Orlistat (Xenical) was approved by the FDA in 1999 for treatment of obesity. In 2007, orlistat (Alli) became available as a nonprescription formulation. The availability may pose an abuse potential for patients with eating disorders, and abuse should be considered in patients presenting with related adverse events. Orlistat is the only FDA approved drug that alters the absorption, distribution, and metabolism of food. Orlistat is a potent inhibitor of gastric and pancreatic lipase, thus reducing lipolysis and increasing fecal fat excretion.25 The drug is not systemically absorbed but exerts its effects locally in the gastrointestinal tract. It inhibits hydrolysis of dietary triglycerides and reduces absorption of the products of lipolysis, monoglycerides, and free fatty acids. Several clinical trials demonstrate that orlistat reduces gastrointestinal fat absorption by as much as 30%.177 When taken in association with a calorie restricted diet, weight loss of approximately 10% body weight can be achieved in 1 year.151 Orlistat is associated with a modestly lower weight gain over a 3 year period when compared to placebo (4.6 kg versus 7 kg, respectively).137
Orlistat should be taken only in conjunction with meals that have a high fat content; it should not be consumed in the absence of food intake. Adverse effects correlate with the amount of dietary fat consumption and include abdominal pain, oily stool, fecal incontinence, fecal urgency, flatus, and increased defecation. Systemic effects, which are rare due to the lack of systemic absorption,51,115,162 include cholestatic hepatitis and hepatocellular necrosis,115,162 but there is an inconsistent demonstration of a temporal relationship. In a cohort of nearly 16,000 patients in England, although there were no cases of serious hepatotoxicity, there were reports of aminotransferase elevations. Two of the cases were deemed as causally related to orlistat, and one had evidence of aminotransferase elevations and elevations on rechallenge.132 Concomitant use of natural fibers (6 g of psyllium mucilloid dissolved in water) may reduce the gastrointestinal side effects of orlistat.26 Because orlistat reduces absorption of fat soluble food constituents, daily ingestion of a multivitamin supplement containing vitamins A, D, and K, and β-carotene is advised to prevent resultant deficiency. Pancreatitis4 and oxalate nephropathy149 are rarely reported after orlistat use. Currently, there are no reported intentional overdoses of orlistat. There are limited data regarding unintentional pediatric exposure to orlistat, and the toxicity appears to be limited to mild gastrointestinal effects.122 In overdose and/or misuse, treatment should be responsive to clinical manifestations.
Chitosan is a weight loss dietary supplement derived from exoskeletons of marine crustaceans. It is thought to act similarly to orlistat by binding to dietary lipids in the gastrointestinal tract and reducing breakdown and absorption of fat. Animal models describe an increase in fecal fat excretion in rats administered chitosan when they are fed high-fat diets.41 The efficacy of chitosan in humans is disputed.60,112,113 Some evidence indicates that chitosan may decrease total serum cholesterol concentration in overweight people, but the majority of clinical studies indicate chitosan is ineffective for weight loss in the absence of dietary and lifestyle modifications.147 It is estimated that in the presence of chitosan, it would take more than 7 months to lose 1 pound of body fat.60 Chitosan is contraindicated in people with shellfish allergy.
Glucomannan is a dietary fiber consisting of glucose and mannose, which is derived from konjac root, a traditional Japanese food. Edible forms of glucomannan include konjac jelly and konjac flour, which are mixed with liquid prior to ingestion. Purified glucomannan is available in capsule form and is found in various proprietary products marketed for weight loss. On contact with water, glucomannan swells to approximately 200 times its original dry volume, turning into a viscous liquid. It lowers blood cholesterol and glucose concentrations and decreases systolic blood pressure,7,167 but significant weight loss benefits are not demonstrated.95 Following several reports of esophageal obstruction, glucomannan tablets were withdrawn from the market in Australia in 1985.73 Serious adverse effects are not described with encapsulated glucomannan, presumably because slower dissolution allows for gastrointestinal transit prior to expansion. Glucomannan capsules are available as a nutritional supplement in the United States, although adequate safety and efficacy studies are not published.
