Pharmacologic Treatment of Obesity

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Introduction

Obesity is now recognized as a major pandemic of the 21^st century afflicting both developed and developing countries, promoting disease prevalence and draining economic resources. Data collected during the 2004 National Health and Nutrition Examination Survey (NHANES) reveals that overweight and obesity prevalence in adults in the United States continues an upward trend. According to most recent NHANES data, obesity, defined as a body mass index (BMI) of >30 kg/m², and overweight, defined as a BMI of > 25 kg/m², are currently estimated at 32 and 66%, respectively (1) The World Health Organizations (WHO) latest projections indicate that globally in 2005 approximately 1.6 billion adults (age 15+) were overweight and at least 400 million adults were obese. The WHO further projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese (2).

The association of obesity, particularly intra-abdominal fat mass gain and an increase in the risk of developing cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), osteoarthritis, certain forms of cancer, sleep apnea, asthma and nonalcoholic fatty liver disease (NAFLD) has been well established (3,4). Cytokines, such as interleukin 6, tumor necrosis factor alpha, resistin and plasminogen activation inhibitor-1, secreted from fat cells have been identified as culprits creating inflammation and thrombosis contributing, in large part to the propagation of disease (5-7). A reduction in body weight of 5-10% results in a significant reduction in inflammatory and pro-thrombotic makers, as well as a reduction in disease incidence (8,9).

Obesity Treatment Options

Lifestyle interventions including changes in diet and physical activity remain the cornerstone of treatment for overweight and obese individuals. However, lifestyle modifications have not been effective in providing lasting weight loss success. Studies reveal that behavioral interventions aimed at reducing calorie intake and increasing calories expended in daily physical activities can result in 9-10% total body weight loss during the first six months of treatment. However, data shows that one-third to two-thirds of lost weight is regained within one-year following end of treatment, and that almost all weight is regained within 5 years post treatment (10).

Overlapping physiological systems aimed at maintaining fat mass as a survival measure, as well as several environmental obstacles in our "obesigenic" environment have been identified as promoting weight regain (11,12). More aggressive treatment of obesity appears necessary. The National Heart, Lung and Blood Institute of the National Institutes of Health, recommends that for Individuals who fail to respond to lifestyle interventions after 6 months of treatment, and have a BMI of > 30 kg/m², or a BMI of > 27 kg/m² and present with weight-induced comorbidity may have weight loss medication added to their treatment plan. (13)

Health care professionals should be familiar with the basic principles regarding the pharmacotherapy of obesity. The goal of treatment is not only to reduce weight, but more importantly to improve the comorbid conditions associated with obesity, such as hyperglycemia, hyperlipidemia, and heart disease. Patients should appreciate the concept that obesity is a chronic disease that will require long-term treatment. They should also understand that the efficacy of the current medication options is limited to 5-!0% body weight loss in the majority of successful patients. Thusly, medication should not be viewed as a panacea for obesity treatment. Medications should only be used as an adjunct to healthy lifestyle changes, including an increase in daily activity and a calorie-deficit diet.

Pharmacological Treatment Options

It has only been within the past 10-15 years that our improved understanding of the endogenous systems influencing body weight regulation has been elucidated. Research and development of medications targeting these systems are on the horizon. Therefore, we presently have a limited selection of medication options to choose from for treating obesity. The United States Food and Drug Administration (FDA) approved phentermine for short-term treatment of obesity in 1959. Sibutramine and Orlistat received FDA approval for long-term treatment of obesity in 1997 and 1999, respectively (14). Both sibutramine and orlistat have been shown to be efficacious in treating obesity, when compared to placebo in several trials (15). Please refer to tables # 1 and # 2.

Table #1 - Sibutramine Efficacy Trials

Table #2 - Orlistat Efficacy Trials

Sibutramine (Meridia): Action, Dosage and Efficacy

Sibutramine reduces food intake by inhibiting the reuptake of norepinephrine, dopamine, and serotonin. Bray and Blackburn conducted a placebo-controlled trial to evaluate different doses of sibutramine over a 24-week period (16). They found a statistically significant weight loss at all doses (1, 5,10,15,20, and 30 mg) as compared to placebo. Sibutramine is available in 5, 10 and 15 mg capsules. It is recommended to begin the dosage at 10 mg per day, and if unpleasant side- effects are noted, dose can be titrated down to 5 mg per day. Conversely, if there is a lack of response from the 10 mg dosage, sibutramine can be increased to 15 mg daily (17). Wirth and Krause showed that intermittent sibutramine was as effective as continuous sibutramine over a 44-week period (18).

