Pharmacotherapy Casebook A Patient-Focused
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Weight-Loss Pharmacotherapy: A Brief Review
The medical treatment of obesity is aimed at decreasing appetite, alterating absorption of calories, and increasing thermogenesis. Two agents are available for the long-term treatment of obesity: sibutramine, a centrally acting anorectic agent, and orlistat, which blocks the absorption of fat by inhibiting the enzyme lipase. Agents approved for short-term treatment include the central anorectic agents phentermine and diethylpropion. Other agents, including endocannabinoid system antagonists, anti-epileptic agents, and combination therapies, are under investigation.
The prevalence of obesity has significantly increased during the past 30 years. In 2004, > 30% of U.S. adults were classified as obese.1 Obesity is associated with many other chronic illnesses, including diabetes, hypertension, hyperlipidemia, and obstructive sleep apnea.2 Modest weight loss of 5-10% has been shown to improve insulin sensitivity, improve glycemic control, and delay the onset of diabetes.3 However, weight loss is difficult for many patients to achieve. This article reviews current pharmacological options for weight loss and provides a brief synopsis of potential future options.
Weight regulation is a complex system of multiple overlying feedback systems. In the simplest terms, obesity results from greater energy intake than energy expenditure, although this balance is affected by genetics and environmental and cultural factors. Three primary mechanisms may be altered to reverse the state of greater energy intake than energy expenditure: food intake, nutrient handling, and energy expenditure (Figure 1). Many of the available and pending weight-loss medications address one of these three mechanisms; they either reduce appetite, decrease nutrient absorption, or increase thermogenesis.
Weight-Loss Medications
Weight-loss medications have had a tainted past. Among the first medications to be used for weight loss were thyroid hormone (1893) and digoxin (1940s), with disastrous results.7 The most infamous weight-loss medication is fenfluramine (part of the phentermine-fenfluramine combination known as “phen-fen”), which was pulled from the U.S. market in 1997 because of its association with valvular heart disease.8 However, many other weight-loss medications have also been pulled from the market. The first was dinitrophenol in 1934, because of an association with the development of cataracts and neuropathy.9 In addition to prescription medications, the U.S. Food and Drug Administration (FDA) has also removed common over-the-counter weight-loss medications from the market, including ephedra (ma-huang) because of its cardiovascular effects, and phenylpropanolamine, because it increased the risk of hemorrhagic stroke.10,11
There are other negative associations with weight-loss medications. In 1937, amphetamines were used to treat obesity and were associated with abuse.12 Since that time, medications with chemical structures similar to amphetamines have been avoided, regardless of whether abuse potential exists.
In addition to the often-negative view of weight-loss medications are their relative lack of efficacy. Most weight-loss medications result in a 5-10% weight loss.13 Many of these are approved for short-term use only, and when stopped, the weight is regained. However, many patients have obesity and obesity-related comorbidities that would be improved with modest weight loss. For some of these patients, the benefits of pharmacotherapy for weight loss may outweigh the risks.
Appetite-Altering Drugs
Several categories of medications alter appetite, including the sympathomimetics, serotonergics, endocannaboid antagonists, and others. When discussing appetite, it is important to appreciate two distinct concepts of hunger. The first—satiety—refers to the sensation of feeling full when eating. A greater satiety means that a person hastens the cessation of eating. The second component of appetite is satiation, which is the length of time a person feels full after eating. Increased length of time between meals is referred to as increased satiation. If a drug reduces the time to satiety by half, but the patient eats twice as many meals, this will not lower total caloric intake. This concept is one of the reasons the phen-fen combination worked as well as it did. Phentermine is a sympathomimetic agent and increases the time between meals, whereas fenfluramine is a serotonergic agent that hastens the time to cessation of eating.14
All of the FDA-approved weight-loss medications that affect appetite are believed to act in the central nervous system to reduce caloric intake. However, there are other potential drug targets that may reduce appetite, including peripheral satiety and adipose signals.15
The centrally acting anorectics—sympathomimietic and serotonergic agents—were the first classes of medications to be approved for weight loss. As described above, both reduce caloric intake. All of the centrally acting anorectic agents except mazindol are derivatives of β-phenylethylamine similar to dopamine, norepinephrine, and epinephrine.16 Amphetamines have a similar chemical structure. These agents also have a wide range of effects. Some agents, such as phentermine, diethylpropion, and phendimetrazine, are similar to amphetamines and stimulate the release of norepinephrine, whereas other agents, such as dexfenfluramine and fenfluramine, affect serotonin release and reuptake.16,17 Sibutramine is in the middle of the spectrum and blocks the reuptake of norepinephrine, serotonin, and dopamine.18
In addition to the sympathomimietic and serotonergic agents, some anti-epileptic agents and antagonists to the endogenous endocannabinoid system (ECS) also reduce appetite. Topiramate is the most studied anti-epileptic agent in weight loss, although its exact mechanism of action is unknown.13 Another anti-epileptic agent, zonisamide, has also been found to have significant weight-loss effects.19 Zonisamide is believed to have dopaminergic and serotonergic activity, although its exact mechanism also remains unclear. No antagonist to the ECS has been approved by the FDA, although rimonabant is approved in the European Union. There have been concerns about the safety of rimonabant, namely increases in depressive and other psychiatric symptoms
Specific agents that reduce appetite
Phentermine was approved by the FDA in 1959 for short-term use in the treatment of obesity. In a recent meta-analysis, the expected weight loss greater than placebo was 3.6 kg (95% confidence interval [CI]: 0.6-6.0 kg).13 Possible side effects of phentermine include tachycardia, palpitations, elevated blood pressure, and gastrointestinal side effects. Phentermine is contraindicated in patients with recent acute myocardial infarction and uncontrolled hypertension.
