Obesity

Obesity is probably the most common chronic disease in our country. As much
as 33% of the population is over-weight, with the percentage higher among
women and minorities. Obesity results from an imbalance between energy
intake and energy expenditure. Genetic, environmental, and behavioral
factors (poor appetite control, unhealthy eating habits, lack of exercise)
all influence the balance between energy intake and output. When intake
exceeds output over the long term, the excess energy is stored as fat. Excess body fat, particularly when distributed on the upper body, increases
the risk of hypertension, coronary artery disease, non-insulin-dependent
diabetes mellitus, gallbladder disease, sleep apnea, gout, and certain types
of cancer (e.g., prostate cancer). Although obesity is a chronic disease
with adverse health consequences, in our society it carries such a stigma
that many people -- including health professionals -- don't believe that the
obese person deserves any sympathy at all, let alone medical treatment for
the condition.

Four Common Misconceptions About Obesity
David S. Weigle (University of Washington School of Medicine, Seattle)
describes four common misconceptions about obesity:
First, that body weight is not a physiologically regulated variable but is
set by acquired food habits and conscious or unconscious desires.
Second, that an individual can set his or her body weight to any desired
level without adverse effects on health.
Third, everyone who weighs more than the numbers set forth in certain life
insurance tables is at increased risk of mortality.
Fourth, that body fat distribution is not an important health consideration.
Despite the trumpeting of the popular press, obesity is not a disorder of
body weight regulation. Obese people regulate their weight appropriately,
but regulation is around an elevated set point. Body weight is usually
highly stable after adolescence, increasing slowly (by a half a pound per
year) over the lifetime. "This degree of weight stability implies a precise
match between energy intake and expenditure over a prolonged period," says
Weigle. Even a slight excess in daily energy intake, such as the calorie
content of a single soda cracker, would result in a 2-pound weight gain a
year. "This precision in balancing daily energy intake and energy
expenditure would be difficult to achieve on a purely volitional basis.

It
is more reasonable to postulate that energy balance reflects the operation
of a physiologic regulatory, or homeostatic, mechanism." This homeostatic
set point is strongly influenced by genetics, as shown by studies of twins,
adoption studies, and metabolic studies.
Weigle suggests that body weight is set at the point of balance between
various feedback loops regulating adipose mass. The genetic influence could
be mediated by circulating factors or factors that regulate satiety. Individuals with a high set point express lower amounts of these factors and
thus have to gain relatively more adipose tissue before appetite and energy
expenditure balance. It is extraordinarily difficult to "cure" obesity by
dietary energy restriction. Indeed, the vast majority of patients who lose
weight through dieting regain that weight, indicating that the
weight-regulating system is very strong. "Only persons with incredibly
strong will power or the ability to tolerate physical discomfort are likely
to be successful in this attempt to defeat a homeostatic mechanism," says
Weigle.

Dieting is not only ineffectual, it carries risks. Severely
energy-restricted or unbalanced diets are linked to deficiency syndromes,
gallstones, arrhythmias, and sudden cardiac death. Even balanced diets lead
to chronic fatigue, impaired concentration, cold intolerance, mood changes,
and malaise as weight drops below the set point. Decreases in fat-free mass
are associated with loss of muscle strength and endurance. Calorie
restriction in children can restrict the growth of lean muscle mass, not a
good way to prevent obesity in adulthood. Cycles of dietary deprivation
followed by refeeding -- "yo-yo" dieting -- may contribute to hypertension,
congestive heart failure, and peripheral edema. And yo-yo dieting may
enhance metabolic efficiency, thus promoting weight gain. It may also lead
to low self-esteem as the dieter fails to either lose weight or maintain a
weight loss. Finally, health-care providers with unrealistic expectations
about weight loss may fail to treat true health hazards, such as
obesity-related diabetes, hypertension, and hyperlipidemia.

Weight reduction is usually recommended for patients whose weight is 20% or
more above desirable the weights listed in the Metropolitan Life Insurance
Company tables, although increased mortality is associated with weights more
than 40% above tabulated weights. Moreover, data used to formulate these
tables were taken from several studies, some with inadequate follow-up, and
some with inadequate control for confounding factors such as age, race,
smoking, body fat distribution, blood pressure, alcohol use, total and
HDL-cholesterol levels, gallbladder disease, blood glucose, and
triglycerides.

Body fat distribution has been widely overlooked, although
excess abdominal visceral fat predisposes to coronary disease,
hyperinsulinemia, and hyperlipidemia.

