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Pharmacologic Treatment of Obesity

, MD, MS and , M.D.

Author Information

Last Update: August 7, 2017.

ABSTRACT

The Federal Drug Administration (FDA) has approved several new medications for the treatment of obesity in the past five years. Using pharmacotherapy for weight management is consistent with treating obesity as a chronic disease that requires a multifaceted approach including behavioral intervention, dietary change, and appropriate medical intervention. Current guidelines recommend that individuals who fail to respond to lifestyle interventions after 6 months of treatment, and have a BMI of > 30 kg/m2 or a BMI of > 27 kg/m2 with an obesity-related comorbidity may be considered for weight loss medication treatment. The anti-obesity medications reviewed in this chapter include the FDA-approved medicines for chronic weight management, FDA-approved medicines for short-term use of weight management, and off-label use of medicines for weight control.

INTRODUCTION

Obesity is now recognized as a major pandemic of the 21st century afflicting both developed and developing countries, contributing to both an increasing chronic disease prevalence and draining economic resources. The World Health Organization (WHO) defines a person with a BMI of 30 kg/m2 or more as obese and person with a BMI between 25 and 30 kg/m2 as overweight. BMI should be used as a crude measurement keeping in mind certain populations are prone to the complications of obesity at lower BMI’s, such as people of South Asian descent (1). During 2013-2014, the prevalence of obesity was 36.5% among U.S. adults and medical costs associated with obesity were estimated at $147 billion in in 2008 US dollars (2). The prevalence of childhood obesity has remained fairly stable from 2011-2014 at about 17% and affects about 12.7 million children and adolescents. Once thought to be a predicament of affluent countries, overweight and obesity are now on the rise in developing countries (3). World Health Organization data reports that overweight and obesity are the fifth leading risk for global deaths. At least 2.8 million adults die each year as a result of being overweight or obese. In addition, 44% of the diabetes burden, 23% of the ischemic heart disease burden and between 7% and 41% of certain cancer burdens are attributable to overweight and obesity (4).

The association between obesity, particularly intra-abdominal/visceral fat and the risk of developing cardiovascular disease (CVD), type 2 diabetes, osteoarthritis, certain forms of cancer, sleep apnea, asthma and nonalcoholic fatty liver disease (NAFLD) has been well established (5,6). Cytokines, such as interleukin 6, tumor necrosis factor alpha, resistin and plasminogen activation inhibitor-1, secreted from fat cells have been implicated in the pathogenesis of these diseases, in part, by promoting local and systemic states of inflammation and thrombosis (7-9). A reduction in body weight of 5-10% significantly lowers inflammatory and pro-thrombotic makers, as well as chronic disease incidence (10,11).

Obesity Treatment Options

Lifestyle interventions including changes in diet and physical activity remain the cornerstone of treatment for overweight and obese individuals. However, lifestyle modifications have not been effective in providing lasting weight loss success. Studies demonstrate that behavioral interventions aimed at reducing calorie intake and increasing calories expended in daily physical activities can result in at best, a 5-8% mean body weight loss during the first six months of treatment. However, one-third to two-thirds of lost weight is regained within one-year following end of treatment, and that almost all weight is regained within 5 years (12).

Overlapping neurohormonal mechanisms aimed at maintaining fat mass as a survival measure, as well as several environmental obstacles in our “obesigenic” environment, have been identified as promoting weight regain and making weight maintenance challenging (13,14). More aggressive treatment of obesity appears necessary. The National Heart, Lung and Blood Institute of the National Institutes of Health, recommends that for individuals who fail to respond to lifestyle interventions after 6 months of treatment, and have a BMI of > 30 kg/m2, or a BMI of > 27 kg/m2 with weight-associated comorbidities, may be considered for weight loss medication treatment (15).

Health care professionals should be familiar with the basic principles regarding the pharmacotherapy of obesity. The goal of treatment is not only to reduce weight, but more importantly to improve the comorbid conditions associated with obesity, such as hyperglycemia, hyperlipidemia, and heart disease, as well as reduce mortality. Patients and physicians should appreciate the concept that obesity is a chronic disease that will require long-term treatment. They should also understand that the efficacy of the current medication options is limited to 5-10% body weight loss in the majority of successful patients. Thus, medication should not be viewed as a panacea for obesity treatment, but as in other chronic diseases, as a next-step treatment option for those continuing a healthy lifestyle regiment, including an increase in daily activity and a calorie-deficit diet. Pharmacotherapy can also be considered an adjunct to bariatric surgery when additional weight loss is required or to prevent weight regain after weight loss surgery.