Diethylpropion is similar in structure to bupropion, a drug used to treat depression and tobacco abuse. Like phentermine, diethylpropion is approved by the FDA for short-term treatment of obesity. The above-mentioned meta-analysis found that diethylpropion users lost an average of 3.0 kg (CI - 1.6 to 11.5 kg) greater than placebo.13 The side effects of diethylpropion are similar to those of amphetamines and include central nervous system stimulation, headache, insomnia, rash, and mild increases in heart rate and blood pressure.
Sibutramine is a newer agent and one of two drugs that is FDA-approved for long-term obesity treatment. The longest randomized controlled trial of sibutramine lasted 54 weeks. The recent meta-analysis found that sibutramine users lost an average of 4.5 kg (CI 3.6-5.3 kg) compared to placebo at 54 weeks.13 The most common adverse effects of sibutramine are headaches, constipation, insomnia, and nausea. In some patients, there is a risk for a substantial increase in blood pressure and heart rate. Patients should be monitored closely for increases in blood pressure and heart rate after initiation of sibutramine. Sibutramine is contraindicated for patients with uncontrolled hypertension, coronary artery disease, or other vascular disease.
Topiramate is FDA-approved for the treatment of seizures. Its exact mechanism of action is unknown. Topiramate has been noted to have a side effect of weight loss. Nine studies have assessed topiramate's weight-loss efficacy. The meta-analysis included six of these studies and found that patients on topiramate therapy lost an average 6.5 kg (CI 4.8-8.3 kg) more than those on placebo. Higher dosages are associated with greater weight loss. In addition, there is some evidence that topiramate may be efficacious in the treatment of binge eating disorder.21 The most common side effects of topiramate are fatigue, memory effects (“word searching”), parasthesias, and changes in taste. In addition, patients using topiramate are at risk for secondary acute angle glaucoma during the first month of therapy. Topiramate is also associated with decreases in serum bicarbonate and development of metabolic acidosis. Electrolytes should be monitored during topiramate therapy. However, topiramate is not FDA-approved for the treatment of obesity or binge eating disorder.
Zonisamide is another FDA-approved agent for the treatment of seizures. Zonisamide has dopaminergic and serotonergic activity.22 There is one published randomized controlled trial of zonisamide in weight loss.19 In that study, zonisamide use was associated with an average 5.0 kg (CI 0.62-9.4 kg) greater weight loss than placebo. The most common side effects of zonisamide are cognitive effects. There is also limited evidence that zonisamide may be efficacious in the treatment of binge eating disorder.23 Again, zonisamide is not FDA-approved for the treatment of obesity or binge eating disorder.