One of the earliest attempts at a pharmaceutical treatment for obesity was 2,4-dinitrophenol (DNP), which was popularized as a weight loss adjuvant in the 1930s.64,160 This chemical, which is used in dyes, wood preservatives, herbicides, and explosives, was never approved as a drug product. DNP was legally available as a dietary supplement prior to enactment of the US Federal Food, Drug, and Cosmetic Act of 1938 and thus remained legal. By increasing metabolic energy expenditure, it reportedly produces weight loss of 1 to 2 pounds per week in doses of 200 to 300 mg per day.31,64 DNP increases metabolic work by uncoupling oxidative phosphorylation in the mitochondria. Through this mechanism, the hydrogen ion gradient that allows ATP synthesis is destroyed and ATP production is stopped, though oxidative metabolism in the Krebs cycle continues (Chap. 13). This mechanism results in inefficient substrate utilization, and the resulting energy loss is dissipated as heat. This wastes calories but also elevates temperature and, occasionally, life-threatening hyperthermia can occur.159 In fact, DNP was reportedly administered to Russian soldiers during World War II to keep them warm during winter battles.64 Symptoms related to DNP toxicity include malaise, skin rash, headache, diaphoresis, thirst, and dyspnea. Severe toxic effects include hyperthermia, hepatotoxicity, agranulocytosis, respiratory failure, coma, and death.15,96,159 Delayed-onset cataracts were a frequent and serious complication of DNP use.15
Epidemic use of DNP occurred in Texas in the 1980s when industrial DNP was used at a physician’s weight loss center. The physician distributed DNP under the trade name, Mitcal. The fatality of a wrestler following an intentional overdose in 1984 led a Texas court to stop the use of this practice.96 DNP continues to reappear sporadically as a weight loss treatment, and cases of serious toxicity still are reported.64,127 Management should emphasize rapid cooling (Chap. 30). Benzodiazepines should also be used as an adjunct therapy for management of delirium and seizures.
Endocannabinoid Receptor Antagonists
In the past decade, the endocannabinoid system (ECS) and its involvement in weight loss sparked excitement and potential for novel xenobiotics. Endocannabinoids, which are the natural ligand for the cannabinoid receptor, have diverse effects on metabolic functions.77 The ECS contributes to the regulation of food intake, body weight, and energy balance, and it may have a role in inflammation and neuropathic pain.83,141,169,174 It has long been known that tetrahydrocannabinol, the active principle in marijuana (Cannabis sativa), stimulates appetite and is an effective antiemetic (Chap. 77).29,131
Several CB1 receptor antagonists showed promise in both animal and human studies of weight loss. Rimonabant was approved for therapeutic use in Europe and clinical trials in the United States were performed. Clinical studies note that these xenobiotics showed a significant and sustained reduction in body weight.135 There was also improvement in insulin resistance with a decline in plasma leptin, insulin, and free fatty acid concentrations, presumably due to the upregulation of the peripheral ECS system in diabetes.74,140 In the clinical trials there was a significant increase in adverse events, including anxiety and depression in the rimonabant groups. This led to a delay in the FDA’s approving this product for therapeutic use. Shortly after approval in Europe, it became evident that the effects of anxiety and depression were far greater than initially expected. Rimonabant was never approved by the FDA, and other Phase III studies, including those involving other endocannabinoid receptor antagonists (eg, tranabant), were terminated early. Rimonabant was removed from the European market. Centrally acting CB1 antagonists proved to have an unfavorable risk–benefit relationship. However, peripherally acting CB1 antagonists have shown some promise for weight loss, and further research is currently underway.48,65
Naltrexone is an opioid receptor antagonist that is currently approved by the FDA for the treatment of alcohol and opioid dependence.168 Bupropion is a norepinephrine and dopamine reuptake inhibitor that is approved for both depression and smoking cessation, and it is known to cause weight loss at therapeutic doses. The combination of naltrexone and bupropion is effective in inducing weight loss and is beneficial in other addictive disorders. The mechanisms by which naltrexone/bupropion cause weight loss is not completely understood.168 Proopiomelanocortin (POMC)-producing neurons in the hypothalamus are stimulated with bupropion, and naltrexone inhibits the opioid mediated POMC autoinhibition. This combination of stimulation and inhibition of the negative feedback loop on POMC neurons is believed to facilitate ongoing weight loss. Additionally, it is believed that there is synergism with naltrexone and bupropion in midbrain dopamine areas resulting in decreased food intake, presumably through modulation of mesolimbic reward systems.63,86,168
This potential synergistic effect has resulted in promising effects. A new drug application for the combination product of Naltrexone SR/Bupropion SR (Contrave/NB32) was submitted to the FDA in 2010.13 The Contrave Obesity Research Program consists of four 56-week, randomized, double-blind, placebo-controlled Phase III trials.63,168 The combination of naltrexone plus bupropion in these studies demonstrated a 5% to 15% weight reduction.168 The naltrexone SR 32 mg/bupropion 360 mg/day per arm resulted in significantly greater weight loss and had improvements in markers of cardiovascular risk. The combination was generally well tolerated, with nausea and headache most frequently reported.63,168 There was no increased depression or suicidality in the treatment groups.