Pharmacological Obesity Treatment Options

Prior to 2012, the only weight loss medicines on the market approved for long-term use by the Federal Drug Administration (FDA) was sibutramine (trade name Meridia, approved in 1997) and orlistat (trade name Xenical/ Alli, approved in 1999) (16). Xenical remains on the market as described below, but sibutramine (a centrally acting serotonin-norepinephrine reuptake inhibitor) was removed from the both the European and US markets in 2010 after results of an outcome study in patients with high-risk cardiovascular conditions, known as the SCOUT trial (17). This study reported that patients with preexisting cardiovascular conditions had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause when treated with sibutramine. It was surprising to experts in the field that sibutramine would be removed from the market based on results of a study that administered the medication to a high-risk population: those with type 2 diabetes and cardiovascular disease. In the SCOUT trial, patients with type 2 diabetes without cardiovascular disease (an appropriate target population for sibutramine) experienced statistically significant weight loss, no increase in adverse cardiovascular events, and a decrease in mortality compared with the placebo group through much of the trial (18).

It has only been within the past 15-20 years that the endogenous systems influencing body weight regulation have been elucidated. Fortunately, advances in research and development of medications targeting these endogenous systems has led to the approval of two new obesity medications by the US in 2012 (phentermine/topamax combination, marketed as Qsymia, and lorcaserin, marketed as Belviq) and a third new weight loss medication in 2014 (liraglutide 3.0, marketed as Saxenda).

FDA-APPROVED MEDICATIONS FOR WEIGHT MANAGEMENT

Orlistat

Orlistat (trade name Xenical) promotes weight loss by inhibiting gastrointestinal lipases, thereby decreasing the absorption of fat from the gastrointestinal tract. On average, 120 mg of orlistat taken three times per day will decrease fat absorption by 30% (19). Orlistat has been found to be more effective in inhibiting the digestion of fat in solid foods, as opposed to liquids (20). Orlistat as a lower dose of 60 mg 3 times daily, called Alli, is approved for over-the-counter use in the United States (21).

Efficacy:

Several trials have supported orlistat’s efficacy as an aid to weight loss and maintenance. Rossner et al (22) found that subjects receiving orlistat lost significantly more weight in the first year of treatment, and fewer regained weight during the second year of treatment than those taking placebo. Subjects taking orlistat had significantly lower serum levels of Vitamins D, E, and B-carotene. However, these nutritional deficiencies are easily treated with oral multivitamin supplementation. Sjostrom et al (23) demonstrated similar results over a two-year period. Subjects in the orlistat group lost significantly more weight in the first year (10.2 vs. 6.1%) and regained half as much weight during the second year of treatment, as compared to the placebo group.

Effect on Metabolic Profile:

In addition to promoting weight loss and maintaining lost weight, orlistat has been shown to improve insulin sensitivity and lower serum glucose levels. In a 2-year trial, Davidson et al (24) reported less weight regain rates in patients maintained on a 120 mg three times per day dose of orlistat, as compared to those on placebo. In addition, subjects in the orlistat group had lower levels of serum glucose and insulin. In the 4-year Xendos (25) study conducted in Sweden, the cumulative incidence of diabetes was 9.0% in the placebo plus diet and lifestyle group and 6.2% in the subjects receiving orlistat. This outcome corresponds to a risk reduction of 37.3% (P = 0.0032)

Hollander el al (26) studied patients with obesity and type 2 diabetes who were not receiving insulin treatment. Orlistat resulted in improved glycemic control, determined via serum blood glucose levels and HbA1c measurements. Reductions in total cholesterol, LDL cholesterol, triglyceride levels, and apolipoprotein B were also noted (26). Kelley showed similar benefits in obese insulin-requiring patients with type 2 diabetes (27). Lindgarde examined the impact of orlistat on cardiovascular profiles in obese subjects with at least one of the following: type 2 diabetes, hypercholesterolemia, and hypertension. Orlistat use was associated with greater weight loss outcome, as well as reductions in HbA1c, LDL, and total cholesterol (28).

