This article is more than 5 years old. Information may no longer be current.
Physicians, cardiologists weigh future of obesity management
Click Here to Manage Email Alerts
During the past decade, the prevalence of obesity has climbed dramatically. Data show a 2.4 million increase between 2007 and 2009 in the number of US adults who are obese, and the epidemic shows no signs of stopping.
The past year was discouraging for weight-loss drugs. Three separate medications went before the FDA for approval — lorcaserin, phentermine plus topiramate, naltrexone plus bupropion — and all three were met with rejection. In addition, sibutramine, a weight-loss drug approved by the FDA more than a decade ago, was pulled from the US market because of safety concerns.
|
Photo by: Mina Dietzius, courtesy of Boston Medical Center |
Caroline M. Apovian, MD, has a positive outlook on investigational obesity
treatments in the pipeline. Many physicians who care for obese patients said the field of weight-loss drug development has been dealt a considerable blow.
“As a physician who cares for patients with obesity, it concerns me globally that once again it looks like we have a barrier toward getting safe and effective treatments for people with obesity,” Steven R. Smith, MD, scientific director of the Florida Hospital/Sanford-Burnham Translational Research Institute for Metabolism and Diabetes, said in an interview.
Despite a prevailing sense of frustration, some physicians harbor hope for the future. Smith said during the past 2 decades, researchers and physicians have learned an exceptional amount about the science of body weight regulation while investigating new treatments and, therefore, should not disregard the potential for other novel therapies.
“There is some hope on the horizon,” Caroline M. Apovian, MD, of Boston University School of Medicine, told Cardiology Today.
A growing epidemic
As obesity statistics skyrocket, the need for medically based obesity treatments increases.
To illustrate this point, Donna Ryan, MD, associate director of clinical research at Pennington Biomedical Research Center in Baton Rouge, La., cited a 2010 JAMA study that examined decade trends using National Health and Nutrition Examination Survey data from 1999 to 2006 compared with 2007 to 2008. Researchers from the CDC found that the age-adjusted prevalence of obesity in recent years was 33.8%, and results also indicated that 6.2% of the US population has a BMI of at least 40.
|
|
“This is a burden of disease that we are going to face in the future that is going to demand more medical approaches,” Ryan said in an interview. “There is no way that we can ignore or deliver surgery to 6.2% of the population.”
Additionally, obesity places a significant burden on the health care system. Recent CDC estimates of the annual medical costs of obesity are as high as $147 billion, with averages suggesting that obese Americans have medical costs that are more than $1,400 than for normal-weight people.
“More than 50 illnesses are caused by obesity,” Louis Aronne, MD, FACP, clinical professor of medicine at Weill Cornell Medical College, said in an interview. “If we are going to have an impact, we need to start thinking about obesity in a different way.”
Robert Kushner, MD, a professor of medicine at the Feinberg School of Medicine, Northwestern University, Chicago, said it may be important to look at obesity as an underlying cause of disease as opposed to a separate health problem. Preventing and treating obesity could considerably cut costs associated with the disease, as well as potentially replace medications used for other related illnesses such as diabetes and CVD.
“The irony is there are medications for every one of these comorbid conditions — of which obesity causes or worsens — but there isn’t a single medication that’s approved other than phentermine and over-the-counter orlistat to treat obesity,” said Kushner.
Current armamentarium
According to most physicians, diet and exercise are the cornerstones of weight-loss management; however, adherence issues are troublesome. Nevertheless, currently available medications have not fared much better for various reasons. Phentermine, which was approved in 1959 for 3-month use, has not undergone any long-term clinical trials since its approval, and any use longer than 3 months is considered off-label. Orlistat (Xenical, Hoffmann-La Roche; Alli, GlaxoSmithKline) is approved for long-term use, but studies only link the drug to an extra 2.9% loss in body weight when compared with placebo. Bariatric surgery induces more weight loss but is considered an extreme method with varying long-term results.
In February, the FDA approved a lower indication for Allergan’s adjustable gastric banding system (Lap-Band). Now, adults who have a BMI between 30 and 40 and at least one obesity-related comorbid condition are eligible for the procedure. Since its approval in 2001, Allergan estimates that more than 300,000 people worldwide have the Lap-Band.
“It is interesting to me that another surgical device was approved for a lower BMI indication before we have another weight-loss drug out there,” Apovian said.
Aronne likened it to “an era where people are going to be going from Weight Watchers to the operating room.” He said surgery is clearly effective, but most patients would prefer trying medical options first.
