Key points

Introduction

Obesity is a global public health concern that has continued to spread. Epidemiologic data from 2014 reported the prevalence of obesity in the United States to be 35% among men and 40% among women. Compared to 25 years ago when less than 15% of the nation was considered obese. The obesity epidemic has placed an economic burden on the US health care system. The annual medical cost of obesity in the United States was estimated at $147 billion in 2008, with per capita medical expenses 42% higher per person with obesity compared with a person with normal weight. In addition, obesity is associated with job absenteeism costing approximately $4.3 billion annually as well as lower productivity while at work, costing employers $506 per worker with obesity per year.

In 2013, obesity was officially recognized as a disease state by the American Medical Association. For adults, the World Health Organization (WHO) defines normal weight as a body mass index (BMI, expressed in kilograms of body weight/height in meters squared) of 18.5 to 24.9 kg/m ² and overweight as a BMI of 25 to 29.9 kg/m ² . Obesity is further classified into class I for BMI 30 to 34.9 kg/m ² , class II for BMI 35 to 39.9 kg/m ² , and class III for 40 kg/m ² and above.

Obesity results in many health complications. There are mechanical consequences of increased fat mass and body weight, such as osteoarthritis, obstructive sleep apnea, and urinary incontinence, as well as metabolic consequences due to the hormonal and inflammatory functions of adipose tissue, such as insulin resistance, type II diabetes, cancer, dyslipidemia, hepatosteatosis, and hypertension. Tissue inflammation is an important mechanism linking obesity to insulin resistance in metabolically active organs, such as liver, skeletal muscle, and adipose tissue. Adipose tissue is an active endocrine organ that secretes a variety of hormones and proinflammatory cytokines, including leptin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), resistin, and adiponectin. The adipose tissue–derived hormone leptin exerts its inhibitory effects on food intake primarily by modulating the function of anorectic stimulating neurons in the arcuate nucleus of the hypothalamus. Under conditions of diet-induced obesity, this body of neurons in the hypothalamus becomes resistant to leptin, and as a result, the signaling process for satiety appears to be blunted. Evidence of gliosis in the mediobasal hypothalamus of obese humans, assessed by MRI, suggests neuronal injury in an area crucial for body weight control. Inflammatory markers IL-6 and TNF-alpha as well as resistin secreted by adipocytes promote insulin resistance linked to obesity.

Because of counterregulatory neurohormonal mechanisms aimed at maintaining fat mass as a survival measure, weight regain is very common after diet-induced weight loss. Antiobesity pharmacotherapy should be considered as an adjunct to diet and behavioral modification in order to facilitate weight loss or promote long-term weight maintenance. In addition to directly promoting weight loss, antiobesity pharmacotherapy can either directly or indirectly treat comorbid conditions associated with obesity, including prediabetes, type 2 diabetes mellitus (T2D), obstructive sleep apnea, hypertension, and dyslipidemia. Patients and physicians should recognize that expected weight loss from obesity pharmacotherapy is 5% to 10% of total body weight (TBW). For patients with severe obesity (class III), multiple medications or pharmacotherapy in addition to surgical intervention may be considered.

Adjuvant pharmacologic treatments should be considered for patients with a BMI greater than 30 or with a BMI greater than 27 who also have concomitant obesity-related diseases and for whom dietary modifications and physical activity has not been successful. Obesity is a chronic disease requiring continuous management and ongoing interventional efforts, including long-term treatment. Several weight-loss agents have been approved by the US Food and Drug Administration (FDA) for weight management, including phentermine, orlistat, phentermine/topiramate ER, lorcaserin, buproprion/naltrexone, and liraglutide ( Table 1 ).

Introduction

Obesity is a global public health concern that has continued to spread. Epidemiologic data from 2014 reported the prevalence of obesity in the United States to be 35% among men and 40% among women. Compared to 25 years ago when less than 15% of the nation was considered obese. The obesity epidemic has placed an economic burden on the US health care system. The annual medical cost of obesity in the United States was estimated at $147 billion in 2008, with per capita medical expenses 42% higher per person with obesity compared with a person with normal weight. In addition, obesity is associated with job absenteeism costing approximately $4.3 billion annually as well as lower productivity while at work, costing employers $506 per worker with obesity per year.

In 2013, obesity was officially recognized as a disease state by the American Medical Association. For adults, the World Health Organization (WHO) defines normal weight as a body mass index (BMI, expressed in kilograms of body weight/height in meters squared) of 18.5 to 24.9 kg/m ² and overweight as a BMI of 25 to 29.9 kg/m ² . Obesity is further classified into class I for BMI 30 to 34.9 kg/m ² , class II for BMI 35 to 39.9 kg/m ² , and class III for 40 kg/m ² and above.

