Three New Drugs to Combat Obesity

Regulators to Review New Drugs to Curb Appetite

A new generation of anti-obesity drugs could hit the market in coming months, the latest attempt in what has proved a difficult medicine to make safe for patients.

Currently, just two anti-obesity drugs are approved for long-term treatment, and medical practitioners say both can cause undesirable side effects in many patients. The three new medications, which have been submitted for approval to the Food and Drug Administration, also can be expected to have side effects for some patients, particularly because treating obesity with drugs involves altering the body's chemistry. But doctors say different weight-loss medications affect people differently, so having more choices should help them match a patient to a therapy that maximizes weight loss while minimizing side effects.

Obesity has many causes, and ferreting out what is going to work in individuals requires more options," said Charles Billington, a professor of medicine at the University of Minnesota and medical director of the obesity program at the Minneapolis VA Medical Center.

The FDA will need to review data on the drugs, and approval isn't assured. The agency is aware of past problems with anti-obesity drugs and plans to evaluate the new drugs under the assumption that patients likely would use them indefinitely, an FDA spokeswoman said.

The three new drugs awaiting regulatory approval are lorcaserin, manufactured by Arena Pharmaceuticals Inc., Vivus Inc.'s Qnexa, and Orexigen Therapeutics Inc.'s Contrave. The companies are small drug developers and each has held talks to partner with a larger pharmaceutical concern to help sell the products, although no agreements have been signed.

The three drugs work by affecting the patient's central nervous system to dampen appetite, Dr. Billington said. "To say that you are going to do that without any side effects is just not understanding how things work in real life," he said.

Typically, medications help moderately obese patients lose about 5% to 10% of their body weight. While not a large percentage, even that much weight loss can mean a big reduction in diabetes and cardiovascular risk, said Jeanine Albu, chief of the Metabolic Clinic at the New York Obesity Research Center at St. Luke's-Roosevelt Hospital. "The problem is keeping the weight off over time. A lot of people just gradually gain it back," said Dr. Albu.

Lifestyle Changes First

For most obesity patients, a physician's first line of treatment is to modify the person's lifestyle, including through dieting, exercise and counseling. When this isn't successful, some patients might move on to one of the few anti-obesity drugs currently available. And in cases of dangerous obesity, doctors might recommend bariatric surgery, which makes the stomach smaller. The Centers for Disease Control and Prevention estimates that about two-thirds of U.S. adults are overweight, while a third are considered obese. Obesity is defined as having a body mass index—a measure of weight in relation to height—of 30 or higher.

Some earlier diet drugs have had a mixed history. The so-called fen-phen drug combination manufactured by Wyeth, now owned by Pfizer Inc., was recalled in the 1990s after one of the medication's components was linked to heart-valve damage.

One drug currently in use also has stirred controversy. Meridia, sold by Abbott Laboratories, was pulled from the market in Europe this year after a study indicated that people with certain health problems who took the prescription drug had more heart attacks, strokes and other cardiovascular problems than people getting a placebo. In the U.S., the FDA required Abbott to put a stronger warning on the Meridia label.

Another drug currently on the market, Orlistat, which is sold over the counter as Alli by GlaxoSmithKline Plc and in prescription form as Xenical by Roche Holding AG, can cause undesirable bowel-related problems in some patients. The drugs haven't been blockbusters. Financial firm Cowen and Co. estimates that Alli had U.S. sales of $150 million last year, while Meridia and Xenical had sales of $40 million and $35 million, respectively. Doctors also regularly prescribe phentermine, which is approved for short-term use of, say, a few weeks, to treat obesity.

Arena Pharmaceuticals said its lorcaserin drug works by stimulating a neurotransmitter receptor in the brain that helps control appetite and metabolism. The mechanism is similar to the one used by a component of the recalled fen-phen drug combination, but with an important difference.

While the older medications worked on multiple versions of the body's receptors, including those in the heart, lorcaserin has a very specific target that is mostly in the brain, Arena said. Clinical trials have shown there is no increase in such heart-related side effects with the new drug, it said.