Safety and Side-Effects:

The gastrointestinal side effects of orlistat including fatty/oily stool, fecal urgency, oily spotting, increased defecation, fecal incontinence, flatus with discharge, and oily evacuation are the main reason for discontinuation of therapy. These symptoms are usually mild to moderate and decrease in frequency the longer the medication is continued. Cavaliere (29) conducted a study to see if concomitant use of natural fibers (psyllium mucilloid) would ameliorate the adverse gastrointestinal events. These researchers found that the subjects who received psyllium experienced far fewer symptoms while taking Orlistat at a dosage of 120 mg three times daily. Only 29% of those taking psyllium with orlistat had GI events compared to 71% of the patients taking placebo along with orlistat.

Phentermine/Topiramate:

The controlled-release, single-tablet combination phentermine plus topiramate (trade name Qsymia) was approved by the FDA in 2012 as a long-term treatment for obesity for adults with a body mass index ≥ 30 kg/m2 or with a BMI ≥27 kg/m2 with at least one weight-related comorbidity. Phentermine is thought to promote weight loss by increasing norepinephrine (more than dopamine) release and decreasing its uptake in hypothalamic nuclei, leading to a decrease in food intake (30). It also acts as an adrenergic agonist that activates the sympathetic nervous system and increases resting energy expenditure (31). Topiramate is an FDA-approved medicine for epilepsy and migraine prophylaxis that has been shown to reduce body weight by promoting taste aversion and decreasing caloric intake (32). Phentermine-topiramate is available in 4 doses: 3.75/23 mg (starting dose), 7.5/46 mg (lowest treatment dose), 11.25/69 mg or 15/92 mg (maximum treatment dose).

Efficacy:

Multiple Phase 1, 2, and 3 studies including more than 5000 subjects have evaluated the efficacy and safety of phentermine/topiramate combination therapy. The one-year EQUIP trial, a phase three 56-week randomized controlled trial enrolled 1267 patients with obesity (mean BMI of 42.0 kg/m2) and showed 3.5% in the starting dose group (3.75 mg P /23 mg) and 9.3% placebo-subtracted weight loss in the top treatment dose (15 mg/92 mg) group (33). The 52-week CONQUER trial randomized 2487 patients with obesity and a mean BMI of 36 kg/m2 with comorbidities including hypertension, dyslipidemia, prediabetes, diabetes, or abdominal obesity to either placebo, mid-dose treatment dose (7.5mg /46 mg), or maximum treatment dose (15/92 mg) with results showing 6.6% and 8.6% placebo-subtracted weight loss in the mid and maximum dose arms, respectively (34). A two-year extension of the CONQUER trial was published (SEQUEL) demonstrating 2-year mean placebo subtracted weight loss of 7.5% in the mid-dose group and 8.7% in the maximum-dose group and (35).

Effect on Metabolic Profile:

Improvement in systolic and diastolic blood pressure, triglyceride levels, and greater increases in HDL were seen in subjects treated with phentermine plus topiramate compared with placebo in both the EQUIP and CONQUER trials (33,34). Improvements in fasting glucose and insulin levels were seen in the SEQUEL study and a 54% and 76% reduction in progression to type 2 diabetes in the two treatment groups was noted in subjects without diabetes at baseline (35).

Safety and Side Effects:

Phentermine-topiramate is not recommended for patients with significant cardiac history such as coronary disease and uncontrolled hypertension. Phentermine/topiramate exposure carries an increased risk of cleft lip/palate in infants exposed to the combination drug during the first trimester of pregnancy. Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it. It is also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken monoamine oxidase inhibitors within 14 days. Topiramate can increase the risk of acidosis and renal stones so should be used cautiously in patients have had stones previously (36).

There is a step-wise dosage titration when using phentermine-topiramate in order to mitigate side effects, which include paresthesia’s, dizziness, dry mouth, constipation, dysguesia, insomnia, and anxiety. The initial dose of phentermine-topiramate is 3.75/23 mg daily for 14 days, followed by 7.5/46 mg daily thereafter. If after 12 weeks a 3 percent loss in baseline bodyweight is not achieved, the dose can be increased to 11.25/69 mg for 14 days, and then to 15/92 mg daily. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine-topiramate should be discontinued gradually because rapid withdrawal of topiramate may provoke seizures.

Phentermine/topiramate exposure carries an increased risk of cleft lip/palate in infants exposed to the combination drug during the first trimester of pregnancy. Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it. Clinicians who prescribe phentermine-topiramate and pharmacists who dispense it should enroll in a Risk Evaluation and Mitigation Strategy (REMS), which includes education on prescribing information, monitoring during treatment and side effects.

