Common disease states in gastroenterology are more effectively treated in an obese patient when weight loss is incorporated into the treatment plan. Strategies that seek to achieve weight loss improve outcomes in the treatment of hepatitis C, non-alcoholic fatty liver disease, and colorectal cancer, as examples. Pharmacologic therapy is an important adjunctive intervention that improves both short-term and long-term outcomes in the management of obese patients. This article reviews currently available drug therapy with a focus on pharmacotherapy approved long-term weight management in non-diabetic obese individuals since 2012, encouraging the use of these tools in the practice of gastroenterology.
Key points
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The gut-brain axis is a major pathway in energy metabolism and is targeted by antiobesity medications to facilitate short- and long-term weight loss.
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The use of antiobesity medication is an important adjunctive intervention in the treatment of morbid obesity.
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Medical weight management that includes pharmacologic interventions improves weight loss outcomes and clinical outcomes in the management of chronic gastrointestinal conditions including hepatitis C, nonalcoholic fatty liver disease, and colon cancer.
Introduction
Common disease states in gastroenterology are more effectively treated in an obese patient when weight loss is incorporated into the treatment plan. Strategies that seek to achieve weight loss improve outcomes in the treatment of hepatitis C, nonalcoholic fatty liver disease, and colorectal cancer. In the management of hepatitis C, obesity is a pretreatment predictor of response and is associated with a lower response to antiviral therapy. Weight reduction also reduces the risk and improves outcomes for colon cancer development. Medical weight management using only dietary modification and behavioral changes as primary methods for the treatment of obesity has been limited by a high recidivism rate and weight regain. Pharmacologic therapy is an important adjunctive intervention that improves short- and long-term outcomes in the management of obese patients. Unfortunately, many of the earlier medications approved for clinical use have been associated with adverse events and complications leading to their withdrawal from the US market. However, the recent development of highly effective pharmacotherapy with fewer side effects has generated a renewed interest in medical weight management. This article reviews currently available drug therapy with a focus on pharmacotherapy-approved long-term weight management in obese individuals without diabetes since 2012, encouraging the use of these tools in the practice of gastroenterology. As the understanding of the pathways that regulate food intake and energy expenditure increase, new drug therapies will emerge and expand the number of available tools. Certain noradrenergic sympathomimetic drugs (benzphatamine, phendimetrazine) that have been approved for short-term use are excluded from this discussion because the general use of sympathomimetic drugs for long-term weight loss is discouraged. Phentermine and tenuate are the notable exceptions.
Introduction
Common disease states in gastroenterology are more effectively treated in an obese patient when weight loss is incorporated into the treatment plan. Strategies that seek to achieve weight loss improve outcomes in the treatment of hepatitis C, nonalcoholic fatty liver disease, and colorectal cancer. In the management of hepatitis C, obesity is a pretreatment predictor of response and is associated with a lower response to antiviral therapy. Weight reduction also reduces the risk and improves outcomes for colon cancer development. Medical weight management using only dietary modification and behavioral changes as primary methods for the treatment of obesity has been limited by a high recidivism rate and weight regain. Pharmacologic therapy is an important adjunctive intervention that improves short- and long-term outcomes in the management of obese patients. Unfortunately, many of the earlier medications approved for clinical use have been associated with adverse events and complications leading to their withdrawal from the US market. However, the recent development of highly effective pharmacotherapy with fewer side effects has generated a renewed interest in medical weight management. This article reviews currently available drug therapy with a focus on pharmacotherapy-approved long-term weight management in obese individuals without diabetes since 2012, encouraging the use of these tools in the practice of gastroenterology. As the understanding of the pathways that regulate food intake and energy expenditure increase, new drug therapies will emerge and expand the number of available tools. Certain noradrenergic sympathomimetic drugs (benzphatamine, phendimetrazine) that have been approved for short-term use are excluded from this discussion because the general use of sympathomimetic drugs for long-term weight loss is discouraged. Phentermine and tenuate are the notable exceptions.