Absorption-Altering Drugs
A parallel to decreasing caloric intake is to reduce the absorption of nutrients in the gastrointestinal system. The two most common drugs that alter absorption are orlistat and acarbose. Orlistat is a lipase inhibitor that reversibly inhibits human gastrointestinal lipases and is FDA-approved for the long-term treatment of obesity. Orlistat effectively blocks 30% of fat absorption.24 It is not absorbed and therefore does not have any systemic effects, although the gastrointestinal side effects may be substantial.25 Acarbose is FDA-approved for the treatment of type 2 diabetes and is an α-glucosidase inhibitor. Acarbose delays absorption of carbohydrate in the small intestine.26 It lowers postprandial glycemia, but it has little weight-loss effect and therefore is not an obesity treatment.27
Orlistat is the most studied weight-loss medication. In a recent meta-analysis that included 29 studies, orlistat was associated with an average increased weight loss of 2.9 kg (CI 2.3-3.5 kg) over placebo. The most common side effects are diarrhea, flatulence, bloating, abdominal pain, and dyspepsia. One study suggested that psyllium (6.0 g before bed) could reduce most of the unpleasant gastrointestinal side effects.28
Thermogenesis-Increasing Drugs
No agent that specifically increases thermogenesis (basal metabolic rate) is available. However, several agents display thermogenic properties. The mechanism of weight loss with sibutramine is often proposed to be by both decreasing appetite and increasing energy expenditure through thermogenesis.29 A recent study found that the use of sibutramine increased thermogenesis after 12 weeks, whereas patients in the placebo arm had a decrease in thermogenesis.30 In addition, sibutramine has been shown to limit the decrease in resting energy expenditure often associated with weight loss.31,32
Some of the centrally acting anorectic agents also display thermogenic properties. Like sibutramine, mazindol is thermogenic in animal models.33-37 These two agents appear to have most thermogenetic properties of the centrally acting anorectics, but diethylpropion and fenfluramine also have thermogenic properties in animals.33,35 Thermogenesis is said to be present because there is stimulation of oxygen consumption or norepinephrine turnover. Unfortunately, the studies in humans are often contradictory, and therefore it is difficult to confirm the animal models of thermogenesis in humans.32,38-42
One of the most studied thermogenic agents is ephedrine (ephedra, or ma huang), which is no longer available on the U.S. over-the-counter market. Ephedrine causes weight loss by reducing appetite and increasing thermogenesis.43 Its mechanism of action is through both release of norepinephrine from the sympathetic nerve endings and as a direct agonist of β-receptors.44 The β-receptors are involved in the peripheral thermogenic effect.45 The thermogenic effects of ephedrine are synergistic with caffeine and aspirin.43,46 The use of these three medications became known as an “ECA stack.
Type : pdf
Size : 11 mb
Pages : 472
Download : yes
Read Online : yes
download from links below:
click here to download from google drive
click here to download from mediafire
read online from here
Weight-Loss Pharmacotherapy: A Brief Review
The medical treatment of obesity is aimed at decreasing appetite, alterating absorption of calories, and increasing thermogenesis. Two agents are available for the long-term treatment of obesity: sibutramine, a centrally acting anorectic agent, and orlistat, which blocks the absorption of fat by inhibiting the enzyme lipase. Agents approved for short-term treatment include the central anorectic agents phentermine and diethylpropion. Other agents, including endocannabinoid system antagonists, anti-epileptic agents, and combination therapies, are under investigation.
The prevalence of obesity has significantly increased during the past 30 years. In 2004, > 30% of U.S. adults were classified as obese.1 Obesity is associated with many other chronic illnesses, including diabetes, hypertension, hyperlipidemia, and obstructive sleep apnea.2 Modest weight loss of 5-10% has been shown to improve insulin sensitivity, improve glycemic control, and delay the onset of diabetes.3 However, weight loss is difficult for many patients to achieve. This article reviews current pharmacological options for weight loss and provides a brief synopsis of potential future options.
Weight regulation is a complex system of multiple overlying feedback systems. In the simplest terms, obesity results from greater energy intake than energy expenditure, although this balance is affected by genetics and environmental and cultural factors. Three primary mechanisms may be altered to reverse the state of greater energy intake than energy expenditure: food intake, nutrient handling, and energy expenditure (Figure 1). Many of the available and pending weight-loss medications address one of these three mechanisms; they either reduce appetite, decrease nutrient absorption, or increase thermogenesis.
Weight-Loss Medications
Weight-loss medications have had a tainted past. Among the first medications to be used for weight loss were thyroid hormone (1893) and digoxin (1940s), with disastrous results.7 The most infamous weight-loss medication is fenfluramine (part of the phentermine-fenfluramine combination known as “phen-fen”), which was pulled from the U.S. market in 1997 because of its association with valvular heart disease.8 However, many other weight-loss medications have also been pulled from the market. The first was dinitrophenol in 1934, because of an association with the development of cataracts and neuropathy.9 In addition to prescription medications, the U.S. Food and Drug Administration (FDA) has also removed common over-the-counter weight-loss medications from the market, including ephedra (ma-huang) because of its cardiovascular effects, and phenylpropanolamine, because it increased the risk of hemorrhagic stroke.10,11
There are other negative associations with weight-loss medications. In 1937, amphetamines were used to treat obesity and were associated with abuse.12 Since that time, medications with chemical structures similar to amphetamines have been avoided, regardless of whether abuse potential exists.
