INVITED REVIEW
Treatment of Obesity in 2015 Alpana P. Shukla, MD, MRCP (UK); William I. Buniak, MS; Louis J. Aronne, MD, FACP
Obesity is a major health priority in the United States, as well as globally. It is associated with multiple comorbidities and reduced life expectancy. Effective management of obesity involves producing an intervention plan tailored to the individual patient. Potential contributory factors to weight gain, including dietary habits, physical inactivity, associated medical conditions, and medications, should be identified and addressed. Lifestyle interventions comprising diet modification, physical activity, and behavior therapy are foundational to the management of obesity. Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. Adjunctive therapies in the form of pharmacotherapy and bariatric surgery are required in patients who do not achieve targeted weight loss and health goals with lifestyle interventions. Currently there are 3 drugs approved for long-term management of obesity, orlistat, phentermine/topiramate extended release, and lorcaserin, and there are 2 on the horizon, bupropion/naltrexone and liraglutide. Bariatric surgery is an effective strategy recognized to produce durable weight loss with amelioration of obesity-related comorbidities and should be considered a treatment option in eligible patients.
K E Y
W O R D S
bariatric surgery lifestyle interventions obesity pharmacotherapy Author Affiliation: Center for Weight Management and Metabolic Clinical Research, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medical College, New York. The authors declare no conflicts of interest. Correspondence: Alpana P. Shukla, MD, MRCP (UK), Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY 10065 ([email protected]. edu). DOI: 10.1097/HCR.0000000000000112
Obesity is a growing epidemic associated with multiple comorbidities and increased risk of all- cause and cardiovascular (CV) mortality. Global estimates of obesity between 1980 and 2008 indicate that the prevalence of obesity doubled in every region of the world.1 The problem is particularly acute in the United States, with more than one-third of the adult population being obese.2 Apart from medical and psychosocial consequences, obesity also places a severe economic burden on affected individuals and health care systems. In 2008, medical costs associated with obesity were estimated at $147 billion, and the medical costs for obese individuals were $1400 more than those of recommended weight.3 Effective management of obesity is clearly a major health priority. www.jcrpjournal.com
Despite ample evidence that weight loss through lifestyle interventions, pharmacotherapy, and bariatric surgery prevents and attenuates the severity of obesity-related comorbidities, survey data indicate that a minority of clinicians actually address the issue of weight management in obese patients.4,5 This stems from several sources, including insufficient training in behavioral and lifestyle counseling, lack of familiarity with and concern about the safety of antiobesity medications, lack of awareness of the indications and outcomes of bariatric surgery, and time restraints during a busy office practice.6 This review summarizes current strategies for management of obesity, including lifestyle interventions, pharmacotherapy, and bariatric surgery. Treatment of Obesity / 81
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EPIDEMIOLOGY AND CLINICAL APPROACHES Overweight is defined as a body mass index (BMI) of 25 kg/m2 to 29.9 kg/m2 and obesity as a BMI of ≥30 kg/m2. Obesity is a complex disorder and may result from a number of variables. While the core issue is excess energy consumption (dietary intake) relative to energy expenditure (energy loss via metabolic and physical activity), several factors, including genetic, physiologic, environmental, psychological, social and economic, interact in varying degrees to promote the development of obesity.7 A trend analysis of data from 9 national surveys conducted by the National Health and Nutrition Examination Survey suggested that the average daily energy intake among US adults increased from 1971 to 2004. Adjusted mean energy intake increased from 1955 kcal/d during 1971-1975 to 2269 kcal/d during 2003-2004 and then declined to 2195 kcal/d during 2009-2010.8 After decades of increases, average energy intake has significantly decreased since 2003-2004. However, the trends observed in energy expenditure from physical activity remain a matter of concern. Church et al9 recently estimated that from 1960 to 2008 the average energy expenditure from occupational physical activity has declined by 140 kcal/d for men and 124 kcal/d for women. Another study looking at the National Health and Nutrition Examination Survey data from 1988 to 2010 found that the proportion of adults who reported no leisure-time physical activity increased from 19.1% to 51.7% in women and from 11.4% to 43.5% in men.10 This has important implications for the development of public health strategies to address the obesity epidemic. Among overweight and obese adults, analyses of continuous BMI show that the greater the BMI, the higher the risk of CV disease, type 2 diabetes mellitus (T2DM), and all-cause mortality.11 Obesity adversely affects most CV risk factors and is also strongly associated with most CV diseases. However, substantial evidence over the past decade derived from observational cohort studies points to the existence of an “obesity paradox,” in that overweight and obese patients with established CV diseases typically have a better prognosis than leaner patients with the same CV disease.12-15 Potential reasons cited for the obesity paradox in CV disease include unintentional weight loss, younger age at presentation, lower atrial natriuretic peptides, attenuated response to renin-angiotensin-aldosterone system, and greater prevalence of high blood pressure, allowing for more cardiac medication and the lower discriminatory power/predictive value of BMI in this cohort.13 Confounding by unmeasured or poorly measured variables is also a
widely recognized bias in analyses of mortality risk factors.16 Moreover, several studies have suggested that fitness markedly alters the relationship between adiposity and prognosis in CV disease. Analysis of data from 9563 men (mean age, 47.4 years) with documented or suspected coronary heart disease (CHD) in the Aerobics Center Longitudinal Study showed the presence of an obesity paradox only in men with low cardiorespiratory fitness, whereas among men with high fitness, there were no significant differences in cardiovascular disease and allcause mortality risk across BMI categories.17 Despite this paradox, the overall body of evidence from several interventional studies supports purposeful weight loss in both primary and secondary preventions of CV disease. The Finnish Diabetes Prevention Study18 and the Diabetes Prevention Program19 provide robust evidence for the beneficial effect of weight loss through lifestyle interventions. Both studies showed that weight loss in the intervention groups was associated with a remarkably similar 58% reduction in the incidence of T2DM. Data from these studies and the LOOK-AHEAD trial additionally document that weight loss in the range of 5% to 9% is associated with a lowering of systolic and diastolic blood pressures by 3 to 7 mmHg.20 The favorable effects of weight loss on dyslipidemia are also well established; changes in levels of triglycerides and high-density lipoprotein (HDL)cholesterol are more significant, whereas changes in low-density lipoprotein (LDL)-cholesterol levels are relatively modest. It is estimated that for every 1 kg of maintained weight loss, a decrease in total cholesterol, triglycerides, and LDL-cholesterol in the range of 1% to 1.3%, 1.6% to 1.9%, and 0.34% to 0.68%, respectively, may be expected while HDL-cholesterol levels are predicted to increase by 2% to 4%.21-23 Studies in patients with established CHD have also demonstrated similar benefits of intentional weight loss on CV risk factors, including lowering of C-reactive protein levels.20,24 While there are few longterm interventional studies of weight loss in patients with established CHD, data from published literature are reassuring. A prospective cohort study of 377 consecutive patients enrolled at a cardiac rehabilitation (CR) program, aged 30 to 85 years with a mean followup of 6.4 ± 1.8 years, showed that purposeful weight loss in CR was associated with a reduced risk of the composite outcome (mortality and CV events).25 A trend toward lower mortality was also observed in another study of 530 patients enrolled in a CR and exercise training program among overweight/obese patients who lost weight.26 More data will be available from the CV outcome trials mandated by the Federal Drug Administration (FDA) for recently approved weight loss medications.