Obesity results in many health complications. There are mechanical consequences of increased fat mass and body weight, such as osteoarthritis, obstructive sleep apnea, and urinary incontinence, as well as metabolic consequences due to the hormonal and inflammatory functions of adipose tissue, such as insulin resistance, type II diabetes, cancer, dyslipidemia, hepatosteatosis, and hypertension. Tissue inflammation is an important mechanism linking obesity to insulin resistance in metabolically active organs, such as liver, skeletal muscle, and adipose tissue. Adipose tissue is an active endocrine organ that secretes a variety of hormones and proinflammatory cytokines, including leptin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), resistin, and adiponectin. The adipose tissue–derived hormone leptin exerts its inhibitory effects on food intake primarily by modulating the function of anorectic stimulating neurons in the arcuate nucleus of the hypothalamus. Under conditions of diet-induced obesity, this body of neurons in the hypothalamus becomes resistant to leptin, and as a result, the signaling process for satiety appears to be blunted. Evidence of gliosis in the mediobasal hypothalamus of obese humans, assessed by MRI, suggests neuronal injury in an area crucial for body weight control. Inflammatory markers IL-6 and TNF-alpha as well as resistin secreted by adipocytes promote insulin resistance linked to obesity.

Because of counterregulatory neurohormonal mechanisms aimed at maintaining fat mass as a survival measure, weight regain is very common after diet-induced weight loss. Antiobesity pharmacotherapy should be considered as an adjunct to diet and behavioral modification in order to facilitate weight loss or promote long-term weight maintenance. In addition to directly promoting weight loss, antiobesity pharmacotherapy can either directly or indirectly treat comorbid conditions associated with obesity, including prediabetes, type 2 diabetes mellitus (T2D), obstructive sleep apnea, hypertension, and dyslipidemia. Patients and physicians should recognize that expected weight loss from obesity pharmacotherapy is 5% to 10% of total body weight (TBW). For patients with severe obesity (class III), multiple medications or pharmacotherapy in addition to surgical intervention may be considered.

Adjuvant pharmacologic treatments should be considered for patients with a BMI greater than 30 or with a BMI greater than 27 who also have concomitant obesity-related diseases and for whom dietary modifications and physical activity has not been successful. Obesity is a chronic disease requiring continuous management and ongoing interventional efforts, including long-term treatment. Several weight-loss agents have been approved by the US Food and Drug Administration (FDA) for weight management, including phentermine, orlistat, phentermine/topiramate ER, lorcaserin, buproprion/naltrexone, and liraglutide ( Table 1 ).

Phentermine

Phentermine was approved by the FDA in 1959 and has been the most commonly prescribed short-term (up to 12 weeks) medication for weight loss. Phentermine is primarily a noradrenergic and possibly dopaminergic sympathomimetic amine. The standard adult dose is up to 37.5 mg daily before breakfast. However, dosages should be individualized to achieve adequate response with the lowest effective dose. A quarter tablet (9.375 mg) or a half tablet (18.75 mg) may be adequate for some patients. A 28-week, randomized, controlled trial compared phentermine 7.5 mg, phentermine 15 mg, topiramate ER 46 mg, topiramate ER 92 mg, with a combination of phentermine and topiramate ER 7.5/46 mg and 15/92 mg. Primary endpoints were percent weight loss and achievement of ≥5% weight loss. Focusing on the phentermine monotherapy arm of the study, individuals taking phentermine 7.5 mg daily and 15 mg daily lost 5.3 kg and 6.0 kg, respectively, compared with 1.5 kg for placebo. The percentage of subjects achieving ≥5% weight loss was 15.5% for placebo, 43.3% for phentermine 7.5 mg, and 46.6% for phentermine 15 mg. Potential side effects of phentermine include dizziness, dry mouth, difficulty sleeping, and irritability.

Orlistat (Xenical)

Orlistat was approved in 1999 by the FDA for weight management in conjunction with reduced calorie diet. Orlistat alters fat digestion by inhibiting gastric and pancreatic lipases, causing approximately 30% fecal fat excretion. Orlistat is prescribed 3 times a day at a dosage of 120 mg to be taken with meals. A lower-dose formulation containing 60 mg per capsule is available over the counter and sold under the brand name Alli.

Several randomized trials have demonstrated the efficacy of orlistat in promoting weight loss. The 4-year XENDOS (Xenical in the Prevention of Diabetes in Obese Subjects) study demonstrated a 5.8-kg weight loss in the orlistat group (120 mg taken 3 times per day) compared with a 3.0-kg weight loss in the placebo group. After 4 years, 52.8% of the patients in the orlistat group had lost ≥5% of TBW and 26.2% of subjects had lost ≥10% TBW. The Xendos study also demonstrated reduced progression from impaired glucose tolerance to overt T2D. The progression of prediabetes to diabetes was seen in 6.2% of the orlistat group compared with 9.0% of subjects in the placebo group; a 42% reduction.

Side effects of orlistat include bloating, flatulence, flatus with discharge, and fecal incontinence. Because orlistat may reduce the absorption of fat-soluble vitamins (A, D, E, K), a multivitamin supplement is advised when treating with this agent.

