A review of pharmacologic treatments for obesity
Obesity pertains to a human condition that is mainly characterized by having a body mass index (BMI) of ³30 kg/m2 (Branca et al., 2007). The incidence of obesity has increased by 300% over the last few decades and this has prompted international groups such as the World Health Organization (WHO) to take an active stand in the campaign for the regulation of body weight and the intake of healthy foods. According to the WHO, if no measures are conducted to regulate the incidence of obesity in the general population, it is highly likely that approximately 700 million adults will be diagnosed with obesity by 2015 (WHO, 2006).
Obesity has been identified as a major factor influencing the development of medical disorders across the globe. Positive correlations have been established between obesity and cardiovascular disorders, as well as different types of cancer. A strong association has also been established between obesity and mortality, as this condition significantly reduces an individual’s life expectancy. Obesity also influences an individual’s quality of life as it affect the quality of social interactions with society. The occurrence of obesity has indirectly increased the healthcare costs of every country, as well as affected its economy due to significant loss in productivity and revenue generation.
PHARMACOLOGIC TREATMENT OF OBESITY
There are currently a number of interventions for obesity, including dietary modification, lifestyle changes, physical exercises, behavioral therapy and surgery. This literature review will focus on the most popular pharmacologic approaches that result in weight loss in an individual who has been diagnosed to be obese. Each pharmaceutical reagent offers a specific mechanism of action, as well as side effects and contraindications.
Sibutramine. One of the most common pharmacologic treatments for obesity is sibutramine, which generally reduces the amount of food that an individual consumes on a daily basis. Consequently, the administration of sibutramine significantly decreases an individual’s lipid profile, as well as regulates degree of glycemia. This drug is often taken together with a modification in the individual’s lifestyle. Sibutramine is commonly administered using 10 – 20 mg/day for 3 to 13 months (Tziomalos et al., 2009).
The reduction of weight through the administration of sibutramine occurs through the selective inhibition of the reuptake of the neurotransmitters serotonin, as well as norepinephrine in the neurons of the hypothalamus. The mechanism of action of this drug is therefore focused on the sympathetic nervous system. The presence of sibutramine also prevents the reabsorption of dopamine, another neurotransmitter traversing nerve endings. The main impact of this pharmaceutical reagent is the suppression of an individual’s appetite and thus any individual, regardless of weight issues, is expected to lose weight when given sibutramine. It has also been reported that sibutramine augments the amount of energy that is used during both basal, as well as fed states. The basal metabolic rate of an individual is also decrease when sibutramine is introduced to the body (Table 1).
In a double-blind, randomized multi-center investigation, approximately 309 obese patients were given 10 mg sibutramine for 6 months, in combination with a hypocaloric diet (Di Francesco et al., 2007). The study participants were observed to loss an average of 8.2 kilograms, as compared to the placebo group, which only showed a reduction of 3.9 kilograms. In addition, the quality of life of these individuals improved, as their waist circumference also significantly decreased. Unfortunately, the effect of the termination of sibutramine intake has not yet been established, as well as the impact of prolonged intake that exceeds 2 years.
Phentermine. Another widely used pharmaceutical drug is phentermine, which has been in circulation since 1959. This formulation is classified to as a b-phenethylamine, which acts as a stimulant that increases the production of adrenaline, as well as noradrenaline. This increased production results in the stimulation of the b-adrenergic receptors, which are responsible for decreases the appetite of an individual. Phentermine has been used in combination with other drugs and is widely marketed around the world due to its low market price.
According to a double-blind, randomized study conducted by Kim et al. (2006), phentermine was administered to approximately 68 obese individuals at a daily dose of 37.5 mg for 14 weeks. The results of such treated were compared to that collected from control subjects (Table 2). The study participants significantly lost body weight, as well as decreased in waist circumference, far higher than that observed among control subjects. Unfortunately, phentermine has been strongly associated with side effects, including the development of valvular heart disease, as well as pulmonary hypertension. In addition, the study participants on phentermine also experiences insomnia, as well as dryness of mouth. The chemical composition of phentermine is highly similar to that of amphetamines and thus an individual taking this drug may also show a heightened level of agitation. This drug is highly effective in stimulating the central nervous system and thus the arterial blood pressure, as well as the heart rate of an individual, generally increases during its administration.
Topiramate. Topiramate is a unique neurotherapeutic drug that imparts a wide spectrum of effects, including that of weight loss, as well as seizure disorders. According to Bray et al. (2003), the administration of various doses of topiramate to approximately 385 study subjects resulting in a decrease in total body weight after 24 weeks (Figure 1). The degree of weight loss was greater as compared to participants assigned to the control group. Unfortunately, the treated study participants also experienced paresthesia, as well as loss of short-term memory. The investigators suggested that these side effects may be influenced by the concentration of topiramate administered, wherein the higher doses of approximately 194 and 384 mg/day were needed to be removed from the study due to the adverse effects of the drug. One shortcoming of the study was that the total effect of topiramate was not fully determined due to the massive withdrawal of most subjects. The end-point pharmacokinetics of the drug thus remains to be determined in future studies.