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Successful management of obesity at the individual level involves producing an intervention plan that is tailored to the patient profile and needs. It is important to identify potential contributory factors to weight gain in the initial clinical assessment. Details of previous weight loss attempts, dietary habits, physical activity, family history of obesity, and other medical conditions or medications that may affect weight may provide useful information about the origins of or maintaining factors for overweight and obesity. While intensive lifestyle intervention is foundational to the management of obesity in all patients, the addition of pharmacotherapy and consideration of bariatric surgery is recommended at higher BMIs and in the presence of weight-related comorbidities, including hypertension, T2DM, dyslipidemia, and/or obstructive sleep apnea (Table 1). Sleep disorders and depression are frequently present in obese patients; these comorbidities should be screened for and addressed concurrently for effective management of obesity. A review of medications currently used by the patient may reveal drugs that promote weight gain such as β-blockers, antihistamines, corticosteroids, neurotropic, and psychotropic agents. Consideration should be given to substituting weightpromoting drugs with weight neutral medications where this is clinically feasible. This is particularly relevant in the management of obese patients with T2DM since it is known that the use of sulfonylureas, glitazones, and insulin is associated with significant weight gain. A “weight-centric” approach rather than a “glucose-centric” approach to management of diabetes in overweight/obese individuals would involve greater use of weight-neutral or weight-reducing drugs such as metformin, GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors, pramlintide, and acarbose.27 Clinicians and patients must determine weight loss and health goals before embarking on any weight loss interventions. Weight loss goals should be realistic
and clinically meaningful. Interventions that produce even modest, sustained weight loss of up to 5% are likely to result in clinically meaningful reductions in triglycerides, blood glucose, glycated hemoglobin (HbA1c), and the risk of developing T2DM; greater amounts of weight loss will additionally reduce blood pressure, improve LDL-cholesterol and HDLcholesterol, and reduce the need for medications to control blood pressure, blood glucose, and lipids.28 As an initial goal, the loss of 5% to 10% of baseline weight over 6 months is recommended. Several studies have shown that this is possible with a comprehensive lifestyle intervention consisting of diet, physical activity, and behavior therapy in a 6-month period of frequent, in-person treatment.11,29
LIFESTYLE INTERVENTIONS IN THE MANAGEMENT OF OBESITY Lifestyle interventions form the cornerstone of therapy for obesity and include diet modification, physical activity, and behavioral therapy. This intervention differs from other lines of treatment for obesity because it demands a greater level of commitment from both the provider and the patient. An individual’s weight is a function of the amount of calories consumed and expended over time.30,31 Weight is lost when fewer calories are being consumed than expended. Unfortunately, there are obdurate systems in the body preventing any change in weight.32 Compensatory changes in energy expenditure oppose the maintenance of a lower body weight. The typical pattern of weight loss in patients undergoing a lifestyle intervention is that maximum weight loss is achieved at 6 months, followed by plateau and then a gradual regain over time. The other 2 components of intensive lifestyle intervention, physical activity and cognitivebehavioral therapy, partially mitigate the impact that the body’s systems have on diet-induced weight loss.
T a b l e 1 • Obesity Treatment Strategies by BMI Categorya BMI, kg/m2 25.0-26.9
27.0-29.9
30.0-34.9
35.0-39.9
≥40
Diet, physical activity, behavior therapy
Yes with comorbidities
Yes with comorbidities
Yes
Yes
Yes
Pharmacotherapy
No
Yes with comorbidities
Yes
Yes
Yes
Weight-loss surgery
No
No
Lap band with comorbidities
Yes with comorbidities
Yes
Abbreviation: BMI, body mass index. a
Adapted from the NHLBI Obesity Education Initiative Working Group.51
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Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. The optimal macronutrient composition of a weight-loss diet is controversial. Several randomized controlled trials have sought to determine the effectiveness of any one diet over another.33–36 These studies have revealed that almost any diet is able to produce weight loss if it induces a calorie deficit.37,38 Caloric restriction can be accomplished by a variety of means including adjusting the macronutrient composition of a diet, restricting the consumption of certain foods, or encouraging the consumption of others.38,39 Among the myriad dietary approaches shown to produce weight loss are low-fat diet, low-carbohydrate diet, lacto-ovo-vegetarian-style diet, higher-protein diet, low-fat vegan diet, Mediterranean style diet, and the American Heart Association-style Step 1 diet. Weight loss tends to be achieved when the diets restrict the patient daily caloric intake to around 1200 to 1500 kcal for women and 1500 to 1800 kcal for men or create a 500-kcal energy deficit per day.11,33-36,39 Maintenance calories for current weight can be estimated using online calculators that incorporate the Harris Benedict or the Mifflin St-Jeor equation for basal energy expenditure and the appropriate activity factor or alternately by multiplying baseline body weight in pounds by 12 (or kilogram by 25).20 A net caloric deficit of 3500 calories per week is expected to result in 1 pound of weight loss. Since adherence to the prescribed diet is key to a successful outcome, the choice of a calorie-restricted diet should be individualized on the basis of the patient preferences and health status. For example, obese patients with T2DM or polycystic ovary syndrome with insulin resistance may benefit from a lowglycemic, higher-protein diet. Physical activity, although ineffective in producing meaningful weight loss as the sole intervention, is beneficial when used in concordance with the other 2 components of obesity intervention. It is not feasible to use physical activity as the sole treatment for weight loss in most cases because of the amount of activity necessary to produce a significant negative energy balance. Physical activity does, however, play a significant role in weight maintenance after a period of weight loss.40 Studies have shown that individuals who exercise frequently after losing weight are less likely to experience the weight regain that tends to occur soon after the weight is lost.41 This is specifically reflected in the records of the National Weight Control Registry, which documents the characteristics of individuals who have successfully maintained a weight loss of 10% or more for 1 or more years.42 The