Lorcaserin:

Lorcaserin (trade name Belviq), a selective serotonin receptor agonist, was approved by the FDA in 2012 as a long-term treatment for obesity for adults with a BMI ≥ 30 kg/m2 or with a BMI ≥ 27 kg/m2 with at least one weight-related comorbidity. Lorcaserin has an ~15-100 fold selectively of the central serotonin 5-HT2C receptor over the 5-HT2A and 5-HT2B receptors (37). It reduces appetite by binding to the 5-HT2C receptors on anorexigenic pro-opiomalocortin (POMC) neurons in the hypothalamus (38). Lorcaserin now comes in a 10 mg tablet meant to be taken twice daily and a once daily 20 mg XR tablet.

Efficacy:

In the phase 3 trial, BLOSSOM, patients were treated with placebo, lorcaserin 10 mg once daily, or lorcaserin 10 mg twice daily. After one year, the group assigned to lorcaserin 10 mg twice daily showed an average placebo-subtracted weight loss of 3.1% (29). Another phase 3 double-blind, randomized, placebo-controlled trial, BLOOM, included 3,182 overweight or obese adults who received either lorcaserin 10 mg or placebo twice daily for 52 weeks, in conjunction with diet and exercise (39). At week 52, all subjects were re-randomized to either placebo or lorcaserin for an additional year. At 1 year, the average placebo-subtracted weight loss was 3.6% and 47% of the subjects taking lorcaserin lost >5% as compared to 20.5% in the control group. Subjects who showed a weight loss of >5% in year 1 and were maintained on lorcaserin treatment in year 2 were able to maintain their weight loss better than those who had been switched to placebo.

Effect of Metabolic Profile:

The BLOOM study results also showed significant improvements in HbA1c, total cholesterol, blood pressure, triglycerides, and heart rate in the lorcaserin vs. placebo group (39). The BLOOM-DM study was conducted in obese subjects with type 2 diabetes. This trial showed that at 52 weeks, 37.5% of patients treated with lorcaserin 10 mg twice daily showed a weight loss of >5%, which was more than twice the percentage in the placebo group (40). There was also a reduction of HbA1c of 0.9% in those on lorcaserin as compared to 0.4% reduction in the placebo group.

Safety and Side Effects:

The most common adverse reactions reported in those taking lorcaserin include headache, dizziness, fatigue, nausea, dry mouth, and constipation. A potentially life-threatening side effect from lorcaserin is serotonin syndrome. Patients on serotonin reuptake inhibitors may be at increased risk for this side effect with lorcaserin. Use of lorcaserin with selective serotonin reuptake inhibitors (SSRIs) has not been investigated. Based on the mechanism of action of lorcaserin and the potential for serotonin syndrome, lorcaserin should be used with extreme caution in combination with other drugs that affect serotonin neurotransmitter systems such as triptans, monamine oxidase inhibitors (MAOIs), SSRIs, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and St. Johns Wort (41).

Increased risk of serotonin-associated cardiac valvular disease has been reported by the previously available weight-loss medications fenfluramine and dexfenfluramine (42). These drugs resulted in nonselective serotonergic receptor activation, including the 5-HT2B receptor located on cardiac valves. Due to its selective agonism of the 5-HT2C receptor, lorcaserin should not be associated with cardiac valvular effects and the lorcaserin development program has focused on excluding this possibility. To date, no statistically significant difference in echocardiographic findings for aortic insufficiency or mitral regurgitation has been noted in lorcaserin vs. placebo in studies up to two years in duration (43,44). Longer term studies to further exclude risk are planned.

Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it.

Bupropion/Naltrexone

The combination tablet of bupropion and naltrexone (trade name Contrave) was FDA approved for weight loss in September 2014. Bupropion’s primary mechanism of action is as a reuptake inhibitor of dopamine and norepinephrine that promotes activation of the central melanocortin pathways (45). The second component is naltrexone, a pure opioid receptor antagonist that diminishes the auto-inhibitory feedback loop on neurons activated by bupropion, thereby allowing for sustained weight loss (46). Bupropion/naltrexone comes in tablets containing 8 mg of naltrexone HCl and 90 mg of bupropion HCl. The recommended starting dose is 1 tablet daily and increasing by 1 tablet each week until a total dose of 2 tabs twice daily is reached (total 32 mg naltrexone/360 mg bupropion).