Efficacy of Sibutramine in Maintaining Lost Weight

Apfelbaum et al (19) conducted a study of obese patients (BMI>30) who lost weight by following a very low calorie diet for 4 weeks. This severe calorie restriction was followed by one year of sibutramine versus placebo. A greater percentage of subjects receiving sibutramine maintained their weight loss at one-year. James et al (20) showed that 18 months after initial weight loss, 43% of the patients in this study maintained = 80% of their original weight loss, versus 9% in the placebo group.

Efficacy of Sibutramine Combined with Other Treatment Modalities

In a landmark study, Wadden and colleagues (21) demonstrated significantly greater weight loss when sibutramine was combined with an intensive behavioral program. Researchers recruited 224 obese adults who were randomized to receive either 15 mg of sibutramine delivered by a primary care provider in eight short visits, lifestyle modification counseling alone delivered in 30 group sessions, sibutramine plus 30 group lifestyle modification sessions (combined therapy) or sibutramine plus brief lifestyle modification counseling delivered by the primary care provider in eight 10-15 minute sessions.

At the end of this 1-year trial, subjects who took medication alone had a mean weight loss of 5.0 kgof body weight. The subjects who received lifestyle counseling alone, and those who received brief counseling along with sibutramine lost a mean of 6.7 and 7.5 kg, respectively. However, those who received sibutramine along with intensive lifestyle modification (combined treatment) lost a mean of 12.1 kg (P<0.001). This study represents the clearest evidence that the appropriate use of medication is to enhance compliance with a program of diet and behavioral change and that the effects of combining weight-loss interventions simultaneously can be additive. This point was replicated by Early et al (22) which showedsibutramine plus a low-calorie-diet using commercially produced meal replacements and behavior modification was both safe and effective for achieving and sustaining weight-loss.These studies illustrate sibutramine’s efficacy as a weight loss and weight-maintenance agent. Additionally, data presented from these studies illuminates the reality that the majority of weight loss will take place during the first 6 months of treatment.

Sibutramine: Safety Issues

McMahon (23) and Sramek (24) each demonstrated the safety of sibutramine in the treatment of obese patients with well-controlled hypertension. These studies found statistically significant increases in pulse rate, but not blood pressure in the sibutramine groups. Sibutramine does not increase blood pressure significantly in hypertensive patients being treated with angiotensin-converting enzyme (ACE) inhibitors (23), Beta-Blockers (24), and Calcium Channel Blockers (25). A recent study (26) illustrated that the weight-reducing effects of sibutramine were not effected by ACE-inhibitors or calcium channel blockers, but were inhibited by beta-blocker and diuretic-based antihypertensive regimens.

the cardiac effects of the combination of other anorexigenic agents dexfenfluramine and fenfluramine led to the withdrawal of these drugs from the market in 1997. However, Zannad et al (27) demonstrated that 6 months of sibutramine had no significant impact on cardiac dimension, valve function, or electrocardiograms. The most frequent side effects associated with sibutramine are dry mouth, anorexia and insomnia. Patients may experience an increase in blood pressure and pulse, and monitoring of these vital signs should be performed on a monthly basis initially, and every 3 months once the patient’s weight has stabilized.

Orlistat (Xenical)

Orlistat promotes weight loss by inhibiting gastrointestinal lipases thereby decreasing the absorption of fat from the gastrointestinal tract. On average, 120mg of orlistat taken 3 times per day will decrease fat absorption by 30% (28). Orlistat has been found to be more effective in inhibiting the digestion of fat in solid foods, as opposed to liquids (29). Orlistat 60 mg 3 times daily was recently approved by the FDA for over-the-counter use in the United States (30,31).

Orlistat: Efficacy

Several trials have supported orlistat’s efficacy as a weight loss and weight loss maintenance aid. Rossner et al (32) found that subjects receiving orlistat lost significantly more weight in the first year of treatment, and fewer regained weight during the second year of treatment than those taking placebo. The orlistat group also had greater improvement in markers for cardiovascular disease (LDL-c, total cholesterol). Subjects taking orlistat had significantly lower serum levels of Vitamins D, E, and -carotene. However, these nutritional deficiencies are easily treated with oral multivitamin supplementation. Sjostrom et al (33) demonstrated similar results over a two-year period. Subjects in the orlistat group lost significantly more weight in the first year (10.2 vs. 6.1%) and regained half as much weight during the second year of treatment, as compared to the placebo group.