American College of Sports Medicine recommends around 250 minutes of aerobic activity per week (around 30-45 minutes a day) to maintain weight loss.43 The literature is mixed on the impact of resistance training on weight loss maintenance. Although it is not recognized to produce significant weight loss, there is evidence to indicate that resistance training may increase the ratio of fat-free mass to fat mass.44 A study by Pasman et al45 showed that individuals who include some resistance training in their physical activity regimen regain less of their weight as fat during the period of weight regain. Although there is a paucity of data from randomized controlled trials on the role of resistance training in weight management, on the basis of current evidence, it is prudent to recommend that obese individuals perform some resistance training to reduce the loss of lean tissue that occurs in conjunction with weight loss.46 Behavioral therapy as a component of lifestyle therapy for obesity is designed to assist patient adherence to prescribed modifications in diet and physical activity. One of the key components of behavioral therapy is self-monitoring and includes maintenance of food diaries and activity logs. Accordingly, patients are encouraged to be mindful of what they are consuming. A study by Lowe et al47 demonstrated that a group of obese subjects who were taught self-monitoring techniques were more successful in maintaining a reduced weight than the control group receiving standard of care management. Other important elements of behavioral therapy are stimulus control (altering the environment that promotes maladaptive eating behavior such as eating while watching television, serving-bowl size, proximity to food) and slowing the pace of eating. Frequent self-weighing (at least weekly) is also associated with better weight maintenance over time.48 The CR setting presents a unique scenario where patients are highly motivated and committed to exercise and, accordingly, the benefits of physical activity may be greater. Ades et al24 performed the first randomized controlled clinical trial to evaluate the effect of high-calorie expenditure exercise (3000-3500 kcal per week exercise-related energy expenditure) compared with standard CR exercise (700-800 kcal/week) on weight loss and risk factors in 74 overweight patients with CHD. Both groups received similar behavioral weight loss counseling. High-calorieexpenditure exercise resulted in double the weight loss (8.2 ± 4 vs 3.7 ± 5 kg) and fat mass loss (5.9 ± 4 vs 2.8 ± 3 kg) and a greater reduction in waist circumference (−7 ± 5 vs −5 ± 5 cm) than standard CR exercise at 5 months. In addition, high-calorie-expenditure exercise reduced insulin resistance, along with
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the ratio of total to HDL-cholesterol and components of the metabolic syndrome, more than standard CR exercise. Subsequently, in another study by the same author, it was shown that the group assigned to highcalorie expenditure exercise also had greater improvements in brachial artery flow mediated dilatation (a predictor of long-term prognosis in patients with CHD) which correlated primarily with changes in weight.49 A recently published study from Denmark, the CUT-IT trial, compared the effect of aerobic interval training (AIT) versus a low-energy diet (LED) on physical fitness, body composition, CV risk factors, and symptoms in overweight and nondiabetic individuals with contemporarily treated coronary artery disease.50 Subjects were randomized to 12 weeks of AIT at 90% peak heart rate 3 times a week or LED (800-1000 kcal/d) for 8 to 10 weeks followed by 2 to 4 weeks using a weight maintenance diet. Weight loss was 10.6% in the LED group compared with 1.6% in the group randomized to AIT. Low-energy diet had superior effects on body composition and blood pressure, whereas effects on lipids, cardiac symptom scores, and anxiety scores were similar in the 2 groups.
PHARMACOTHERAPY OF OBESITY While lifestyle intervention is the first line of treatment for obesity management, patients may require adjunctive therapies to meet their weight loss and health goals due to the recalcitrant nature of obesity. According to the 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults, pharmacotherapy for the treatment of obesity can be considered if a patient has a BMI ≥ 30, or has a BMI ≥ 27 if weight-related comorbidities, including hypertension, T2DM, dyslipidemia, and/ or obstructive sleep apnea, are present.11,51 The criteria set forth by the FDA in 2007 in order for a drug to be approved for the treatment of obesity requires at least 5% statistically significant placeboadjusted weight loss at 1 year or >35% of patients achieving >5% weight loss (which must be twice that of placebo).52 The FDA also requires that the medication show evidence of improvement in metabolic biomarkers, including blood pressure, lipids, and glycaemia. Currently there are 3 drugs approved for long-term management of obesity: orlistat, phentermine/topiramate (Phen/TPM) ER, and lorcaserin. Phentermine alone and other centrally acting adrenergic agents (benzphetamine, phendimetrazine, diethylpropion) are approved only for short-term (3 months) use. www.jcrpjournal.com
Phentermine Phentermine, approved in 1959, is the most commonly prescribed antiobesity agent in the United States. A sympathomimetic amine, phentermine is thought to suppress appetite primarily via the enhancement of norepinephrine release.53 Although approved only for 3 months of treatment due to lack of longterm safety trials, long-term use is common in clinical practice to both achieve and maintain weight-loss outcomes. Data show that as monotherapy, phentermine 15 mg can provide a 5% greater weight loss than placebo.54 Side effects due to sympathetic activation include increases in heart rate and blood pressure, dry mouth, nervousness, insomnia, and constipation. Phentermine should be used with caution in people at significant risk for hemodynamic or CV complications of tachycardia and those with uncontrolled hypertension.