Efficacy:

Four 56-week multicenter, double-blind, placebo-controlled trials (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of bupropion/naltrexone in conjunction with lifestyle modification compared to a placebo-controlled cohort of 4536 patients. The COR-I, COR-II, and COR-BMOD trials enrolled patients with BMI 30 kg/m² or greater or overweight (BMI 27 kg/m² or greater) and at least one comorbidity (47-49). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m² with type 2 diabetes with or without hypertension and/or dyslipidemia (50). The primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight. In the 56-week COR-I trial, significantly greater mean weight loss (6.1%) occurred in patients assigned to naltrexone 32 mg/bupropion 360 mg dose compared with the placebo group (1.3%) (47). The clinically significant cut-off of 5% reduction in body weight from baseline occurred in 48% of active treatment group (naltrexone 32 mg/bupropion 360 mg) patients vs. 16% of placebo treated patients. Similar weight loss efficacy after 56 weeks of the same dose of bupropion/naltrexone was reported in COR-II (48) and COR-Diabetes (50) trials, but both placebo and bupropion/naltrexone groups achieved greater weight loss (-5.2% and -9.3% respectively) after 1 year when they were given an intensive behavior modification program (49).

Effect on Metabolic Profile:

In all of the COR trials, secondary cardiovascular endpoints were met, including statistically significant greater improvements in waist circumference (WC), visceral fat, HDL cholesterol, and triglyceride levels in the participants treated with the naltrexone 32 mg/bupropion 360 mg dose compared with placebo-treated participants (47-50). Participants with diabetes in the COR-Diabetes trial using bupropion/naltrexone also showed a significantly greater 0.6% reduction in HbA1c from baseline, compared to a 0.1% reduction in placebo (50).

Safety and side effects:

The most common side effects of bupropion/naltrexone include nausea/vomiting, constipation, headache, dizziness, insomnia, and dry mouth. Medication interactions include MAO inhibitors (use during or within 14 days of administration), opioids and opioid agonists (including partial agonists) that are inactive in the presence of naltrexone, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs. Bupropion/naltrexone should be avoided in patients with uncontrolled hypertension, history of seizures, if there is a history of bulimia or anorexia nervosa, and those who need narcotics for pain control.

The FDA recommends monitoring patients for worsening or emergence of suicidal thoughts or behaviors and women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it.

Liraglutide 3.0:

Liraglutide 3.0 mg (trade name Saxenda) was approved by the US FDA in December 2014. Liraglutide is a GLP-1 receptor agonist that has been used for type 2 diabetes in doses up to 1.8 mg. In animal studies, peripheral administration of liraglutide results in uptake in specific brain regions regulating appetite, including the hypothalamus and brainstem (51). In a short-term study (5 weeks) involving obese individuals without diabetes demonstrated that liraglutide 3.0 mg/day suppressed acute food intake, subjective hunger, and delayed gastric emptying (52). Conversely, energy expenditure in subjects treated with liraglutide 3.0 mg/day decreased, even when corrected for weight loss (52), which was probably reflective of metabolic adaptation to weight loss.

Efficacy:

SCALE Obesity and Prediabetes (n=3731) and SCALE Diabetes (n=846) evaluated the effect of liraglutide 3.0 mg on overweight and obese subjects with normoglycemia, prediabetes, and diabetes respectively (53,54). Both 56-week, randomized, placebo-controlled, double-blind clinical trials demonstrated significantly greater mean weight loss than placebo (8% vs. 2.6% in SCALE Obesity and Prediabetes (53) and 6.0% vs. 2% in SCALE Diabetes (54). The efficacy of liraglutide 3.0 in maintaining weight loss was examined in the SCALE Maintain study. Four hundred and twenty-two overweight and obese subjects who lost ≥ 5% of their initial body weight on a low-calorie diet were randomly assigned to liraglutide 3.0 mg daily or placebo for 56 weeks. Mean weight loss on the initial diet was 6.0%. By the end of the study, participants in the liraglutide 3.0 group lost an additional 6.2% compared to 0.2% with placebo (P < 0.0001) (55).