Orlistat’s Effect on Lipid Profile and Glucose Metabolism

In addition to promoting weight loss and maintaining lost weight, orlistat has been shown to improve insulin sensitivity and lower serum glucose levels. In a 2-year trial, Davidson et al(34) reported lower weight regain rates in patients maintained on a 360 mg per day dose of orlistat, as compared to those on placebo. In addition, subjects in the orlistat group had lower levels of serum glucose and insulin. In the 4-year Xendos (35) study conduced in Sweden, the cumulative incidence of diabetes was 9.0% in the placebo plus diet and lifestyle group and 6.2% in the subjects receiving orlistat. This outcome corresponds to a risk reduction of 37.3% (P = 0.0032)

Hollander el al (36) studied obese patients with T2DM who were not receiving insulin treatment. Orlistat resulted in improved glycemic control, determined via serum blood glucose levels and HbA1C measurements. Reductions in total cholesterol, LDL-c, triglycerides, and apo-lipoprotein B were also noted (36). Kelley showed similar benefits in obese insulin-requiring diabetics (37). Lindgarde examined the impact of orlistat on cardiovascular profiles in obese subjects with at least one of the following: T2DM, hypercholesterolemia, and hypertension. Orlistat use was associated with greater weight loss outcome, as well as reductions in HbA1c, LDL, and total cholesterol (38).

Orlistat: Side-Effects

The gastrointestinal side effects of orlistat including fatty/oily stool, fecal urgency, oily spotting, increased defecation, fecal incontinence, flatus with discharge, and oily evacuation are the main reason for discontinuation of therapy. These symptoms are usually mild to moderate and decrease in frequency the longer the medication is continued. Cavaliere (39) conducted a study to see if concomitant use of natural fibers (psyllium mucilloid) would ameliorate the adverse gastrointestinal events. Researchers found that the subjects who received psyllium experienced far fewer symptoms while taking Orlistat at a dosage of 120 mg tid. Only 29% of those taking psyllium with orlistat had GI events compared to 71% of the patients taking placebo along with orlistat.

Phentermine

Phentermine was the first FDA approved medication for weight loss, and remains available today. Phentermine (fastin) is a sympathomimetic anorexogenic agent. A study from 1968 is the only longer-term controlled trial of Phentermine (40). In this study, 64 patients completed 36 weeks of placebo, phentermine, or placebo and phentermine on alternating days. Both phentermine groups lost approximately 13% of their initial weight, while the placebo group lost only 5%. Phentermine’s main side effects are related to its sympathomimetic properties such as elevation in blood pressure and pulse, insomnia, constipation and dry mouth. Phentermine and other sympathomimetics such as diethylpropion and phendimetrazine have not been studied for long-term safety and efficacy and their use beyond 3 months is "off-label".

Off-Label Medication Use for Obesity Treatment

Several medications prescribed for conditions other than obesity have been found to be effective in supporting weight loss. These medications are prescribed off-label.

Bupropion (Wellbutrin)

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

Anderson et al (41) conducted a 48-week randomized placebo-controlled trial investigating the efficacy of bupropion in promoting weight loss. There were 3 study arms: placebo, 300 mg, and 400 mg of sustained release (SR) bupropion. Percentage losses of initial body weight for subjects completing 24 weeks were 5.0%, 7.2%, and 10.1% for placebo, bupropion SR 300, and 400 mg/d, respectively. In obese subjects with depressive symptoms (42) bupropion SR was more effective than placebo in achieving weight-loss when combined with a 500 kcal deficit diet (4.6% vs 1.8% loss of baseline body weight, p < 0.001). Bupropion is contraindicated in patients with seizures.

Antihyperglycemic Agents and Weight Loss

Metformin (Glucophage)

Metformin is an antihyperglycemic agent that acts by decreasing production of glucose by the liver and possibly increasing peripheral insulin sensitivity. Gokcel et al (43) demonstrated that metformin achieved weight loss over a 6-month period. In the landmark Diabetes Prevention Program it was demonstrated that in patients with fasting hyperglycemia, metformin accounted for greater weight loss than placebo, but less than life-style changes alone. The average weight loss was 0.1, 2.1, and 5.6 kg in the placebo, metformin, and lifestyle-intervention groups, respectively (P<0.001) (9).

