%) took phentermine and older agents for more than 3 months). Of interest is the other classes of drugs these users were taking including narcotic analgesics, macrolides, upper respiratory agents, antidepressants and nonsteroidal anti-inflammatory drugs. The use of narcotic analgesics suggested to the authors that higher rates of osteoarthritis and joint pain might be responsible or users are at a higher risk of substance abuse. 5 These reports are consistent with data which indicate that none of these drugs are among top selling pharmaceutical products. In 2008, sales of Xenical were $272 million, Meridia $106 million and phentermine $57 million.
2. Many users of anorexigens should not be taking them. These drugs are being abused.
As indicated in the Cawley study, 41% of users of anti-obesity drugs did not meet medical criteria. The authors speculated that the patients may have met criteria when they began taking the drugs and then achieved a lower weight. They tended to discount this as the weight loss effects were modest. However, for some users modest effects might have been all they were seeking, even if overall, most patients have unreaslistically high expectations of weight loss via any modality. Alternatively, they speculated they might have a number of false negatives due to the fact that they did not account for those with sleep apnea. Another possibility is that people who were not obese but valued weight loss were able to convince their physicians to prescribe the drug.
These may be people who have taken to heart the government’s pervasive public health messages on the importance of preventing weight gain or who have a history of obesity in their families and want to avoid or delay the onset of the disease and its related conditions. Indeed, it appears that messages to influence attitudes towards the prevention of weight gain and risk perception may affect people who are not yet motivated to prevent weight gain. 6
Another possibility is that some fall into the category of having a normal BMI but being metabolically obese which speaks to the issues around the reliability of BMI for those with normal BMI but high visceral adiposity.7 The inaccuracy of the BMI tool is particularly pronounced in Asian Indians8 and Hispanics.9
The argument of wide-spread usage depends on another assumption. Namely, that many physicians inappropriately write prescriptions. That some physicians abuse this process is clear. But patients do not need to go to their doctor to get a weight loss product. Thousands are sold every day in the nation’s supermarkets and drug stores as dietary supplements on television or the Internet in an unregulated environment.
In fact, physicians are not too anxious to treat their patients with obesity. Quite the contrary. Most physicians do not measure BMI and most do not counsel their patients, even those with morbid or severe obesity, on weight loss strategies. Ma et al, in examining the 2005-6 National Ambulatory Medical Care Survey found that of visits by patients with a BMI of 30 or more, 70% were not diagnosed with obesity and 63% received no counseling for diet, exercise or weight reduction. The percentage of visits not being screened (48%), diagnosed (66%), or counseled (54%) for obesity was also notably higher than expected even for patient with know obesity comorbidities. Performance was no better than 50% of eight quality indicators which related to the prevention and treatment of obesity comorbidities, e.g. coronary artery disease, hypertension, hyperlipdemia, asthma and depression.”10 A study of New Jersey physicians found high prevalence of negative attitudes to obese people. Almost 80% or respondents reported that patients frequently or almost always lacked discipline and 52% felt patients lacked motivation to lose weight. 50% believed treatment of obesity is often ineffective. “Similar to others, we found that bariatric surgery and weight loss medications are infrequently recommended as approaches to weight loss, especially by physicians with higher volume of extremely obese patients. Poor insurance coverage was cited as a major barrier to care of extremely obese patients. 11 Another study found that higher BMI was associated with lower physician respect. 12 Unfortunately, negative attitudes of physicians toward persons with obesity appears to be increasing. 13
It might also be asked whether the FDA label criteria are themselves appropriate. There are two components to the label criteria: BMI of 30 or greater or a BMI of 27 with comorbidities. It is well established that the BMI is valuable tool for population-wide analyses but a crude instrument to measure excess adipose tissue in individuals. In a recent study comparing BMI with DEXA scans, researchers at Mayo Clinic found that BMI value alone misclassified the degree of body fat in 41% of patients. 14 So rigid adherence to the BMI for determining which individual should receive drug therapy is perhaps unwarranted. It should certainly not be assumed that just because a person’s BMI is outside of the categories, that weight loss is not medically justified for that individual.
As to recognized comorbidities for use of drugs from BMI of 27 to 30, the FDA Guidelines cite only 5 conditions: type 2 diabetes, hypertension, dyslipidemia, sleep apnea, and cardiovascular disease. Other common conditions such as some cancers, non-alcoholic fatty liver disease, GERD, PCOS, reproductive disorders, birth defects, are not mentioned. In fact, there are over 50 conditions associated with obesity with varying degrees of strength in the medical literature. In one study of employees, 147 conditions out of 261 specific disease categories identified by the Agency for Healthcare Research and Quality were statistically more prevalent in patients with morbid or severe obesity. 15
While the focus in most of these advisory committee meetings is on the cardiometabolic effects such as lipids, blood pressure and HbA1c, the literature is replete with evidence on the psychological toll obesity takes. Individuals with obesity have higher rates of depression, mood or anxiety disorders and suicide than the general population. Obese individuals experience stigma and discrimination, reduced employment status and educational opportunities as well as social isolation.16 Medical profession and researchers have focused on the long term increase in risk for type 2 diabetes and cardiovascular disease due to obesity. Patients actually seeking weight reduction may have other issues in mind. My personal hypothesis is that many patients seek medical management of obesity not for long term risk reduction but for immediate health reasons. For some, it is no doubt “cosmetic.” But other factors are also present for some patients. These may include:
- Responding to discrimination and stigma. The population most likely to use antiobesity agents, white women, is also the population which experiences the greatest stigmatization due to obesity.