Effect on Metabolic Profile:

Secondary endpoints in the SCALE Obesity and Prediabetes included waist circumference, lipids, hemoglobin A1c, and blood pressure, all of which showed significantly greater improvement than placebo (53). Systolic blood pressure dropped by 4.2 mmHg vs 1.5 mmg in the liraglutide 3.0 mg vs placebo groups. Diastolic blood pressured was reduced by 2.6 mm Hg vs 1.9 mm Hg. The most significant change in lipid profile was in the triglycerides that were reduced by 13 mg/dl in the liraglutide 3.0 mg group vs 5.5 mg/dl in the placebo group. The participants assigned to liraglutide 3.0 had a lower frequency of prediabetes and were less likely to develop type 2 diabetes than those assigned to placebo (53), an outcome that persisted in a 3-year extension analysis (56). In participants with obesity and moderate/severe OSA, liraglutide 3.0 mg treatment resulted in significantly greater reductions than placebo in apnea-hypopnea index, body weight, systolic blood pressure, and HbA1c levels (57).

In the SCALE Diabetes study, hemoglobin A1c levels were 0.93% lower in the liraglutide 3.0 vs. placebo treated group, and similar significant benefits on triglyceride (lower) and HDL cholesterol (higher) as in the SCALE Obesity study were reported (54).

Safety and side effects:

Gastrointestinal symptoms, such as nausea, vomiting and abdominal pain, were the most common reason subjects withdrew from the SCALE trials. In a secondary analysis of these trials, treatment with liraglutide 3.0 resulted in dose-independent, reversible increases in amylase/lipase activity (7% for amylase and 31% for lipase) (58). Thirteen subjects (0.4%) in the liraglutide 3.0 group compared to one (0.1%) with placebo developed pancreatitis, but nearly half of these had evidence for gallstones as well (58). Even though liraglutide treatment showed improvements in blood pressure and lipids, it was found to increase heart rate by 2.0/min in SCALE Diabetes (54). Animal studies with liraglutide showing an association with medullary thyroid cancer have led to FDA label warnings. Even though the relevance of this observation to humans has not been determined, a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) is considered a contraindication for treatment with this medication.

Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it.

Phentermine and Diethylpropion

Phentermine (separate from the phentermine/topiramate combination) was the first FDA approved short-term medication for weight loss, and remains available today. Phentermine is a sympathomimetic anorexogenic agent. A study from 1968 is the only longer-term controlled trial of phentermine (59). In this study, 64 patients completed 36 weeks of placebo, phentermine, or placebo and phentermine on alternating days. Both phentermine groups lost approximately 13% of their initial weight, while the placebo group lost only 5%. Phentermine’s main side effects are related to its sympathomimetic properties, including elevation in blood pressure and pulse, insomnia, constipation and dry mouth. Diethylpropion or “Tenuate”, another sympthatomimetic and derivative of bupropion, is also an approved short-term drug for treating obesity. It acts through modulation of norepinephrine action.

Non-FDA APPROVED (OFF-LABEL) MEDICATIONS THAT CAUSE WEIGHT LOSS

Several medications prescribed for conditions other than obesity have been found to be effective weight loss drugs in obese subjects. If used for weight loss, the prescribed use of these medications would be off-label.

Bupropion

Bupropion (trade name Wellbutrin) is an atypical antidepressant that has anecdotally been found to induce weight loss. While the mean weight loss seen with bupropion is small, as an antidepressant it is preferable to the many drugs which may induce weight gain.

Anderson et al (60) conducted a 48-week randomized placebo-controlled trial investigating the efficacy of bupropion in promoting weight loss. There were 3 study arms: placebo, 300 mg, and 400 mg of sustained release (SR) bupropion. Percentage losses of initial body weight for subjects completing 24 weeks were 5.0%, 7.2%, and 10.1% for placebo, bupropion SR 300, and 400 mg/d, respectively. In obese subjects with depressive symptoms bupropion SR was more effective than placebo in achieving weight-loss when combined with a 500 kcal deficit diet (4.6% vs 1.8% loss of baseline body weight, p < 0.001) (61). Bupropion is contraindicated in patients with seizures.

Metformin

Metformin (trade name Glucophage) is an antihyperglycemic agent that acts by decreasing production of glucose by the liver and possibly increasing peripheral insulin sensitivity. Although the mechanism of action on body weight is unknown, Gokcel et al (62) demonstrated that metformin achieved ~10% weight loss in obese women over a 6-month period. In the landmark Diabetes Prevention Program study, it was demonstrated that in patients with fasting hyperglycemia, metformin accounted for greater weight loss than placebo, but less than life-style changes alone. The average weight loss was 0.1, 2.1, and 5.6 kg in the placebo, metformin, and lifestyle-intervention groups, respectively (P<0.001, cross-group comparison) (11).