Based on this evidence metformin should be the first line drug in treating obese diabetic patients. The most common side effects of metformin are nausea, flatulence, diarrhea, and bloating. The most serious side effect is lactic acidosis, but this is rare (<1/100,000). Gockel et al (43) compared the effects of three different medications used in the management of obesity; sibutramine (10 mg twice daily) vs. Orlistat (150 mg three times per day) vs. metformin (850mg twice daily). All subjects were females with BMI>30. After 6 months of treatment all three groups showed significant improvements in ipid profile, insulin resistance, serum glucose and blood pressure. The sibutramine group displayed a statistically significant (p<0.0001) greater reduction in BMI (13.57%) when compared to orlistat (9.06%) and metformin (9.9%).

Extenatide

Extenatide is a new injectable treatment for T2DM that mimics the actions of the pancreatic incretin hormone glucagon-like-peptide-1, and thereby enhances insulin secretion. In addition to its glucose lowering benefit, extenatide has demonstrated weight loss efficacy in trials with diabetics. DeFranzo el al (44) investigated the effect of exenatide on glycemic control in 336 obese patients with diabetes with a mean BMI of 34 and who had failed to achieve adequate glycemic control on metformin. Patients were randomized into 3 groups to either receive exenatide (5 g or 10 g twice daily) or placebo in addition to metformin. There was no dietary intervention offered during this trial. At week 30 hemoglobin A_1c (Hb A_1c) change from baseline for the twice-daily 5 and 10 g extenatide groups were -0.40 and -0.78%, respectively. Placebo group revealed a change in baseline Hb A_1c of + 0.08% (P<0.002).

In addition to a significant reduction iin Hb A_1c measurement, extenatide treated patients

demonstrated a dose-dependent decline in weight of -2.8 kg in the 10 g and -1.6 kg in the 5 g group. Extenatide is generally well-tolerated and did not increase the incidence of hypoglycemia.

Pramlintide

Pramlintide is another injectable agent that is FDA-approved for the treatment of type 1 and type 2 diabetes. Pramlintide mimics the action of the pancreatic hormone amylin, which along with insulin regulates postprandial glucose control. In a pooled post hoc analysis of overweight and obese insulin-treated patients with T2DM, pramlintide-treated patients (receiving 120 g twice daily),had a body weight reduction of -1.8 kg (P<0.0001) compared with placebo-treated patients. In addition, pramlintide-treated patients experienced a 3-fold increase in successfully achieving a total body weight loss of > 5%, when compared to those who received placebo (45).

Topiramate (Topamax)

Currently in Clinical Trials

Rimonabant

Rimonabant is a cannabinoid receptor antagonist which acts both peripherally and centrally to improve cardiometabolic risk factors and reduce weight. Rimonabant has been approved by 51 countries including the European Union. RIO-Europe (48), RIO-Lipids (49), RIO-North America (50), and RIO-Diabetes (51) have published 1 and 2 year results demonstrating that treatment with rimonabant resulted in modest, but significant weight loss. Pooled data reports the weight loss from the RIO trials averaged about 5% of body weight (52). In addition, improvements were significant in waist circumference measurements, glucose, HDL-c, triglycerides, insulin resistance, C-reactive protein, adiponectin and prevalence of the metabolic syndrome. Rimonabant has also been shown to improve HbA1C in patients with Type 2 Diabetes and is approved for the treatment of obese diabetics in several countries. Of interest, the improvements in metabolic parameters are about twice the magnitude expected from weight loss alone, and suggest an independent, peripheral of mechanism of action on target tissues (53). Side effects of Rimonabant include depressed mood and anxiety, nausea and vomiting, diarrhea, headache, dizziness (48-51). Please refer to table #3 for a review of the mechanism of action, placebo-corrected weight loss and side effects of several weight loss medications.

Table #3 Review of Medications for Weight Loss (14,15, 52 )

Medication induced Obesity

The role of medications as a factor that can induce weight gain is often overlooked. Several commonly prescribed medications are associated with significant weight gain. This list includes medications used to treat diabetes, depression, schizophrenia, and hypertension (54). When evaluating an obese patient for the first time, the clinician should perform a thorough review of all current prescription and over-the-counter medications to investigate for potential weight gaining medications. Whenever possible the clinician should consider alternatives to medications known to cause weight gain, or should consider measures that would ameliorate the weight gaining effect of the prescribed drug (55).

Conclusion

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