- Responding to mobility and pain problems. Osteoarthritis in obese patients is reported to be 17% at the knee, 5% at spine level and 10% in other areas. The prevalence of low back pain is 22% in obese adults. 17
- Responding to weight gain caused by FDA approved medication. A large number of FDA approved medications cause increases in body weight.18
- Responding to weight gain following smoking cessation.19
- Responding to pre- and peri-conceptional risks 20 and reproductive disorders, including erectile dysfunction. 21
Incontinence, back pain, knee and hip pain and joint replacements, shortness of breath and mobility limitations are, perhaps, as likely to drive patients to seek medical attention today than risks which may not materialize for 5 or 10 years, if ever. Therefore, the number of patients taking obesity medications outside of the label may not constitute an “abuse” of the drug as that term is commonly used but a failing by the FDA to appropriately describe the population which can benefit from the product.
3. Wide-spread usage will disclose unforeseen adverse events, such as was seen with the fen phen combination.
The approval and subsequent withdrawal of the fen-phen combination in the late 1990s has been a looming specter over these meetings. According to some voices, fen-phen must have caused a great public health disaster, resulting in increased mortality and morbidity. It is therefore important to make sure that the right lessons are learned from the fen-phen experience.
Some predicted that the fen-phen combination would increase deaths due to primary pulmonary hypertension (PPH). Contrary to many assumptions, there appears to have been few to no appreciable increase in deaths attributed to the fen-phen combination. Lilienfeld, Engin and Rubino did find an increase in primary pulmonary hypertension mortality in the United States from 1979 to 1996. They surmised that the increase might be due to the introduction of anorexigens but also to improved diagnosis. The highest increases were seen in elderly black women and infants, two groups with low use of anorexigens. They also speculated that the increase could actually be attributable to the AIDS epidemic rather then the use of fen-phen.22
In a letter response, Richard Rothman reported that he had queried the CDC mortality database for PPH deaths using an age range more typical of patients who enroll in weight loss programs. Data from 1990-1991, before fen-phen usage was taken as the baseline and compared to fen-phen exposure from 1992 to 1997 among 7,329 patients enrolled in weight loss programs in the Washington, DC area. He stated, “The results show that the age-adjusted PPH mortality rates in the years immediately preceding the use of phen-fen are not different from those reported during the years of widespread phen/fen use for patients aged 20 to 54 years. This analysis fails to support he hypothesis that the widespread use of phen/fen in the years from 1992 to 1997 increased the incidence of PPH. If the use of phen/fen during these years created an ”epidemic” of PPH, as some have declared, such an epidemic is not yet reflected in the mortality database maintained by the CDC. 23 The only reported deaths I was able to find in the literature occurred in 3 patients who underwent cardiac surgery. 24
Morbidity: Heart Valve Abnormalities
Many studies performed after withdrawal of fen-phen from the market revealed that the association with valvular abnormalities was associated with usage exceeding 6 months, was resolved in most cases by withdrawal from the drugs and resulted primarily in mild aortic regurgitation which was not accompanied by significant differences in cardiovascular symptoms nor physical findings other than a higher prevalence of heart murmurs. 25
A study by Fleming and Boyd looked at the longitudinal effects on patients who took fen-phen and patients with similar BMIs and patients with non-fen-phen induced heart disease. They found three classes of patients: those who showed an overall reduction in valvular regurgitation; those whose regurgitation worsened and those who develop severe mitral or aortic regurgitation requiring valve replacement. Determining which patients are in each group would require serial echocardiograms and close clinical monitoring. They state, “The primary cardiovascular problem appears to be the long-term development of aortic insufficiency in a minority of individuals, which, at least to date, appear to respond to angiotensin-converting enzyme (ACE) inhibitors.” 26 Seghatol and Rigolin recommended echocardiograms and Doppler examination in patients with exposure to fen-phen and repeated physical examination 6 months later. 27
At the time of withdrawal, the FDA reported a prevalence of valuopathy of 32.8% The reported prevalence by Jollis was 17.4%. A meta-analysis by Sachdev et al indicated that valvular regurgitation is “less common than initially reported but still present in 1 in 8 patients treated for more than 90 days.” 28 Dahl study of over 1,000 patients found nearly 20% of the women and 12% of men had at least mild regurgitation, again, more likely in the longer usage of the drugs. Surgery was performed on 38 patients (0.66%), 25 (0.44%) with clear evidence of fenfluramine-related etiology.They found that valvulopathy, after one year improved in a substantial number of patients and worsened in a small but still significant number. 29