Metformin is therefore considered a first line drug in treating patients with type 2 diabetes and obesity. The most common side effects of metformin are nausea, flatulence, diarrhea, and bloating. The most serious side effect is lactic acidosis, but this is rare (<1/100,000) (63). Gockel et al (62) compared the effects of three different medications used in the management of obesity; sibutramine (10 mg twice daily) vs. Orlistat (150 mg three times per day) vs. metformin (850mg twice daily). All subjects were females with BMI >30 kg/m2. After six months of treatment all three groups showed significant improvements in lipid profile, insulin resistance, serum glucose and blood pressure. The sibutramine group displayed a statistically significant (p<0.0001) greater reduction in BMI (13.57%) when compared to orlistat (9.06%) and metformin (9.9%).

Pramlintide

Pramlintide acetate (trade name Symlin) is an injectable agent that is FDA-approved for the treatment of type 1 and type 2 diabetes. Pramlintide mimics the action of the pancreatic hormone amylin, which along with insulin regulates postprandial glucose control. Its effect on weight loss is thought to be mediated through central (brain) receptors (64) that improve appetite control (65). In a pooled, post-hoc analysis of overweight and obese insulin-treated patients with type 2 diabetes, pramlintide-treated patients (receiving 120 mg twice daily) had a body weight reduction of -1.8 kg (P<0.0001) compared with placebo-treated patients (66). In this study, pramlintide-treated patients experienced a 3-fold increase in successfully achieving a total body weight loss of > 5%, when compared to those who received placebo. Subsequently, randomized trials combining pramlintide or placebo with a lifestyle intervention were undertaken in obese participants without diabetes. Treatment with pramlintide (up to 240 mg three time daily) for 16 weeks resulted in a placebo-corrected reduction in body weight of 3.7 % (P < 0.001) and 31% of pramlintide-treated subjects achieved ≥5% weight loss vs. 2% with placebo (P < 0.001) (67). In another study with one year follow-up, placebo-corrected weight loss in those taking 120 mg three time daily and 360 mg twice daily averaged 5.6% and 6.8% (both P < 0.01) (68). Nausea is the most common adverse event with pramlintide treatment in these studies.

Topiramate

Topiramate (trade name Topamax) is an antiepileptic agent that has been found to reduce body weight in patients with a variety of disorders including epilepsy, bipolar disorder, and binge eating disorder (69). Randomized-controlled studies have shown that Topiramate has been reported as both tolerable and effective in promoting weight loss (32). In addition to use for epilepsy, topiramate has received FDA approval for the prevention of migraine headaches. Topiramate has also been used “off-label” for the treatment of neuropathic pain, as it causes weight loss rather than the weight gain usually seen with other antiepileptic agents. Topiramate can cause paresthesia’s, cognitive side effects, as well as renal stones and, rarely, acute angle glaucoma.

Zonisamide

Zonisamide (trade name Zonegran) is another antiepileptic medication that has also been found to reduce body weight in patients. Short (16 weeks) and longer (one year) randomized-controlled studies in patients with obesity have shown that 400 mg of zonisamide daily is effective in promoting modest weight loss (~ 5 kg placebo-subtracted weight) (70,71). The most commonly reported side effects compared to placebo were gastrointestinal (nausea/vomiting), nervous system (headaches), and cognitive (anxiety, impaired memory, language problems) (71). Zonisamide should not be given to patients hypersensitive to sulfonamides.

MEDICATION INDUCED OBESITY

The role of medications as a factor that can induce weight gain is often overlooked. Several commonly prescribed medications are associated with significant weight gain. This list includes medications used to treat diabetes, hypertension, depression and schizophrenia (72). When evaluating patient with obesity for the first time, the clinician should perform a thorough review of all current prescription and over-the-counter medications to investigate for potential weight gaining medications. Whenever possible the clinician should consider alternatives to medications known to cause weight gain, or should consider measures that would ameliorate the weight gaining effect of the prescribed drug (73).

Conclusion

The obesity epidemic continues to grow at an alarming rate. Pharmacotherapy has been shown to be effective in promoting weight reduction and improvement of comorbid conditions. As our understanding of obesity grows so too will our armamentarium to combat this disease. There are several promising medications currently in clinical trials that induce weight loss through several separate mechanisms. Ultimately obesity will most likely be treated with combinations of medications, similar to other chronic diseases such as heart disease, hypertension, and diabetes.

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