Molecular biology will ultimately provide the "cure" for obesity. In the
mean time, says Weigle, managing obesity involves recognizing that the
health hazards of moderate obesity may have been somewhat overstated and
probably do not justify calorie-restricted diets that are ineffective,
counter-productive, and associated with adverse effects. Proper food choices
and regular aerobic exercise are preferable to calorie restriction. When
body weight drops below the set point by exercise, energy expenditure
appears to adapt to the new weight, unlike weight loss by calorie
restriction, which elicits strong counterregulatory mechanisms. Exercise
also has other important benefits. Since upper body obesity carries higher
risks, patients with central obesity, particularly younger patients, should
be targeted (waist-to-hip ratio greater than 0.95 in men and greater than
0.85 in women). Weight reduction won't change the waist-to-hip ratio, but
absolute weight loss does help. Health professionals should stress exercise
and correct food choices, keep dietary weight loss goals moderate, and treat
obesity-related disorders such as hypertension, hyperglycemia, and
hyperlipidemia rather than waiting for the pounds to "melt away." (Weigle
DS. West J Med. 1990; 153: 421-428. Leibel RL. West J Med. 1990; 153:
429-431. NIH Panel. Ann Intern Med. 1993; 119: 764-770.)

The Public Nature of Obesity
Obesity is a physical disability that is intensely stigmatized in our
society. Studies have shown a striking inverse relationship between obesity
and socioeconomic status in the developed world, especially among women. Gortmaker et al. found that being overweight during adolescence has a
particularly deleterious effect on subsequent socioeconomic attainment. They
studied the relationship between overweight (body-mass index above the 95th
percentile for age and sex -- which in many cases is not even obese) and
educational attainment, marital status, household income, and self-esteem in
10,039 randomly selected individuals aged 16 to 24 years in 1981. To assess
the social consequences of obesity, the investigators compared disability
from obesity with that associated with other forms of chronic illness.
The prevalence of overweight was 3.4% in males and 3.0% in females (5.8% in
black females versus 2.5% in non-Hispanic whites).

Seven years later, the
overweight women were less educated (0.3 fewer years of school), less likely
to be married (10%), had lower household incomes ($6,710 less), and had 10%
higher rates of household poverty than women who had not been overweight,
independent of baseline socioeconomic status and aptitude test scores. Interestingly, the investigators found no evidence of an effect of
overweight on self- esteem. Similar trends (although weaker) were found
among the men. It has been said that obesity is due to low socioeconomic
status, yet the results of this study indicate that the inverse is also
true: low socioeconomic status is influenced by obesity.

It has been said that obesity causes chronic health problems that influence
job status, yet subjects with chronic health problems who were not obese did
not suffer from the same low attainments. The final hypothesis -- that
obesity is a stigma that results in discrimination -- is a likely
explanation for the social disability. It is the public nature of obesity
that invites discrimination. The US Equal Opportunity Commission, responding
to complaints of widespread discrimination against obese persons, has now
declared obesity a protected category under the federal Americans With
Disabilities Act. (Gortmaker SL et al. N Engl J Med. 1993: 329: 1008-1012.)

In a recent letter in JAMA, Robert Yaes wrote, "Certainly, at a time when it
is fashionable to claim that alcoholism and drug abuse are illnesses whose
treatment should be covered by health insurance, it is inconsistent to blame
fat people for their own condition." While it's possible to lose weight by
decreasing food intake and increasing exercise, "consciously overriding
one's homeostatic control mechanisms requires constant attention and
vigilance, which takes time and energy away from other duties. As soon as
that vigilance is relaxed, the natural control mechanism will once again
take over." Yaes, a physician who is himself obese, concluded, "In our
culture, obesity is perceived as more of a cosmetic problem than a medical
problem. The majority of patients who enter weight-control programs do so
because of concerns about their physical attractiveness, notÉtheir health. This perception could partially explain why so few physicians and so many
charlatans are involved in the treatment of obesity." (Yaes RJ. JAMA. 1993;
270: 1423.)

Combination Drug Therapy for Obesity
Obesity is a chronic disease that requires lifelong management. Drug
treatment can play an important role in any management strategy, and
combination therapy with two anorectic drugs may be the best approach. Combining two anorectics permits reducing the dose of both agents, which
reduces adverse effects.

Physicians who prescribe appetite-control drugs
should plan to continue therapy for at least 5 to 10 years. (It's either
that or plan for long-term drug therapy for obesity-related disorders such
as hypertension, hyperlipidemia, and diabetes.)
Centrally acting drugs that promote weight loss include agents that act at
adrenergic receptors in the brain (e.g., sympathomimetic amines such as
amphetamine) and agents that act at serotonergic receptors (e.g.,
fenfluramine, fluoxetine). Although most serotonergics are approved only as
antidepressants, they do induce weight loss in the short term. Weight loss
slows after the first few months, is minimal by the 6th to 10th months, and
is maintained only so long as the drug is taken, with immediate reversal of
the weight loss upon drug discontinuation. The sympathomimetic amines
(Schedule IV, low abuse potential) include phentermine (Fastin/SmithKline
Beecham), mazindol (Sanorex/Sandoz, Mazanor/Wyeth-Ayerst), and
diethylpropion (Tenuate/Marion Merrell Dow). One sympathomimetic amine with
no abuse potential is phenylpropanolamine. Generally safe and efficacious,
phenylpropanolamine can cause transient hypertensive reactions (although
obese persons appear to be the least sensitive to the pressor effects of the
drug, presumably because of higher baseline blood pressure). Patients taking
any sympathomimetic should be monitored for hypertensive effects and
associated risks. It should be noted that obesity itself increases the risk
of stroke (both hemorrhagic and thrombotic), and weight loss reduces this
risk.