Diethylpropion. The pharmaceutical drug, diethylpropion, is similar to phentermine because it also acts as a sympathomimetic reagent that suppresses an individual’s appetite. The chemical structure of diethylproprion is similar to that of bupropion, imparting its effect on the central nervous system to control depression, as well as weight loss. In a study conducted by Li et al. (2005), the administration of diethylproprion resulted in the weight loss of study participants after 6 months of treatment.
The usual dose employed for diethylpropion is 75 mg, administered in combination with changes in the lifestyle of the individual. Treatment with diethyproprion usually results in the loss of approximately 3 kilograms, as compared to placebo subjects. The mode of administration involves intake of a 25 mg capsule around 1 hour before a meal. It is also possible to take diethylpropion as a single dose of 75 mg using an extended release format. Unfortunately, no reports have been published that describe the long-term effects of this drug, although there are anecdotal publications that report the occurrence of anorexia in some individuals.
A number of side effects have also been observed from the intake of diethylproprion and most of these are associated with the central nervous system. An individual taking diethylpropion may thus experience headaches, as well as variations in arterial blood pressure. Diethylproprion is not recommended for individuals who are also taking other medications for mental health disorders, as well as anorexia and insomnia. The drug is also contraindicated for diabetes mellitus and hypertension.
Orlistat. A relatively new drug for the treatment of obesity is orlistat, which is a synthetic lipase inhibitor. This formulation is derived from Streptomyces toxytricini, a bacterial strain that is capable of inducing the hydrolysis of triglyceride molecules. It has been reported that orlistat is capable of generating loss in body weight simply by inclusion in the daily diet. However, the intake of orlistat is also associated with the development of adverse side effects, especially when the individual does not adhere to the suggested low-fat regimen of food intake.
In a study conducted by Enc et al. (2009), the mechanism of action of orlistat was investigated in terms of gastric emptying, as well as postprandial effects. The study involved the integration of orlistat to the daily meals that were classified as to provide a moderate amount of energy. Using scintigraphy as a measurement tool for the determination of gastric emptying, the study showed that orlistat is capable of shortening the secretion of the production of polypeptides associated with gluconeogenesis. In addition, the plasma response of the glucagon-like peptide was inversely correlated to orlistat administration. The results of the study thus suggested that orlistat enhances the process of gastric emptying, thus increasing the chances of load excess energy resources that could possibly be derived from heavy meals. Despite the promise results presented in this study, there is still a need to perform further investigations regarding the role of orlistat in weight control.
COMPARATIVE STUDIES OF PHARMACOLOGIC TREATMENTS FOR OBESITY
The effects of two pharmacologic treatments were recently reported by Tziomalos et al. (2009). The drugs sibutramine and orlistat were administered to obese individuals for a similar duration of period. Sibutramine, administered using a daily dose of approximately 10 to 20 mg/day for a treatment range of 3 to 12 months, showed a decrease in total body weight among study participants. On the other hand, orlistat that was administered using a daily dose of 360 mg for 3 to 6 months also showed a reduction in total body weight.
Comparison of weight loss using these two pharmaceutical reagents indicated that sibutramine was more effective than orlistat, based on the degree of weight loss among the study participants. Other studies, however, reported that sibutramine and orlistat resulted in the same degree of weight loss in their study population of approximately 259 obese individuals. There are also other reports that describe the opposite observation, wherein orlistat showed a greater degree of weight loss as compared to the effects of sibutramine. Given these discrepancies, it is possible that the employment of pharmaceutical reagents does not fully assist in the achievement of the desired goal of weight loss. A number of factors may thus influence the effectiveness and success of weight loss using pharmaceutical drugs.
Physical exercise. Obesity is generally described as an excess accumulation of body weight in an individual due to diet, hormonal or physical conditions. The administration of pharmaceutical formulations may somehow result in the loss of a modest amount of weight, yet the effect of such treatment may be maximally observed when it is combined with other activities such as physical exercise. Performance of aerobic movement stimulates the production of lactic acid, which is turn serves as a good by-product of muscle contraction. In addition, physical exercise also results in the active use of the respiratory system, as the individual attempts to take in addition air for breathing. The increased rate of respiration during exercise thus allows the body to burn any stored fats and in combination with stimulatory drugs for weight loss, obesity may be corrected in due time.
