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Keywords:

  • adherence;
  • dietary treatments;
  • drug treatments;
  • obesity;
  • positive energy imbalance

Abstract

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

Obesity results from a prolonged small positive energy imbalance, and treatment needs to reverse this imbalance. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that supports the superiority of one macronutrient composition for diets over any other. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Obesity drugs have been developed that tap brain mechanisms for controlling feeding and the gastrointestinal tract and its peptides. Orlistat blocks intestinal lipase and produces modest weight loss. Sibutramine is a serotonin-norepinephrine reuptake inhibitor that has a warning on its label from the US Food and Drug Administration because of cardiovascular risk. Its marketing has been suspended in Europe. Several drug combinations are on the horizon for treatment of obesity.Mt Sinai J Med 77:407–417, 2010.. © 2010 Mount Sinai School of Medicine

The prevalence of obesity now exceeds 30% of US adults,1 but may be leveling off at an unacceptably high level. More than two-thirds of Americans are overweight,1 and excessive weight is a problem for children and adolescents too.2 The fundamental problem is the result of a small, but prolonged, positive energy balance, where energy from food exceeds energy needed for everyday living.3,4

More than two-thirds of Americans, including children and adolescents, are overweight.

REALITIES IN TREATING AN OBESE PATIENT

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

One of the key messages for obese patients is that when caloric intake is reduced below that needed for daily energy expenditure, there is a predictable rate of weight loss.4 Men generally lose weight faster than women of similar height and weight on any given diet, because men have more lean body mass and therefore higher energy expenditure. Similarly, older patients have a lower metabolic expenditure and as a rule lose weight more slowly than do younger subjects with similar adherence to weight-loss programs. Thus, adherence to any program is an essential component of success.

MODEL FOR ADDRESSING THE PROBLEM

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

If obesity is the result of a prolonged small difference between energy intake and energy expenditure, then losing body fat requires reversing this imbalance. The relationship between energy intake and expenditure is shown at the top of Figure 1. Below this are various strategies that can be used to treat this imbalance.

thumbnail image

Figure 1. A model relating energy balance to treatments for obesity. The top shows that changes in energy stores are the result of changes in intake or/and energy expenditure. The other boxes show ways in which these 2 components of the system can be altered therapeutically

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DIET AND THE TREATMENT OF OBESITY

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

Reducing energy intake from food is one strategy for weight loss.4 This can be done by reducing calories or by changing the intake of carbohydrate, fat, or protein that will in turn reduce total caloric intake. We will discuss each of these in turn.

Very-Low-Calorie Diets

Very-low-calorie diets (VLCD) or very-low-energy diets specify energy levels between 200 and 800 kcal/day. The theory behind them is that the lower the energy intake, the more rapid the weight and fat loss. Contrary to this theory are data showing that weight loss from a 400-kcal/day VLCD as compared with an 800-kcal/day diet was not different.4 Most weight-loss diets can produce a decline in energy expenditure with a drop in triiodothyronine and leptin. Treatment with leptin partially corrects these changes.5

Balanced-Deficit Diets

Diets that reduce carbohydrate, protein, and fat, the so-called “balanced-deficit diets” or “prudent diets,” have been widely used in treating obesity. In a meta-analysis of low-calorie diets, Avenell and colleagues6 found that after 12 months the difference between control and treated groups was 5.31 kg (95% confidence interval [CI], − 5.86 to − 4.77 kg), favoring the diets. In another systematic review of 16 studies that used diet but without pharmacological intervention, and that had > 100 subjects in each group and a duration of > 1 year, weight loss after 2–3 years was usually < 5 kg below baseline (3.5 ± 2.4 kg; range, 0.9–10.0 kg), and after 4–7 years where there were data, it was 3.6 kg ± 2.6 kg below baseline.7

Portion-controlled diets are one way of achieving a balanced caloric deficit. This can be done most simply by using individually packaged foods. Frozen low-calorie meals containing 250–350 kcal/package can be a convenient way to do this, except for the high salt content of many of these foods. In one 4-year study, this approach resulted in early initial weight loss, which then was maintained.8

One approach to achieve a balanced caloric deficit is a portion-controlled diet. In one 4-year study, this approach resulted in early initial weight loss, which then was maintained.