Drug targets
Obesity occurs when there is an imbalance between energy intake and energy expenditure. There are peripheral and central signals as well as hormonal and neural pathways that regulate food intake and body fat mass. Although a detailed discussion is beyond the scope of this article, clinicians should have a basic understanding of these mechanisms because the signals regulate when an individual eats, how much they eat, and when they achieve satiety. Furthermore, following intentional weight loss, these signals result in adaptations that stimulate hunger, increase food intake, reduce the metabolic rate, and predispose to weight regain. These influences directly impact the management of gastrointestinal (GI) diseases and general medical weight management. Figs. 1 and 2 summarize the interactions between the central and peripheral pathways that regulate food intake. Food intake is driven by the sum of the signals as opposed to an individual signal. There is also redundancy in the pathways such that alternate paths can override or bypass signals from the primary pathways. Leptin, derived from the adipose tissue, and insulin from the pancreas are the main long-term signals and act at the level of the arcuate nucleus in the brain. They also modulate the peripheral short-term signals that regulate food intake. In the arcuate nucleus, leptin and ghrelin interface with two major populations of neurons that result in either increased food intake or reduced food intake. The neurons that promote food intake express agouti-related peptide and neuropeptide Y. The other neurons that inhibit food intake express pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript. In addition to signals from leptin and ghrelin, these neurons are regulated by short-term signals from the periphery including glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY, and oxyntomodulin. Of physiologic and clinical significance, neurotransmitters (dopamine, serotonin, γ-aminobutyric acid [GABA], and norepinephrine) from other parts of the brain impact and regulate the POMC neuronal activity.
The short-term signals of energy intake and metabolism originate from the stomach and intestines. The stomach produces the hormone ghrelin, which stimulates hunger before a meal. It is the only orexigenic signal in the periphery. There are also mechanoreceptors on the stomach wall that signal fullness and satiety following a meal via vagal afferent neurons. The vagus nerve is involved in nutrient sensing along the length of the GI tract. It provides information to the brain regarding digestibility, pH, and perceptions of taste, and detects changes in leptin and ghrelin levels. In the proximal intestine, intraluminal nutrients (ie, protein and fat) stimulate the release of cholecystokinin from intestinal I cells, which suppresses hunger when it is transmitted centrally via the vagus nerve. There are specialized enteroendocrine cells called L cells in the gut that produce a metabolically active peptide, peptide YY, which slows intestinal motility resulting in increased satiety and is the so-called “ileal brake.” Another regulatory signal comes from incretins that are gut-derived peptide hormones that increase insulin release from the pancreas and inhibit glucagon release from the pancreas. These signals are released into circulation in proportion to the calories ingested. The net result is a lowering of the blood glucose level and modulation of the insulin signal. Incretins also slow gastric emptying and may directly reduce food intake. They are involved in vagal and central nervous system effects related to appetite regulation. The two most studied incretins are GLP-1 and glucose-dependent insulinotrophic polypeptide. They are inactivated by the enzyme dipeptidyl peptidase-4. Understanding the role of incretins in glucose homeostasis and their effect on insulin has led to the development of new drug therapies (eg, Liraglutide) used in the treatment of diabetes. Other incretins are pancreatic polypeptide, oxyntomodulin, and amylin, which will serve as future drug targets in the management of diabetes and obesity in patients without diabetes. Of interest, gut organisms or microbiota can activate the vagus nerve and may directly influence energy homeostasis. These gut organisms are thought to cause a low-grade inflammatory state that alters the signaling in the gut and contribute to the development of obesity and other conditions, such as inflammatory bowel syndrome. Hence, the emergence of prebiotics and probiotics to treat such clinical conditions.
Current antiobesity drug targets are designed to disrupt the gut-brain axis. Most agents are focused on disrupting mechanisms that control appetite and are designed to stimulate the POMC neurons promoting satiety with small food intake. The net result is less food intake and increased weight loss, particularly when there is a simultaneous increase in energy expenditure. The exception is the pancreatic and gastric lipase inhibitor, orlistat, which decreases the absorption of fat calories promoting weight loss by a reduction in caloric intake.