The FDA has mandated a clinical trial evaluating cardiovascular risk of naltrexone SR 32 mg/bupropion SR 360 mg in subjects with underlying cardiovascular risk factors. The status of the FDA approval of this combination therapy is pending the results of the current clinical trial. It is unclear if the combination drug will receive FDA approval despite its promising results on weight reduction.
Adverse events from this product result from the known toxicity of each individual xenobiotic. Naltrexone is generally expected to be safe and well tolerated in opioid naive patients; however, it will cause prolonged opioid withdrawal symptoms in opioid tolerant patients and will significantly reduce the efficacy of opioids if they are required. Bupropion toxicity is well described in the literature. Seizures may occur after bupropion at doses greater than 450 mg per day.38,145 The amount of bupropion available in this formulation is of particular concern as is the potential for misuse/overdose. Bupropion toxicity is discussed in detail in Chap. 75.
Alternative Pharmaceutical Approaches
In an attempt to find the perfect therapeutic alternative for weight loss, there is an continuing approach to utilize currently approved xenobiotics for weight loss. Similar to topiramate, xenobiotics that are known to cause weight loss at therapeutic doses such as metformin, bupropion, and zonisamide, continue to be investigated for both label and off label use. Combination therapy aimed at multiple systems likely will prove most efficacious. Although these xenobiotics may provide a beneficial weight loss, each of them has their own inherent toxicities. Metformin can cause a metabolic acidosis with elevated lactate concentration, particularly in patients with underlying kidney dysfunction and after large intentional overdoses (Chap. 53). Zonisamide, an adjunct anticonvulsant that is not used commonly, is associated with adverse events including CNS depression and hypersensitivity120,175 (Chap. 48).
Future Targets for Xenobiotic Development
The desire to identify new biochemical pathways and pharmacologic approaches to weight loss began in antiquity. Research continues to evolve in an ongoing effort to determine the underlying etiology of obesity as well as develop new, more advanced pharmacologic interventions (Table 42–3).3,29,69 Gut peptides play an important physiologic role in normal gastrointestinal functions, including cessation of meals. Some gut peptides affect feeding control and show promise in the treatment of obesity.36,69,108,116
TABLE 42–3.Potential Future of Xenobiotics for Obesity ||Download (.pdf) TABLE 42–3. Potential Future of Xenobiotics for Obesity
|Drug Name ||Drug Class ||FDA Approval Status ||FDA Approved Indication ||Route of Administration |
|Pramlintide ||Synthetic analog of amylin ||Approved ||Type 1 diabetes ||Subcutaneous |
|Metreleptin ||Recombinant analog of leptin ||Phase III ||N/A ||Subcutaneous |
|Exenatide (Byetta); extended-release exenatide (Bydureon) ||Glucagonlike peptide-1 agonist ||Approved ||Type 2 diabetes ||Subcutaneous |
|PYY 3-36 ||Peptide YY ||Phase II ||N/A ||Intranasal |
|NOX-B11 ||Ghrelin antagonist ||Phase I ||N/A ||Subcutaneous |
|GSK-598809 ||Dopamine3 antagonist ||Phase I ||N/A ||Oral |
Leptin and the leptin gene are being explored as a basis for obesity and as a therapeutic strategy.28,78 Much of the enthusiasm about the potential role for leptin as an antiobesity therapy has subsided because leptin administration does not induce the expected response on weight control and is transient.134,142,161 In fact, obese people have elevated leptin concentrations, and obesity is believed to cause leptin resistance in the brain.47 Amylin is cosecreted from the β islet cells in the pancreas and contributes to short-term energy regulation. The combination of leptin and amylin reduce food intake and body weight even in the setting of leptin resistance.161 Pramlintide acetate (a synthetic analog of amylin) and metreleptin (a recombinant analog of leptin) combination therapy has been studied in animals and humans for weight loss with promising results. The combination therapy was stalled in Phase II clinical trials because of safety concerns. It remains unclear if this potential combination therapy and novel approach will be continued in drug development.161 This suggests that combination therapy in the management of obesity is increasingly important.
Ghrelin antagonists are also suggested as a possible adjunct therapy for weight loss. Ghrelin is a growth hormone releasing agent produced by the stomach that stimulates appetite.93,94,163 Data suggest that ghrelin and leptin work together to stimulate food consumption.39,107 Ghrelin antagonists may decrease the increased appetite that often occurs with dietary modifications for weight loss and such agents are under investigation.116 Neuropeptide Y, a peptide found in the arcuate and paraventricular nucleus of the hypothalamus, is a potent central appetite stimulant.