Low-Fat Diets

Low-fat diets are a standard strategy to help patients lose weight. A meta-analysis of 5 randomized controlled trials of low-fat diets showed that these diets produced significant weight loss, but not more so than did the control diets.9 Subsequently, the Women's Health Initiative initiated a comparison of a low-fat diet and normal dietary pattern on disease outcomes. Weight loss was a secondary outcome in this large clinical trial10 that randomly assigned 48,835 women to either low-fat or control diets. Weight loss was 2.2 kg below baseline at year 1 and 0.6 kg after an average of 7.5 years of follow-up. At both time points the low-fat diet group was significantly lighter than the normal-fat diet group. There was a clear relationship between the decrease in percent fat and weight loss (P < 0.001 for trend).

Low-Carbohydrate Diets

Two strategies have been used to lower carbohydrate intake. One is to use foods with a lower glycemic index or lower glycemic load, and the other is to reduce the total amount of carbohydrate. The glycemic index is based on the rise in blood glucose in response to the test food compared with the rise after a 50-g portion of white bread; glycemic load is the product of glycemic index and amount of carbohydrate in the food.

The effect of low–glycemic index diets on weight loss has been studied in a number of randomized clinical trials in adults.11 Thomas et al. identified 6 studies including 202 participants that met their inclusion criteria. Three of these studies compared low–glycemic index diets with higher–glycemic index diets, whereas the other 3 compared an ad-lib reduced–glycemic load diet with a conventional energy-restricted, reduced-fat diet, or an energy-restricted low–glycemic index diet with a normal energy-restricted diet. Interventions were relatively short, ranging from 5 weeks to 6 months at the longest. There was a small significant difference in body weight of 1.1 kg (95% CI, − 2.0 to − 0.2) that favored the low–glycemic index diets. The body mass decreased by 1.1 kg (P < 0.05) and fat mass by a similar amount compared with the change of weight in the control diet group. Both total cholesterol and low-density lipoprotein cholesterol fell more with the low–glycemic index diets.11

High-Protein Diets

High-protein diets have also been touted as weight-loss diets. One study compared 15%-protein and 25%-protein diets as part of a low-fat intake. Weight loss over 6 months was greater with the higher-protein diet, and this difference was maintained at 12 and 24 months. Higher-protein diets may also enhance weight maintenance.12 Following weight loss with a VLCD for 4 weeks, 148 male and female subjects were stratified by age, body mass index (BMI), body weight, restrained eating, and resting energy expenditure, and randomized to a control condition or a supplement of 48.2 g/day of additional protein. At the end of 3 months, the group receiving the protein supplement to bring protein up to 18% had a 50% reduction in weight regain.12

Comparison of Diets with Different Macronutrient Composition

Several randomized clinical trials lasting 1 year13–15 or 2 years16,17 have compared diets head-to-head. In the first, 169 obese individuals were randomized to one of 4 popular diets: the Atkins Diet, the Ornish Diet, the Weight Watchers Diet, and the Zone Diet.13 At the end of 12 months, each diet produced weight loss of about 5 kg, but there was no difference between diets. Adherence to the diet was the single most important criterion of success in this trial, and the Atkins and Ornish diets were apparently more difficult to adhere to. In a second 1-year trial, the Atkins, Zone, Ornish, and Lifestyle, Exercise, Attitudes, Relationships, and Nutrition (LEARN) diets were compared.14 This trial found that the Atkins diet produced more weight loss at 6 and 12 months than the other 3 diets, which had similar results. In this study, too, a post-hoc analysis showed that adherence was the best predictor for weight loss and that the level of adherence to any diet was not very good.18 Two reasons are proposed for the differences. First, the study by Gardner and colleagues14 had a more homogeneous population, including only premenopausal women. Second, the Gardner study was larger and thus had more statistical power to detect differences.