Examining risks, overall weight loss
Concerns about adverse events associated with the investigational drugs up for approval in 2001 and 2010 took center stage at the FDA meetings. The panels discussed data that linked lorcaserin (Lorqess, Arena Pharmaceuticals) to mammary tumors, mammary adenocarcinoma and brain astrocytoma. Combination phentermine plus topiramate (Qnexa, Vivus) met similar resistance because of links to psychiatric and cognitive events, teratogenicity, metabolic acidosis and major CV events. Although naltrexone plus bupropion (Contrave, Orexigen) received recommendation for approval from an FDA advisory committee, the agency ultimately viewed the risks for elevated BP as outweighing the drug’s benefits. Finally, sibutramine (Meridia, Abbott Laboratories) was removed after 10 years of market availability after data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial linked the drug to major CV events, including nonfatal MI and stroke.
The amount of weight loss associated with obesity medications has been scrutinized as well. For example, the investigational naltrexone/bupropion combination reportedly induced a modest 5% body-weight reduction — a number that has increased to 8% in later trials — as compared with placebo.
Some said, however, that these data do not denote a significant benefit in terms of weight loss.
“These are averages,” Kushner said. “An average is a statistical analysis, but patients don’t respond as an average. They respond as individuals.”
Therefore, he said efficacy data should be interpreted in terms of responders and nonresponders. With each medication, clinical trials demonstrated that certain populations lost at least 10% of their body weight, and those are the ones for which treatment would be appropriate.
Most experts agree that one drug will not work for everyone, a reason why approval of more treatments in the weight-loss toolbox is important.
“This is how we manage hypertension; we need to start doing this with obesity. One drug isn’t going to do it. There are multiple pathways going to the brain. The desire to eat is linked to survival; we can’t just knock out one path; another path is going to come in and take over,” Apovian said.
|
|
Aronne said if 10 drugs were available for weight loss, such as with hypertension, patients would most likely be able to eat better and maintain their overall weight loss.
“If a patient is taking BP medicine and their BP is not going down, then you switch to a different category [of medication],” Aronne said. “But with BP medicine, there are a hundred drugs in nine different categories. Unfortunately, we are not in that situation.”
Part of the problem with getting new drugs approved is that investigational weight-loss drugs are not positioned for medical intervention, according to Ryan.
On the horizon
In light of the recent FDA decisions, many are uneasy about the future of obesity drugs. However, the outlook is not completely bleak.
“These drugs are still in the running,” Ryan said. “They are down, but they are not out.”
She said combination phentermine plus topiramate seems to be the most promising obesity drug. However, the future for other drugs in the current pipeline seems less positive. The FDA requested a large-scale, multicenter, randomized, CV-endpoint trial for Contrave, which will cost Orexigen millions of dollars. Because of this, and other similar instances, some question the ability of the company to proceed financially.
Nevertheless, there is hope, as other approaches populate the pipeline. Ryan said there have been great advances in understanding the biology and energy balance that underlie obesity.
|
|
“Even surgery has reinforced the importance of gut peptides in appetite regulation and weight loss. There are many avenues to pursue: gut peptides; leptin; renewed interest in brown fat,” she said.
Additionally, other research has focused on naturally occurring hormonal systems, shifting the focus way from the central nervous system as the target organ for obesity treatment, according to Smith.
Apovian said she remains positive about investigational injectable compounds. She and colleagues are conducting early trials on the roles of leptin and pramlintide in obesity. Although final results are still a few years away, it appears that weight loss may exceed 12%. Because leptin is an adipocyte hormone and pramlintide a pancreatic hormone, the adverse effect profile is “excellent” and without CV issues, she added.
“I think of the treatment gap like this: We’re going to fill it,” Smith said. “It may take a long time, but we have to stay the course and recognize that we can be smarter about it.” – by Melissa Foster and Katie Kalvaitis
For more information:
- Astrup A. Lancet. 2009;374:1606-1616.
- Bergenstal R. Lancet. 2010;376:431-439.
- CDC. MMWR. 2010;59:1-5.
- Flegal K. JAMA. 2010;303:235-241.
Disclosures: Dr. Apovian is a paid consultant for Arena Pharmaceuticals, Orexigen and Vivus. Dr. Aronne is a paid consultant for Amylin, Allergan, GlaxoSmithKline, Novo Nordisk, Orexigen and Vivus. Dr. Kushner is on the advisory board for Orexigen and Vivus. Dr. Ryan reports no relevant financial disclosures. Dr. Smith is a cosultant for Amylin and Arena Pharmaceuticals, and has received research support from Orexigen.
|
|
Most of us in cardiology deal with a lot of obese patients. The results that we see with phentermine and orlistat have been variable, but most of my patients do not stay on them long-term. Phentermine is also supposed to be given for just 3 months, but many weight loss specialists prescribe it a few weeks out of the month for long-term use. On average, orlistat produces an extra 3% loss in body weight. However, I have had a few patients who seem to respond much better. Clearly, obesity is a major cause of dyslipidemia, hypertension and diabetes. It is also directly related to the risk of atrial fibrillation.