In addition to the often-negative view of weight-loss medications are their relative lack of efficacy. Most weight-loss medications result in a 5-10% weight loss.13 Many of these are approved for short-term use only, and when stopped, the weight is regained. However, many patients have obesity and obesity-related comorbidities that would be improved with modest weight loss. For some of these patients, the benefits of pharmacotherapy for weight loss may outweigh the risks.
Appetite-Altering Drugs
Several categories of medications alter appetite, including the sympathomimetics, serotonergics, endocannaboid antagonists, and others. When discussing appetite, it is important to appreciate two distinct concepts of hunger. The first—satiety—refers to the sensation of feeling full when eating. A greater satiety means that a person hastens the cessation of eating. The second component of appetite is satiation, which is the length of time a person feels full after eating. Increased length of time between meals is referred to as increased satiation. If a drug reduces the time to satiety by half, but the patient eats twice as many meals, this will not lower total caloric intake. This concept is one of the reasons the phen-fen combination worked as well as it did. Phentermine is a sympathomimetic agent and increases the time between meals, whereas fenfluramine is a serotonergic agent that hastens the time to cessation of eating.14
All of the FDA-approved weight-loss medications that affect appetite are believed to act in the central nervous system to reduce caloric intake. However, there are other potential drug targets that may reduce appetite, including peripheral satiety and adipose signals.15
The centrally acting anorectics—sympathomimietic and serotonergic agents—were the first classes of medications to be approved for weight loss. As described above, both reduce caloric intake. All of the centrally acting anorectic agents except mazindol are derivatives of β-phenylethylamine similar to dopamine, norepinephrine, and epinephrine.16 Amphetamines have a similar chemical structure. These agents also have a wide range of effects. Some agents, such as phentermine, diethylpropion, and phendimetrazine, are similar to amphetamines and stimulate the release of norepinephrine, whereas other agents, such as dexfenfluramine and fenfluramine, affect serotonin release and reuptake.16,17 Sibutramine is in the middle of the spectrum and blocks the reuptake of norepinephrine, serotonin, and dopamine.18
In addition to the sympathomimietic and serotonergic agents, some anti-epileptic agents and antagonists to the endogenous endocannabinoid system (ECS) also reduce appetite. Topiramate is the most studied anti-epileptic agent in weight loss, although its exact mechanism of action is unknown.13 Another anti-epileptic agent, zonisamide, has also been found to have significant weight-loss effects.19 Zonisamide is believed to have dopaminergic and serotonergic activity, although its exact mechanism also remains unclear. No antagonist to the ECS has been approved by the FDA, although rimonabant is approved in the European Union. There have been concerns about the safety of rimonabant, namely increases in depressive and other psychiatric symptoms
Specific agents that reduce appetite
Phentermine was approved by the FDA in 1959 for short-term use in the treatment of obesity. In a recent meta-analysis, the expected weight loss greater than placebo was 3.6 kg (95% confidence interval [CI]: 0.6-6.0 kg).13 Possible side effects of phentermine include tachycardia, palpitations, elevated blood pressure, and gastrointestinal side effects. Phentermine is contraindicated in patients with recent acute myocardial infarction and uncontrolled hypertension.
Diethylpropion is similar in structure to bupropion, a drug used to treat depression and tobacco abuse. Like phentermine, diethylpropion is approved by the FDA for short-term treatment of obesity. The above-mentioned meta-analysis found that diethylpropion users lost an average of 3.0 kg (CI - 1.6 to 11.5 kg) greater than placebo.13 The side effects of diethylpropion are similar to those of amphetamines and include central nervous system stimulation, headache, insomnia, rash, and mild increases in heart rate and blood pressure.
Sibutramine is a newer agent and one of two drugs that is FDA-approved for long-term obesity treatment. The longest randomized controlled trial of sibutramine lasted 54 weeks. The recent meta-analysis found that sibutramine users lost an average of 4.5 kg (CI 3.6-5.3 kg) compared to placebo at 54 weeks.13 The most common adverse effects of sibutramine are headaches, constipation, insomnia, and nausea. In some patients, there is a risk for a substantial increase in blood pressure and heart rate. Patients should be monitored closely for increases in blood pressure and heart rate after initiation of sibutramine. Sibutramine is contraindicated for patients with uncontrolled hypertension, coronary artery disease, or other vascular disease.