A meta-analysis by Loke and colleagues examined 1279 patients. Pooled data from six controlled cohort studies found a relative risk ratio of 2.32 for aortic regurgitation and an attributable rate of 4.9% and for mitral regurgitation a relative risk of 1.55 and an attributable risk of 1.9%. Only one case of valvular heart disease was detected in 57 randomized controlled trials but this was judged unrelated to drug therapy. They conclude, “The risk of valvular heart disease is significantly increased by the appetite suppressants reviewed here. Nevertheless, when considering all the evidence, valvulopathy is much less common than suggested by the initial, less methodologically rigorous studies.” Yet, they have some cautionary notes, “There is a definite danger that useful drugs may be cast aside prematurely following “knee-jerk” reactions to safety scares founded on poor evidence.” They ask pertinent questions which should be asked if one wants to make such drugs work, “Why wasn’t routine echocardiography part of the safety monitoring protocols in the clinical trials, when there had been so much controversy in the past with pulmonary hypertension and appetite suppressants? Furthermore, in view of the lack of comprehensive safety data, prescribers of appetite suppressants should perhaps have attempted to limit the treatment duration (as advised by the regulatory authorities) and avoided the use of unlicensed drug combinations.”30
Thus it appears there are no published studies which support the assertion that the fen-phen combination was not responsible for increased deaths. The increases in valve abnormalities are certainly serious. We will not know if they could have been better prevented and managed. What we do know is that a product like Avandia with known increases in deaths and heart attacks remains on the market while this combination therapy for obesity was removed from the market on the basis of a handful of case reports.
4. Therefore, long term studies are needed before approval.
It is axiomatic that long term studies are a valuable tool in evaluating any therapy. That is not in dispute. What is in dispute is whether long term studies need to be undertaken prior to approval of an obesity drug or after approval. Historically, the FDA Guidance for weight loss medications did require 2 year data. During the period 2003-2004, this issue was discussed several times by experts convened by the American Obesity Association and officials of the FDA. It was the subject of considerable debate by the Endocrinologic and Metabolic Advisory Committee in 2004 and resulted in a change in the FDA Guidance in 2007 to only require one year studies. The 2007 Guidance state, “A reasonable estimation of the safety of a weight management product upon which to base approval generally can be made when a total of approximately 3,000 subjects are randomized to active doses of the product and no fewer than 1,500 subjects are randomized to placebo for 1 year of treatment.” (at p. 6) It was therefore somewhat inexplicable when, during the discussion of the Vivus Pharmaceutical drug Qnexa, that the FDA allowed the committee members to criticize the lack of two year data when the FDA had determined that one year data was sufficient to identify a safety signal.
It was also clear from the Avandia hearings on July 14-15, 2010 that long term studies of chronic diseases are fraught with difficulty. In the obesity/diabetes area, the difficulties are clear: drop-out rates may increase, dietary patterns may change, levels of physical activity may change, normal aging may affect results, medications for other conditions may change and the dosage and drug interactions may also change.
5. Since drugs provide modest efficacy at best, they will not reverse the obesity epidemic. This constitutes an unacceptable human experiment.
Efficacy standards are discussed in Part Three, below. Does this constitute human experimentation? In one way clearly not. Drugs are routinely put on the market after relatively short, limited clinical trials. They are monitored. If problems arise, labeling can change and in some cases the drug is withdrawn. If this constitutes illegal or unethical ‘human experimentation’ than every drug approved by the FDA is equally guilty for most have never been studied long term in all possible patient populations and with every conceivable drug interaction.
PART TWO CONSIDERATION OF SIBUTRAMINE
Sibutramine (Meridia) was approved by the FDA for the treatment of obesity in 1997. Sibutramine has two effects. It reduces food intake and attenuated the fall in metabolic rate which occurs during weight loss. In one study of adult men, average intake reduction was 312 kcal during the day versus placebo. In non-dieting adult women, the reduction was 356 kcal a day. 31 The label for sibutramine lists Contraindications, “MERIDIA is contraindicated in patients: with a history of coronary artery disease (e.g. angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA); with inadequately controlled hypertension > 145/90 mm Hg; over 65 years of age; receiving monoamine oxidase inhibitbors (MAOIs); hypersensitivity to sibutramine or any of the active ingredients of MERIDIA; who have a major eating disorder (anorexia nervosa or bulimia nervosa); taking other centrally acting weight loss drugs. Due to an increased risk of heart attack and stroke in patients with cardiovascular disease, MERIDIA should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke.”