The first 2-year study was conducted at a single site in Israel with a predominantly worksite population that was predominantly (83%) male.16 There were 3 diets: a very-low-carbohydrate diet (Atkins-like), a low-fat diet, and a Mediterranean-style diet. During the first 6 months, the very-low-carbohydrate group lost the most weight, with those on the other 2 diets losing somewhat less. In the next 6 months, there was an acceleration of weight loss in the Mediterranean diet group to reach the same weight at the end of 2 years as the very-low-carbohydrate diet, with the low-fat diet group losing less weight.

The largest study, larger than the previous 3 combined, was conducted at 2 sites in the United States.17 In total, 811 men and women were randomized to 1 of 4 diets, and 80% of them provided their weights at the end of 2 years. The diets were: (1) 20% fat and 15% protein, (2) 20% fat and 25% protein, (3) 40% fat and 15% protein, and (4) 40% fat and 25% protein. The foods used for all 4 diets were the same, only the quantities were varied. At the end of 6 months, 12 months, and 2 years, the weight loss was similar for all 4 diets. The principal determinant of success was adherence to the diet, a finding made by Dansinger et al.13 and Alhassan et al.18 as well.

The largest US study comparing alternative weight-loss diets involved 811 men and women over a period of 2 years. The subjects were randomized to 1 of 4 diets that involved the same foods in varying proportions. At the end of 6 months, 12 months, and 2 years, the weight loss was similar for all 4 diets. The principal determinant of success was adherence to the diet.

MEDICATIONS AND THE TREATMENT OF OBESITY

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

Mechanisms Underlying Drug Therapy of Obesity

Currently available medications to treat obesity work in the brain and on the gut.4,19 A number of neurotransmitter systems, including monoamines, amino acids, and neuropeptides, are involved in modulating food intake. Serotonin 5-HT2C receptors modulate fat and caloric intake. Mice that cannot express the 5-HT2C receptor are obese and have increased food intake. Sibutramine blocks serotonin and norepinephrine reuptake. Lorcaserin, a drug in clinical trials, works directly on serotonin-2C receptors in the brain. These receptors may work through modulation of downstream melanocortin-4 receptors.20

Alpha11) receptors also modulate feeding. Some α1 receptor drugs that are used to treat hypertension produce weight gain, indicating that this receptor is clinically important. In contrast, stimulation of α2 receptors increases food intake, and a polymorphism in the α2a adrenoceptor is associated with reduced metabolic rate in humans. Activation of β2 receptors in the brain reduces food intake, and β-blocker drugs can increase body weight.

Other drugs act in the periphery. Blockade of intestinal lipase with orlistat will produce weight loss. Glucagon-like peptide 1 (GLP-1) released from intestinal L cells acts on the pancreas and brain to reduce food intake. Amylin is secreted from the pancreas and can reduce food intake.

Drugs Approved in the United States for the Treatment of Obesity

Several drugs are currently approved by the US Food and Drug Administration (FDA) for the treatment of obesity (Table 1).

Table 1. Drugs Approved by the US Food and Drug Administration That Produce Weight Loss19
Generic NameTrade Name(s)Usual DoseComments
  • *

    US Drug Enforcement Agency Schedule IV.

  • US Drug Enforcement Agency Schedule III.

For long-term treatment of obesity (12 months)
OrlistatXenical120 mg, 3 times a dayMay have gastrointestinal side effects
Sibutramine*Meridia (United States), Reductil (elsewhere)5–15 mg, once dailyNorepinephrine-serotonin reuptake inhibitor; may raise blood pressure
For short-term treatment of obesity (12 weeks)
Diethylpropion*  Sympathomimetic drugs;
TabletsTenuate25 mg, 3 times a dayapproved for only a short
Extended releaseTenuate75 mg, in AMtime
Phentermine HCl*   
CapsulesPhentridol, Tetramine, Adipex-P15–37.5 mg, in AM 
TabletsTetramine, Adipex-P15–37.5 mg, in AM 
Extended releaseIonamin15 or 30 mg/day, in AM 
BenzphetamineDidrex25–150 mg/day, in single or divided doses 
Phendimetrazine   
Extended-release capsulesAdipost, Bontril, Melfiat, Prelu-2, X-trozine105 mg, once daily 
TabletsBontril, Obezine35 mg, 2 or 3 times a day 
Sibutramine