Topiramate is FDA-approved for the treatment of seizures. Its exact mechanism of action is unknown. Topiramate has been noted to have a side effect of weight loss. Nine studies have assessed topiramate's weight-loss efficacy. The meta-analysis included six of these studies and found that patients on topiramate therapy lost an average 6.5 kg (CI 4.8-8.3 kg) more than those on placebo. Higher dosages are associated with greater weight loss. In addition, there is some evidence that topiramate may be efficacious in the treatment of binge eating disorder.21 The most common side effects of topiramate are fatigue, memory effects (“word searching”), parasthesias, and changes in taste. In addition, patients using topiramate are at risk for secondary acute angle glaucoma during the first month of therapy. Topiramate is also associated with decreases in serum bicarbonate and development of metabolic acidosis. Electrolytes should be monitored during topiramate therapy. However, topiramate is not FDA-approved for the treatment of obesity or binge eating disorder.
Zonisamide is another FDA-approved agent for the treatment of seizures. Zonisamide has dopaminergic and serotonergic activity.22 There is one published randomized controlled trial of zonisamide in weight loss.19 In that study, zonisamide use was associated with an average 5.0 kg (CI 0.62-9.4 kg) greater weight loss than placebo. The most common side effects of zonisamide are cognitive effects. There is also limited evidence that zonisamide may be efficacious in the treatment of binge eating disorder.23 Again, zonisamide is not FDA-approved for the treatment of obesity or binge eating disorder.
Absorption-Altering Drugs
A parallel to decreasing caloric intake is to reduce the absorption of nutrients in the gastrointestinal system. The two most common drugs that alter absorption are orlistat and acarbose. Orlistat is a lipase inhibitor that reversibly inhibits human gastrointestinal lipases and is FDA-approved for the long-term treatment of obesity. Orlistat effectively blocks 30% of fat absorption.24 It is not absorbed and therefore does not have any systemic effects, although the gastrointestinal side effects may be substantial.25 Acarbose is FDA-approved for the treatment of type 2 diabetes and is an α-glucosidase inhibitor. Acarbose delays absorption of carbohydrate in the small intestine.26 It lowers postprandial glycemia, but it has little weight-loss effect and therefore is not an obesity treatment.27
Orlistat is the most studied weight-loss medication. In a recent meta-analysis that included 29 studies, orlistat was associated with an average increased weight loss of 2.9 kg (CI 2.3-3.5 kg) over placebo. The most common side effects are diarrhea, flatulence, bloating, abdominal pain, and dyspepsia. One study suggested that psyllium (6.0 g before bed) could reduce most of the unpleasant gastrointestinal side effects.28
Thermogenesis-Increasing Drugs
No agent that specifically increases thermogenesis (basal metabolic rate) is available. However, several agents display thermogenic properties. The mechanism of weight loss with sibutramine is often proposed to be by both decreasing appetite and increasing energy expenditure through thermogenesis.29 A recent study found that the use of sibutramine increased thermogenesis after 12 weeks, whereas patients in the placebo arm had a decrease in thermogenesis.30 In addition, sibutramine has been shown to limit the decrease in resting energy expenditure often associated with weight loss.31,32
Some of the centrally acting anorectic agents also display thermogenic properties. Like sibutramine, mazindol is thermogenic in animal models.33-37 These two agents appear to have most thermogenetic properties of the centrally acting anorectics, but diethylpropion and fenfluramine also have thermogenic properties in animals.33,35 Thermogenesis is said to be present because there is stimulation of oxygen consumption or norepinephrine turnover. Unfortunately, the studies in humans are often contradictory, and therefore it is difficult to confirm the animal models of thermogenesis in humans.32,38-42
One of the most studied thermogenic agents is ephedrine (ephedra, or ma huang), which is no longer available on the U.S. over-the-counter market. Ephedrine causes weight loss by reducing appetite and increasing thermogenesis.43 Its mechanism of action is through both release of norepinephrine from the sympathetic nerve endings and as a direct agonist of β-receptors.44 The β-receptors are involved in the peripheral thermogenic effect.45 The thermogenic effects of ephedrine are synergistic with caffeine and aspirin.43,46 The use of these three medications became known as an “ECA stack.