Orlistat Orlistat is a gastric and pancreatic lipase inhibitor that acts by reducing the absorption of dietary fat by approximately 30%. It is available for long-term management of obesity in conjunction with a reduced calorie diet and also as an over-the-counter medication at half the prescription dose. Multiple randomized controlled trials have shown that after 1 to 2 years, mean weight loss is ∼2.7 to 3.19 kg greater than placebo-treated patients.55 The proportion of patients who respond to achieve more than 5% weight loss after 1 year of therapy is 15% to 30% more than placebo-treated patients.56 As seen with other therapies, weight loss from orlistat treatment is associated with improvements in several comorbidities of obesity, including blood pressure, insulin resistance, and serum lipid levels, although total and LDL-cholesterol improve more than expected because of direct inhibition of fat absorption. Adjunctive orlistat administration over a 4-year period was demonstrated to reduce the risk of progression to T2DM in an at-risk population more than diet and exercise alone.57 The most common side effects are gastrointestinal, including oily spotting, flatus with discharge, fecal urgency, and steatorrhea. Reductions in fat-soluble vitamins A, D, E, and K have been noted in some patients. As a result, a daily vitamin supplement containing these vitamins can be considered, taken at least 2 hours before or after orlistat.
Phentermine/Topiramate Phentermine/topiramate was approved in 2012 as the first combination drug for long-term management of obesity. It is well recognized that obesity is a complex Treatment of Obesity / 85
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disorder of dysregulation of multiple signaling pathways involved in satiety and body weight regulation. Targeting different sites simultaneously is more likely to produce significant and durable weight loss. The rationale for combining these 2 drugs was that lower doses of each drug would minimize side effects while using drugs acting on different pathways would have an additive effect on weight loss.58 The combination Phen/TPM incorporates phentermine, a centrally acting adrenergic agent, and topiramate, an anticonvulsant that modulates GABAergic transmission.59 The exact mechanisms by which topiramate induces weight loss remain to be clearly elucidated. Putative mechanisms for its anorectic effect include modulation of γ-aminobutyric acid receptors, inhibition of carbonic anhydrase, and antagonism of glutamate.60 The efficacy and safety of this combination have been tested in two 1-year pivotal randomized, placebocontrolled, double-blind trials: EQUIP61 and CONQUER.62 In a third study, SEQUEL,63 78% of CONQUER participants continued to receive their blinded treatment for an additional year. The CONQUER trial enrolled 2487 patients with a BMI between 27 and 45 kg/m2 with at least 2 obesityrelated comorbidities at baseline (including hypertension, hypertriglyceridemia, diabetes, or increased waist circumference).61 Participants were randomized to either placebo or once-daily phentermine 7.5 mg plus topiramate 46 mg extended release or once-daily phentermine 15 mg plus topiramate 92 mg extended release. At 56 weeks, average weight loss was 1.2%, 7.8%, and 9.8% of baseline body weight for the patients assigned to placebo, phentermine 7.5 mg plus topiramate 46 mg, and phentermine 15 mg plus topiramate 92 mg, respectively.62 Statistically significant improvements were observed in both treatment groups compared with placebo with respect to blood pressure, waist circumference, glycaemia, lipid concentrations, and blood inflammatory biomarkers. Significant improvements in diastolic blood pressure and low-density cholesterol were noted in the higherdose group only. In addition, patients with diabetes in both treatment groups had greater reductions in HbA1c (−0.4%) compared with placebo (−0.1%). Weight loss was sustained at the end of 2 years in those patients who continued to receive Phen/TPM in the SEQUEL extension study.63 The most common side effects for the mid- and full-dose treatment groups included dry mouth and paresthesias (20%). Other events occurring with rates of at least 5% included headache, blurred vision, upper respiratory tract infections, altered taste, insomnia, and constipation. Since side effects with Phen/TPM are dose dependent, it is recommended that treatment be initi-
ated with the low dose with uptitration as tolerated. If a patient has not lost at least 3% of baseline body weight on this dose, discontinuation of the medication or escalation of the dose to Phen/TPM 15 mg/92 mg (top dose) is suggested. Reevaluation after a further 12 weeks of treatment should result in at least 5% weight loss from baseline; otherwise, the drug should be discontinued. This is a practical approach to identify “responders” who will benefit from long-term therapy and “nonresponders” for whom the benefitto-risk ratio may not be favorable.
Lorcaserin Lorcaserin is a selective 5-HT2C receptor agonist thought to decrease food intake through the proopiomelanocortin system of neurons. It has an affinity for 5-HT2C receptors that is approximately 15 times that for the 5-HT2A receptors and 100 times that for the 5-HT2B receptors. This is important since it has been shown that the activation of 5-HT2A receptors can lead to neuropsychiatric side effects, while 5-HT2B receptor activation is associated with the development of valvulopathy and primary pulmonary hypertension observed previously with fenfluramine and dexfenfluramine that were subsequently withdrawn from the market.64-66 The efficacy and safety of lorcaserin have been tested in 3 Phase III trials. In the first trial (BLOOM), overweight and obese subjects with at least 1 comorbid condition (hypertension, dyslipidemia, CV disease, impaired glucose tolerance, or sleep apnea) were randomly assigned to receive lorcaserin 10 mg twice daily or placebo for 52 weeks, in conjunction with diet and exercise.67 At 1 year, average weight loss was 5.8% in the treatment group compared with 2.2% in the placebo group. Significant improvements in markers of CV risk, including systolic and diastolic blood pressures and levels of fibrinogen and high sensitivity C-reactive protein, were observed with lorcaserin compared with placebo. In a second Phase III trial (BLOSSOM), weight loss of at least 10% was achieved by 22.6% and 17.4% of patients receiving lorcaserin 10 mg twice daily and daily, respectively, and 9.7% of patients in the placebo group.68 The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in obese patients with T2DM treated with metformin and/or sulfonylurea. The average weight loss was similar for both doses of lorcaserin: 4.5% for lorcaserin twice daily and 5% for lorcaserin 10 mg daily. HbA1c decreased 0.9 ± 0.06 with lorcaserin twice daily, 1.0 ± 0.09 with lorcaserin daily, and 0.4 ± 0.06 with placebo (P < .001 for each). Although the study was not designed to optimize or evaluate glycemia primarily, approximately half of the patients
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assigned to lorcaserin achieved the recommended HbA1c level of 30 and
Treatment of Obesity in 2015 Alpana P. Shukla, MD, MRCP (UK); William I. Buniak, MS; Louis J. Aronne, MD, FACP
Obesity is a major health priority in the United States, as well as globally. It is associated with multiple comorbidities and reduced life expectancy. Effective management of obesity involves producing an intervention plan tailored to the individual patient. Potential contributory factors to weight gain, including dietary habits, physical inactivity, associated medical conditions, and medications, should be identified and addressed. Lifestyle interventions comprising diet modification, physical activity, and behavior therapy are foundational to the management of obesity. Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. Adjunctive therapies in the form of pharmacotherapy and bariatric surgery are required in patients who do not achieve targeted weight loss and health goals with lifestyle interventions. Currently there are 3 drugs approved for long-term management of obesity, orlistat, phentermine/topiramate extended release, and lorcaserin, and there are 2 on the horizon, bupropion/naltrexone and liraglutide. Bariatric surgery is an effective strategy recognized to produce durable weight loss with amelioration of obesity-related comorbidities and should be considered a treatment option in eligible patients.
