The term obesity is given to individuals with a body mass index (BMI) of 30 kg/m2 or greater. Obesity is due in part to an energy imbalance. Simply put, calorie consumption exceeds calorie expenditure. However, it is now well understood that genetics, metabolism, behavior, environment, culture, and socioeconomic status play a role in obesity, as well. An individual whose BMI is greater than 30 or greater than 27 with at least two comorbidities (for example, hypertension and diabetes) is considered a potential candidate for pharmacological treatment of obesity.
The majority of drugs approved to treat obesity have short-term indications for usage. However, some of the newer medications have been approved for long-term weight management. The older medications approved for short-term usage are the anorexiants phentermine and diethylpropion. There is a much larger list of anorexiants used off-label for weight loss; The lipase inhibitor, orlistat, has been available for several years, and other lipase inhibitors are being considered for approval. Recently, a serotonin agonist, lorcaserin, and a combination drug, phentermine and topiramate, were also approved for the treatment of obesity. Drugs for obesity are considered effective if they demonstrate at least a 5% greater reduction in body weight as compared to placebo (no treatment). The medications discussed in this chapter have been shown in clinical trials to help patients lose approximately 5% to 10% of their body weight.
Drugs for Obesity: ANOREXIANTS (APPETITE SUPPRESSANTS)
Focus topic: Drugs for Obesity
Phentermine [FEN-ter-meen] and diethylpropion [dye-eth-ill-PROE-peeon] are considered appetite suppressants.
- Mechanism of action: Phentermine exerts its pharmacologic action by increasing the release of norepinephrine and dopamine from the nerve terminals and by inhibiting reuptake of these neurotransmitters, thereby increasing levels of neurotransmitters in the brain. The increase in norepinephrine signals a “fight-or-flight” response by the body, which, in turn, decreases appetite. Diethylpropion has similar effects on norepinephrine. Tolerance to the weight loss effect of these agents develops within weeks, and weight loss typically plateaus. An increase in the dosage generally does not result in further weight loss, and discontinuation of the drug is usually recommended once the plateau is reached.
- Pharmacokinetics: Limited information is available regarding the pharmacokinetics of phentermine. The duration of activity is dependent on the formulation, and the primary route of excretion is via the kidneys. Diethylpropion is rapidly absorbed and undergoes extensive first-pass metabolism. Many of the metabolites are active. Diethylpropion and its metabolites are excreted mainly via the kidneys. The half-life of the metabolites is 4 to 8 hours.
- Adverse effects: All of the anorexiants are classified as controlled substances due to the potential for dependence or abuse. Dry mouth, headache, insomnia, and constipation are common adverse effects. Heart rate and blood pressure may be increased with these agents. Therefore, these drugs should be avoided in patients with a history of uncontrolled hypertension, cardiovascular disease, arrhythmias, heart failure, or stroke. Concomitant use of anorexiants with monoamine oxidase inhibitors (MAOIs) or other sympathomimetics should be avoided.
Drugs for Obesity: LIPASE INHIBITORS
Focus topic: Drugs for Obesity
Orlistat [OR-lih-stat] is currently the only available agent in a class of anti-obesity drugs known as lipase inhibitors. It is indicated for weight loss or weight maintenance. The clinical utility of orlistat is limited by gastrointestinal adverse effects.
- Mechanism of action: Orlistat is a pentanoic acid ester that inhibits gastric and pancreatic lipases, thus decreasing the breakdown of dietary fat into smaller molecules that can be absorbed. Administration of orlistat decreases fat absorption by about 30%. The loss of calories from decreased absorption of fat is the main cause of weight loss. However, adverse gastrointestinal effects associated with the drug may also contribute to an overall decreased intake of food.
- Pharmacokinetics: Orlistat is administered orally with each meal that contains fat. It has minimal systemic absorption and is mainly excreted in the feces. No dosage adjustments are required in patients with renal or hepatic dysfunction.