The Sibutramine SCOUT study inclusion criteria were men and women over 55 years of age, BMI of 27 or greater or 25 and greater with a high waist circumference, diagnosed type 2 diabetes together with at least one other defined risk factor (hypertension, dyslipidemia, current smoker or diabetic nephropathy) or a history of cardiovascular disease defined as coronary artery disease, peripheral arterial occlusive disease or stroke. Due to lower than expected enrollment, the criteria were adjusted to amplify the recruitment of the highest risk patients 15 months after the first patient was enrolled. In particular, patients enrolled under the later restricted criteria were required to have both a history of CVD and a history of type 2 diabetes with at least one additional risk factor. 32
The subjects in SCOUT were almost precisely the category of patients for whom sibutramine is contraindicated. Indeed, only 8.1% of patients met label criteria, 91.9% were non-conformers, 84% had type 2 diabetes. The median age was 63.2 years, ranging from 51 to 88. The drug was administered continuously at a daily dose of 10-15 mg over the duration of the trial (mean duration was 3.4 years) whatever the impact on body weight.33 The label indicates that, “if a patient has not lost at least 4 pounds in the first four weeks of treatment, the physician should consider reevaluation of therapy which may include increasing the dose or discontinuation of MERIDIA.” In practice the drug is generally stopped in the absence of significant weight loss. 34
It appears that the SCOUT study only confirms the validity the exclusion criteria in the FDA label.
There was a rate of nonfatal cardiovascular endpoints (nonfatal myocardial infarctions (MIs) or stroke) in 11.4% percent on drug compared to 10.0% percent in the placebo group. How great a difference is that really? In terms of the raw numbers, 561 persons in the sibutramine group had a primary outcome compared to 490 in the placebo group. That is a difference of 71 persons out of the total study population of 9,804. In other words, if just 35 people shifted from the sibutramine group to the placebo group or, if some MIs and stroke were missed in the placebo group, the study results would be null. 35 is a small number – just one third of one percent or 0.0035 of the entire study population.
Since there are only three prescription medications for obesity and the panel today may vote to take one off the market, it might be help to make sure that the population is correctly identified as having their nonfatal cardiovascular outcome caused by sibutramine. Have we excluded all other possible explanations? The published study33 gives us a comparison between the treated group and the placebo group. It does not provide information comparing those experiencing a MI or stroke with non-experiencers. We do not know that the drug caused the increased number of events in the treatment group. Indeed, the Kaplan-Meier plots in the Supplementary Appendix to the NEJM article indicate that there was almost no difference between placebo and the Diabetes only group throughout the trial. The differences occurred between the sibutramine and the Cardiovascular only group and the Cardiovascular and Diabetes group and then only after approximately 20 months of treatment
There are several factors which may be responsible for the reported for the small numerical difference in events between those experiencing an MI or stroke. There are many unanswered questions.
1 Were there regional, gender and ethnic variations? How reliable was the coding? Did any patients have multiple events which were all counted separately? Was their a difference in events between the group recruited in the second phase (who were sicker) than those recruited in the first phase? Was duration on drug a factor?
2 Were the rates of smoking the same in the treatment and control groups and did they change over time? There does not appear to be any data on this aspect. We know that smoking is a major risk factor for cardiovascular disease. We know that smoking with previous cardiovascular disease significantly increases the risk of further cardiovascular events.35
3. What were the ages of the persons experiencing cardiac events? Were the events more prevalent at higher ages as we would expect? We would expect to see higher rates among older participants.
4. What are the levels of physical activity ? Low physical activity is associated with mortality and morbidity cardiovascular disease. 36
5. What was the difference in aspirin usage? Aspirin consumption is associated with reduced cardiovascular mortality. 37 We know how many participants in the different groups were taking aspirin but we do not have a comparison between affected and non affected groups.
6. Is there a difference in MIs and stroke events by those with multiple healthy behaviors and those with fewer or only weight loss? Multiple positive lifestyle behaviors have shown a significant influence on cardiovascular causes. 38
7. Did the group experiencing MIs and stroke events differ from those not experiencing these events according to presence of alleles of the FTO gene? The FTO rs9939609 genotype is associated with lower plasma high-density lipoprotein cholesterol, higher triglycerides, higher atherogenic index of plasma and increased body mass index. The “A” allele is associated with increased risk of fatal and nonfatal myocardial infarction. This effect may be mitigated by statin use but, again, we do not know if statin used differed between those with MIs and stroke and those not experiencing those events. 39
8. Did the group experiencing MIs and stroke differ from the other subjects in terms of their medication usage during the trial? How many in each group had their hypertension, cholesterol and type 2 diabetes under control? Were patients taking drugs which cause weight gain? Did the patients accurately inform the physicians if they were taking dietary supplements or other weight loss products?
9. Did the two groups differ according to dietary pattern? Differences in dietary patterns have been found to affect mortality from cardiovascular disease. 40
10. Related to dietary patterns, was asymmetric dimethylarginine (ADMA) measured? ADMA has been identified as a product of high fat food consumption patterns and may contribute to abnormal blood flow responses and to atherogenesis in type 2 diabetics. 41
11. Did the two groups differ by body composition? That is was there an equal prevalence of abdominal obesity in both groups? Abdominal obesity has been shown to increase the risk of cardiovascular disease. 42
12. Finally, what was the Vitamin D status? Vitamin D deficiency may be a cause of increase in cardiovascular risk 43
The sibutramine SCOUT study has been criticized for low efficacy in a very sick and elderly population The weight loss is the lead-in phase was 2.6 kg. During the trial an additional 1.7 kg was lost by subjects on drug. Meanwhile the placebo group’s weight increased 0.7 kg. Therefore the treatment group prevented a 0.7 kg gain and had an additional 4.3kg loss for a net effect of 5 kg or 11 pounds or about 2 BMI units. In other words, a 5’6” person weighing 186 lbs would have a BMI of 30. The loss of 11 pounds would give a BMI of roughly 28.5. No small improvement.