K E Y
W O R D S
bariatric surgery lifestyle interventions obesity pharmacotherapy Author Affiliation: Center for Weight Management and Metabolic Clinical Research, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medical College, New York. The authors declare no conflicts of interest. Correspondence: Alpana P. Shukla, MD, MRCP (UK), Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY 10065 ([email protected]. edu). DOI: 10.1097/HCR.0000000000000112
Obesity is a growing epidemic associated with multiple comorbidities and increased risk of all- cause and cardiovascular (CV) mortality. Global estimates of obesity between 1980 and 2008 indicate that the prevalence of obesity doubled in every region of the world.1 The problem is particularly acute in the United States, with more than one-third of the adult population being obese.2 Apart from medical and psychosocial consequences, obesity also places a severe economic burden on affected individuals and health care systems. In 2008, medical costs associated with obesity were estimated at $147 billion, and the medical costs for obese individuals were $1400 more than those of recommended weight.3 Effective management of obesity is clearly a major health priority. www.jcrpjournal.com
Despite ample evidence that weight loss through lifestyle interventions, pharmacotherapy, and bariatric surgery prevents and attenuates the severity of obesity-related comorbidities, survey data indicate that a minority of clinicians actually address the issue of weight management in obese patients.4,5 This stems from several sources, including insufficient training in behavioral and lifestyle counseling, lack of familiarity with and concern about the safety of antiobesity medications, lack of awareness of the indications and outcomes of bariatric surgery, and time restraints during a busy office practice.6 This review summarizes current strategies for management of obesity, including lifestyle interventions, pharmacotherapy, and bariatric surgery. Treatment of Obesity / 81
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
JCRP-D-14-00175_LR 81
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EPIDEMIOLOGY AND CLINICAL APPROACHES Overweight is defined as a body mass index (BMI) of 25 kg/m2 to 29.9 kg/m2 and obesity as a BMI of ≥30 kg/m2. Obesity is a complex disorder and may result from a number of variables. While the core issue is excess energy consumption (dietary intake) relative to energy expenditure (energy loss via metabolic and physical activity), several factors, including genetic, physiologic, environmental, psychological, social and economic, interact in varying degrees to promote the development of obesity.7 A trend analysis of data from 9 national surveys conducted by the National Health and Nutrition Examination Survey suggested that the average daily energy intake among US adults increased from 1971 to 2004. Adjusted mean energy intake increased from 1955 kcal/d during 1971-1975 to 2269 kcal/d during 2003-2004 and then declined to 2195 kcal/d during 2009-2010.8 After decades of increases, average energy intake has significantly decreased since 2003-2004. However, the trends observed in energy expenditure from physical activity remain a matter of concern. Church et al9 recently estimated that from 1960 to 2008 the average energy expenditure from occupational physical activity has declined by 140 kcal/d for men and 124 kcal/d for women. Another study looking at the National Health and Nutrition Examination Survey data from 1988 to 2010 found that the proportion of adults who reported no leisure-time physical activity increased from 19.1% to 51.7% in women and from 11.4% to 43.5% in men.10 This has important implications for the development of public health strategies to address the obesity epidemic. Among overweight and obese adults, analyses of continuous BMI show that the greater the BMI, the higher the risk of CV disease, type 2 diabetes mellitus (T2DM), and all-cause mortality.11 Obesity adversely affects most CV risk factors and is also strongly associated with most CV diseases. However, substantial evidence over the past decade derived from observational cohort studies points to the existence of an “obesity paradox,” in that overweight and obese patients with established CV diseases typically have a better prognosis than leaner patients with the same CV disease.12-15 Potential reasons cited for the obesity paradox in CV disease include unintentional weight loss, younger age at presentation, lower atrial natriuretic peptides, attenuated response to renin-angiotensin-aldosterone system, and greater prevalence of high blood pressure, allowing for more cardiac medication and the lower discriminatory power/predictive value of BMI in this cohort.13 Confounding by unmeasured or poorly measured variables is also a
widely recognized bias in analyses of mortality risk factors.16 Moreover, several studies have suggested that fitness markedly alters the relationship between adiposity and prognosis in CV disease. Analysis of data from 9563 men (mean age, 47.4 years) with documented or suspected coronary heart disease (CHD) in the Aerobics Center Longitudinal Study showed the presence of an obesity paradox only in men with low cardiorespiratory fitness, whereas among men with high fitness, there were no significant differences in cardiovascular disease and allcause mortality risk across BMI categories.17 Despite this paradox, the overall body of evidence from several interventional studies supports purposeful weight loss in both primary and secondary preventions of CV disease. The Finnish Diabetes Prevention Study18 and the Diabetes Prevention Program19 provide robust evidence for the beneficial effect of weight loss through lifestyle interventions. Both studies showed that weight loss in the intervention groups was associated with a remarkably similar 58% reduction in the incidence of T2DM. Data from these studies and the LOOK-AHEAD trial additionally document that weight loss in the range of 5% to 9% is associated with a lowering of systolic and diastolic blood pressures by 3 to 7 mmHg.20 The favorable effects of weight loss on dyslipidemia are also well established; changes in levels of triglycerides and high-density lipoprotein (HDL)cholesterol are more significant, whereas changes in low-density lipoprotein (LDL)-cholesterol levels are relatively modest. It is estimated that for every 1 kg of maintained weight loss, a decrease in total cholesterol, triglycerides, and LDL-cholesterol in the range of 1% to 1.3%, 1.6% to 1.9%, and 0.34% to 0.68%, respectively, may be expected while HDL-cholesterol levels are predicted to increase by 2% to 4%.21-23 Studies in patients with established CHD have also demonstrated similar benefits of intentional weight loss on CV risk factors, including lowering of C-reactive protein levels.20,24 While there are few longterm interventional studies of weight loss in patients with established CHD, data from published literature are reassuring. A prospective cohort study of 377 consecutive patients enrolled at a cardiac rehabilitation (CR) program, aged 30 to 85 years with a mean followup of 6.4 ± 1.8 years, showed that purposeful weight loss in CR was associated with a reduced risk of the composite outcome (mortality and CV events).25 A trend toward lower mortality was also observed in another study of 530 patients enrolled in a CR and exercise training program among overweight/obese patients who lost weight.26 More data will be available from the CV outcome trials mandated by the Federal Drug Administration (FDA) for recently approved weight loss medications.
