Anti-Obesity Drugs

Obesity is on the rise
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Obesity has become a prominent health problem in the last few decades[1]. It can be caused by both genetic and environmental factors; however, its recent increase is mostly attributed to the sedentary lifestyle adopted by much of the population living in industrialized areas [2]. It is associated with comorbidities such as type II diabetes and hypertension, as well as a reduced lifespan [3]. Anti-obesity drugs are an appealing solution to this significant health issue. It is important to remember that while using anti-obesity drugs, optimum weight loss results are achieved when the drugs are paired with a healthier diet and exercise. There are several types of anti-obesity drugs, such as serotonin inhibitors, androgenic drugs, stimulants and inhibitors of fat absorption [4]. Since the early 1900’s anti-obesity drugs have been tied to low efficiency and other serious side effects leading to a discontinuation of a majority of these drugs [4].

Introduction

The Need for Anti-Obesity Drugs

Obesity is a chronic condition characterized by an excess of adipose tissue [5]. An increase in the number of triglycerides in the body can result in an increase of adipose cell size (hypertrophic, mild obesity) or an increase in adipose cell numbers (hyperplastic, severe obesity) [6]. Theoretically, adipose cells can expand infinitely, however, they are limited by the amount of fat they can store [6]. The World Health Organization defines obesity in terms of Body Mass Index (BMI). An individual's BMI is calculated using his or her weight and height. A BMI over 30.0kg.m2 is considered obese and a BMI of 25-29.9ky.m2 is characterized as overweight [5]. Obesity is a significant health concern, especially when it presents with comorbidities such as diabetes and hypertension, it is also associated with increased cancer risk and gallstones [5]. The recent increase in obesity rates can be considered the direct consequence of an increase of urbanization and a move towards a more sedentary lifestyle [6]. With these recent lifestyle changes it is unlikely that at risk individuals make the necessary choices and effort to lose the excess weight. In such an environment anti-obesity drugs may provide a good solution to the obesity epidemic [7]. Anti-obesity drugs have been marketed since the early nineteenth century, however, many have subsequently failed health and safety standards across the world [7]. Anti-obesity drugs can be characterized using their mechanism of action. There are three categories, sertonergic, androgenic and fat absorption inhibitors. With a better understanding of feeding, and satiety mechanisms more effective, less health hazardous drugs have been developed. The future of anti-obesity drugs is a promising one.

Past

Fenfluramine

Heart Valves
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Fenfluramine was discontinued because it caused heart valve damage

3-trifluoromethyl-N-ethylamphetamine was introduced in 1973, it increases the release of serotonin by mobilizing serotonin stores and thereby decreasing a patient's appetite and, therefore, food intake [8]. Fenfluramine also acts by disrupting gastric motility by postponing the emptying of solid food from the stomach. It has not been found to have an effect on the emptying fluids from the stomach. It is thought that 5-hydroxytryptamine (serotonin) receptors play a role in gastric motility, this also contributes to fenfluramine’s weight loss effects [9]. Unfortunately it has been found that fenfluramine may be less effective in adolescents [10]. Fenfluramine was marketed together with phentramine under the name fen-phen [11]. This strategy allowed lower doses of each drug to be administered which decreased the side effects. Fen-phen was discontinued in 1997 with the discovery of heart valve damage, the damage was mainly associated with Flenfluramine [12]. Fenfluramin’s effect on the body is similar to amphetamines such as MDMA and cocaine and like amphetamines it can lead to a psychological dependence. It is known to increase heart rate, blood pressure and cause serious heart valve damage. Fenfluramine lost its approval from the Food and Drug Association (FDA) in 1997 and was taken off the market. Studies conducted after its removal showed that it caused substantial heart valve damage in 30% of users [13].

Phentermine

Phenyl-tertiary-butyltamine was introduced in 1959, it stimulates noradrenaline release in the hypothalamus and acts as an appetite suppressant [14]. Phentermine also stimulates adrenaline outside the brain resulting in the destruction of fat cells [14]. In addition, phentermine causes the release of dopamine and serotonin, although the amount released is too low to have a significant impact on its weight loss properties [14]. It is now marketed with the anti-epileptic drug topirmate.