Therefore, I submit the questions the committee should be asked are the following:
- First, is the real world use of sibutramine in practice in the United States the same as the SCOUT population
- Do actual real world users of sibutarmine in the US take the drug for as long as the subjects in the SCOUT trial?
- What other studies point to adverse cardiovascular events with sibutramine? How many AEs have been reported to the FDA?
- Does the analysis of the SCOUT trial satisfactorily exclude all other possible causes for the differential in nonfatal cardiac events between those experiencing events and those not?
- Is the safety profile of Meridia significantly worse than Avandia thereby justifying its withdrawal from the US market? If Meridia is safer than Avandia, how can taking Meridia off the market be justified?
PART THREE FDA’s FAILED RISK-BENEFIT CALCULUS
The FDA is required to evaluate a drug’s safety and effectiveness. In 2004 when the American Obesity Association submitted draft revisions of the guidance for weight loss drugs, I wrote:
The history of drugs for the treatment of obesity is an unfortunate one. Early medications too often proved to be so unsafe to be removed from the market. This experience has colored the thinking of many dispensing physicians, consumers, and the general public. Unfortunately, experiences with previous weight loss drugs have created a negative perception on the utility of any future drug to treat obesity. Where researchers on obesity medicines see millions of cases of very sick persons who need to lose weight to improve their health (e.g. there are over 8 million persons with morbid obesity alone), the FDA is perceived as anticipating that any weight loss drug will be widely used by persons who are not overweight or obese or who desire cosmetic weight loss only or will be widely abused. Where these researchers see many individuals unresponsive to diet and physical activity intervention, they perceive that the FDA as seeing diet and physical activity as the optimum strategy to improve all or almost all cases of excess weight. Where researchers on obesity medicines see many drugs carrying as significant health risks as obesity medications, they perceive the FDA as holding weight loss drugs to a higher standard of safety. 44
Unfortunately, I believe these statements are more true today than when written. I would like to address the issue of the benefits of weigh loss.
1. Benefits of weight loss
A. Societal effects
On many occasions committee members, witnesses or staff have commented that 5-10% weight loss is barely acceptable. This is in contrast to a host of studies, clinical practice and official government positions that 5-10% weight loss is both attainable and accompanied by meaningful improvements in personal health and societal costs.
Both the US Department of Health and Human Services (DHHS) and the US Department of Agriculture (USDA) have provided real metrics for evaluating obesity reduction.
As part of the health care reform legislation passed by Congress, health plans will have to incorporate preventive health services as identified by the US Preventive Services Task Force. One of their recommendations is for screening for adult obesity and intensive behavioral counseling by physicians and others. On July 19, 2010, the Department issued Interim Final Regulations implementing this provision for group health plans and health insurance issurers. The Department points to the following benefits of preventive services in general, stating, “First, individuals will experience improved health as a result of reduced transmission, prevention or delayed onset, and earlier treatment of disease. Second, healthier workers and children will be more productive with fewer missed days of work or school. Three, some of the recommended preventive services will result in savings due to lower health care costs.” (at. P. 41733) While the Department foresees only a modest uptake of 5 to 10% in utilization of the preventive services, they find profound impacts in general and in obesity in particular. The Department states,
Another area where prevention could achieve sayings is obesity prevention and reduction. Obesity is widely recognized as an important driver of higher health care expenditures… Assuming midpoint reduction of six percent of body weight, the BMI for an individual taking up such an intervention would fall by six percent as well as height would remain constant. Based on the aforementioned McKinsey Global Institute analysis, a six percent reduction in a BMI for an obese individual (from 32 to around 30, for example) would result in a reduction in health care costs of approximately 5%. (After calculating the effect on health insurance premiums the regulation continues.) Doing so results in a potential private premium reduction of 0.05 percent to 0.1 percent from lower health care costs due to a reduction in obesity for enrollees in non-grandfathered plans. This does not account for potential savings in Medicaid, Medicare or other health programs. 45
In a recent publication, economists at the Economic Research Service looked at the effect of a putative 20% price increase on sweetened beverages. They estimated an average reduction of 37 calories a day or 3.8 pounds a year for adults, resulting in a decline in overweight prevalence from 66.9% to 62.4% and obesity prevalence reduction from 32.3% to 27.0%. While the actual impact may and probably would be less, the study nevertheless demonstrates the powerful effect of small changes in body weight. 46
B. Individual effects of moderate weight loss
As little as a 1 pound reduction in weight results in a 4-fold reduction in the load exerted on the knee per step during daily activities. According to the authors of this study, “a reduction of this magnitude would appear to be clinically meaningful.” 47 Functional improvement in older obese adults with knee osteoarthritis was greater with larger weight loss. 48