Drug therapy
Diethylpropion
One of the oldest drugs available is diethylpropion (Tenuate), which was approved in the 1960s for short-term use (ie, 3 months) in weight management, at a dose of 75 mg po TID, one hour before meals. It is a norepinephrine-releasing agent that typically results in a 3.0-kg weight loss above diet alone. Its use is limited by side effects including cardiac (palpitations, elevated blood pressure, ischemic events), GI (dry mouth, constipation, diarrhea), and central nervous system (anxiety, overstimulation, insomnia, dysphoria, psychosis) to name a few. Contraindications include anxiety disorders, uncontrolled hypertension, seizures, cardiac disease, hyperthyroidism, the use of monoamine oxidase inhibitors (MOAI), glaucoma, and a history of drug abuse. As with all obesity medications, use during pregnancy and breastfeeding is contraindicated.
Phentermine
Phentermine is also a norepinephrine-releasing agent similar to dietylpropion. It was also released in the 1960s for short-term use of 3 months for weight management but was withdrawn from the market because of the emergence of valvular heat disease when used in combination with fenfluramine, a serotonin 5-HT 2B receptor agonist that functioned as a serotonin reuptake inhibitor. The use of the medication and duration of therapy has been debated since the phentermine-fenfluramine (“phen-fen”) combination was withdrawn from the market but it has been safely used as a single agent for up to 1 year. As a single agent, it produces an average weight loss of 3.6 kg above diet and lifestyle changes alone. It is marketed as Adipex in 15- to 37.5-mg capsules and 37.5-mg tablets. There is a dispersible oral tablet, Suprenza, available in 15-, 30-, and 37.5-mg strengths. The side effect profile and contraindications are the same as dietylpropion given the same mechanism of action. Pregnancy and breastfeeding are contraindications.
Orlistat
Orlistat (Xenical or Alli) is a pancreatic and gastric lipase inhibitor. It prevents the absorption of approximately 30% of the fat calories in the diet, resulting in a net reduction of total calories metabolized. It was approved in 1999 as one of the first drugs for long-term medical weight management. The net weight loss above dietary management is 2.9 to 3.4 kg with mean weight loss of 2.9% to 3.4% at 1 year, at doses of 60-120 mg TID. Orlistat is associated with decreased absorption of the fat-soluble vitamins, steatorrhea, oily spotting, increased flatulence, fecal urgency, increased defecation, and fecal incontinence. In 2010, there was a black box warning added because of the occurrence of severe liver injury that had been reported rarely with use of this medication. There is also a risk of increased urinary oxalate excretion leading to oxalate nephrolithiasis and oxalate nephropathy with renal failure in some patients. During orlistat administration, the addition of a multivitamin daily but temporally separated from the orlistat dose by at least 2 hours is recommended. Contraindications include cyclosporine use, chronic malabsorption, and cholestasis. Patients taking warfarin, levothyroxine, antiepileptic drugs, paricalcitol, vitamin D analogues, and amiodarone are encouraged to avoid use of this medication. Pregnancy and breastfeeding are contraindications.
Lorcaserin
Locaserin (Belviq) is a serotonin 5-HT 2c receptor agonist that is an anorexiant. Approved in 2012 for use in chronic weight management, it may be used in obese patients with diabetes, hypertension, and/or dyslipidemia and the general obese patient. It produces weight reduction of 3.6 kg above diet alone and a 3.6% weight reduction at 1 year, at a maximal dose of 20 mg per day in 1-2 divided doses. Because the drug has a greater affinity for the serotonin 5-HT 2c receptor as opposed to the serotonin 5-HT 2B receptor (eg, fenfluramine) at therapeutic doses, the risk of valvular heart disease is thought to be low. To minimize risk of an adverse event, locaserin should be discontinued if patients do not lose 5% of the starting body weight in 12 weeks. Side effects include headache, nausea, dry mouth, fatigue, dizziness, and constipation. This medication should be used with extreme caution in patients taking selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitor/MOAI, triptans, St. John’s wort, bupropion, and dextromethorphan. Because there are multiple drug interactions, use of a drug reference or consultation with a pharmacist may be indicated. Pregnancy and breastfeeding are contraindications.