I find that obese patients need to improve their physical activity on a consistent basis if they have any hope of maintaining weight loss. We often recommend that our patients get a pedometer and achieve a minimum number of steps a day (eg, >5,000) and work their way up to the target of 10,000 steps per day if at all possible. We would adjust these numbers downward if the patient has been very sedentary. Achieving minimum goals on a steady basis builds self-esteem. Ideally, we would like obese patients to go to a clinical exercise program at a health club.
Many of us have been impressed by the Lap-Band and related procedures. It is certainly a viable option for many patients. It would be great if we have new, safe and effective weight-loss medications approved in the coming years.
– Roger Blumenthal, MD
Cardiology Today Section Editor
Disclosure: Dr. Blumenthal reports no relevant financial disclosures.
|
|
The FDA has plugged up the anti-obesity drug pipeline for the foreseeable future, primarily for safety issues. While all of the obesity drugs available, or in the pipeline, result in fairly good weight loss, their safety profile, especially over the long term, is not favorable. The problem is that none of these drugs were developed to be used for long periods of time, but when they are discontinued, the weight comes back. New data just published out of Canada raises concerns about xenical (Alli OTC), the remaining obesity drug, indicating a risk of acute kidney injury within the first 12 months of taking xenical.
Overweight and obesity is a huge public health concern and we need to get patients to look beyond a “pill” to cure the problem. Instead of prescribing weight-loss drugs, maybe we should be prescribing exercise programs, which some insurance companies will pay for. Until there are safe, reliable obesity drugs available, getting back to the basics with “calories in and calories burned” is really all we have before bariatric surgery. Although bariatric surgery is very effective for weight loss, it isn’t for everyone, and without continued, vigilant weight management, it isn’t always durable.
– Rhonda Cooper-DeHoff, PharmD, MS
Cardiology Today Editorial Board member
Disclosures:: Dr. Cooper-DeHoff reports no relevant financial disclosures.
|
|
It appears that prominent endocrinologists cannot agree whether obesity is a disease or not. I side with Dr. Peter W.F. Wilson that obesity by itself is not a disease and is a co-morbidity in the majority of adults and patients with cardiovascular disease, hypertension, heart failure and diabetes. I believe obesity is often self inflicted by overindulgence in eating and reduced physical activity.
This article also highlights the poor track record of weight reduction by lifestyle changes alone, and the need for adjunct pharmacotherapy or surgical procedures to facilitate weight loss.
Unfortunately, as outlined in the article, pharmacotherapy to date has been disappointing due to adverse CV and neuropsychiatric events caused by weight-loss medications.
As a cardiologist, I see patients who already have coronary artery disease, peripheral arterial disease, hypertension, and HF with a co-morbidity of obesity or overweight. Weight reduction to facilitate efficacious cardiovascular therapy for underlying disease is an important consideration in these patients. I tell my patients the importance of losing weight by life style changes and regular exercise. Unfortunately, the current environment does not facilitate achievement of this goal. Exercise rehabilitation and dietary counseling on a constant basis is often expensive, and patients often do not adhere to lifestyle changes due to the lack of frequent supervision. As a cardiologist, I do seriously consider bariatric gastric reduction surgery in morbidly obese patients and gastric banding in obese patients. I do not use weight-reducing medications due to their adverse CV effects.
I feel strongly that health care dollars would be better spent by providing free dietary advice and exercise facilities and consistent supervision and encouragement by allied health care professionals, to all obese and overweight individuals.
- Udho Thadani, MD
Cardiology Today Editorial Board member
Disclosures: Dr. Thadani reports having consulted for to various pharmaceutical companies, including Gilead Sciences, Merck, Pfizer and MAP Pharmaceuticals. and I speak for Elli Lilly, BI Pharmaceuticals, Gilead Sciences, and reports giving CME talks on management of patients with ischemic heart disease , hypertension, HF and AF funded by various pharmaceutical companies.
|
|
Cardiologists would like to have more options, as any physician would, however are cognizant that many of the “off-target” adverse effects of the metabolism drugs are cardiac. Safe drug therapy remains a goal – more work is needed. The bariatric surgery trials for morbid obesity have impressed treating physicians that this is viable and life-saving option for these severe cases. Less severe obesity and overweight remains a challenge without clear risk and without clear evidence for treatment benefit. More research is needed.
- C. Noel Bairey Merz, MD
Cardiology Today Editorial Board member
Disclosures: Dr. Bairey Merz reports no relevant financial disclosures.