Aucott and colleagues reviewed the effects of weigh loss in obese diabetic and non-diabetic individuals. Reviewing 11 long term studies with follow up of more than 2 years, they concluded, “Results show that those with diabetes who lost weight intentionally significantly reduced their mortality risks by 25%. Additionaly, weight loss of 9-13 kg was the most protective. Patients with the risk of developing diabetes due to either family history of diabetes or impaired glucose tolerance, saw a reduction in this risk.” 49
In one study of obese women who lost 10% of body weight, there was positive short term improvements on perceived functional limitations including a much better ability to rise if they had fallen, to walk up and down stairs, to lift heavy things and they had less urinary stress incontinence. Even after some regain, most benefits persisted. 50
In the paper, “Re-Visioning Success: How Stigma, Perceptions of Treatment, and Definitions of Success Impact Obesity and Weight Management in America,” a Research Report for the Strategies to Overcome and Prevent (STOP) Obesity Alliance by the George Washington University School of Public Health and Health Services, Department of Health Policy, the authors write,
The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, examining a wide-array of randomly controlled studies, recommended a 10-percent reduction in weight to lower blood pressure, lower blood glucose levels and incidence of Type-2 diabetes, lower LDL-cholesterol and triglycerides, and increase HDL-cholesterol. Diabetes incidence was found to be reduced by 58 percent in two studies, one with weight loss ranging between 5.9-7.5 pounds, and another with an average weight loss of 12.3 pounds. Research also found a 23 percent improvement in blood pressure control associated with a net weight loss of only 4.4 – 8.8 pounds, suggesting that even a modest weight loss can help maintain a normal blood pressure.
One paper stated that a 10 percent decline in weight among people with obesity obese corresponded with a 30 percent loss of intra-abdominal fat, and was associated with several positive metabolic health outcomes, including blood insulin and glucose, risk factors for thrombosis, endothelial (blood vessel) function, and risk of coronary heart disease. Another study found that each 2.2 pounds (1 kg) of weight lost lowered C-reactive protein (a measure of blood sugar control) levels by 0.13 mg/L. Finally, one study found that an average weight loss of 11.2 pounds decreased osteoarthritis of the knee in women by 50%. (Citations in original) 51
Weight loss is often offset by weight regain. However, the benefits of weight loss may persist. In a 10 year follow up of participants in the Diabetes Prevention Program, funded by the National Institutes of Health, the cumulative incidence of diabetes was reduced in both the lifestyle and metformin group. 52
2. Risk Calculation
As mentioned earlier, it is widely believed that any adverse event signal will cause the FDA to either disapprove an obesity drug or withdraw it from the market. Unfortunately, the July Advisory Committee meeting to consider Vivus Pharmaceutial candidate drug, Qnexa, has added to this perception. In this case, a product combining low doses of two drugs (phentermine and topiramate) which have been on the market for a total of 65 combined years was disapproved The candidate drug was probably the most efficacious ever presented to the FDA, with a weight loss of 10.4 to 11% in the top dose with 67 to 70% of treated subjects losing at least 5%. 53 The safety profile of the candidate drug was also considered virtually clean.
Nonetheless, the committee focused on perceived adverse events from the full dosage drugs as approved by the FDA, specifically the teratogenic effects (abnormalities of psychological development, e.g. birth defects) of topiramate and voted to not approve Qnexa. If the Advisory Committee were truly concerned with the safety of patients, one might assume that they would have recommend removal from the market of topiramate. They did no such thing. So the drug at the full dosage approved by the FDA where the Committee felt there was a health risk remain on the market with no effort to take it off while their components at fractions of the full dosage with no adverse safety signal are disapproved. Does this make sense? The safe drug is spiked; the ‘dangerous’ drug continues on the market? One might argue that topiramate should continue on the market because epilepsy is a more serious disorder than obesity. But topiramate is also approved for the prevention of migraines. Does the FDA believe the prevention of migraines is of such a higher value than a remedy for obesity that topiramate’s teratogenic effects are acceptable? Evidently it does.
What about Chantix (varenictine)? The FDA approved Chantix for smoking cessation in spite of an association between Chantix and “serious neuropsychiatric symptoms including changes in behavior, agitation, depressed mood, suicidal ideation and actual suicidal behavior.” 54 This is not very different from the adverse effects observed with rimonabant. Yet, rimonabant for obesity was disapproved; Chantix gets a Public Health Advisory. Is smoking so much a greater health risk than obesity that it deserves products with higher risk levels? If Chantix were a product for obesity, would it have been approved with this safety profile? Not likely, in my opinion.
In short, it continues to appear that the FDA, contrary to professional opinion and scientific research, demands high weight loss as opposed to moderate weight loss. Nonetheless, it assumes that the weight loss will be transient and trivial. On the other hand, it assumes that adverse events will be universal and that dangerous, unforeseen events will arise. The pattern of the FDA is:
- If a drug is highly effective in weight loss, so many people will take it there will be unforeseen side effects and we will have to take it off the market……………………………Result: Non approval.
- If a drug has moderate effectiveness, any risk is unacceptable………………Result: Non-approval.