In clinical trials, patients taking lorcaserin lost about 6% of their weight on average, while patients taking a placebo lost between 2% and 3%. The most common side effects of the pill, which would be taken twice a day, were headache and nausea, although both symptoms disappeared after an initial period of use.

Combination Therapies

The two other drugs under FDA review are both combination treatments of compounds that are already on the market, but will be delivered in new dosages and methods. Using two drugs at once can be more effective in treating obesity because the brain has multiple ways of making sure that appetite is preserved, as a survival mechanism. Blocking multiple pathways, therefore, can help ensure that a therapy will work.

Orexigen said its Contrave drug works by stimulating a group of neurons in the brain, known as POMC, which, when activated, seem to result in reduced food intake and increased metabolism. The first drug in the combination, the antidepressant bupropion, turns on POMC. But that action also causes the release of a hormone that subsequently switches POMC back off in order to prevent perpetual weight loss. So the second drug in the combination, addiction-treating naltrexone, blocks that hormone in order to allow weight loss to continue, the company said.

Giving the two together as Contrave, in a sustained-release formulation taken twice a day, led to average weight loss that ranged from 5% to 9.3% of a patient's body weight in four clinical trials. Trial participants who took a placebo lost between 1.2% and 5.1% of their body weight. The medication's most common side effects were nausea, constipation and headache, all of which tended to go away after an initial period.

The third drug, Qnexa from Vivus, was the most effective in clinical trials at taking off pounds. In two separate trials, patients lost an average of 10.4% and 11%, respectively, of their body weight, while those taking a placebo lost 1.8% and 1.6%.

Vivus said Qnexa is a controlled-release formulation that combines low doses of the stimulant phentermine, which leads to the release of the stress hormone norepinephrine to cut the body's appetite, and topiramate, which works in various ways to increase satiety, or the sense of feeling full. Combining the two underlying drugs also seems to counteract some of their individual effects: Topirimate can cause cognitive slowing, which phentermine negates, and topirimate counters the blood-pressure raising of phentermine, the company said.

In clinical trials, the most common side effects of the once-daily Qnexa were constipation and dry mouth, along with mild tingling in the finger tips, all of which eventually went away.

From The Wall Street Journal, by Thomas Gryta
Reviewed / Posted by: Scott W Yates, MD, MBA, MS, FACP

Comments:

Of these three, Qnexa appears to be the most promising in general.  However, topimirate can also cause confusion also and this may limit the use of this combination.

SWY

Link Between Successful Weight Loss And Vitamin D Levels

Vitamin D levels in the body at the start of a low-calorie diet predict weight loss success, a new study found. The results, which suggest a possible role for vitamin D in weight loss, were presented at The Endocrine Society's 91st Annual Meeting in Washington, D.C.

"Vitamin D deficiency is associated with obesity, but it is not clear if inadequate vitamin D causes obesity or the other way around," said the study's lead author, Shalamar Sibley, MD, MPH, an assistant professor of medicine at the University of Minnesota.

In this study, the authors attempted to determine whether baseline vitamin D levels before calorie restriction affect subsequent weight loss. They measured circulating blood levels of vitamin D in 38 overweight men and women before and after the subjects followed a diet plan for 11 weeks consisting of 750 calories a day fewer than their estimated total needs. Subjects also had their fat distribution measured with DXA (bone densitometry) scans.

On average, subjects had vitamin D levels that many experts would consider to be in the insufficient range, according to Sibley. However, the authors found that baseline, or pre-diet, vitamin D levels predicted weight loss in a linear relationship. For every increase of 1 ng/mL in level of 25-hydroxycholecalciferol - the precursor form of vitamin D and a commonly used indicator of vitamin D status - subjects ended up losing almost a half pound (0.196 kg) more on their calorie-restricted diet. For each 1-ng/mL increase in the active or "hormonal" form of vitamin D (1,25-dihydroxycholecalciferol), subjects lost nearly one-quarter pound (0.107 kg) more.

Additionally, higher baseline vitamin D levels (both the precursor and active forms) predicted greater loss of abdominal fat.