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Successful management of obesity at the individual level involves producing an intervention plan that is tailored to the patient profile and needs. It is important to identify potential contributory factors to weight gain in the initial clinical assessment. Details of previous weight loss attempts, dietary habits, physical activity, family history of obesity, and other medical conditions or medications that may affect weight may provide useful information about the origins of or maintaining factors for overweight and obesity. While intensive lifestyle intervention is foundational to the management of obesity in all patients, the addition of pharmacotherapy and consideration of bariatric surgery is recommended at higher BMIs and in the presence of weight-related comorbidities, including hypertension, T2DM, dyslipidemia, and/or obstructive sleep apnea (Table 1). Sleep disorders and depression are frequently present in obese patients; these comorbidities should be screened for and addressed concurrently for effective management of obesity. A review of medications currently used by the patient may reveal drugs that promote weight gain such as β-blockers, antihistamines, corticosteroids, neurotropic, and psychotropic agents. Consideration should be given to substituting weightpromoting drugs with weight neutral medications where this is clinically feasible. This is particularly relevant in the management of obese patients with T2DM since it is known that the use of sulfonylureas, glitazones, and insulin is associated with significant weight gain. A “weight-centric” approach rather than a “glucose-centric” approach to management of diabetes in overweight/obese individuals would involve greater use of weight-neutral or weight-reducing drugs such as metformin, GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors, pramlintide, and acarbose.27 Clinicians and patients must determine weight loss and health goals before embarking on any weight loss interventions. Weight loss goals should be realistic
and clinically meaningful. Interventions that produce even modest, sustained weight loss of up to 5% are likely to result in clinically meaningful reductions in triglycerides, blood glucose, glycated hemoglobin (HbA1c), and the risk of developing T2DM; greater amounts of weight loss will additionally reduce blood pressure, improve LDL-cholesterol and HDLcholesterol, and reduce the need for medications to control blood pressure, blood glucose, and lipids.28 As an initial goal, the loss of 5% to 10% of baseline weight over 6 months is recommended. Several studies have shown that this is possible with a comprehensive lifestyle intervention consisting of diet, physical activity, and behavior therapy in a 6-month period of frequent, in-person treatment.11,29
LIFESTYLE INTERVENTIONS IN THE MANAGEMENT OF OBESITY Lifestyle interventions form the cornerstone of therapy for obesity and include diet modification, physical activity, and behavioral therapy. This intervention differs from other lines of treatment for obesity because it demands a greater level of commitment from both the provider and the patient. An individual’s weight is a function of the amount of calories consumed and expended over time.30,31 Weight is lost when fewer calories are being consumed than expended. Unfortunately, there are obdurate systems in the body preventing any change in weight.32 Compensatory changes in energy expenditure oppose the maintenance of a lower body weight. The typical pattern of weight loss in patients undergoing a lifestyle intervention is that maximum weight loss is achieved at 6 months, followed by plateau and then a gradual regain over time. The other 2 components of intensive lifestyle intervention, physical activity and cognitivebehavioral therapy, partially mitigate the impact that the body’s systems have on diet-induced weight loss.
T a b l e 1 • Obesity Treatment Strategies by BMI Categorya BMI, kg/m2 25.0-26.9
27.0-29.9
30.0-34.9
35.0-39.9
≥40
Diet, physical activity, behavior therapy
Yes with comorbidities
Yes with comorbidities
Yes
Yes
Yes
Pharmacotherapy
No
Yes with comorbidities
Yes
Yes
Yes
Weight-loss surgery
No
No
Lap band with comorbidities
Yes with comorbidities
Yes
Abbreviation: BMI, body mass index. a
Adapted from the NHLBI Obesity Education Initiative Working Group.51
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Caloric restriction is the most important component in achieving weight loss through negative energy balance, whereas sustained physical activity is important in maintaining the weight loss. The optimal macronutrient composition of a weight-loss diet is controversial. Several randomized controlled trials have sought to determine the effectiveness of any one diet over another.33–36 These studies have revealed that almost any diet is able to produce weight loss if it induces a calorie deficit.37,38 Caloric restriction can be accomplished by a variety of means including adjusting the macronutrient composition of a diet, restricting the consumption of certain foods, or encouraging the consumption of others.38,39 Among the myriad dietary approaches shown to produce weight loss are low-fat diet, low-carbohydrate diet, lacto-ovo-vegetarian-style diet, higher-protein diet, low-fat vegan diet, Mediterranean style diet, and the American Heart Association-style Step 1 diet. Weight loss tends to be achieved when the diets restrict the patient daily caloric intake to around 1200 to 1500 kcal for women and 1500 to 1800 kcal for men or create a 500-kcal energy deficit per day.11,33-36,39 Maintenance calories for current weight can be estimated using online calculators that incorporate the Harris Benedict or the Mifflin St-Jeor equation for basal energy expenditure and the appropriate activity factor or alternately by multiplying baseline body weight in pounds by 12 (or kilogram by 25).20 A net caloric deficit of 3500 calories per week is expected to result in 1 pound of weight loss. Since adherence to the prescribed diet is key to a successful outcome, the choice of a calorie-restricted diet should be individualized on the basis of the patient preferences and health status. For example, obese patients with T2DM or polycystic ovary syndrome with insulin resistance may benefit from a lowglycemic, higher-protein diet. Physical activity, although ineffective in producing meaningful weight loss as the sole intervention, is beneficial when used in concordance with the other 2 components of obesity intervention. It is not feasible to use physical activity as the sole treatment for weight loss in most cases because of the amount of activity necessary to produce a significant negative energy balance. Physical activity does, however, play a significant role in weight maintenance after a period of weight loss.40 Studies have shown that individuals who exercise frequently after losing weight are less likely to experience the weight regain that tends to occur soon after the weight is lost.41 This is specifically reflected in the records of the National Weight Control Registry, which documents the characteristics of individuals who have successfully maintained a weight loss of 10% or more for 1 or more years.42 The