- If another drug causes serious side effects, like Avandia, Topamax or Chantix…………Keep on the market.
- If an obesity drug causes minor side effects…………………………take off the market or Disapprove.
- If a drug causes weight gain, no problem…………………………………………………………………..Approved!
This situation does not help anyone. Physicians do not have tools with which to help and counsel patients. Patients are left with dietary supplements on the one hand or surgery on the other. Research is hurt as company after company decides to avoid the obesity field for drugs where the regulatory environment is more balanced. The obesity epidemic continues to grow. We all want safe and effective medications for obesity. This nihilism about treating obesity must be changed. We cannot allow the pursuit of perfection be the enemy of the good. We need to be driven by facts, not fear; data not doubts, science not cynicism. Thank you.
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14 Oreopoulous A, et al, Association between direct measures of body composition and prognostic factors in chronic heart failure, Mayo Clin Proc 2010 Jul;85(7)609-17
15 Kleinman NL et al. The impact of morbid obesity and bariatric surgery on comorbid conditions: a comprehensive examination of comorbidities in an employed population J Occup Enviorn Med 2009 Feb;51 (2):170-9
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18 Baptista T et al. Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics Curr Drug Targets 2004 Apr; 5(3):279-99
19 Kleppinger A, et al. Effects of smoking cessation on body composition in postmenopausal women. J Womens Health 2010 Sep;19(9):1651-7
20 Jungheim ES, Moley KH Current knowledge of obesity’s effects in the pre- and periconceptional periods and avenues for future research Am J Obstet Gynecol 2010 Aug. 23, epub. Accessed Sept. 8, 2010
21 Hannan JL et al Beneficial impact of exercise and obesity interventions on erectile function and its risk factors J Sex Med 2009 Mar; 6 Suppl3:254-61)
22 Lilienfeld DE, Engin MS, Rubin LJ, Mortality from Primary Pulmonary Hypertension in the United States, 1979-1996.Chest 2000;117:796-800
23 Rothman RB, The Age-Adjusted Mortality Rate From Primary Pulmonary Hypertension, in Age Range 20 to 54 years, Did Not Increase During the Years of Peak “ Phen/Fen” Use. Chest 2000; 118: 1516-1517
24 MMWR, CDC, Nov. 14, 1997, 46;45
25 Jollis JG et al, Fenfluramine and Phentermine and Cardiovascular Findings: Effect of Treatment Duration on Prevalence of Valve Abnormalities. Circulation, 2000;1012071-2077. See also, Weissman NH, Panza JA et al, Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy Ann Intern Med 2001;134:261-266 , Gardin JM et al, Clinical and Echocardiographic Follow-up of Patients Previously Treated with Dexfenfluramine or Phentermine/Fenfluramine, JAMA, 2001;286:2011-2014, and Hensrud DD, Connolly HM et al, Echocardiographic improvements over time after cessation of use of fenfluramine and phentermine Mayo Clin Proc 1999,;74:1191-97
26 Fleming RM, Boyd LB, The Longitudinal Effects of Fenfluramine-Phentermine Use Angiology 2007;58:353
27 Seghatol FF, Rigolin VH, Appetite suppressants and valvular heart disease. Current Opinion in Cardiology 2002, 17:486-492
28 Sachdev M, Miller WC et al, Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies Am Heart J 2002;144:1065-73
29 Dahl CF, Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals BMC Medicine 2008;6:34
30 Loke YK, Derry S, Pritchard-Copley A, Appetite suppressants and valvular heart disease – systematic review, BMC Clinical Pharmacology 2002;2:6
31 Filippatos TD et al. A Review of the metabolic effects of sibutramine, Current Medical Research and Opinion, 2006; 21(3):457-466
32 Weeke P et al, The weight lowering effect of sibutramine and its impact on serum lipids in cardiovascular high risk patients with and without type 2 diabetes mellitus – an analysis from the SCOUT lead-in period. BMC Endocrine Disorders 2010;10:3
33 James WPT et al, Effect of Sibutramine on Cardiovascualr Outcomes in Overweight and Obese Subjects. NEJM 2010;363:905-17
34 Scheen AJ, Controversy about the Cardiovascular Safety of Sibutramine. Drug Saf 2010;33:615-618
35 Critchley JA Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review JAMA 2003;2911) 86-97
36 Fogelholm M, Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systemic review Obesity Reviews (2010) 11, 202-221)
37 Ong G, et al, Aspirin is Associated with Reduced Cardiovascular and All-Cause Mortality in Type 2 Diabetes in a Primary Prevention Stetting Diabetes Care 2010 Feb;33(2): 317-21
38 Khaw KY, Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study, PLOS Medicine 2008, March 255 (3) e70
39 Doney ASF, et al, The FTO Gene Is Associated with an Atherogenic Lipid Profile and Myocardial Infarction in Patients with Type 2 Diabetes. Circ Cardiovasc Genet. 2009;2:255-259
40 Heidemann C, et al Dietary Patterns and Risk of Mortality from Cardiovascular Disease, Cancer, and All-Causes in a Prospective Cohort of Women Circulation 2008 July 15;118(3): 230-237)
41 Fard A et al. Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vaqsc Biol. 2000:20:2039-2044
42 Cameron AJ Health and mortality consequences of abdominal obesity: evidence from the AusDiab study, Med J Aust 2009 Aug 17;191(4):202-8