Sibutramine is a serotonin-norepinephrine reuptake inhibitor. In a 6-month trial in which 1047 patients were randomized to placebo or doses of sibutramine ranging from 1 to 30 mg/day, there was a clear dose-response effect.21 Longer trials with sibutramine have been conducted in uncomplicated obese patients, in patients with hypertension, in diabetics, and in children.4,19

Efficacy In a meta-analysis of long-term studies of sibutramine, the placebo group had a weighted mean weight loss of 2.18 ± 5.23 kg. The drug-treated group had a weighted mean weight loss of 6.35 ± 6.47 kg, for a net, or placebo-subtracted, weight loss of 4.16 kg (95% CI, − 4.73 to − 3.59).22 Sibutramine can be used as intermittent therapy.23 During this 12-month trial, the continuous-therapy and intermittent-therapy groups lost the same amount of weight. Sibutramine has been used in children.24 In a large 12-month multicenter trial with 498 adolescents aged 12–16 years, the mean absolute change in BMI was 2.9 kg/m2 (8.2%) in the sibutramine group compared with 0.3 kg/m2 (0.8%) in the placebo group (P < 0.001).25 Sibutramine has also been studied as part of a behavioral weight-loss program. With sibutramine alone and minimal behavioral intervention, the weight loss over 12 months was approximately 5.0 ± 7.4 kg. Behavior modification alone produced a weight loss of 6.7 ± 7.9 kg. Adding a brief behavioral therapy session to a group that also received sibutramine produced a slightly larger weight loss of 7.5 ± 8.0 kg. When the intensive lifestyle intervention was combined with sibutramine, the weight loss increased to 12.1 ± 9.8 kg.26

In a meta-analysis of long-term studies of sibutramine, the placebo group had a weighted mean weight loss of 2.18 ± 5.23 kg. The drug-treated group had a weighted mean weight loss of 6.35 ± 6.47 kg, for a net, or placebo-subtracted, weight loss of 4.16 kg (95% CI, − 4.73 to − 3.59).

Safety Sibutramine increases blood pressure (BP) levels in normotensive patients or blunts the decrease that might have occurred with weight loss. Systolic and diastolic BP increased an average of + 0.8 mm Hg and + 0.6 mm Hg, respectively, and pulse increased approximately 4–5 beats per minute.19,26 Caution should be used when combining sibutramine with other drugs that may increase BP. Sibutramine is contraindicated in patients with a history of coronary artery disease, congestive heart failure, cardiac arrhythmias, or stroke. Sibutramine should not be used with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, and there should be a 2-week interval between terminating monoamine oxidase inhibitors and beginning sibutramine. Because sibutramine is metabolized by the cytochrome P-450 enzyme system (isozyme CYP3A4), it may interfere with the metabolism of erythromycin and ketoconazole, and it has a small effect (7% increase in area under the curve) on metabolism of simvastatin, but not other statins. An outcomes trial begun when sibutramine was approved, the Sibutramine Cardiovascular Outcomes Trial (SCOUT), has shown that there are increased deaths among those treated with sibutramine. For this reason, the marketing of this drug has been suspended in Europe.

An outcomes trial begun when sibutramine was approved, the Sibutramine Cardiovascular Outcomes Trial, has shown that there are increased deaths among those treated with sibutramine. For this reason, the marketing of this drug has been suspended in Europe.

Sympathomimetic Drugs

The sympathomimetic drugs benzphetamine, diethylpropion, phendimetrazine, and phentermine are grouped together because they act like norepinephrine and were tested before 1975.