Phentermine/Topiramate
Topiramate is a GABA receptor modulator. GABA is an inhibitory neurotransmitter in the central nervous system that reduces food intake beyond the effects of the POMC and cocaine- and amphetamine-regulated transcript receptors. Topiramate is thought to reduce food intake by a variety of steps including augmentation of GABA activity. The result is appetite suppression and satiety enhancement. However, because of side effects at a therapeutic dose when used as a single agent, it is not indicated as monotherapy for weight management. At a lower dose in combination with phentermine, topiramate is approved for medical weight management. The fixed drug combination is marketed as Qsymia. The starting dose is 3.75 mg of phentermine and 23 mg of topiramate administered daily for 2 weeks. The recommended daily dose is increased to 7.5 mg of phentermine and 46 mg of topiramate. Although seldom done, the dose can be adjusted to the high-dose regimen of 15 mg of phentermine and 92 mg of topiramate if weight loss is inadequate. The weight loss with standard dosing is 6.6 kg and with the higher dosing is 8.6 kg above diet alone. The weight loss at 1 year for the standard dose and the high dose are 6.6% and 8.6%, respectively. The most common side effects reported are insomnia, dry mouth, constipation, dizziness, and dysguesia. Other side effects include adverse reactions from each of the components as noted with phentermine and topiramate components. Birth defects have been reported because of the use of this fixed-dose combination therapy. It is best to avoid use in pregnant women, those who are planning pregnancy, and those of child-bearing age. If the use of the medication is indicated in this high-risk population, contraception is encouraged. Women who become pregnant while using phentermine/topiramate are asked to enroll themselves in the AED Pregnancy Registry (1-888-233-2334). Additional information is available at www.aedpregnancyregistry.org . Additional contraindications to therapy are breastfeeding, hyperthyroidism, concurrent therapy with MOAI, and the use of sympathomimetic amines. Of interest, Qsymia is not available worldwide. The European Medicine Agency rejected its application for approval citing its adverse reactions and potential long-term effects.
Naltrexone/Bupropion
The fixed-dose combination of naltrexone-bupropion (Contrave) is administered in an increasing stair-step fashion. During Week 1, one tablet with 8 mg naltrexone and 90 mg of bupropion is given once a day. During the second week, the dose is increased to one tablet twice a day. In Week 3, two tablets are taken in the morning and one at night. By Week 4, the dose is increased to two tablets orally twice a day. At maximal therapy (32 mg of naltrexone and 390 mg of bupropion), the expected weight loss is 4.8% at 1 year. If patients have not lost 5% of their starting weight by 12 weeks, the medication should be discontinued. Because the combination drug causes moderate delay in gastric emptying, nausea with vomiting is a common side effect. Individuals may also experience constipation, headache, insomnia, and dry mouth. There may be a transient rise in blood pressure (1–2 mm Hg) and increased heart rate during the first 12 weeks of therapy. The use of this combination therapy is contraindicated in patients with uncontrolled hypertension, seizure disorders, eating disorders, drug or alcohol withdrawal, and those using MOAI, and during pregnancy and breastfeeding.
Liraglutide
Liraglutide is a GLP-1 agonist marketed under the brand name Saxenda. Although it is primarily used in the management of type 2 diabetes, it was approved for chronic weight management in 2014. Unlike the other therapies for medical weight management that are available in capsule or pill form, liraglutide is administered by subcutaneous injection once a day. However, it is generally well tolerated. The initial dose is 0.6 mg subcutaneously daily for 1 week. The dose is then increased weekly by 0.6-mg doses to the target dose of 3 mg daily. The typical weight loss is 5.8% at 1 year. Regular monitoring on this therapy is required. In 34% of patients, there is an increase in heart rate greater than 10 beats per minute. In 5%, the resting heart rate increases greater than 20 beats per minute, and in 6% there is a resting tachycardia greater than 100 beats per minute. The medication should be stopped if there is a sustained tachycardia. If a weight loss of 4% has not occurred by Week 16, the medication should be stopped. If one experiences an adverse reaction at the higher dose, the medication should be stopped because weight loss at the lower levels has not been established. Limitations to its use include injection site reaction, nausea, vomiting, pancreatitis, constipation, diarrhea, gallbladder disease, increased resting heart rate, suicidal behavior, worsening depression, unusual changes in mood or behavior, and hypoglycemia when taken in combination with other medications for diabetes. Of note, in rats and mice, liraglutide has been shown to cause thyroid cancer. Therefore, if the patient or their family members have or have had medullary thyroid cancer or multiple endocrine neoplasia type 2, the drug should not be used. The use of a different antiobesity medication should be considered if there is a history of suicidal thoughts or actions.
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