- Adverse effects: The most common adverse effects associated with orlistat are gastrointestinal symptoms, such as oily spotting, flatulence with discharge, fecal urgency, and increased defecation. These effects may be minimized through a low-fat diet and the use of concomitant cholestyramine. Pancreatitis and liver injury have occurred rarely in people taking orlistat. Orlistat is contraindicated in pregnancy and in patients with chronic malabsorption syndrome or cholestasis. The drug also interferes with the absorption of fat-soluble vitamins and β-carotene. Thus, patients should be advised to take a multivitamin supplement that contains vitamins A, D, E, and K and also β-carotene. The vitamin supplement should not be taken within 2 hours of orlistat. Orlistat can also interfere with the absorption of other medications, such as amiodarone, cyclosporine, and levothyroxine, and clinical response to these medications should be monitored if orlistat is initiated. The dose of levothyroxine should be separated from orlistat by at least 4 hours.
Drugs for Obesity: SEROTONIN AGONISTS
Focus topic: Drugs for Obesity
Lorcaserin [lor-KAS-er-in] is a newer serotonin agonist, with selectivity for the 2C serotonin receptor (5-HT2C). It is used for chronic weight management. Previous serotonin agonists used for weight loss were pulled from the market following an increase in potentially fatal adverse effects, including valvular heart disease. It is believed that valvulopathy, which may lead to pulmonary hypertension, is linked to 5-HT2B receptors.
- Mechanism of action: Lorcaserin selectively activates 5-HT2C receptors, which are almost exclusively found in the central nervous system. This activation, in turn, stimulates pro-opiomelanocortin neurons, which activate melanocortin receptors, thereby causing a decrease in appetite. If a patient does not lose at least 5% of their body weight after 12 weeks of use, the drug should be discontinued.
- Pharmacokinetics: Lorcaserin is extensively metabolized in the liver to two inactive metabolites that are then eliminated in the urine. Lorcaserin has not been studied for use in severe hepatic impairment and is not recommended in severe renal impairment.
- Adverse effects: The most common adverse effects observed with lorcaserin are nausea, headache, dry mouth, dizziness, constipation, and lethargy. Although rare, mood changes and suicidal ideation can occur. The development of life-threatening serotonin syndrome or neuroleptic malignant syndrome has been reported with the use of serotonin agonists. Therefore, patients should be monitored for the emergence of these conditions while on lorcaserin. Because of the increased risk of serotonin syndrome, concomitant use of lorcaserin with selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, MAOIs, or other serotonergic drugs should be avoided. As mentioned above, valvulopathy has been associated with the use of 5-HT2B receptor agonists. Although the incidence of valvulopathy was not significantly increased in studies of lorcaserin, a 5-HT2C receptor agonist, patients should still be monitored for the development of this condition. For that reason, individuals with a history of heart failure should use this agent with caution.
Drugs for Obesity: COMBINATION DRUGS
Focus topic: Drugs for Obesity
The combination of phentermine and topiramate has been approved for long-term use in the treatment of obesity. In initial studies of the anticonvulsant topiramate, it was observed that patients lost weight while taking the medication. This prompted further investigation into the use of topiramate for weight loss in obese individuals. Because of the sedating effects of topiramate, the stimulant phentermine was added to counteract the sedation and promote additional weight loss. The phentermine/topiramate combination is dosed in steps, escalating the dose every 2 weeks, depending on the response. If a patient does not achieve a 5% weight loss after 12 weeks on the highest dose of this medication, then it should be discontinued. It is also important to note that this medication should not be stopped abruptly as seizures may be precipitated. Topiramate has been associated with birth defects including cleft palate, and, thus, the combination of phentermine/topiramate is contraindicated in pregnancy. Other serious adverse effects with the topiramate component include paresthesias, suicidal ideation, and cognitive dysfunction. As discussed previously, potential adverse effects such as increased heart rate may be observed with the phentermine component. Several drug interactions may occur with this combination. Concomitant use of MAOIs should be avoided due to the possibility of serotonin syndrome with the phentermine component. The use of non–potassium-sparing diuretics with this combination may increase the risk of hypokalemia (low potassium). Topiramate is also a weak carbonic anhydrase inhibitor, and use of other carbonic anhydrase inhibitors with this combination increases the risk of kidney stones. Topiramate may reduce the efficacy of oral contraceptives, and this is a concern, given the risk of birth defects with this agent.