Efficacy One of the longest of the clinical trials of drugs in this group lasted 36 weeks and compared placebo treatment with continuous phentermine or intermittent phentermine.19 Both continuous and intermittent phentermine therapy produced more weight loss than did placebo. In one survey of bariatric physicians, use of these sympathomimetic amines was found to be more frequent than sibutramine or orlistat, and they were often used for longer than approved by the FDA.27

Safety Sympathomimetic drugs produce insomnia, dry mouth, asthenia, and constipation. They are scheduled by the US Drug Enforcement Agency, suggesting the government's view that they may be abused. Sympathomimetic drugs can also increase BP. If a physician decides to use any of these drugs more than 3 months in succession, it would be appropriate to obtain written informed consent from the patient.

Orlistat

Orlistat is a potent and selective inhibitor of pancreatic lipase that reduces intestinal digestion of fat. It is available as a prescription drug, and at half the dose as an over-the-counter preparation.

Efficacy A number of long-term clinical trials with orlistat have been published using uncomplicated obese patients and obese patients with diabetes. A 4-year, double-blind, randomized, placebo-controlled trial with orlistat in 3304 overweight patients, 21% of whom had impaired glucose tolerance,28 achieved a weight loss during the first year of > 11% below baseline in the orlistat-treated group compared with 6% below baseline in the placebo-treated group. Over the remaining 3 years of the trial, there was a small regain in weight, such that by the end of 4 years, the orlistat-treated patients were 6.9% below baseline, compared with 4.1% for those receiving placebo. There was a reduction of 37% in the conversion of patients from impaired glucose tolerance to diabetes. Orlistat has also been studied in adolescents. In 539 adolescents, orlistat 120 mg 3 times/day decreased BMI by 0.55 kg/m2 in the drug-treated group compared with an increase of + 0.31 kg/m2 in the placebo group.29 In a meta-analysis of trials with orlistat, the weighted mean weight loss in the placebo group was 2.40 ± 6.99 kg and the weight loss in those treated with orlistat was 5.70 ± 7.28 kg, for a net effect of 2.87 (95% CI, − 3.21 to − 2.53).22

A 4-year, double-blind, randomized, placebo-controlled trial with orlistat in 3304 overweight patients, 21% of whom had impaired glucose tolerance, achieved a weight loss during the first year of more than 11% below baseline in the orlistat-treated group compared with 6% below baseline in the placebo-treated group.

Safety Orlistat is not absorbed to any significant degree, and its side effects are thus related to the blockade of triglyceride digestion in the intestine.19 Fecal fat loss and related gastrointestinal symptoms are common initially, but they subside as patients learn to use the drug. Orlistat can cause small but significant decreases in fat-soluble vitamins. Levels usually remain within the normal range, but a few patients may need vitamin supplementation. Because it is impossible to tell which patients need vitamins, it is wise to provide a multivitamin routinely, with instructions to take it before bedtime. Orlistat does not seem to affect the absorption of other drugs, except acyclovir. Rare cases of severe liver injury have been reported with the use of orlistat; only 1 occurred in the United States and 13 occurred elsewhere over 10 years, during which period an estimated 40 million people took orlistat.30 A causal relationship has not been established, but patients who take orlistat should contact their healthcare provider if itching, jaundice, pale-colored stools, or anorexia develop.

Combining Orlistat and Sibutramine

When orlistat was combined with sibutramine in a 4-month trial initiated at the end of a 12-month treatment period with sibutramine, there was no further weight loss.31 Thus, we have no data that combining orlistat and sibutramine is beneficial.

Drugs Used to Treat Obesity but Not Approved for This Purpose

Several drugs approved by the FDA for purposes other than weight loss have been used for the treatment of obesity, including metformin, fluoxetine, bupropion, topiramate, and zonisamide.4 Physicians who decide to try these agents are using them off-label and would be well advised to do so only with signed informed consent from the patient.32