Daily diet. Another factor that may influence the effectiveness of pharmaceutical drugs for the treatment of obesity is diet. The optimal condition for a individual who needs to undergo a weight reduction program is to monitor and regulate food intake despite his active participation in drug administration. One prime example for this scenario is that of orlistat, which is a lipase inhibitor. Orlistat collects any fat globules that are derived from fat-rich food items, sequestering these molecules out of the digestive tract. In addition, the presence of orlistat also prevents maximal absorption of fat molecules by the epithelial cells of the gastrointestinal lining. However, the effect of orlistat can only be maximally observed if the individual also monitors the quality of food that he consumes on a daily basis. Such action will enhance the effects of orlistat, as it actively filters out the fat molecules that are released during the digestion of food. It may be more difficult to achieve weight loss if an individual continuously consumes fatty foods despite the intake of this lipase inhibitor.
Presence of other pharmaceutical drugs in the body. Most of the drugs administered for the treatment of obesity act directly on components of the central nervous system and the digestive system. One complication that may hinder the effect of these drugs is the presence of other pharmaceutical reagents that an individual may be concurrently taking. It should be understood that obesity is also associated with the development of other medical conditions, such as cardiovascular diseases, as well as diabetes and depression. The individual is therefore likely to be taking additional drugs together with anti-obesity formulations. The combinatorial effect of anti-obesity drugs in the presence of other reagents should thus be considered each time a prescription is made because it is possible that one of the drugs may be suppressed in terms of its mechanism of action.
Obesity pertains to the condition associated with an extremely high body mass index. A number of treatment options are currently available to correct this condition. Pharmaceutical drugs that act on the eentral nervous system are generally administered to individuals positively diagnosed as obese. Central nervous system-acting drugs include sibutramine, as well as phentermine and topiramate, imparting their effects on the secretion of adrenaline and noradrenaline. The drugs have the capability to decrease the appetite of an individual, thus decreasing the amount of food consumed on a daily basis. Another type of anti-obesity drug is the lipase inhibitor, such as orlistat. This drug sequesters fat molecules that are derived from the food consumed. These fat molecules are immediately released from the gastrointestinal system, further preventing its accumulation in the body. There have been attempts to compare the effectiveness of each anti-obesity drug, yet there is still a great need to employ a more reliable method of analysis.
Branca, F., Nikogosian, H. & Lobstein, T. (2007). The challenge of obesity in the WHO European Region and the strategies for response: Summary. ISBN 978 92 890 1407 6 (ebook), Downloaded from http://www.euro.who.int/__data/assets/pdf_file/0008/98243/E89858.pdf on June 3, 2010.
Bray, G.A., Hollander, P., Klein, S., Kushner, R., Levy, B., Fitchet, B. & Perry, B.H. for the U.S. Topiramate Research Group. (2003). A 6-Month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obesity Research, 11, 722-733.
Di Francesco, V., Sacco, T., Zamboni, M., Bissoli, L., Zoico, E., Mazzali, G., Minniti, A., Salanitri, T., Cancelli, F. & Bosello, O. for the Gruppo Italiano Studio Sibutramina: Weight loss and quality of life improvement in obese subjects treated with sibutramine: A double-blind randomized multicenter study. Annals of Nutrition and Metabolism, 51, 75–81.
Enç, F.Y., Ones, T., Akin, H.L., Dede, F., Turo?lu, H.T., Ulfer, G., Bekiro?lu, N., Haklar, G., Rehfeld, J.F., Holst, J.J., Ulusoy, N.B. & Imeryüz, N. (2009). Orlistat accelerates gastric emptying and attenuates GIP release in healthy subjects. American Journal of Physiology and Gastrointestinal Liver Physiology, 296(3), 482-489.
Kim, K., Cho, H.J., Kang, H.C., Youn, B.B. & Lee, K.R. (2006). Effects on weight reduction and safety of short-term phentermine administration in Korean obese people. Yonsei Medical Journal, 47(5), 614-625.
Li, Z., Maglione, M., Tu, W., Mojica, W., Arterburn, D., Shugarman, L.R., Hilton, L., Suttorp, M., Solomon, V., Shekelle, P.G. & Morton, S.C. (2005). Meta-analysis: Pharmacologic treatment of obesity. Annals of Internal Medicine, 142, 532-546.
Tziomalos, K., Krassas, G.E. & Tzotzas, T. (2009). The use of sibutramine in the management of obesity and related disorders: An update. Vascular Health and Risk Management, 5, 441–452.
World Health Organization. (2006). Fact sheet no. 311: Obesity and overweight. Downloaded on from http://www.who.int/mediacentre/factsheets/fs311/en/index.html on June 3, 2010.
Table 1. General effects observed in obese individuals under sibutramine treatment (Adapted from Tziomalos et al. 2009).
Table 2. Comparative results of phentermine and control groups based on specific physical features (Adapted from Kim et al., 2006).
Figure 1. Results collected from the treated of obese individuals with topiramate for 24 weeks (Adapted from Bray et al., 2003).