Cardiovascular System in Obesity: Effect of Treatment
Condition: Heart Diseases; Obesity; Vascular Diseases
MeSH terms: Heart Diseases; Vascular Diseases; Obesity
Study type: Interventional
Phase: Phase 2

Summary: 
      To determine the long-term efficacy of the combination therapy of phentermine and
      fenfluramine in conjunction with diet, exercise, and behavior modification in the treatment
      of simple, moderate obesity.
    

Detailed description: 
      BACKGROUND:

      Obesity is a problem of significant public health concern both in this and other western
      countries. One reason is that it is a risk factor for cardiovascular disease, most notably
      hypertension. For example, in the Framingham study it was found that relative body weight,
      weight change during observation, and skin fold thickness were related to existing blood
      pressure levels and to the subsequent rate of development of hypertension. Additionally, for
      previously normotensive individuals, the risk of developing hypertension was proportional to
      the degree of overweight. Obesity is also a major risk factor for type II diabetes mellitus.
      On the other hand, some overweight individuals are physically healthy but suffer from the
      psychosocial consequences of their condition so that losing weight would be desirable for
      them as well as for individuals more at risk for physical illness.

      Like essential hypertension, obesity is not only a chronic condition for many individuals but
      it is also a heterogeneous condition with many underlying causes and interacting factors. It
      is generally difficult to treat because it is a chronic problem, success comes slowly, and
      physicians in practice generally understand the condition rather poorly and do not manage it
      well. Results from studies of caloric restriction, behavior modification and medication have
      often been disappointing both to the subjects and their physicians. In practice, dropout
      rates from exercise programs, as well as various dietary self-help programs have been
      relatively high.

      Similarly, in clinical trials dropout rates have often been quite high. Compounding the
      problem of weight management has been a rather universal negative bias on the part of
      physicians to prescribing anorexiant medications. It was previously generally held that these
      agents were either only effective in the short term or not at all. Additionally, there has
      always been concern about the potential adverse effects of anorexiants as well as their
      potential for abuse. Physicians who used appetite suppressants often prescribed them for only
      four to six weeks which was inappropriate in the management of a chronic condition.

      In several relatively short term clinical trials (e.g., 16 weeks), it has been shown that
      appetite control medications such as fenfluramine and phentermine were more effective than
      placebo in inducing weight loss. It has been less clear from the trials performed heretofore
      how effective anorectic medications were when used as an adjunct to behavior modification and
      diet. This aspect was addressed in the first two years of the clinical trial under
      consideration here.

      A second controversial issue concerned the duration of efficacy of anorexiant agents.
      Originally it was felt that tolerance developed, hence the recommendations for short courses
      of treatment. A few long-term double-blind studies using anorexiants have since demonstrated
      that they exert beneficial effects for up to 24 weeks, as evidenced by weight loss and
      maintenance of weight loss. This was an important finding given, as noted earlier, the
      chronicity of the problem of obesity.

      The so-called stimulant anorexiants, like phentermine, are believed to act via central
      catecholamine mechanisms. Side-effects include nervousness, insomnia, increased motor
      activity and cardiovascular disturbances such as tachycardia and elevation of blood pressure.
      The latter effects led physicians to feel that their use in obese hypertensive patients was
      very limited. Fenfluramine, although chemically related to the stimulant anorexiants, appears
      to act via serotonergic mechanisms. It reportedly causes sedation, occasionally diarrhea and
      few cardiovascular effects.

      DESIGN NARRATIVE:

      Double-blind, fixed sample. After a six-week single-blind placebo controlled diet and
      behavior modification period, participants entered a parallel-group comparison of
      fenfluramine plus phentermine versus placebo. In the third and fourth years of the study,
      patients were randomly assigned to either continuous therapy or intermittent therapy. The
      intermittent therapy group received the medication for three months from April through June
      and during the period between Thanksgiving and New Year's day.

      The study completion date listed in this record was obtained from the Query/View/Report (QVR)
      System.
    

Intervention name(s): fenfluramine; phentermine
Intervention type(s): Drug; Drug
Intervention MeSH terms: Phentermine; Fenfluramine
Allocation: Randomized
Intervention model: Parallel Assignment
Primary purpose: Treatment