Antidiabetic Drugs that Lower Body Weight

Exenatide Exenatide (Exendin-4) is a 39 amino acid peptide that is produced in the salivary gland of the Gila monster, a species of lizard native to the southwestern United States and Mexico. It has 53% homology with GLP-1, but it has a much longer half-life. Exenatide has been approved by the FDA for treatment of type 2 diabetics who are inadequately controlled while being treated with either metformin or sulfonylureas. In human beings, exenatide reduces fasting and postprandial glucose levels, slows gastric emptying, and decreases food intake by 19%.33 A systematic review of incretin therapy in type 2 diabetes34 showed a weight loss of 2.37 kg for all GLP-1 analogs versus control, 1.44 for exenatide versus placebo injection, and 4.76 for exenatide versus insulin (which often leads to weight gain). A 24-week, multicenter, randomized, placebo-controlled clinical trial of exenatide enrolled diabetics poorly controlled with either metformin or sulfonylurea with a HbA1C between 6.6% and 10.0% and a BMI between 25.0 and 39.9 kg/m2. The decrease in caloric intake by exenatide (378 ± 58 kcal/day) was not significantly different from placebo (295 ± 58 kcal/day). Weight loss was significantly greater and HbA1C and BP were reduced more in the exenatide-treated patients.35 The side effects of exenatide in humans are headache, nausea, and vomiting; they are lessened by gradual dose escalation.36 The interesting feature of this weight loss is that it occurred without prescribing lifestyle modification, diet, or exercise. A 26-week randomized control trial of exenatide produced a 2.3-kg weight loss compared with a gain of 1.8 kg in the group receiving the glargine form of insulin.37

In a 24-week, multicenter, randomized, placebo-controlled clinical trial comparing exenatide with placebo in the treatment of poorly controlled diabetic patients, exenatide produced significantly greater decreases in weight, HbA1C, and blood pressure. The interesting feature of the weight loss is that it occurred with no prescription for lifestyle modification, diet, or exercise.

Liraglutide Liraglutide is another GLP-1 agonist that has a 97% homology to GLP-1. This molecular change extends the circulating half-life from 1–2 minutes to 13 hours. Liraglutide reduces body weight. In a 20-week, multicenter European clinical trial, Astrup et al.38 reported that daily injections of liraglutide at 1.2, 1.8, 2.4, or 3.0 mg produced weight losses of 4.8, 5.5, 6.3, and 7.2 kg, respectively, compared with 2.8 kg in the placebo-treated group and 4.1 kg in the orlistat-treated comparator group. In the group treated with 3.0 mg/day, 76% achieved a > 5% weight loss, compared with 30% in the placebo group. BP was significantly reduced, but there was no change in lipids. The prevalence of prediabetes was reduced by liraglutide. In a head-to-head comparison, liraglutide and exenatide produced similar amounts of weight loss, 3.24 kg with liraglutide versus 2.87 kg with exenatide. In poorly controlled type 2 diabetics on maximally tolerated doses of metformin and/or sulfonylurea, liraglutide reduced mean HbA1C significantly more than did exenatide (−1.12% versus − 0.79%).39 Liraglutide has been approved by the European Medicines Agency and the FDA for the treatment of diabetes.

Combinations of Drugs that Produce Weight Loss

The first important clinical trial for weight loss combining drugs that acted by separate mechanisms used phentermine and fenfluramine.40 This trial showed a highly significant weight loss of nearly 15% below baseline with fewer side effects by using combination therapy. This combination became very popular, but due to reports of aortic valvular regurgitation associated with its use,41 fenfluramine was withdrawn from the market worldwide on September 15, 1997. Several other combinations of existing drugs are now under development and may be the next therapeutic option for treatment of obesity.

Topiramate and Phentermine Topiramate is an anticonvulsant drug that was shown to reduce food intake, but it was not developed clinically because of the side effects at the doses selected for trial. Phentermine is a long-established sympathomimetic drug approved for the short-term treatment of obesity in 1968. It is a “scheduled” drug, meaning that the US Drug Enforcement Agency has concluded that this drug carries risk for habituation and/or addiction. Topiramate and phentermine have been combined in one of 3 combinations: 3.75, 7.5, or 15 mg of phentermine combined, respectively, with 23, 46, or 92 mg of topiramate.

