**STATEMENT ON PHENYLPROPANOLAMINE**

David E. Schteingart M.D.

Professor

Department of Internal Medicine

Division of Endocrinology and Metabolism

Director, Obesity Rehabilitation Program

University of Michigan, Ann Arbor

**Background**

It is accepted by the medical community and confirmed by consensus
development conferences that overweight and obesity are a major medical
problem because of their co-morbidities and associated risk for
increased mortality. These major co-morbidities include type 2 diabetes,
dyslipidemia, hypertension and atherosclerotic cardiovascular disease
and stroke. Excessive weight also causes osteoarthritis, obstructive
sleep apnea and alveolar hypoventilation common ailments in people with
severe obesity. There are also significant psychosocial and economic
consequences of being obese. Periodic National Health and Examination
Surveys (NHANES) have shown a progressive increase in the prevalence of
obesity in the United states over the past decade in spite of efforts at
public education and the availability of foods with reduced fat content
and clear nutrient composition labeling. Currently 22.5 % of the
population is obese and up to 24 % of American children are overweight.
Obesity afflicts in greater preponderance certain segments of the
population such as African-American, Hispanic and Native-American
citizens. These individuals also lag in health care access and proper
nutrition counseling. Obesity also has a major impact on the cost of
health care in this country. It was estimated that in 1995, the cost of
treatment of obesity amounted to approximately 100 billion dollars per
year. To make things worse, most people seeking treatment of obesity
were not covered by their health insurance and had to pay for this
treatment out of pocket.

**Treatment of obesity**

Treatment of obesity results in major health improvement an reversal of
its co-morbidities with discontinuation of treatments such as insulin
therapy and anti-hypertensive drugs. This improvement may also lead to a
decrease in mortality risk.

Treatment of obesity involves medical or surgical approaches. The
mainstay of medical treatment includes reduced calorie diets, exercise,
behavior therapy, and medications that reduce appetite or decrease food
absorption. Drug treatment of obesity by currently approved prescription
drugs is expensive and not covered by most health insurance. PPA is the
only approved over-the-counter, non-prescription appetite suppressant.
Its cost is much lower than that of most prescription drugs. PPA has
been recommended for short- term treatment of obesity based on studies
on the efficacy and safety of the drug published periodically over the
past two decades. In 11/16 double-blind placebo-controlled studies
employing 900 subjects the weight loss achieved with PPA was
significantly greater than placebo. Two of the most recent studies
published in the early 1990\'s by Greenway and by our group confirmed
the efficacy of the drug for short term treatment of obesity and its
relative safety. Our study involved 101 subjects, 15-45 % overweight but
otherwise healthy. During a double blind placebo-controlled phase, all
subjects took placebo for 2 weeks and then were randomized to placebo or
PPA for 6 weeks. The subjects on PPA showed a statistically significant
greater weight loss than the placebo group. A subset of these subjects
chose to continue on their medication, (placebo or PPA) for a total of
20 weeks. The difference in weight loss continued; the PPA group losing
5.1 kg and the placebo group 0.4 kg by the end of the study. No
difference was observed in blood pressure, pulse rate or subjective
complaints between the two groups and no serious adverse events were
reported.

These studies concluded that PPA is an effective and safe adjunct in the
treatment of obesity. These studies, because of their design, were
considered by the FDA to be the most convincing evidence of the
effectiveness and safety of PPA in the treatment of people with mild or
moderate obesity. The degree of weight loss achieved with PPA was
comparable to that obtained with currently approved prescription drugs.

**Comment on the studies on PPA and risk of hemorrhagic stroke**

I have reviewed the final report of the \"Hemorrhagic stroke project\"
by Horowitz et al. This was a study to investigate the possibility that
the use of PPA for weight reduction was associated with a higher
incidence of hemorrhagic stroke. What this study shows is that
hemorrhagic stroke is quite rare among PPA users. It is likely from
these data that subjects that took PPA had risk factors for hemorrhagic
stroke, not shared by the control group. Among the patients who took PPA
and sustained hemorrhagic stroke only one met the definition of obesity
with a BMI of 31. One other subject was in the overweight category, BMI
27.49 but the rest were either of normal weight or underweight,
suggesting the possibility that PPA was used inappropriately by these
subjects. It is important to consider the fact that other commonly
available over-the-counter drugs such as aspirin could cause serious
complications if taken inappropriately. For example, it could cause
upper gastrointestinal bleeding in somebody with peptic ulcer disease or
gastritis. In addition, any assessment of potential risks must take into
account the significant benefit conferred by PPA when used as an
appetite suppressant.

**Conclusion**

Obesity is a serious chronic medical disease without effective cure.
Weight reduction improves morbidity and mortality. As with other
pharmacological treatments, idiosyncratic reactions may lead to serious
side effects. These side effects depend on pharmacogenetic variability
and frequency of risk factors among patients. The low incidence of side
effects with PPA relative to the benefits of weight reduction should
help place this issue into proper perspective.

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