American College of Sports Medicine recommends around 250 minutes of aerobic activity per week (around 30-45 minutes a day) to maintain weight loss.43 The literature is mixed on the impact of resistance training on weight loss maintenance. Although it is not recognized to produce significant weight loss, there is evidence to indicate that resistance training may increase the ratio of fat-free mass to fat mass.44 A study by Pasman et al45 showed that individuals who include some resistance training in their physical activity regimen regain less of their weight as fat during the period of weight regain. Although there is a paucity of data from randomized controlled trials on the role of resistance training in weight management, on the basis of current evidence, it is prudent to recommend that obese individuals perform some resistance training to reduce the loss of lean tissue that occurs in conjunction with weight loss.46 Behavioral therapy as a component of lifestyle therapy for obesity is designed to assist patient adherence to prescribed modifications in diet and physical activity. One of the key components of behavioral therapy is self-monitoring and includes maintenance of food diaries and activity logs. Accordingly, patients are encouraged to be mindful of what they are consuming. A study by Lowe et al47 demonstrated that a group of obese subjects who were taught self-monitoring techniques were more successful in maintaining a reduced weight than the control group receiving standard of care management. Other important elements of behavioral therapy are stimulus control (altering the environment that promotes maladaptive eating behavior such as eating while watching television, serving-bowl size, proximity to food) and slowing the pace of eating. Frequent self-weighing (at least weekly) is also associated with better weight maintenance over time.48 The CR setting presents a unique scenario where patients are highly motivated and committed to exercise and, accordingly, the benefits of physical activity may be greater. Ades et al24 performed the first randomized controlled clinical trial to evaluate the effect of high-calorie expenditure exercise (3000-3500 kcal per week exercise-related energy expenditure) compared with standard CR exercise (700-800 kcal/week) on weight loss and risk factors in 74 overweight patients with CHD. Both groups received similar behavioral weight loss counseling. High-calorieexpenditure exercise resulted in double the weight loss (8.2 ± 4 vs 3.7 ± 5 kg) and fat mass loss (5.9 ± 4 vs 2.8 ± 3 kg) and a greater reduction in waist circumference (−7 ± 5 vs −5 ± 5 cm) than standard CR exercise at 5 months. In addition, high-calorie-expenditure exercise reduced insulin resistance, along with
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the ratio of total to HDL-cholesterol and components of the metabolic syndrome, more than standard CR exercise. Subsequently, in another study by the same author, it was shown that the group assigned to highcalorie expenditure exercise also had greater improvements in brachial artery flow mediated dilatation (a predictor of long-term prognosis in patients with CHD) which correlated primarily with changes in weight.49 A recently published study from Denmark, the CUT-IT trial, compared the effect of aerobic interval training (AIT) versus a low-energy diet (LED) on physical fitness, body composition, CV risk factors, and symptoms in overweight and nondiabetic individuals with contemporarily treated coronary artery disease.50 Subjects were randomized to 12 weeks of AIT at 90% peak heart rate 3 times a week or LED (800-1000 kcal/d) for 8 to 10 weeks followed by 2 to 4 weeks using a weight maintenance diet. Weight loss was 10.6% in the LED group compared with 1.6% in the group randomized to AIT. Low-energy diet had superior effects on body composition and blood pressure, whereas effects on lipids, cardiac symptom scores, and anxiety scores were similar in the 2 groups.
PHARMACOTHERAPY OF OBESITY While lifestyle intervention is the first line of treatment for obesity management, patients may require adjunctive therapies to meet their weight loss and health goals due to the recalcitrant nature of obesity. According to the 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults, pharmacotherapy for the treatment of obesity can be considered if a patient has a BMI ≥ 30, or has a BMI ≥ 27 if weight-related comorbidities, including hypertension, T2DM, dyslipidemia, and/ or obstructive sleep apnea, are present.11,51 The criteria set forth by the FDA in 2007 in order for a drug to be approved for the treatment of obesity requires at least 5% statistically significant placeboadjusted weight loss at 1 year or >35% of patients achieving >5% weight loss (which must be twice that of placebo).52 The FDA also requires that the medication show evidence of improvement in metabolic biomarkers, including blood pressure, lipids, and glycaemia. Currently there are 3 drugs approved for long-term management of obesity: orlistat, phentermine/topiramate (Phen/TPM) ER, and lorcaserin. Phentermine alone and other centrally acting adrenergic agents (benzphetamine, phendimetrazine, diethylpropion) are approved only for short-term (3 months) use. www.jcrpjournal.com
Phentermine Phentermine, approved in 1959, is the most commonly prescribed antiobesity agent in the United States. A sympathomimetic amine, phentermine is thought to suppress appetite primarily via the enhancement of norepinephrine release.53 Although approved only for 3 months of treatment due to lack of longterm safety trials, long-term use is common in clinical practice to both achieve and maintain weight-loss outcomes. Data show that as monotherapy, phentermine 15 mg can provide a 5% greater weight loss than placebo.54 Side effects due to sympathetic activation include increases in heart rate and blood pressure, dry mouth, nervousness, insomnia, and constipation. Phentermine should be used with caution in people at significant risk for hemodynamic or CV complications of tachycardia and those with uncontrolled hypertension.