Lorcaserin (Belviq)

Lorcaserin was approved by the FDA in 2012 for long-term weight management. Lorcaserin is a selective serotonin 2c receptor agonist. Lorcaserin decreases food consumption and promotes satiety by selectively activating the 5HT-2c receptor on anorexigenic POMC neurons located in the hypothalamus. At the recommended daily dose of 10 mg twice a day, lorcaserin selectively interacts with 5-HT2c receptors as opposed to 5-HT2a and 5HT2b, which have been implicated in the risk of both depression and cardiac valve insufficiency, respectively.

Three randomized, double-blinded, placebo-controlled studies were conducted to evaluate the efficacy of lorcaserin on weight loss: BLOOM (Behavioral Modification and Lorcaserin for Overweight and Obesity Management), BLOSSOM (Behavioral Modification and Lorcaserin Second Study for Obesity Management), and BLOOM-DM performed specifically in adults with T2D.

The BLOOM trial included 3182 patients with obesity or overweight who were randomized to receive lorcaserin 10 mg twice a day or placebo for 52 weeks, along with diet and exercise counseling. Primary outcomes were weight loss at 52 weeks and weight maintenance at 104 weeks. At 52 weeks, the lorcaserin group lost 5.8 kg compared with 2.2 kg in the placebo group. The percentage of patients taking lorcaserin who achieved TBW loss of ≥5% TBW at year 1 was 47% compared with 20.5% of the placebo group. At 52 weeks, patients in the lorcaserin group were randomly reassigned to receive treatment or placebo for another 52 weeks. Among patients in the lorcaserin group, those who continued to receive lorcaserin had better maintenance of weight loss compared with those who were reassigned to receive placebo.

The most common adverse effects seen in patients on lorcaserin are headaches, dizziness, and nausea. The most common side effect noted in patients with T2D on lorcaserin was symptomatic hypoglycemia, requiring a reduction in diabetic medication dosage.

Phentermine/topiramate ER (Qsymia)

A low-dose, fixed-release capsule combining extended release phentermine and topiramate was approved by the FDA in 2012 as adjuvant therapy for individuals with obesity or overweight with at least one comorbid condition. Phentermine increases norepinephrine in the hypothalamus, enhancing POMC neuron pathway signaling to increase alpha-MSH, which binds to melanocortin 4 receptor and suppresses appetite. The exact mechanism of action for weight loss with topiramate is not known, although animal studies suggest that topiramate-induced weight loss results from increased energy expenditure, decreased energetic efficiency, and decreased caloric intake as an appetite suppressant. Phentermine/Topiramate ER comes in 4 dosages: 3.75/23 mg (starting dose), 7.5/46 mg (treatment dose) 11.25/69 mg, or 15/92 mg (maximum dose). Phentermine/Topiramate ER is initiated through a stepwise approach, starting at 3.75/23 mg once daily for 2 weeks before increasing to the recommended dose of 7.5/46 mg once daily. Further titration to a maximum dose of 15/92 mg once daily may be considered for individuals who do not achieve 3% weight loss after 12 weeks. If 5% weight loss is not achieved after 12 weeks at 15/92 mg per day, then phentermine/topiramate ER dose should be gradually reduced for discontinuation.

The CONQUER trial, a 1-year double-blinded, placebo-controlled study of 2487 adults whom are overweight or obese with 2 or more comorbidities were randomized to receive phentermine/topiramate ER 7.5/46 mg, phentermine/topiramate ER15/92 mg or placebo. At 1 year, both groups assigned to active treatment had significantly greater weight loss than the placebo group. In the phentermine/topiramate ER 7.5/46 mg and phentermine/topiramate 15/92 mg arms of the study, 62% and 70% of patients, respectively, lost ≥5% TBW compared with 21% with placebo. SEQUEL was a 108-week extension study in which participants who completed the CONQUER study continued their previously assigned treatment. Patients in both active treatment arms experienced greater weight loss compared with those in the placebo arm. Phentermine/Topiramate ER 7.5/46 mg had a 9.6-kg weight loss and phentermine/topiramate 15/92 mg had a 10.9-kg weight loss from baseline compared with 2.1-kg weight loss with placebo. In addition, 75% of the phentermine/topiramate ER 7.5/46-mg group and 79.3% of the phentermine/topiramate 15/92-mg group achieved ≥5% weight loss compared with 30% of the placebo-treated patients. In all groups treated with phentermine/topiramate ER, greater reductions in systolic blood pressure, hemoglobin A1c, prediabetes, low-density lipoprotein cholesterol, triglycerides, and waist circumference were seen compared with placebo.

The most common side effects noted with phentermine/topiramate ER were paresthesias, dizziness, dysgeusia, and dry mouth. The FDA required a Risk Evaluation and Mitigation Strategy for phentermine/topiramate ER to inform women of reproductive age about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to the topiramate component of the drug during the first trimester of pregnancy.