43 Wang, L, et al. Systematic Review: Vitamin D and Calcium Supplementation in Prevention of Cardiovascular Events Ann Intern Med 2010;152:315-323) and Lee JH et al Vitamin D deficiency an important, common, easily treatable cardiovascular risk factor? J Am Coll Cardiol 2008 Dec.9;52(24):1949-56
44 Docket No. 2003D-0570
45 Fed. Reg. 75;137:41731 et seq
46 Smith TA et al Taxing Caloric Sweetened beverages: Potential Effects on Beverage Consumption, Calorie Intake and Obesity, ERR-100. U.S Department of Agriculture, Economic Research Service, July 2010
47 Messier SP et al, Weight loss reduces knee-joint loads in overweight and obese adults with knee osteoarthritis. Arthritis Rheum 2005 Jul;52(7):2026-32
48 Miller GD, Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis. Obesity, 2006 Jul;14(7):1219-30
49 Aucott L et al, Weight loss in obese diabetic and non-diabetic individuals and long-term diabetes outcomes – a systematic review. Diabetes, Obesity and Metabolism 2004;6:85-94
50 Larsson UE, Influence of weight loss on pain, perceived disability and observed functional limitations in obese women. Intl J Obesity (2004) 28:269-277
51 http://www.stopobesityalliance.org/wp-content/assets/2009/06/report_re-visioning_success.pdf, accessed September 3, 2010
52 Diabetes Prevention Program Research Group, 10 year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009 Nov 14;374(9702) 1677-86
53. Transcript July 15, 2010 meeting of Endocrinologic and Metabolic Advisory Committee, at p. 41
54 FDA Press Release, February 1, 1008
Should the BMI for bariatric surgery be lowered to 30?
That’s the question the Agency for Health Care Quality and Research is asking. If you are interested in commenting, go to http://effectivehealthcare.ahrq.gov/index.cfm/research-available-for-comment/comment-key-questions/?pageaction=displayquestions&topicid=227&questionset=139
FDA crack downs on fraudulent weight loss products:
Alli: warning of liver problems: Consumer Updates > Weight-Loss Drugs and Risk of Liver Failure
Que She Dietary Supplement: Consumer Updates > FDA’s MedWatch Safety Alerts: July 2010
September 8, 2010
New York Times looks at evidence for ‘endocrine disruptors’ which some believe have an impact on childhood obesity. In Feast of Data on BPA Plastic, No Final Answer – NYTimes.com
September 8, 2010
Congressional Budget Office issues new report on health care spending attributable to obesity. Congressional Budget Office – How Does Obesity in Adults Affect Spending on Health Care?
Other reports you may have missed. The USDA looks at the effects of a tax on sweetened beverages. Taxing Caloric Sweetened Beverages To Curb Obesity – Amber Waves, September 2010, Feature
The Trust for America’s health has issued its annual “F as in Fat.” See F as in Fat: How Obesity Threatens America’s Future 2010 – Trust for America’s Health
Important new regulations issued. Opportunity to comment. Deadline Sept. 17, 2010
As part of the health care reform legislation passed by Congress, health plans will have to incorporate preventive health services as identified by the US Preventive Services Task Force. One of their recommendations is for adult screening for obesity and intensive behavioral counseling by physicians and others. On July 19, 2010, the Department issued Interim Final Regulations implementing this provision for group health plans and health insurance issurers. The Federal Register notice (Fed. Reg. 75;137:41731 et seq) The regulations point to the following benefits of preventive services in general, stating, “ First, individuals will experience improved health as a result of reduced transmission, prevention or delayed onset, and earlier treatment of disease. Second, healthier workers and children will be more productive with fewer missed days of work or school. Three, some of the recommended preventive services will result in savings due to lower health care costs.” (at. P. 41733) While the Department forsees only a modest uptake of 5 to 10% in utilization of the preventive services, they find profound impacts in general and in obesity in particular. The Department states,
Another area where prevention could achieve sayings is obesity prevention and reduction. Obesity is an widely recognized as an important driver of higher health care expenditures… Assuming midpoint reduction of six percent of body weight, the BMI for an individual taking up such an intervention would fall by six percent as well as height would remain constant. Based on the aforementioned McKinsey Global Institute analysis, a six percent reduction in a BMI for an obese individual (from 32 to around 30, for example) would result in a reduction in health care costs of approximately 5%. (After calculating the effect on health insurance premiums the regulation continues…Doing so results in a potential private premium reduction of 0.05 percent to 0.1 percent from lower health care costs due to a reduction in obesity for enrollees in non-grandfathered plans. This does not account for potential savings in Medicaid, Medicare or other health programs.
See http://edocket.access.gpo.gov/2010/pdf/2010-17242.pdf for the full regulations and links to comment.