Two clinical trials have been conducted to evaluate long-term efficacy and safety. One is in obese individuals with a BMI ≥ 35 kg/m2 and a normal cardiometabolic profile (BP < 140/90 mm HG, fasting plasma glucose < 110 mg/dL, triglycerides < 200 mg/dL; Healthy Obese Trial). The other is in people with obesity combined with comorbidities (BMI 27–45 kg/m2 and 2 or more of the components for the metabolic syndrome, including treatment for hypertension, diabetes, or dyslipidemia; Obesity with Comorbidities). The LEARN manual provided the behavioral program for both trials. In the Healthy Obese trial, the low and high doses of topiramate/phentermine were used. In the Obesity with Comorbidities trial, topiramate and phentermine were used at the mid and high dose. The medication was titrated over 4 weeks due to the side effects from topiramate. All together, more than 2500 patients were included in these clinical trials. By design, the Obesity with Comorbidities trial had an older population with many more comorbidities but a lower BMI than the other trial. Weight loss among those who completed the trial was similar for the high dose in both trials. The percentage of those losing > 5%, > 10%, or > 15% was also similar between the 2 trials. At the end of 1 year, there was an improvement in all risk factors in the high-dose group, and all but diastolic BP and low-density lipoprotein cholesterol in the middle-dose group. Side effects in both trials included tingling and paresthesias. The prevalence of mental and behavioral side effects noted with topiramate alone was not as prominent in these trials. Using the intent-to-treat basis for analyzing data, the full dose of the combination produced an 11% weight loss at 1 year compared with 1.6% in the placebo-treated group.

Two clinical trials compared a combination of topiramate and phentermine with placebo in the treatment of more than 2500 obese patients with and without comorbidities. Using the intent-to-treat basis for analyzing data, the full dose of the combination produced an 11% weight loss at 1 year compared with 1.6% in the placebo-treated group.

Bupropion and Naltrexone Bupropion reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. Naltrexone is an opioid receptor antagonist with minimal weight-loss effect on its own. The rationale for combining bupropion with naltrexone is the idea that bupropion, acting on adrenergic receptors, is stimulating the production of a prohormone, proopiomelanocortin, which contains several other peptides within it, including α-melanocyte stimulating hormone (α-MSH), adrenocorticotropin, and β-endorphin. The α-MSH reduces food intake, but β-endorphin stimulates food intake. Naltrexone blocks β-endorphin and increases the release of α-MSH, which can continue to inhibit feeding.42 In a 24-week dose-ranging study, 419 subjects were randomized but only 244 (64%) completed the trial. Among the completers, weight loss was 1.2 kg in the placebo group, 3.1 kg in the bupropion-treated group, but only 1.6 kg with the highest (48 mg/day) dose of naltrexone. When combined, weight loss was greater and similar at all 3 doses of naltrexone, combined with bupropion (7.1 kg at 16 mg/day naltrexone + bupropion, 6.6 kg at 32 mg/day naltrexone + bupropion, and 6.9 kg at 48 mg/day naltrexone + bupropion). Nausea was the predominant side effect.43

Four main trials have been done to evaluate this combination. One trial used both 16 and 32 mg of naltrexone with 360 mg/day of bupropion, and the second used a single dose of naltrexone/bupropion (32 mg/360 mg per day), with rerandomization to 32 mg/day or 48 mg/day of naltrexone + bupropion for nonresponders at week 28. A clinical trial including behavior modification included 793 participants who were randomized in a 1:3 ratio to the combination of naltrexone 32 mg with bupropion 360 mg, provided in 2 doses per day with 2 pills at each containing 8 mg of naltrexone and 90 mg of bupropion. The dose was escalated over 4 weeks. At 56 weeks, weight loss was 5.1% in the placebo group compared with 9.3% in the naltrexone 32 mg/bupropion 360 mg group.44 When only those who completed the trial were examined, the weight loss was 7.3% in the control group and 11.5% in the naltrexone/bupropion group. Nausea, constipation, and headache were among the more prominent side effects. There was no evidence of increased suicidal thoughts.

A randomized clinical trial compared a combination of bupropion, naltrexone, and behavior modification with placebo in the treatment of 793 obese patients. At 56 weeks, weight loss was 5.1% in the placebo group compared with 9.3% in the naltrexone 32 mg/bupropion 360 mg group.