"Our results suggest the possibility that the addition of vitamin D to a reduced-calorie diet will lead to better weight loss," Sibley said.

She cautioned, however, that more research is needed. "Our findings," she said, "need to be followed up by the right kind of controlled clinical trial to determine if there is a role for vitamin D supplementation in helping people lose weight when they attempt to cut back on what they eat."

The National Institutes of Health, the University of Minnesota, and the Pennock Family Endowment at the University of Minnesota funded this study.

Source: Aaron Lohr, The Endocrine Society

Reviewed / Posted by: Scott W. Yates, MD, MBA, MS, FACP

Adequate Vitamin D Levels May Aid Weight Loss in Obese Patients

Adequate plasma levels of vitamin D, both the precursor and active
forms, may play a role in promotion of weight loss in obese patients,
perhaps through effects on adipose metabolism, according to research
reported Thursday at The Endocrine Society's annual meeting in
Washington, D.C.

While vitamin D deficiency is associated with obesity, "there are
limited data on the temporal relationship between vitamin D and weight
loss -- an important step in establishing a cause-effect link between
vitamin D deficiency and obesity," Dr. Shalamar Sibley from the
University of Minnesota in Minneapolis told the conference.

She and colleagues investigated the temporal relationship between
baseline vitamin D levels and subsequent weight loss success in 38
overweight and obese men and women.

They measured plasma vitamin D (25-hydroxyvitamin D and
1,25-dihydroxyvitamin D) concentrations before and after an 11-week
weight loss intervention consisting of a 750 calorie per day deficit
from estimated total daily calorie needs. They used dual-energy X-ray
absorptiometry and computed tomography to measure body composition and
fat distribution.

On average, vitamin D levels in study subjects were in the insufficient
range.

According to the investigators, in separate models adjusted for gender,
baseline (pre-diet) 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
levels predicted subsequent weight loss success (p = 0.020 and p =
0.015, respectively) on a reduced calorie diet.

For each 1-ng/mL increase in level of 25-hydroxyvitamin D, obese
patients lost almost half a pound (0.196 kg) more on their
calorie-restricted diet. For each 1-ng/mL increase in
1,25-dihydroxyvitamin D, subjects lost nearly one-quarter pound (0.107
kg) more.

"Abdominal fat loss, in particular, tended to be related to baseline
vitamin D concentrations, with the effect being stronger with the active
form of vitamin D," Dr. Sibley reported. "Vitamin D status did not
predict lean body mass changes, so there was relative preservation of
lean tissue."

The researchers say studies are needed to confirm these findings and
define underlying mechanisms.

"If it is established," Dr. Sibley said, "that vitamin D does indeed
synergistically contribute to standard weight loss approaches, such as a
reduced calorie diet, then identification and treatment of inadequate
vitamin D status could ultimately have a large public health impact on
the obesity epidemic. Our findings suggest that vitamin D may play an
important role in promoting optimal weight management," she concluded.

From Reuters Health, by Megan Rauscher

Reviewed / Posted by: Scott W. Yates, MD, MBA, MS, FACP

Obesity Epidemic Increases, Mississippi Weighs In As Heaviest State

Adult obesity rates increased in 23 states and did not decrease in a
single state in the past year, according to F as in Fat: How Obesity
Policies Are Failing in America 2009, a report released today by the
Trust for America's Health (TFAH) and the Robert Wood Johnson Foundation
(RWJF). In addition, the percentage of obese or overweight children is
at or above 30 percent in 30 states.

"Our health care costs have grown along with our waist lines," said Jeff
Levi, Ph.D., executive director of TFAH. "The obesity epidemic is a big
contributor to the skyrocketing health care costs in the United States.
How are we going to compete with the rest of the world if our economy
and workforce are weighed down by bad health?"

Mississippi had the highest rate of adult obesity at 32.5 percent,
making it the fifth year in a row that the state topped the list. Four
states now have rates above 30 percent, including Mississippi, West
Virginia (31.2 percent), Alabama (31.1 percent) and Tennessee (30.2
percent). Eight of the 10 states with the highest percentage of obese
adults are in the South. Colorado continued to have the lowest
percentage of obese adults at 18.9 percent.

