Ho V

HO Glycerol

Figure 8 Conversion of triglyceride to free fatty acids.

concerns about potential cardiovascular side effects and orlistat's use is limited because of patient unhappiness with the gastrointestinal side effects. Evaluation of overall weight loss with these agents is somewhat difficult to assess because of differences in study design, in placebo response, and in study length. In general, it appears that sustained weight loss of 5-10% of starting weight is about the average that can be seen with these drugs. It also appears that better results can be achieved when drug therapy is accompanied by a complete weight management program.

6.18.7 Unmet Medical Needs

As noted in Section 6.18.1, obesity has reached epidemic proportions in the developed nations of the world. From what is known about the genesis of obesity it is clear that a combination of dietary caloric restriction and exercise is the safest and surest way to achieve and maintain a healthy body weight. It is also clear that most overweight individuals cannot maintain a diet and exercise regimen that will allow them to achieve a healthy body weight in the face of a calorie-rich environment and a society that promotes a sedentary lifestyle.

Thus, pharmacotherapy would seem to be in an excellent position to aid in the battle to achieve a healthy weight. However, as pointed out in previous sections of this chapter, currently available pharmacotherapies for obesity leave large unmet medical needs. The following summarizes some of the key issues or needs regarding the unmet needs for the current pharmacotherapy for obesity.

6.18.7.1 Safety/Tolerability

Safety is a paramount concern for the pharmacologic treatment of obesity for a variety of reasons. First, it is generally agreed that obesity is typically not acutely life-threatening, that the health concerns are cumulative over time. Second, a large proportion of the treated population will be women of child-bearing age. Third, there is the potential of many patients taking pharmacotherapy for cosmetic obesity treatment rather than for medically necessary treatment. Fourth, given the large percentage of the population that is obese or overweight, the numbers of individuals that might take a compound is potentially very large, so that even a low incidence of a serious side effect will result in a large number of affected individuals. Given these concerns, an antiobesity agent has to be very safe to provide an acceptable benefit-to-risk ratio. Tolerability for antiobesity agents has to be high in order to achieve good patient compliance. If patients cannot maintain an appropriate diet and level of exercise to manage weight, it is unrealistic to expect them to comply with long-term pharmacotherapy that has any significant level of unpleasant side effects. A current example of this can be found with the lipase inhibitor orlistat. Patients do not like having to watch the amount of fat in their diets to minimize the unpleasant side effects of having unabsorbed fat pass through the intestines. A key component of safety and tolerability is that these have to be maintained over very long periods of time, i.e., periods measured in years of treatment.

6.18.7.2 Efficacy

There is a clear need for pharmacotherapies that have better overall efficacy than currently available agents. While there is continuing debate about what the minimal efficacy should be, there seems be a somewhat general consensus that pharmacotherapy should produce at least a 10% reduction in body weight in excess of that produced by placebo. Ideally, this weight loss should occur at a rate that keeps the patient motivated to continue therapy and this minimal (or better) effect should occur in a large proportion of patients taking the compound. Coupled to this is the need for durability or sustainability of effect. Once a stable weight has been achieved, it is desirable that this plateau be maintained for at least a year and preferably longer. One of the issues with the current therapies targeting central NE systems is that with time the antiobesity effect often begins to wane.

6.18.7.3 Multiple Mechanisms

As noted previously, the currently available agents that focus on neuronal systems are less than ideal because the magnitude of weight loss is generally small and the effect often diminishes with chronic treatment. Humans are programmed to eat, since survival of the species is dependent on an adequate nutritional state that supports individual survival and procreation. As such, it is not surprising that we would have multiple redundant systems that keep us eating. From an evolutionary standpoint, it would be undesirable if interfering with any one system could prevent maintenance of that adequate nutritional state, and it might be expected that chronic interference with one system would result in other components gradually adapting to minimize that effect. Thus, it is likely that adequate pharmacotherapy of obesity will require either individual molecules that have multiple pharmacologies or molecules with a single mechanism that can be combined with other molecules having different mechanisms of antiobesity action. This is analogous to other successful therapies that target neuronal systems. For example, the most efficacious treatments for schizophrenia or depression are those that target multiple different neuronal systems or processes. The success of the combination of phentermine with fenfluramine also argues for the concept of the polypharmacology approach.

6.18.7.4 Patient Selection

This is an area of unmet medical need that is certainly not unique to the treatment of obesity, and it affects each of the other areas of need described above. It is clear that genetic differences among individuals can affect the safety, tolerability, and efficacy of all drug therapies. Because of the strict requirements for a large benefit-to-risk ratio for antiobesity drugs, it will be especially important to understand genetic differences that affect antiobesity efficacy so that compounds (or mechanisms) can be selected for individual patients that have the highest likelihood of producing successful weight loss.

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