GLP-1 is produced in the brain and distal intestine. During a meal, GLP-1 concentrations increase and remain elevated for several hours after. GLP-1 inhibits food intake, inhibits glucagon secretion, decreases gastric acid secretion, and delays gastric emptying. Exendin-4, extracted from the venom of the Gila monster, is a pharmaceutically available GLP-1 agonist, exenatide (Byetta), and is approved by the FDA for diabetes mellitus. It decreases food intake and produces a 2 to 5 kilogram sustained weight loss. Extended release exenatide (Bydureon) is available and has an FDA approved indication for type 2 diabetes. It is dosed every 7 days, and although it does not have an FDA approved indication for weight loss, it will likely be used off-label for weight loss. Acute overdoses of exenatide are rarely reported; however, the potential for hypoglycemia remains a significant concern, although it has not yet been reported.30,31
Peptide YY is similar to GLP-1 and has been investigated for weight loss. Preliminary data suggest that intranasal peptide YY failed to induce a significant body weight reduction when compared to placebo and had a high incidence of nausea and vomiting.116
Because β2-adrenergic receptors mediate lipolysis in adipose tissue, β2-selective agonists also are under investigation to enhance weight loss.139 Future drug therapy may target these genes, receptors, and proteins to modify metabolism. As obesity research proceeds and the biologic basis for obesity is defined, new approaches and mechanisms for therapy may be identified.19
Hypocaloric Diets and Cathartic/Emetic Abuse
Starvation, as well as abuse of laxatives, syrup of ipecac, diuretics, and anorectics, has led to morbidity and mortality, often in young patients.56,81 Fad diets and laxative abuse should be strongly considered in young people with unexplained salt and water depletion, syncope, hypokalemia, and metabolic alkalosis. A variety of extreme calorie-restricted diets resulting in profound weight loss were very popular in the late 1970s, but reports of a possible association between these diets and sudden death followed.150 Myocardial atrophy was a consistent finding on autopsy. Torsade de pointes and other ventricular dysrhythmias may have occurred as a result of hypokalemia150,154 and protein-calorie malnutrition are proposed as causes of death.45,150, 154
Following the negative reports and FDA warnings, the enthusiasm for liquid protein diets waned. Several current diets (Atkin’s plan, South Beach diet) advocate intake of high protein, high fat, and low carbohydrates while allowing unlimited amounts of meat, fish, eggs, and cheese. Lack of carbohydrates induces ketosis, which results in salt and water depletion, giving the user the appearance of rapid weight loss. With rehydration and resumption of a normal diet, weight gain generally occurs. In addition, salt and water depletion may cause orthostatic hypotension and ureterolithiasis. Atherosclerosis and hypercholesterolemia may occur as a result of substitution of high-calorie, high fat foods for carbohydrates. Despite the rapid weight loss early on with these diets, once carbohydrates are reintroduced, weight gain occurs rapidly and significantly.46
Dieter’s teas that contain combinations of herbal laxatives, including senna and Cascara sagrada, can produce profound diarrhea, salt and water depletion, and hypokalemia. They are associated with sudden death, presumably as a result of cardiac dysrhythmias. Despite FDA warnings of the dangers of these weight loss regimens, dieter’s teas remain available in retail stores that sell nutritional supplements and are easily accessible to adolescents.
Chronic laxative use can result in an atonic colon (“cathartic bowel”) and development of tolerance, with the subsequent need to increase dosing to achieve catharsis. Because cathartics do not decrease food absorption, they have limited effects on weight control.10 Various test methods can be used to detect laxative abuse.40 Phenolphthalein can be detected as a pink or red coloration to stool or urine following alkalinization. Colonoscopy reveals the benign, pathognomonic “melanosis coli,” the dark staining of the colonic mucosa secondary to anthraquinone laxative abuse. The combination of misuse/abuse of laxatives in conjunction with orlistat has the potential to cause severe diarrhea and subsequent fluid and electrolyte imbalances. Now that orlistat is readily available, there is a greater likelihood of these two xenobiotics being used together.35
Chronic use of syrup of ipecac to induce emesis by patients with eating disorders, such as bulimia nervosa, leads to the development of cardiomyopathy, subsequent dysrhythmias, and death.56,128 Emetine, a component of syrup of ipecac, is the alkaloid responsible for the severe myopathy. Chronic administration of syrup of ipecac results in tolerance to the emetic effects and increased systemic absorption of emetine.128 Emetine can be detected in serum by high pressure liquid chromatography or thin-layer chromatography. It persists for weeks to months after chronic ingestion. In 2003, an FDA advisory committee recommended that the nonprescription drug status of syrup of ipecac be rescinded because of its use by patients with bulimic disorders.