Adult obesity rates now exceed 25 percent in 31 states and exceed 20
percent in 49 states and Washington, D.C. Two-thirds of American adults
are either obese or overweight. In 1991, no state had an obesity rate
above 20 percent. In 1980, the national average for adult obesity was 15
percent. Sixteen states experienced an increase for the second year in a
row, and 11 states experienced an increase for the third straight year.

Mississippi also had the highest rate of obese and overweight children
(ages 10 to 17) at 44.4 percent. Minnesota and Utah had the lowest rate
at 23.1 percent. Eight of the 10 states with the highest rates of obese
and overweight children are in the South. Childhood obesity rates have
more than tripled since 1980.

"Reversing the childhood obesity epidemic is a critical ingredient for
delivering a healthier population and making health reform work," said
Risa Lavizzo-Mourey, M.D., M.B.A., RWJF president and CEO. "If we can
prevent the current generation of young people from developing the
serious and costly chronic conditions related to obesity, we can not
only improve health and quality of life, but we can also save billions
of dollars and make our health care systems more efficient and
sustainable."

The F as in Fat report contains rankings of state obesity rates and a
review of federal and state government policies aimed at reducing or
preventing obesity. Some additional key findings from F as in Fat 2009
include:

-- The current economic crisis could exacerbate the obesity epidemic.
Food prices, particularly for more nutritious foods, are expected to
rise, making it more difficult for families to eat healthy foods. At the
same time, safety-net programs and services are becoming increasingly
overextended as the numbers of unemployed, uninsured and underinsured
continue to grow. In addition, due to the strain of the recession, rates
of depression, anxiety and stress, which are linked to obesity for many
individuals, also are increasing.

-- Nineteen states now have nutritional standards for school lunches,
breakfasts and snacks that are stricter than current USDA requirements.
Five years ago, only four states had legislation requiring stricter
standards.

-- Twenty-seven states have nutritional standards for competitive foods
sold a la carte, in vending machines, in school stores or in school bake
sales. Five years ago, only six states had nutritional standards for
competitive foods.

-- Twenty states have passed requirements for body mass index (BMI)
screenings of children and adolescents or have passed legislation
requiring other forms of weight-related assessments in schools. Five
years ago, only four states had passed screening requirements.

-- A recent analysis commissioned by TFAH found that the Baby Boomer
generation has a higher rate of obesity compared with previous
generations. As the Baby Boomer generation ages, obesity-related costs
to Medicare and Medicaid are likely to grow significantly because of the
large number of people in this population and its high rate of obesity.
And, as Baby Boomers become Medicare-eligible, the percentage of obese
adults age 65 and older could increase significantly. Estimates of the
increase in percentage of obese adults range from 5.2 percent in New
York to 16.3 percent in Alabama.

Key report recommendations for addressing obesity within health reform
include:

-- Ensuring every adult and child has access to coverage for preventive
medical services, including nutrition and obesity counseling and
screening for obesity-related diseases, such as type 2 diabetes;

-- Increasing the number of programs available in communities, schools,
and childcare settings that help make nutritious foods more affordable
and accessible and provide safe and healthy places for people to engage
in physical activity; and

-- Reducing Medicare expenditures by promoting proven programs that
improve nutrition and increase physical activity among adults ages 55 to
64.

The report also calls for a National Strategy to Combat Obesity that
would define roles and responsibilities for federal, state and local
governments and promote collaboration among businesses, communities,
schools and families. It would seek to advance policies that

-- Provide healthy foods and beverages to students at schools;

-- Increase the availability of affordable healthy foods in all
communities;

-- Increase the frequency, intensity, and duration of physical activity
at school;

-- Improve access to safe and healthy places to live, work, learn, and
play;

-- Limit screen time; and

-- Encourage employers to provide workplace wellness programs.

Source: Trust for America's Health

Reviewed / Posted by: Scott W. Yates, MD, MBA, MS, FACP