Several promising anorectics are under investigation. One is d-fenfluramine
(not to be confused with the racemic mixture, d/l-fenfluramine, available in
the United States as Pondimin). Although d-fenfluramine induces weight loss,
no reduction in food intake or increase in energy expenditure appears to
account for the loss, suggesting that the drug acts by potentiating the
thermic effects of food. Also under investigation is sibutramine, a
monoamine that blocks the reuptake of norepinephrine and, to a lesser
extent, serotonin and dopamine. Other promising agents include
chlorocitrate, which inhibits gastric emptying, and tetrahydrolipstatin,
which inhibits gastrointestinal lipase, thus blocking hydrolysis of
triglycerides, decreasing absorption of ingested fat, and increasing fecal
fat content.

Until the biochemists and pharmacologists come up with the ideal anorectic,
combination therapy with existing agents is a good approach to treating
obesity.

Successful regimens include fenfluramine 20 mg twice daily in
combination with phentermine 15 mg twice daily or with phenylpropanolamine
25 mg three times daily before meals; and phentermine 15 mg twice daily plus
phenylpropanolamine 25 mg three times daily. Weintraub et al. studied the
effects of phentermine 15 mg/day plus fenfluramine 60 mg/day (versus
placebo) in 121 patients 120% to 180% of ideal weight. After 34 weeks of
drug therapy or placebo therapy, along with calorie restriction, behavior
modification, and exercise, patients in the treated group had lost an
average of 15.9% of initial weight, compared with an average loss of 5.9% in
the placebo group. Patients continued in the study for up to 3Ęyears. Weight
loss slowed (and in some cases reversed) after week 20, but drug treatment
helped many patients maintain their weight loss. (Weintraub et al. Clin
Pharmacol Ther. 1992; 51: 586-594; 595-601; 602-607.)

At any given time, up to 40% of women (44% of high school girls) and 24% of
men are trying to lose weight. Many of these people do not need to lose
weight, and of those that do, the majority will fail. But this failure
should not lead medical professionals to abandon their obese patients. According to physician Arthur Frank (George Washington University Obesity
Management Program), obesity is an orphan disease of monumental size: "We
are much better at managing patients even though we are only a little bit
closer to understanding the mystery of how we weigh what we weigh. We should
not leave the mystery to the profiteers and quacks." (Frank A. JAMA. 1993;
269: 2132-2133. NIH Panel. Ann Intern Med. 1993; 119: 764-770. Blackburn GL
et al. Drug Ther. 1993; 23: 17-29. Bray GA. Ann Intern Med. 1993; 19:
707-713.)

Does Aminophylline Cream Really Shrink Thighs?
An obesity researcher reported at a recent scientific meeting that a topical
preparation of aminophylline, applied to the thighs, has an interesting
effect: it shrinks fat cells. Aminophylline, the ethylenediamine salt of
theophylline, has long been used as a bronchodilator for symptomatic relief
of asthma. Frank Greenway (Harbor-UCLA Medical Center in Los Angeles) and
George Bray (Director, Louisiana State University's Pennington Biomedical
Research Center) have been studying the effects of their "patented"
aminophylline cream in topical application to the thighs. At the annual
meeting of the North American Association for the Study of Obesity, Greenway
described results from two studies, each involving 12 women. In the first
study, the women applied 5 mL of aminophylline cream each day to one thigh
and a placebo cream to the other.

After 5 weeks, the treated thighs had
shrunk in circumference an average of one half inch. One woman withdrew from
the trial because of skin irritation. In the second study, a less potent
cream produced even more promising results: a 1.5- inch reduction in the
treated thighs. The cream reportedly reduced thigh size even in women who
didn't lose weight. The researchers speculated that the reduction in thigh
size is due to loss of fat. Greenway said the cream probably wouldn't work
on fat elsewhere on the body, because it appears effective only for the type
of tissue found in the thighs. The aminophylline cream is currently licensed
to an entrepreneur, and "could be marketed as a cosmetic fairly soon."
(Annual scientific meeting of the North American Association for the Study
of Obesity, Milwaukee, WI, October 1993.).