Sibutramine

Sibutramine and its metbolites
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Sibutramine is converted into the active metabolites,
N-desmethyl and N-bidesmethyl sibutramine in the body,

Sibutramine was introduced in 1997, it is a selective serotonin and noradrenaline reuptake inhibitor [15]. It also inhibits the reuptake of dopamine to a lesser extent. Sibutramine works mainly as an appetite suppressant but is also known to increase thermogensis which contributes to weight loss [15]. Preliminary studies showed that sibutramine decreased obesity comorbidities such as cardiovascular disease, it was found that sibutramine caused a 4.45kg weight decrease in a year long study in individuals with a BMI of 25kg.m2 or greater [16]. In later placebo trials sibutramine was shown to increase heart rate, the placebo group did not show an increase in heart rate. Because sibutramine works on the central nervous system it appeared to result in an imbalance between peripheral stimulation and central inhibition in the sympathetic nervous system [16]. Sibutramine was discontinued in 2010 after the results of a meta analysis called sibutramine cardiovascular outcome (SCOUT) came to light. This analysis showed that sibutramine increased the risk of cardiovascular incidents [17].

Rimonabant

Mechanism for Rimonabant

Rimonabant was introduced in 2006, it is an appetite suppressant that functions as an inverse agonist for the canaboid receptor CB1 [18] . The CB1 receptor is located in gastrointestinal tract, adipose tissue and the liver and assists in the breakdown of fat and glucose. A year long study with rimbonabant resulted in an average of a 4.78kg weight loss [19].Rimonabant has been shown to cause severe psychological problems, in a meta analysis it induced depression and anxiety in patients who had no previous psychological disorders [20]. The same study showed that the placebo group did not experience the same symptoms. Subsequent studies found similar adverse psychological effects caused by this lead to the eventual discontinuation of rimonabant in most countries in 2010 [20].

Present

Orlistat

Tetrahydrolipstatin inhibits carboxyester lipase and phospholipase A2. Orlistat is in essence a fat absorption inhibitor that gained FDA approval in 2003 [21]. Phospholipase A2 in the gastrointestinal tract metabolises fatty acids into monoacylglycerols. A year long study with orlistat showed an average weight loss of 2.89kg. Orlistat was also shown to decrease the circumference of the waist, blood pressure and insulin resistance. As orlistat targets molecules in the gastrointestinal tracts, the most prominent side effects can be observed there. It may result in diarrhea, bloating and abdominal pain [22]. Symptoms subside as the usage of the drug continues. Orlistat has also been shown to help prevent weight gain after discontinuation, when compared to a placebo. Individuals who had taken orlistat for a year had significantly less weight gain than those who had been in the placebo group. To date, no serious side effects of orlistat have been discovered [22].

Qsymia

Qsymia is a combination of phentermine and topirmate. It acts as an appetite suppressant, but is also known to increase satiety [23]. It was approved by the FDA in 2012. As Topiramate is primarily used to treat epilepsy, its mechanism of action in weight loss is currently unknown. It terms of its anti-elliptic properties it is known to block voltage dependent sodium channels and glutamate receptors. It has been shown to lower blood pressure and decrease cholesterol. It has also shown promise in the control of Diabetes II [23]. Clinical trials to extensively study any potential side effects of qsymia are currently underway

Future

Metformin

Metformin
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Metformin suppresses glucose production in the liver

Metformin has primarily been used to treat Type II Diabetes. Recently, it usage in the treatment of insulin resistant diseases such as Poly Cystic Ovary Syndrome (PCOS) and Fatty Acid Liver Disease (FALD) [24]. Metformin works by suppressing glucose production in the liver, thereby decreasing blood glucose levels. It is thought to work in weight loss because of its appetite suppressing properties [25]. It is rarely shown to cause hypoglycemia. In the treatment of obesity it has also decreased cardiovascular comorbidities usually associated with obesity. Recently the use of metformin as a weight los drug has been explored. Placebo trials have shown that metformin causes weight loss in a dosage dependent manner. Metformin may lead to acidosis by the accumulation of lactate in the blood, however, trials have found that metformin causes as much lactate accumulation as other antihyperglycemic drugs and the amount is not a significant health concern[26] . It is likely that in the very near future we will see metformin prescribed an anti-obesity drug.

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