Pramlintide and Leptin Pramlintide is a modified form of amylin, a peptide secreted from the beta cells of the pancreas along with insulin. Pramlintide has been approved by the FDA for treatment of diabetes and produced weight loss in clinical trials. Leptin is a secretory product, primarily from adipocytes, that can act as a negative feedback signal to the brain and inhibit food intake. In clinical trials, leptin produced disappointing weight loss.45 The combination of leptin with pramlintide, however, produced additive weight loss in a 6-month clinical trial that may offer promise for the future.46

Clinical trials have shown weight-loss results with leptin alone to be disappointing, but a 6-month trial combining leptin with pramlintide produced an additive weight loss that may offer promise for the future.

Drugs in Clinical Trials

Lorcaserin

The neurotransmitter serotonin is involved in the regulation of food intake and food preference.4,19 Mice lacking the serotonin 5-HT2C receptor have increased food intake because they take longer to become satiated. These mice are also resistant to fenfluramine, a serotonin agonist that causes weight loss. Lorcaserin is a potent, selective serotonin 5-HT2C agonist with ∼15-fold and 100-fold selectivity versus 5-HT2A and 5-HT2B receptors, respectively. In a 12 week dose-ranging study, a total of 459 male and female subjects with a BMI between 29 and 46 kg/m2, with an average weight of 100 kg, were enrolled in a randomized, double-blind, controlled trial comparing placebo against 10 and 15 mg given once daily and 10 mg given twice daily (20 mg/day). The placebo group lost 0.32 kg compared with 1.8 kg in the 10 mg/day dose given twice daily, 2.6 kg in the 15 mg/day dose, and 3.6 kg in the 10 mg/day dose given twice daily (20 mg total). The proportions of completers achieving ≥ 5% of initial body weight were 12.8%, 19.5%, 31.2%, and 2.3% in the 10-mg once daily group, 15 mg once daily, 10 mg twice daily, and placebo groups, respectively. The most frequent adverse events were transient headache, nausea, and dizziness. Echocardiograms showed no apparent drug-related effects on heart valves or pulmonary artery pressure.47

In a 2-year, double-blind, multicenter study, 1595 obese men and women were randomized to lorcaserin 10 mg twice daily and 1587 to placebo. Participants received a 600 kcal/day deficit diet and a healthy lifestyle program with occasional meetings with a dietitian and a recommendation to walk 30 minutes/day. Of the 883 subjects in the lorcaserin group, 716 entered the second year. Body weight reached a minimum of 9.7 kg below baseline by 48 weeks, but had risen to 6.0 kg below baseline at 102 weeks in those who remained on lorcaserin throughout. In those switched to placebo, the weight increase was greater, rising to 4.2 kg below baseline at 48 weeks, compared with 3.85 kg below baseline at 48 weeks and 2.7 kg below baseline at 102 weeks in the placebo group. BP, heart rate, triglycerides, glucose, homeostasis model assessment of insulin resistance, and C-reactive protein improved, but there was no change in high-density lipoprotein cholesterol.48

Tesofensine

Tesofensine is a multiamine reuptake inhibitor. In one 6-month clinical trial, this drug produced dose-related weight loss, with the highest dose producing > 10% weight loss.49

CONCLUSION

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES

Both diet and medications are useful in treatment of the obese patient. Weight loss of about 10% below baseline is seen with both, and there is no evidence that the composition of the diet, by itself, has any influence on weight loss. There are presently only 2 drugs approved for long-term treatment of overweight patients, and their effectiveness is limited to palliation of the chronic disease of obesity. Combinations of medications and antidiabetic drugs that produce weight loss are being evaluated.

Dr. Bray has served as a consultant to Herbalife and VIVUS.

REFERENCES

  1. Top of page
  2. Abstract
  3. REALITIES IN TREATING AN OBESE PATIENT
  4. MODEL FOR ADDRESSING THE PROBLEM
  5. DIET AND THE TREATMENT OF OBESITY
  6. MEDICATIONS AND THE TREATMENT OF OBESITY
  7. CONCLUSION
  8. REFERENCES