Orlistat Orlistat is a gastric and pancreatic lipase inhibitor that acts by reducing the absorption of dietary fat by approximately 30%. It is available for long-term management of obesity in conjunction with a reduced calorie diet and also as an over-the-counter medication at half the prescription dose. Multiple randomized controlled trials have shown that after 1 to 2 years, mean weight loss is ∼2.7 to 3.19 kg greater than placebo-treated patients.55 The proportion of patients who respond to achieve more than 5% weight loss after 1 year of therapy is 15% to 30% more than placebo-treated patients.56 As seen with other therapies, weight loss from orlistat treatment is associated with improvements in several comorbidities of obesity, including blood pressure, insulin resistance, and serum lipid levels, although total and LDL-cholesterol improve more than expected because of direct inhibition of fat absorption. Adjunctive orlistat administration over a 4-year period was demonstrated to reduce the risk of progression to T2DM in an at-risk population more than diet and exercise alone.57 The most common side effects are gastrointestinal, including oily spotting, flatus with discharge, fecal urgency, and steatorrhea. Reductions in fat-soluble vitamins A, D, E, and K have been noted in some patients. As a result, a daily vitamin supplement containing these vitamins can be considered, taken at least 2 hours before or after orlistat.
Phentermine/Topiramate Phentermine/topiramate was approved in 2012 as the first combination drug for long-term management of obesity. It is well recognized that obesity is a complex Treatment of Obesity / 85
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disorder of dysregulation of multiple signaling pathways involved in satiety and body weight regulation. Targeting different sites simultaneously is more likely to produce significant and durable weight loss. The rationale for combining these 2 drugs was that lower doses of each drug would minimize side effects while using drugs acting on different pathways would have an additive effect on weight loss.58 The combination Phen/TPM incorporates phentermine, a centrally acting adrenergic agent, and topiramate, an anticonvulsant that modulates GABAergic transmission.59 The exact mechanisms by which topiramate induces weight loss remain to be clearly elucidated. Putative mechanisms for its anorectic effect include modulation of γ-aminobutyric acid receptors, inhibition of carbonic anhydrase, and antagonism of glutamate.60 The efficacy and safety of this combination have been tested in two 1-year pivotal randomized, placebocontrolled, double-blind trials: EQUIP61 and CONQUER.62 In a third study, SEQUEL,63 78% of CONQUER participants continued to receive their blinded treatment for an additional year. The CONQUER trial enrolled 2487 patients with a BMI between 27 and 45 kg/m2 with at least 2 obesityrelated comorbidities at baseline (including hypertension, hypertriglyceridemia, diabetes, or increased waist circumference).61 Participants were randomized to either placebo or once-daily phentermine 7.5 mg plus topiramate 46 mg extended release or once-daily phentermine 15 mg plus topiramate 92 mg extended release. At 56 weeks, average weight loss was 1.2%, 7.8%, and 9.8% of baseline body weight for the patients assigned to placebo, phentermine 7.5 mg plus topiramate 46 mg, and phentermine 15 mg plus topiramate 92 mg, respectively.62 Statistically significant improvements were observed in both treatment groups compared with placebo with respect to blood pressure, waist circumference, glycaemia, lipid concentrations, and blood inflammatory biomarkers. Significant improvements in diastolic blood pressure and low-density cholesterol were noted in the higherdose group only. In addition, patients with diabetes in both treatment groups had greater reductions in HbA1c (−0.4%) compared with placebo (−0.1%). Weight loss was sustained at the end of 2 years in those patients who continued to receive Phen/TPM in the SEQUEL extension study.63 The most common side effects for the mid- and full-dose treatment groups included dry mouth and paresthesias (20%). Other events occurring with rates of at least 5% included headache, blurred vision, upper respiratory tract infections, altered taste, insomnia, and constipation. Since side effects with Phen/TPM are dose dependent, it is recommended that treatment be initi-
ated with the low dose with uptitration as tolerated. If a patient has not lost at least 3% of baseline body weight on this dose, discontinuation of the medication or escalation of the dose to Phen/TPM 15 mg/92 mg (top dose) is suggested. Reevaluation after a further 12 weeks of treatment should result in at least 5% weight loss from baseline; otherwise, the drug should be discontinued. This is a practical approach to identify “responders” who will benefit from long-term therapy and “nonresponders” for whom the benefitto-risk ratio may not be favorable.
Lorcaserin Lorcaserin is a selective 5-HT2C receptor agonist thought to decrease food intake through the proopiomelanocortin system of neurons. It has an affinity for 5-HT2C receptors that is approximately 15 times that for the 5-HT2A receptors and 100 times that for the 5-HT2B receptors. This is important since it has been shown that the activation of 5-HT2A receptors can lead to neuropsychiatric side effects, while 5-HT2B receptor activation is associated with the development of valvulopathy and primary pulmonary hypertension observed previously with fenfluramine and dexfenfluramine that were subsequently withdrawn from the market.64-66 The efficacy and safety of lorcaserin have been tested in 3 Phase III trials. In the first trial (BLOOM), overweight and obese subjects with at least 1 comorbid condition (hypertension, dyslipidemia, CV disease, impaired glucose tolerance, or sleep apnea) were randomly assigned to receive lorcaserin 10 mg twice daily or placebo for 52 weeks, in conjunction with diet and exercise.67 At 1 year, average weight loss was 5.8% in the treatment group compared with 2.2% in the placebo group. Significant improvements in markers of CV risk, including systolic and diastolic blood pressures and levels of fibrinogen and high sensitivity C-reactive protein, were observed with lorcaserin compared with placebo. In a second Phase III trial (BLOSSOM), weight loss of at least 10% was achieved by 22.6% and 17.4% of patients receiving lorcaserin 10 mg twice daily and daily, respectively, and 9.7% of patients in the placebo group.68 The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in obese patients with T2DM treated with metformin and/or sulfonylurea. The average weight loss was similar for both doses of lorcaserin: 4.5% for lorcaserin twice daily and 5% for lorcaserin 10 mg daily. HbA1c decreased 0.9 ± 0.06 with lorcaserin twice daily, 1.0 ± 0.09 with lorcaserin daily, and 0.4 ± 0.06 with placebo (P < .001 for each). Although the study was not designed to optimize or evaluate glycemia primarily, approximately half of the patients
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assigned to lorcaserin achieved the recommended HbA1c level of 30 and
